1Laboratory of Membrane Active Compounds and Beta-Diketones Latvian Institute of Organic Synthesis Riga LV-1006 Latvia2Ruđer Boskovic Institute Bijenicka cesta 54 10000 Zagreb Croatia
Correspondence should be addressed to Astrida Velena astridaosilv and Neven Zarkovic zarkovicirbhr
Received 14 August 2015 Accepted 7 October 2015
Academic Editor Luciano Saso
Copyright copy 2016 Astrida Velena et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited
Many 14-dihydropyridines (DHPs) possess redox properties In this reviewDHPs are surveyed as protectors against oxidative stress(OS) and related disorders considering the DHPs as specific group of potential antioxidants with bioprotective capacities Theyhave several peculiarities related to antioxidant activity (AOA) Several commercially available calcium antagonist 14-DHP drugstheir metabolites and calcium agonists were shown to express AOA Synthesis hydrogen donor properties AOA and methodsand approaches used to reveal biological activities of various groups of 14-DHPs are presented Examples of DHPs antioxidantactivities and protective effects of DHPs against OS induced damage in low density lipoproteins (LDL) mitochondria microsomesisolated cells and cell cultures are highlighted Comparison of the AOA of different DHPs and other antioxidants is also givenAccording to the data presented the DHPs might be considered as bellwether among synthetic compounds targeting OS andpotential pharmacological model compounds targeting oxidative stress important for medicinal chemistry
1 Introduction
14-Dihydropyridines (DHPs) [1] including Ca2+ antagonist(CA) drugs [2] are large group of structurally diversecompounds Functionally they are similar to dihydroni-cotinamide redox-active synthetic compounds with radicalscavenging and antioxidant (AO) properties and may beconsidered as protectors against oxidative stress (OS) andassociated disorders [3]
Oxidative stress is extremely important for molecularpathogenesis especially influencing the redox regulation ofcellular signaling pathways [4ndash7] Oxidative stress closelyrelates to presence of oxygen and nitrogen free radicalsknown as reactive oxygen species and reactive nitrogenspecies (ROS and RNS resp) They cumulatively increaseupon cellular exposure to various endogenous andor exoge-nous insults ROS and RNS have the ldquotwo-facedrdquo characterand play a dual role as both deleterious and beneficialspecies [8 9] Although explored in many diseases variousphenomena related to OS have been probably best studied
in cancer cells in which depending on various factors OSmay have anticancer-like effects Its protumorigenic effectsare primarily related to induction of oxidative DNA lesions(8-OH-G) and consequential increase of DNA mutationsthat may if not repaired lead to genome instability and anincreased rate of cellular proliferation [10] On the otherhand antitumorigenic actions of OS have been closely linkedto cellular processes of senescence and apoptosis two majormolecular mechanisms that counteract tumor developmentWhich of these two actions will dominate depends on manyfactors including the metabolic status of the cell as recentlyreviewed by Kujundzic et al 2014 [11]
Antioxidants (AOs) are defined as substances that evenwhen present in low concentrations compared to those ofan oxidizable substrate prevent or significantly delay theoxidation process (Halliwell and Gutteridge 1995 [12]) Theiractivity depends on complex factors including the nature ofthe antioxidants the condition of oxidation the propertiesof substrate oxidized and the level of oxidation (reviewedin Kancheva and Kasaikina 2013 [13]) Accordingly an
Hindawi Publishing CorporationOxidative Medicine and Cellular LongevityVolume 2016 Article ID 1892412 35 pageshttpdxdoiorg10115520161892412
2 Oxidative Medicine and Cellular Longevity
antioxidative effect may be direct resulting from direct ROSscavenging or indirect from the influence on various signal-ing pathways related to cellular defense that is stress res-ponses In relation to human physiology antioxidants are tra-ditionally classified as exogenous (supplied mostly throughfood) and endogenous and are further subclassified as enzy-matic (ie superoxide dismutase (SOD) and catalase (CAT))and nonenzymatic (ie glutathione vitamins A C and Eetc) [3]
DHPs could be classified as the separate group of syn-thetic nonenzymatic however biomimetic AOs
2 Oxidative Stress andIts Prevention Wavy Scientific ProcessDevelopmentmdashPro et Contra
There are opposite views both towards the role of oxidativestress and about potential applications of exogenous antioxi-dants in onset of OS [14ndash16]
Herewith we need to mention that antioxidants havebeen studied for decades (starting from 1970s) as the toolsfor the treatment of various disorders The role of native andsynthetic antioxidants (acting on lipid peroxidation (LP) inbiological membranes) in radiation damage and malignantgrowth was seriously evaluated [17] The overall conclusionspoint out antioxidants role in decreasing the damage ofcells by reducing oxidants before the occurrence of cellulardamage [14] It was elicited and accented (Burlakova et al[15]) that
(i) antioxidants nontoxic inhibitors of free radical pro-cesses exhibit a wide gamut (pleiotropy) of biologicalactivity (as further will be reported this phenomenonis also characteristic for theDHP antioxidants group)
(ii) the biological effectiveness of AOs correlates withtheir antioxidant activity (AOA)
(iii) depending on dose AOs may either increase ordecrease the AOA
(iv) the efficacy of AO depends on the time of introduc-tion in the course of medical treatment because thedevelopment of the disease may be accompanied bystages of changing the AOA
In relation to dose-effect dependence Burlakova et al [15]have found the nonlinear pattern after addition of an AOthere is an initial increase of AOA followed by returning tonormal and finally decreasing drastically below the normalvalue Therefore antioxidants may produce a specific effectby decreasing (at low doses) or increasing (at high doses)the rate of free radical reactions Hence the compound maybe efficient AO only if it is introduced in a low dose atthe stage of reduced AOA or in a high dose at the stage ofAOA elevation The widespread opinion of opponents wasthat the antioxidant function even that of tocopherol wasa side effect of its activity and important only for in vitroprocesses andwithout any role in bioobjects lifeThis opinionwas supported by the fact that the deficiency of natural AOtocopherol (E-avitaminosis) cannot be cured completely by
applying synthetic AO Eventually it was not certain alsothat detected lipid peroxides have been generated in vivoin the intact organs and were not artificially formed duringthe isolation [15] All these objections and skepticism wererejected in due time
However some other research directions were suggestedFang et al [18] reported two different therapeutic strate-
gies for modulating OS in cancer and inflammation includ-ing (1) antioxidant therapy and (2) ldquooxidation therapyrdquo
For (1) polymeric superoxide dismutase (eg pyrancopolymer-SOD) xanthine oxidase (XO) inhibitor devel-oped water-soluble form of 4-amino-6-hydroxypyrazolo[34-d]pyrimidine (AHPP) heme oxygenase-1 (HO-1) inducers(eg hemin and its polymeric form) and other antioxidantsor radical scavengers (eg phenolic compound canolol 4-vinyl-26-dimethoxyphenol) were used
About (2) besides neurodegenerative diseases cancermay represent yet another very interesting field for exploringantioxidants and prooxidants as therapeutic substances dueto their cytotoxic effects (including overproduction of ROS)that if achieving proper selectivity may be used for cancercells destruction (Fang et al [18]) To achieve this goal aunique therapeutic strategy was developed named as ldquooxida-tion therapyrdquo by delivering cytotoxic ROSdirectly to the solidtumor or alternatively inhibiting the antioxidative enzymesystem such as HO-1 in tumor This anticancer strategywas examined by use of O
2
∙minus or H2O2-generating enzymes
(ie XO and d-amino acid oxidase [DAO] resp) and bydiscovering the inhibitor of HO-1 (ie zinc protoporphyrin[ZnPP] and its polymeric derivatives)
While deleterious when present at high concentra-tions low concentrations of ROS exhibit beneficial proper-ties needed for controlling physiological cellular processes(reviewed in Valko et al 2007 [19])
Jimenez-Del-Rio and Velez-Pardo [20] have discussedoxidative stress as an important etiopathogenic factor foroccurrence and development of neurodegenerative diseases(notably Alzheimerrsquos disease and Parkinsonrsquos disease) andcancer As an extension possible preventive and therapeuticvalues of antioxidants were also discussed Indeed if con-sidered within a narrow context of oxidative homeostasisantioxidants may seem to be ideal weapon in preventingand fighting these diseases However the context of humanpathology is very broad and so far there was little benefitof exogenous antioxidants in human intervention studies orclinical trials There are numerous reasons for these failuresMaybe themost important one is the design of the preclinicalstudies especially related to concentration of the antioxidantused and time parameters relevant to the clinical setting(Kamat et al 2008 [21]) The imbalance between uncriticalacceptance of antioxidants as powerful ldquodrugsrdquo for variouspathological conditions and disappointing results obtainedin clinical studies has made a sort of confusion This issuewas addressed by Bast and Haenen [16] through listing tenmisconceptions related to commercialized applications ofantioxidants (a) ldquoprosrdquo (1) antioxidants can cure any disease(2) the more the better (3) any AO will do (the trick) (4)AO status measures the level of health (5) natural AOs aresuperior (over synthesized ones) and (b) ldquocontrasrdquo (1) AOs
Oxidative Medicine and Cellular Longevity 3
increase mortality (2) when present at high doses antioxi-dants become prooxidant (3) theoretically antioxidants can-not behave as such (4) once used antioxidants are inactive(5) antioxidant drugs do not work
The first three ldquoprosrdquo clearly cross the line of realistic wayof thinking and cannot be considered seriously The ldquoprordquo4 was very informatively discussed by Pompella et al [22]who comprehensively presented current problems with themethods (ORAC oxygen radical absorbance capacity ferric-reducing ability of plasma and TEAC Trolox equivalentantioxidant capacity) routinely used formeasurement of totalantioxidant capacity (TAC) in plasma (Pompella et al 2014[22]) These include lack of needed specificity especially rel-evant for ORAC related measurements Instead precise mea-surement of specific compounds is recommended Regardingthe ldquoprordquo 5 the situation does not seem entirely clearas some published metastudies related to protective role ofvitamin C in coronary heart disease showed some contra-dictions (better protection with dietary vitamin C versussynthetic vitamin C) (Ye and Song [23] Knekt et al [24])In any event this kind of research is anything but simple asobserved health effects of fruit and vegetable ingestion arecertainly related not only to the content of vitamin C butalso to other macro- and micronutrients and phytochemi-cals proven to confer additional health benefits (Carr andVissers [25]) Similar to ldquoprosrdquo stated ldquocontrasrdquo seem to bea common misconcept related to the design of the study (thisis especially relevant for epidemiological studies) relevanceof a specific pathological condition and measurement of itsoutcomes and finally complexity of a living organism Forall these reasons there is the realistic need for well-designedepidemiological clinical and molecular studies that wouldoffer firm evidence and undoubtful conclusions on the role ofantioxidants on human health (see also Sections 38 and 39)
There are still unanswered questions related to oxidativestress and its mediators in pathogenesis of OS-associateddiseases However it is clear that overproduction of ROShas harmful cellular effects For that reason small syntheticantioxidants molecular scavengers have been developed tobe used in various pathological conditions The first oneimplemented in the clinic for acute brain infarction was3-methyl-1-phenyl-2-pyrazolin-5-one (MCI-186 EdaravoneRadicut norphenazone) approved until now only in Japan(Tabrizchi 2000 [26]) So far its free radical scavengingproperties were revealed by various biological effects (antiox-idant attenuation of cytokine production antiapoptoticantinecrotic and some other effects) as recently reviewed(Kikuchi et al [27])
3 14-Dihydropyridines A SeparateGroup of Bioantioxidants
14-Dihydropyridines could be used as model compounds forstudying molecular mechanisms of action modulated by cel-lular enzymes NADH and NAD(P)H due to their structuralanalogy to 14-dihydronicotinamide [28] This structure rep-resents the active part of these reduced coenzymes which areimportant modulators of various enzymatic redox reactionsand are involved in electron transfer
Chemically 14-dihydropyridines are synthetic hydro-genated N-heteroaromatic compounds They may have var-ious substituents at positions 26- 35- and 14- (Figures1ndash3) Their derivatives can be obtained synthetically in theHantzsch type cyclic condensation reactions
Bossert and Vater [29] postulated DHPs as a basis fordevelopment of new cardiovascular drugs Today there aremany marketed drugs which contain 14-DHP ring as basicscaffold [30ndash32] (Figures 1 and 2)
Grover et al [33] classified dihydropyridine nucleus (skel-eton) as a novel pharmacophore and offered some examplesrelated to DHPs pleiotropy So far AOAs have been revealedfor several groups of DHP compounds andDHP-based drugs[34ndash36] contributing to their well-known pleiotropic ways ofaction (antiaging neuroprotective anticancer antibacterial[37] and many more) These features are promising fordevelopment of novel drugs in the future [32 38]
It is well known that hydrogen donors such as aminesthiols (aminothiols) or phenols (plant phenols and polyphe-nols aswell as synthetic hindered phenols) act as antioxidantsprimarily through inhibition of oxidation reactions of variouschemical targetssubstrates Similarly depending on theirparticular chemical structure 14-dihydropyridines have sig-nificant hydrogen donor ability (see further in Section 32)This feature allows them to act as direct inhibitors of freeradical reactions It further classifies them as specific group ofdihydropyridine type of antioxidantsHowever under certainconditions primarily dependent on individual structure andapplied dose DHPs can act as prooxidants (see further inSection 38)
On the other hand some DHPs may exert synergisticeffects when applied together with other types of AOs [39]They can also be involved in the redox regulation of Ca2+ion channels [40] Namely oxidative stress characterized bysignificant increase of ROS closely relates to cellular imbal-ance of Ca2+ ions Such a CA activity of DHPs can also resultin the indirect OS modulation as an additional positive sideeffect Accordingly DHPs acting as CA and as antioxidantsmay modify various OS-associated pathological processes byinfluencing cellular redox signaling potential Additionallymultiple biological effects of DHPs attenuating OS could beimportant at drug-drug interactions by combination therapyusing DHPs and other CA andor antioxidants
It should be mentioned that the studies on the possibleAOA of 14-DHPs have begun due to the assumption thatthese substances could be useful for the design for novelantioxidants intended to be used primarily in the food tech-nology notably as animal chow stabilizers [41ndash43]TheAOAsof 14-dihydropyridine derivatives 26-dimethyl-35-dieth-oxycarbonyl-14-dihydropyridine (Hantzsch ester (HEH)diludine) and its close analogues 4-unsubstituted 14-DHPswere discovered by Latvian scientists that intended to usethem for the termination of the lipid peroxidation (LPO) invarious chemical lipid substratesmixtures target (solutionsemulsions and liposomes) [44 45] Afterwards antioxi-dant properties of several calcium antagonists DHPs werediscovered [31 46ndash53] Interestingly research on the AOAof DHPs on LPO continues nowadays including several
Figure 1 Structures of the most known 14-dihydropyridine derivatives and some non-DHP Ca2+ antagonists
interdisciplinary projects funded by EU in particular theCOST B35 action [51 52]
31 Synthesis of 14-Dihydropyridines Routes and ApproachesClassical 3-component Hantzsch synthesis of DHP com-pounds [54ndash57] is usually performed in solutions (includingionic liquids) by heating Discoveries related to this process
and published between 1986 and 1990 are summarized in thereview of Sausins and Duburs [57] In 1993 Kazda [58] hasreviewed ldquotwenty years of dihydropyridinesrdquo including theirsynthesis chemistry progress in pharmacology and therapyand some other applications Since then there were manyimportant discoveries in this field and there is a time fora review on ldquoanother twenty years of DHPsrdquo It has to be
Oxidative Medicine and Cellular Longevity 5
NH
Lercanidipine
NH
Cl
Felodipine
Cl
NH
Lacidipine
NH
Nicardipine
NH
Isradipine
NO
N
NH
COO
Azelnidipine
N
NH
Bay O 5572
NH
COO
Benidipine
N
NH
Manidipine
N N
NH
NC
Nivaldipine
NH
COOC(CH3)3
COOCH(CH3)2
Mebudipine
N
S
O
Diltiazem
N
S
O
O
H
O
Semotiadil
NH
COO
Barnidipine
N
H3C
H3C H3C
H3C
H3C
H3C
H3C
H3CO
H3C
H3C
H3C
H3CCH3
CH3 CH3CH3
CH3
CH3
OCH3
OCOCH3
CH3
CH3
CH3
CH3CH3
NH2
CH3
NO2NO2
H3COOC
H3COOC H3COOC
H3COOC
H3COOC
H3COOC
H3COOC
H3COOC H3COOC
H3COOCCOOC(CH3)2CH2N(CH3)CH2CH2CHPh2
COOCH(CH3)2
N(CH3)COOCH2 CH2CH2 Ph
COOC2H5 COOC2H5C2H5OOC
COOC(CH3)3
NO2NO2
NO2NO2
NO2
NO2
NO2
CH2Ph
CH2Ph
CH 2Ph
CH 2Ph
COO(CH2)7CH3(H3C)2HCOOC
COOCH2CH2
O(CH2)3N(CH3)CH2CH2O
N(CH3CH )2 2CH2
Figure 2 Structures of the most known 14-dihydropyridine derivatives and some non-DHP Ca2+ antagonists
mentioned that nearby this classical multicomponent synthe-sis also a process to obtain structurally diversified 14-dihyd-ropyridines at sophisticated conditions was recently reviewedby Wan and Liu [59]
Many discoveries relevant for novel routes in DHPdesigning and synthesis were published and deposited in
various databases (see httpwwworganic-chemistryorgnamedreactionshantzsch-dihydropyridine-synthesisshtm[60]) For example httpwwwscifindercom [1] databaselists approximately 1000 citations on the simple DHP com-pound diludine Reaxys database [61] contains data relatedto variations in starting materials intermediates as building
6 Oxidative Medicine and Cellular Longevity
NH
SCH3
CN
Cl
O
NH
SCH3 SCH3 SCH3
CN
O
NH
CN
O
NH
CN
OCl OCHF2 OCHF2
OSI-3701OSI-9642OSI-3761OSI-1146
H3C
H3C H3C
H3C H3C H2N
H3C H3C
Figure 3 Molecular structures of OSI-1146 OSI-3701 OSI-3761 and OSI-9642 (according to [146])
blocks media and reactions routes Water and ionic liquidsas reaction media microwave and infrared irradiation newcatalysts solid phase synthesis and biotechnology based andgreen chemistry approaches were also proposed as attractiveoptions for syntheses of DHPs [62ndash66]
Furthermore several new dihydropyrimidin-(2H)-ones(DHPMs) close analogues of DHPs were prepared in theBiginelli reaction under ultrasound irradiation and in thepresence of NH
4Cl Some of these compounds when tested
in vitro at concentrations higher than 100 120583M [67] showedAOAs manifested as inhibition of LPO induced by complexFe + EDTA and reduction of ROS levels
Recently Sun et al [68] reported about the synthesis andantioxidant activity of a series of novel 3-chalcone-substituted14-dihydropyridine derivatives based on dimethyl or diethyl26-dimethyl-4-phenyl-14-DHP-35-dicarboxylate
32 14-Dihydropyridines as Hydrogen Donors Steric elec-trostatic and hydrophobic descriptors in DHP moleculecould serve as its potential pharmacophores [2] In caseof Hantzsch ester this implies partly hydrogenated N-heteroaromatic DHP nucleus itself or its fragments that isNH group or C-4 H- atom as hydrogen donors necessaryfor the AO activity andor carboxylic ester side groups (itsC=O group and O atom as hydrogen bond acceptors) inpositions 3- and 5- and alkyl side groups in positions 2-and 6- (as hydrophobic features) (Grover et al [33] andTikhonov and Zhorov [69]) The presence of labile hydrogenatoms (mainly in positions 14-) in DHPs molecule assignssignificant hydrogen donating ability to these compounds
DHPs (26-dimethyl-14-dihydropyridine-35-dicarboxy-lic acid esters) can be oxidized in chemical (Dubur andUldrikis [70]) electrochemical enzymatic (Duburs et al[71]) and biological (including metabolism and biotransfor-mation) systems As already stated dihydropyridines (espe-cially unsubstituted in position 4) may transfer the hydro-gen similar to the reduced diphosphopyridine nucleotidesNADH and NADPH (Scheme 1) (Mauzerall and Westheimer[28]) while HEH hydrogen transfer studies and search fornovel NADHmodel compounds are continuously developing(Xie et al [72])
Tamagaki et al [73] observedmetal-ion-facilitated oxida-tions ofDHPswithmolecular oxygen andhydrogenperoxideOn the other side Tirzite et al [74] studied some 14-DHP derivatives as reductants in relation to trivalent iron
Hantzsch esters have been extensively utilized as stoichio-metric biomimetic reducing agents Recent summarized lit-erature about DHPs as reducing agents including referenceson diludine may be found on specialized websites httpwwworganic-chemistryorgchemicalsreductions [75]
DHPs form free radicals in chemical electrochemicaland biological oxidation processes The kinetic parametersand pathways of decay of the cationic radicals formed asprimary products in the course of electrooxidation of theesters of 12- and 14-dihydropyridine have been extensivelystudied [76]
The regenerative system of nicotinamide cofactors mayinvolve oxidizing or reducing reagents regulating enzymesand photochemical reactions Thus in situ regenerationof the consumed cofactors was observed in the biosys-tems engineering which create superior biocatalysts by thereduction of NAD(P)+ which can lead to the 14-DHPproduct (which is the only active form) and to the 16-DHP compound [77] The NADPH models of HEHs can beregenerated in situ as biomimetic hydrogen sources bymeansof transition metalBroslashnsted acid catalyzed relay asymmetrichydrogenation [78] General regeneration strategies werereviewed by Chenault and Whitesides [79] Based on thesestrategies particularly related to methods of preparation andpractical use of esters of 26-dimethyl-14-dihydropyridine-35-dicarboxylic acid as antioxidants that might be probablyapplicable for radioprotection and adjuvant treatment againstmetastases several patents were prepared [80]
Sambongi et al [81] have found that the novel water-soluble Hantzsch 14-dihydropyridine compound (the potas-sium salt of 26-dimethyl-14-dihydropyridine-35-dicar-boxylic acid monomethyl ester) functions in biological pro-cesses through regeneration of NADH Various parametersrelated to nicotinamide coenzymes regeneration especiallyin a light of chiral compounds have been published recently[82] while Okamura et al [83] reported the use of theoxidative conversion of dihydropyridine to pyridinium ionand the metabolic trapping principle as an approach formeasuring in vivo cerebral redox states
33 Antioxidant Activity (AOA) and Antiradical Activity(ARA) of 14-Dihydropyridines Antioxidative activity of 14-DHPs was first evaluated and studied in the Latvian IOS(Tirzit and Duburs [39] Zilber et al [44] and Dubur et al[45])
Oxidative Medicine and Cellular Longevity 7
N
O O
N
O O
R R
N
O Ominuseminus minuseminusminuseminus
minusH+
minusH+minusHminus
minusH∙
R998400(H)R998400H R998400(H)
oplus
R=H
Scheme 1 Reactions of 14-dihydropyridines leading to the formation of pyridine derivatives
In the field of ARA pioneering work was made by Schel-lenberg and Westheimer [84] in 1965 In 1979 Schellenberg[85] revealed the free radical oxidation of a dihydropyridinefollowing Huyser et al [86] who reported hydroxyl radicalquenching by DHPs especially Hantzsch ester studying freeradical oxidation of DHPs in vitro in the Fenton system
AOA and ARA of various 14-DHPs were further studiedby several different methods in both in vitro and ex vivoinvivo systems [3 31 44ndash53] CA nisoldipine nimodipinenitrendipine nifedipine and nicardipine have AOA thatcorrelates with their lipophilicity (modified Buege and Austrsquosmethod of TBA determination applied in model of rat braincortex ischemiareperfusion) [87]
N-Aryl-DHPs designed as sirtuin activators were furtherreported as suitable agents for neuroprotection due to theirradical avoidance properties (Hardeland [88])
14-DHPs inhibit free radicals and consequentially thecascade of events related to lipid peroxidation They mayinfluence several stages (initiation andor propagation) of thelipid peroxidation cascade which consist of sim10 reactions[89] (detailed discussion in Section 331 (2)-(b) Scheme 2)
However considering the great number of AO com-pounds (including DHPs) and the diversity in their actionmechanisms [90] in vivo studies are not always convincingand conclusive Therefore concise in vitro models are neces-sary to screen each compound with antioxidative propertiesAntioxidants are designed to react readily with oxidizingspecies and are often extensively oxidized already duringincubations at atmospheric oxygen tension (oxidation ofsome water-soluble DHPs in water (buffer) solutions is veryfast especially in the presence of light) Even during arelatively short incubation period the concentration can dropdrastically and the real potency of the compound could beunderestimated [90]
331 Common AOA and ARA Features of Some DHPs
(1) In Vitro (in Solutions Emulsions and Liposomes) Basicmolecular principles related to antioxidative and antiradi-cal activity of various antioxidants including DHPs werepublished recently [91] These data show that DHPs reactwith various types of free radical species stable free radicals(DPPH ao) and alkyl radicals and with oxygen and nitrogenfree radicals Some derivatives of DHPs may quench a singletoxygen and may react with peroxynitrite anion [92ndash95]
Reactivity of DHPs toward alkyl radicals was studiedelectrochemically [96]
The activity against DPPH radical was found for the5-acetyl-2-alkylthio-4-aryl-6-methyl-14-dihydropyridine-3-carboxylic acid nitriles [97] structural analogues of the5-acetyl(carbamoyl)-6-methylsulfanyl-14-DHP-carbonitrile(studied as mitochondriotropic compounds see further inthe text Section 331 (2)-(b))The highest antiradical activityoccurred for a compound which contains two hydroxylgroups in the 4-phenyl substituent
DHPs were proved to decrease oxygen uptake (2-3-fold) in the heme (methemoglobin hematin hemin andcytochrome C) catalysis by oxidation of emulsions of estersof unsaturated fatty acids and liposomes of phospholipidphosphatidylcholine (Zilber et al [44] and Dubur et al [45])
Reactivity of nitrosoaryl and nitroaryl derivatives of 14-DHPs toward alkyl alkylperoxyl radicals and ABTS radicalcation was found in various LP modeling systems suitablefor determination of DHPs AOA and ARE features [98ndash104] Diludine and foridone and its analogues were shown toinhibit lipid peroxidation through inhibitory effect on lipoxy-genase in emulsions and in reversed micelles (Tsetlin et al[105] and Panek et al [106]) In addition to inhibition of ther-mally initiated oxidation of methyloleate in the solution [107](where AOA of 4-unsubstituted 35-dicarbonylderivativesof 26-dimethyl-14-DHPs is not linearly dependent onthe inhibitor concentration) DHPs derivatives containinghydroxy alkoxy or dimethylaminophenyl substituents inposition 4 were shown to prevent loss of 120573-carotene in thedisperse system of 120573-carotene and methyllinoleate (Plotnieceet al [108])
The AOA of DHPs has been detected using differentmethods in various systems where lipid free radical gen-eration (nonenzymatic Fe2+-dependent andor enzymaticNADPH-dependent) took the place [109ndash112] This activitywas further confirmed in vivo through prevention of damagecaused by renal ischemia and reperfusion as shown fordiludine [113]
Some redox properties of calcium antagonist dihydropy-ridines were revealed through electroanalytical studies [114]Competitive kinetic procedure was used for exploring theAO capacity of five (four 14-DHPs lacidipine felodipinenifedipine and amlodipine and one 12-DHP compoundGR44966) CA and one calcium ion agonist (Bay K 8644) Allbut one (amlodipine) antagonist displayed an unambiguousAO capacity (crocin test) The calcium agonist DHP revealedno reaction with peroxyl radicals Lacidipine was the mosteffective A calcium agonist Bay K 8644 is quite resistant tooxidation and does not bind H+ This could be important
8 Oxidative Medicine and Cellular Longevity
fact in the interaction with the target proteins (it should bementioned that there are no studies on LP with other Ca2+agonists)
The decreased oxidation potential correlates with AOcapacity and increased basic characterThese findings suggestthe relevance of the electron density on the DHP ring
For all the DHP compounds investigated the overalloxidation process proceeds through two consecutive one-electron releases a primary one-electron step accompaniedby a fast proton release and the formation of a neutral radical(PyH∙) undergoing a second much easier one-electron step[114]
The final product is the protonated form of the parentpyridine derivative This pattern is relevant for the antioxida-tive activity since the radical intermediate is far less prone tobe reduced than oxidized
In the case of CA DHPs the release of protons compli-cates the overall oxidation process by introducing a ldquopara-siticrdquo side reaction where a coupling between protons and thestarting species takes place
This DHP self-protonation subtracts part of the originalspecies from the electrode process because the parent cationicspecies are no longer electroactive
Conversely the calcium agonist DHP which is less proneto be oxidized turned out to be so weak base to be evenunable to undergo the self-protonation reaction
Thus the combined effect of oxidation potentials andproton binding capacity of DHPs is a key element for theredox transition relevant for their AO activity Yet opposingeffects (antagonistic versus agonistic) on protein targets ascalcium ion channels connected with protein thiol oxidationto disulfide should be also considered [114]
Kourimska et al [115] found AO effect of diludine (HEH)in edible oil Reactivity of 14-DHPs toward SIN-1-derivedperoxynitrite was shown by Lopez-Alarcon et al [116] Oleket al [117] discovered antioxidative activity of NADH and itsanalogue in vitro
Further see as referred in several subparts below Sections34 35 and 37
(2) Ex Vivo (on Lipid Peroxidation in LDL MitochondriaMicrosomes and Cells) Main chemical structures of DHPsexamined in numerous studies and reviewed in this paper arepresented in Figures 1 and 2
(a) Various DHPs Calcium Antagonists as Inhibitors of LDLPeroxidation Free radicals induce peroxidation of LDLThis process proceeds by a chain mechanism which revealsphosphatidylcholine hydroperoxides and cholesteryl esterhydroperoxides as themajor primary products [118] Calciumantagonist DHPs could act as antioxidants on LDL at leastin three ways (1) as inhibitors of isolated LDL peroxi-dation caused by various inducers (Cu2+ ions UV lightand xanthinexanthine oxidase system) (2) if preincubatedwith cells preventing against intracellular LDL oxidation (3)preventing against the harmful effect of oxidized LDL on cellsand decreasing cytotoxicity [119ndash131]
Combined application of ascorbic acid and CA DHPs(amlodipine and felodipine) has an additive (cytoprotective
and LDL antioxidant activity) effect [120] It includes acombination of peroxide-degrading and peroxyl radical scav-enging reactions thus demonstrating the importance of LPduring LDL oxidation and cytotoxicity induced by oxidizedLDL Cytoprotection is associated with inhibition of oxidant-induced increases in intracellular free calcium
Similar to the othermodel systems the recorded values ofthe tested DHPs related to AO activity on LDL LP and relatedevents [119ndash131] depend on the prooxidant model system andmethods used for activity measuring (see Tables 1ndash5)
Commercial Ca2+ antagonists (including 14-DHP deri-vatives) as well as some other 14-DHPs with less CA activitywere shown to decrease the rate of oxidation (detected asTBARS) of low-density lipoprotein (LDL) induced by Cu2+ions (CuSO
4) in two different cell lines U937 human mono-
cyte-like and J774A1 murine monocyte-macrophage cellline (Rojstaczer and Triggle [119]) The strongest effect wasrecorded for vitamin E followed by felodipine 2-Cl analogueof nifedipine nifedipine amlodipine nitrendipine vera-pamil and diltiazem
Rojstaczer and Triggle [119] found that CA from differentchemical groups had a concentration-dependent effect asantioxidants against LDL oxidation (see Table 1) Howeverthe order of potency (activity rank order ARO) of the drug(s)again depends on the oxidation system and the antioxidantassay Both CA and antioxidative effects relate to the 2- (or o-orto-) substituent of the 4-phenyl ring in the same potencyorder 119900 gt 119898 ≫ 119901 [119] On the other hand the require-ment for the 14-DHP ring is essential for both AOA andCa2+channel antagonism A charged substituent at the position C-2 of the 14-DHP ring influences the AO activity (analogousto [46ndash53]) However some other factors should not beneglected for example although amlodipine has a positivelycharged amine at this position this modificationmakes it lesslipophilic and indirectly less potent antioxidant
Similar results were obtained when testing antioxidanteffect of CA on LDL peroxidation in bovine aortic endothelialcells (BAECs) (Cominacini et al [123] see Tables 2 and 3) aswell as in HUVECs (Lupo et al [129]) (see Table 4)
Cominacini et al [123] observed antioxidant effect ofCCBs and 120572-tocopherol in BAECs The order of potency(see Tables 2 and 3) [123] was however different than inU937 human monocyte-like and J774A1 murine monocyte-macrophage cells (see Rojstaczer and Triggle [119] Table 1)The tested DHPs were lacidipine amlodipine lercanidipinenimodipine and nifedipine (in two different intracellularconcentrations 2 and 4 fmol) ROS production was signif-icantly lowered only by lacidipine (which is the compoundwith the highest lipophilicity) and lercanidipine the effectof lacidipine was much more evident than lercanidipineSurprisingly amlodipine nimodipine and nifedipine had noeffect on ROS formation suggesting that the positive effectson the earliest events of atherosclerosis are a peculiarity oflacidipine molecule through its antioxidant activity
The strong AO action of lacidipine may be related tothe lipophilic cinnamic acid side chain which favors a drugpartitioning in the membrane due to favorable physicochem-ical (hydrophobic) interactions of drug hydrophobic residues
Oxidative Medicine and Cellular Longevity 9
Table 1 Relative structure-function relationships of calcium antagonists (DHPs verapamil and diltiazem) and vitamin E Effect on oxidativemodification of isolated ex vivo human low-density lipoprotein using two various oxidation systems (copper (II) ions induced and monocyteinduced) Compiled according to data presented by Rojstaczer and Triggle [119]
Compound
Systems of LDL oxidation
Copper (II) ions induced system (comparison of three methods) Monocyte induced celloxidation system
Methods
Reduction of TBARS level of LDL(relative efficacy)
Degradation of oxidized[125I] LDL by J774
macrophages
Relative electrophoreticmobility of LDL on
agarose gel
TBARS content of LDL(in )
Relative efficacy (activity rank order (ARO) ARO = I for the most effective) effective inhibitor concentration [IC] in120583M
with polyunsaturated groups of membrane phospholipidsHowever DHPs can also reduce the oxLDL-induced ROSconcentration by affecting some intracellular ROS producerssuch as NADPH oxidases xanthine oxidase and cyclooxyge-nase enzymes The activity of these enzymes contributes tointracellular ROS elevation [125]
Preincubation of HUVECs with lacidipine inhibited anincrease of intracellular ROS caused by oxidized LDL [124]
Lupo et al [129] have studied the dose-dependent (1 510 and 50 120583M) AOA of various CA (verapamil diltiazemand DHPs nifedipine amlodipine isradipine or lacidipine)
Table 3Modulation of ROS formation in BAECs by CA (DHPs andverapamil) and vitamin E Compiled according to data presented byCominacini et al [123]
Compound
Method of flow cytometry (reduced2101584071015840-dichlorofluorescein diacetate(DCFH-DA) oxidation by ROS)
Activity rank order(ARO = I for the highest activity ARO = III for
the mindest activity)(Effective [IC] 1 5 10 50 120583M)
Lacidipine + + + (ARO = I)Lercanidipine + + (ARO = II)Amlodipine No effectNifedipine No effectNimodipine No effectVerapamil + (ARO = III)120572-Tocopherol + + + (ARO = I)
against normolipidemic human blood LDL oxidation com-pared with 120572-tocopherol by measuring the content of TBARSand the diene formation (see Table 4)
10 Oxidative Medicine and Cellular Longevity
Table 4 Normolipidemic human blood LDL (025mgmL) in vitro oxidation in the presence of 5 120583M CuSO4and CA of 3 types (DHPs
verapamil and diltiazem) and vitamin E Compiled according to Lupo et al [129]
Compound
MethodsTBARS method (fluorimetry at 515 nm533 nm 4 hours
preincubation of LDL with compounds and copper (II)ions 320 TBARS increase in control during 4 h
period)
Inhibition of conjugated diene formation (at 234 nm)expressed as prolongation of induction period (in
of control) 119905contr = 368min
Effective [IC] (in 120583M)1 120583M 10120583M 50 120583M
Activity rank order (ARO= I for the highest activity
ARO = VII for themindest activity)
Effective [IC] (in 120583M)1 120583M 5 120583M 10120583M 50 120583M
Activity rank order (ARO= I for the highest activity
ARO = VII for themindest activity)
Nifedipine 10120583M50 120583M ARO = III
5 120583M10120583M 15050 120583M 213
ARO = III
Amlodipine 50 120583M ARO = IV5 120583M
10120583M 12250120583M 138
ARO = IVndashVI
Isradipine 50 120583M ARO = VI 10120583M 15050 120583M 183 ARO = IVndashVI
Lacidipine1 120583M10120583M50 120583M
ARO = II5 120583M
10120583M 19250 120583M 283
ARO = II
Verapamil 50 120583M ARO = V 10120583M 15050 120583M 178 ARO = IVndashVI
Diltiazem No effect No effect (ARO = VII) No effect No effect (ARO = VII)
Vitamin E1 120583M
10120583M (IC50)
50 120583M (20 of control)ARO = I
5 120583M10 120583M 23050 120583M 370
ARO = I
Table 5 Antiproliferative effect (oxLDL-induced HUVSMCs proliferation) of CA DHPs and simultaneous oxLDL-induced ROS productionscavenging Comparison with N-acetyl-L-cysteine NAC (intracellular ROS scavenger) Compiled according to data presented by Zou et al2012 [130]
DHP compound
MethodsAntiproliferative effect against proproliferative effectinduced by oxLDL (50 120583gmL) (UV detection of
formazan production from tetrazolium salt)
oxLDL-induced ROS production (fluorescent DCF(2101584071015840-dichlorofluorescein) production)
Effective [IC] in120583M and I in
Amlodipine 3 120583M I = 18 3 120583M 10 120583M No effectI = 20
S(minus)-Amlodipine No effect No effect
Lacidipine 10 120583M30 120583M
I = 21I = 27 10120583M Isim23 of control
N-Acetyl-L-cysteineNAC
mdash 5000 120583M(5mM) I = 28
As presented (Table 4 according to [129]) for diltiazem(poor lipid solubility) noAOwas detected whereas the otherCA and 120572-tocopherol have demonstrated AOA at least atconcentrations of 10 and 50120583M 120572-tocopherol gt lacidipinegt nifedipine gt isradipine verapamil and amlodipine Addi-tionally120572-tocopherol and lacidipinewere able to significantlyattenuate in vitro LDL oxidation at 1 and 5120583M Theseresults have confirmed the highest activity for the stronglylipophilic DHP type CA compound lacidipine This might be
a possible antiatherogenic mechanism of CA since oxidativemodification enhances the atherogenic potential of LDL
The lipid peroxidation of LDL promoted either by UVradiation or by copper ions was inhibited (antioxidant effect)by nisoldipine in a dose-dependentmanner (IC
50values were
evaluated at around 10 120583M) nimodipine was less potent (IC50
around 50ndash100 120583M) and nicardipine almost inactive In addi-tion to this indirect protective effect CA DHPs nisoldipineand nimodipine exerted direct protective effect on lymphoid
Oxidative Medicine and Cellular Longevity 11
cells against toxicity of previously oxidized LDL The IC50
values were 6 plusmn 2 and 80 plusmn 20 120583M respectively [122] Theinhibition of the cytotoxic effect of LDL oxidized in thepresence of DHP type Ca2+ channel blockers correlated wellwith protection from oxidation by these compounds Com-plete protection cannot be obtained because the DHPs arecytotoxic themselves The potential relevance to the preven-tion of atherogenesis is envisaged
DHP typeCCBnifedipinewas themost effective inhibitorof oxidation promoted either by UV radiation or by copperions in experiments with cultured lymphoid cells LDL (2mgapoBmL) CCBs from other two CCB classes diltiazem andverapamil were only poorly active or completely ineffective[121] The protective effect of nifedipine occurs at two levelsbesides its direct antioxidant effect by inhibition of LDLoxidation it also exhibits a direct cytoprotective effect againstcytotoxicity of oxidized LDL by yet unknown mechanismsThe protective effect of CCBs was not due to an inhibitionof LDL uptake This effect seems to be independent of theinhibition of LDL oxidation per se since LDL was oxidizedin the absence of the drug before the incubation withcells Moreover this direct protective effect was observedat lower concentrations (IC
50of 1 plusmn 02 120583M) compared to
the antioxidant effect (IC50
of TBARS inhibition is around10 plusmn 2 120583M at UV promoted and 4 plusmn 05 120583M by Cu2+ ionsinitiated) The AO effect of nifedipine is also correlated withthe protection of endogenous tocopherols (IC
50= 50 120583M)
It was suggested that the AO effect of CCBs protected cellsindirectly from the cytotoxic effect of oxidized LDL [121]
A recent study has reported that beneficial vascular effectsof lercanidipine in diabetic rats depend on its antioxidantactivity related to attenuating the increase in oxidativestress and in vascular matrix metalloproteinase-2 (MMP-2) (Martinez et al [126]) Lesnik et al [127] studied theimpact of a combination of this calcium antagonist and a120573-blocker atenolol on cell- and copper-mediated oxidationof LDL and on the accumulation and efflux of cholesterolin human macrophages and murine J774 cells They realizedthat lercanidipine reduced the oxidative modification of LDLrather than diminished cholesterol accumulation in humanfoam cells
Comparing the antioxidative action of CA (DHPs amlo-dipine lacidipine nifedipine and isradipine as well as diltia-zem and semotiadil) in the copper-catalyzed oxidation oflow-density lipoprotein (LDL) with that of glycated (g)gly-coxidated (go) LDL demonstrated that the strongest AOeffects during long-term LDL glycation are seen for isradip-ine lacidipine nifedipine and semotiadil [128] Inhibitoryeffects were in the range 10minus5ndash10minus3MAuthors suggested thatdue to the increased generation of ROS by glucose-modifiedLDL the chain-breaking capacity of CA may be overriddenThe AOA of CA depends on their lipophilicity and theirability to incorporate into the LDL particle that is to reachthe site of peroxidation CA like other AOs significantlyretards advanced glycation end products (AGE) formationwhereas initial glycation reactions such as Amadori productformation are only weakly inhibited The observation thatboth oxidative changes and at least long-termglycation effectsare indeed drastically reduced by CA is corroborated by
fluorescence analysis AGE-ELISA quantitation of lipid per-oxidation and TBARS measurement of long-term ggo LDL
The effects of lipophilic DHP calcium channel blockerson oxidized LDL-induced proliferation and oxidative stressof vascular smooth muscle cells were also studied [130] (seeTable 5)
Lacidipine and amlodipine reduced carotid intima-media thickness by decreasing proliferative effect of oxLDLwhereas (S-)-amlodipine had no antiproliferative effect ROS-MAPKs (mitogen-activated protein kinases) pathway mightbe involved in the mechanism
Both 14-DHP CCBs lacidipine and nifedipine reduceplasma and LDL oxidation and formation of oxidation-specific epitopes Their application may also relate to pro-longed survival of rats independently of blood pressuremod-ifications (in the SPSHR model 1mgkg per day lacidipineand 80mgkg per day nifedipine) These results suggestedthat the protective effect of these two 14-DHP drugs invivo as shown in cerebral ischemia and stroke may in partresult from inhibition of LDL oxidative process althoughthese two drugs possess different lipophilic properties [131]Both lacidipine (03 and 10mgkg) andnifedipine (80mgkg)prolonged lag time of the conjugated diene formation inLDL isolated from arterial wall and 119905max These drugssignificantly reduced electrophoreticmobility of oxLDL fromSPSHR subjected to XXO oxidation system 14-DHP CCBsalso protected apolipoprotein B which is important for thebinding with macrophage LDL receptor lysine residues Thedoses used (gt10minus6molL for SPSHR and normotensive WKYrats) however are 2 to 3 orders of magnitude higher thanthose inhibiting vascular smooth muscle contraction in vitroand in vivo They also exceed values that are commonlyused in clinical practice The daily dose of lacidipine forhypertensive patients is 007mgkg asymp4- to 14-fold lower thanthe 2 doses used in SPSHR The maximum daily dose ofnifedipine given to hypertensive patients is 20mgkg asymp40-fold lower thanwhatwere used [131]These discrepanciesmaybe related to differences in bioavailability of CA between ratsand humans [131]
Accordingly in routine clinical use 14-DHPCCBs donotreach the concentrations required for antioxidant activity invitro [131]
Another data concerning the effect of CA DHPs on OSrelated to LDL is presented under Section 35
(b) Effect of DHPs on Isolated Rat Liver and Heart Mitochon-dria As a major cellular source of oxygen radicals (Cadenas[4 5]) mitochondria are promising targets for pharmaco-logical and toxicological actions of various membrane-activecompounds including several 14-DHP derivatives Zernig etal [132] have discovered CA binding sites associated with aninner mitochondrial membrane anion channel
More than 40-year long research onmitochondrial effectsof the DHPs (on their bioenergetics chemiosmotic proper-ties and ion fluxes) clearly points them out as mitochondri-otropic compounds
The activity of the first 35 synthesized compounds(derivatives of 14-DHP their heteroaromatic analogues
12 Oxidative Medicine and Cellular Longevity
NAD-H+ and butylated hydroxytoluene (BHT BOT)) orig-inally was examined in rat liver mitochondrial LP system inthe presence of Fe2+ ions and using the ultraweak chemilu-minescence method (Dubur et al [89])
Several 14-DHP derivatives Hantzsch ester diludine andits analogues were found to be effective antioxidants in thisexperimental system changing the kinetics of LP lengtheningthe time of the appearance of the maximum of the slowburst of the chemiluminescence (latency latent period) anddiminishing the reaction rate (the tangent of the slope angleduring the time in which the amplitude of the slow burstcharacterizing LP rate increases) and its peak value Theirpresence has influenced the reaction constant 119870
6 in relation
to a very significant reduction of lipid hydroperoxides andorinactivation of free radicals as follows
ROO∙ + ROO∙ 997888rarr P + h]lowast termination (1)
(P = molecular products) or
ROO∙ + ROO∙ +H2O 997888rarr ROH + RO∙ + 1O
2
lowast (2)
In this study diludine was one of themost active compoundsDHPs had activity similar to the standard synthetic AO-BHT(ionol) However when plotted against applied concentrationand time window diludinersquos activity profile differed from thatof BHT
There were also similar studies (using different LP rateexperimental detection system and method Hunter et al[133]) based on exploring a group of 26 26-dimethyl-35-disubstituted- and 26-dimethyl-345-trisubstituted-14-dihydropyridines (14-H
2Py=14-DHPs) and five related pyri-
dines as inhibitors of rat liver Mit swelling (Δ119860520119905) and O
2
uptake by ascorbic acid- (AsA-) dependent lipid peroxidationand as modulators of Mit swelling induced by Na+-linoleateor Na+-pyrophosphate (Velena et al [112])
Some of tested 4-DHPs (4-unsubstituted 35-dialkoxy-carbonyl-26-dimethyl-14-DHPs and 35-diamido-26-dim-ethyl-14-DHPs both 4-unsubstituted or those possessinglipophilic 4-aryl- groups) have shown significant AO andmembrane stabilizing activity These studies further revealedthat 14-DHPs preferably act as AO during the stages ofinitiation and prolongation of LP chain reactions at lowconcentrations The studied 14-DHPs had IC
50(when 119881
0119881
or 1205911205910= 2) 01 120583M to 100 120583M and the minimal activity was
scored for oxidized (heteroaromatized) derivativesAt the concentration of 100120583M 35-di-n-butyloxycarbo-
nyl-26-dimethyl-14-DHP entirely stops mitochondrialswelling in the presence of 08mM Na+-pyrophosphateAt the same concentration the following compoundsalter the mitochondrial swelling rate in the presence ofnatural protonophore Na+-linoleate 35-di-p-hydroxyphen-oxycarbonyl- and 35-di-p-tolyloxycarbonyl-26-dimethyl-14-DHPs 35-diethoxycarbonyl-26-dimethyl-pyridine (oxi-dized form of Hantzsch ester) and more lipophilic 35-diamyloxycarbonyl-26-dimethyl-pyridine The alteration ofswelling may be scored as prolonged promoted acceleratedor inhibited The type of alteration depends on the structureand concentration of 14-DHPs the type of initiators of theswelling process and the medium composition
In accord with previously published Janerorsquos results (lackof AO for Ca2+ antagonists nifedipine and nicardipine evenat 500120583M concentration in LP tests performed on heartmembrane [134]) no antioxidative activity for 4-phenyl sub-stituted derivatives of 35-dialkoxycarbonyl 14-DHP (closeanalogues of Ca2+ antagonists) was found contrary to various4-nitrophenyl 14-DHP derivatives calcium antagonists forwhich the significant antioxidant activity was reported [3146ndash53]
Studies made on phosphatidylcholine liposomes (ourunpublished data) suggest approximately three and twotimes more antioxidative activity for 100 120583M 4-unsubstitutedDHP compound diludine when compared to 4-substitutedDHPs riodipinenifedipine and nicardipine respectively atmethemoglobin-induced LP (oxygraphy)
Inhibition of mitochondrial AsA-dependent LP and sta-bilization ofmitochondriawere shown to be characteristic fora large group of 14-DHP compounds [112] showing to pos-sess the AOA in simplest in vitro systems (Tirzit andDuburs [39] Zilber et al [44] and Dubur et al [45])based on reactions with the stable free radical 11-diphenyl-2-picrylhydrazyl (DPPH) LP of fatty acid ester (linethole andmethyloleate) emulsions and phospholipid (phosphatidyl-choline) liposomes Generally these properties did not coin-cide with Ca2+ antagonism Depending on DHP structure itseems that AOA properties are less specific than Ca2+ antago-nist properties Both properties may be interrelated but notinterdependent
These data show that the presence and the nature ofa substituent in position 4 as well as 35-substituentsare important factors for 14-DHP antioxidant effects invarious systems that is AsA-dependent nonenzymatic aswell as enzymatic NADPH-dependent lipid peroxidationSometimes the efficacy of inhibition of nonenzymatic LPby 14-DHPs is higher than the inhibition of the enzymaticLP However the action may be opposite stimulation of theLP Hantzsch ester (HEH diludine) and its close analoguesexhibited significant AOA and membrane stabilizing prop-erties in both AsA-dependent nonenzymatic peroxidationof mitochondria and NADPH-dependent enzymatic LP ofmicrosomes usually at similar 10 to 100120583M concentrations[112]
The order of AOpotency (IC50
values) in vitro depends ondrug structure as well as on the experimental conditions andspecificity of the biological system Eachmethod for determi-nation of AOA and ARA has advantages and disadvantages(Karadag et al [135])
Accordingly as reported by Gubskiı et al [136] IC50
forthe AsA-dependent LP was 025 120583M and 20 120583M for 14-DHPCa2+ antagonists nitrepine (nitrendipine) and nifedipinerespectively Takei et alrsquos [137 138] studies on mitochondrialswelling induced by LP or arachidonic acid in the rat braindetermined the IC
50values of 127 105 1568 and 384 120583Mfor
efonidipine nicardipine nifedipine and nimodipine respec-tively For LDL in the copper-induced oxidation system theorder of potencywas vitamin Egt felodipinegt 2-chlorophenylanalogue of nifedipine gt nifedipine gt amlodipine nitrendip-ine verapamil and diltiazem (Rojstaczer and Triggle [119])
Oxidative Medicine and Cellular Longevity 13
It was interesting to compare the AOAofDHPswith theirsusceptibility to oxidation that is electron and hydrogendonating properties
It has been estimated that electron donor substituentsin positions 2 and 6 of 14-DHP cycle usually promoteoxidation while electron acceptor substituents promotequench oxidation Stronger electron acceptors in positions 3and 5 also significantly quench oxidation These estimationsare based on studies including chemical enzymatic andelectrochemical oxidation of 14-DHPderivatives (Dubur andUldrikis [70] Duburs et al [71] and Stradin et al [139])
On the other hand diminished AOA of 14-DHP relatesto presence of substituents in position 4 (both electron donorand electron acceptor) (Velena et al [112])
35-Dicarbamoyl substituents possess minimal quench-ing feature and are followed by benzoyl- acetyl- andalkoxycarbonyl- groups Maximal decrease was obtainedwith condensed substituents (ie oxoindeno- or oxocyclo-hexeno- groups) and a CN-group 4-Unsubstituted 35-dicar-bamoyl derivatives can be easily oxidized and consequen-tially inactivated whereas 4-substituted 35-dicarbamoyl-14-DHPs possess an oxidation potential analogous to the 4-unsubstituted 35-COOR derivatives Therefore they haveadequate electron donor properties and are considerablystableThismay be the reason for significantmembrane stabi-lization upon exposure to 4-substituted derivatives Ofimportance their AOA was usually more pronounced incomparison to 4-unsubstituted derivatives
Among them 26-dimethyl-35-difurfuryloxycarbonyl-14-DHP showed the highest antioxidative activity In thegroup of 35-dialkoxycarbonyl derivatives the strongestactivity was attributed to compounds with medium lengthalkyl chains (i-butyl- t-butyl- and i-amyl- substituents) highlevel of lipophilicity minimal electron acceptor propertiesand moderate steric hindrance as contrasted to short or longalkyl chain ester derivatives (35-dimethoxycarbonyl- 35-diethoxycarbonyl derivatives and 35-didodecyloxycarbonylderivative) These data demonstrate the bell-shaped depen-dence of AOA on alkyl chain length [112] and are in accordwith results obtained in liposomes However these datadiffer from those obtained in emulsions where diludine wasthe most active compound Finally oxidized heteroaromaticderivatives showed only minimal activity
In both LP systems studied (AsA-dependent in mito-chondria and NADPH-dependent in microsomes) some of14-DHPs showed activity similar to classical antioxidantbutylated hydroxytoluene (ionol BHT) (Velena et al [112])However there was a significant difference related to con-centration and incubation time It allowed us to postu-late that 14-dihydropyridines (InH) acting as antioxidants-reductants and scavengers of reactive oxygen species and lipidfree radicals preferably influence initiation and propagation(prolongation) of lipid peroxidation chain reactions (1)ndash(5) according to Scheme 2 The phenomenon is particularlyprominent in the presence of Fe2+ and other ions of variablevalency
Chain break and termination reactions (6)ndash(10) of theLP reaction cascade [89] were influenced by 14-DHPs in alesser degree than were initiation and propagation steps This
may be important for their therapeutic effects even in theadvanced stages of LP
Scheme 2 (stages of initiation propagation and terminationof lipid peroxidation chain reactions (1ndash10)) Initiation andpropagation reactions are as follows
(8) RO∙ + In∙minus rarr Y (Y = molecular products)(9) ROO∙ + Fe2+ rarr Fe3+ + X (X = molecular products)(10) RO∙ + RO∙minus rarr Y (Y = molecular products)
In the reversible swelling of mitochondria accompanyingLP (initiated by mixture of 5mM GSSG1mM GSH) several14-DHPs showed low or no activity manifested only as adecrease of the swelling amplitude without a rate decreaseAn addition of GSH (4mM) or ATP to swollenmitochondriacaused their contraction in both control and tested systemIt may be suggested that 14-DHPs acting as antioxidantsin mitochondria preferably influence LP reactions initiatedby ions with variable valency or their complexes with hemetype compounds methemoglobin hemin hematin and soforth (Velena et al [112]) If the peroxidation process has amaximal velocity and 50 percent of initial O
2were consumed
14-DHPs cannot completely break the chain reactions andprevent subsequent membrane damage by addition of DHPsubstance at 10 120583M concentration at the moment of 50percent oxygen consumption the subsequent oxygen uptakeproceeded unchanged This observation is important for theapplication of DHPs as inhibitors of initiation and to a lesserdegree propagation stages of LP chain reactions
The influence of 14-DHPs on Mit swelling is not strictlyassociated with their own oxidation There is the possibilitythat the labilizing (or stabilizing) effect relates to surfaceactivity (connected with substituent lipophilicity) or may bethe consequence of complexation with some -OH (or -CH
3)
group sensitive receptors at the mitochondrial membraneNamely a bathochromic shift of the absorption band maxi-mum (about 10 nm) was observed in the visible region beforeswelling However after swelling in the presence of Na+linoleate the spectrum returns to its initial value [112]
Some 14-DHPs not only protect mitochondria againstswelling caused by AsA-dependent LP salts of fatty acids
14 Oxidative Medicine and Cellular Longevity
in vitro [112] but also have beneficial effects on repairingtheir integrity in vivo after exposure to irradiation hepato-toxins ischemia hypoxia or hypothermia Some of themwere shown to normalize the process of intracellular repara-tion and physiological regeneration of ultrastructures Theywere also shown to stimulate reparative processes If pre-treated with 14-DHPs irradiatedmitochondria will not swell(Ivanov et al [140 141])
Diludine ionol and some other AOs mitochondria pro-tectors act as anti-ischemic agents If applied prophylacticallyin vivo they may prevent ischemic and reperfusion lesionsin heart kidney and other organs (Bilenko et al [113]) Theeffect is dependent on applied dose timing and way ofapplicationWhen added onto the cryoconservationmediumfor mitochondria preservation 14-DHPs prevented decreaseof membrane potential normalized facilitated respirationand prevented loss of mitochondrial Na+ and Ca2+ ionsafter thawing ([112] see citation number 36 (Subbota et alKharkov 1984) therein) Diludine was stronger protectorwhen compared to ionol
CA drug foridone (riodipine) was shown to possesscardioprotective features primarily due to is protective effecton mitochondria exposed to OS [142 143]
Similarly the DHP water-soluble antiarrhythmic com-pound glutapyrone inhibits initiation of LP by free radicalsin erythrocytes and heart mitochondria Its cardioprotectiveeffect has been experimentally shown in heart mitochondrialmembranes especially during deep hypothermia (Utno et al[144])
Cerebrocrast was effective in several translation modelsmimicking pathological situations known to be associatedwith cellular OS The potential protective action of 14-DHP derivatives (4-substituted compounds cerebrocrastgammapyrone glutapyrone and 4-unsubstituted drug dieth-one) has been studied in rat liver in experimental modelsrelevant for oxidative stress and mitochondrial bioenergetics(Fernandes et al [145]) When succinate was used as therespiratory substrate higher concentrations (gt25 120583M) ofcerebrocrast depressed respiratory control ratio (RCR) ADPto oxygen ratio (ADPO) state 3 and uncoupled respirationrates transmembrane potential (deltapsi) and the phosphatecarrier rate At the same time state 4 respiration rate wasthree times increased At concentrations lower than 25120583Mcerebrocrast inhibited mitochondrial IMAC and partiallyprevented Ca2+-induced opening of the mitochondrial PTPGammapyrone glutapyrone and diethone did not inducethese phenomena When applied at concentrations up to100 120583M cerebrocrast gammapyrone and glutapyrone didnot affect ADPFe2+-induced LP of mitochondria in rat liver(as measured by oxygen consumption and TBARS forma-tion) On the other hand low diethone concentrations (upto 5 120583M) inhibited it in a dose-dependent manner Diethonealso prevented against deltapsi dissipation induced by LPinitiated by ADPFe2+ Based on these data it may bespeculated that cerebrocrast (inhibition of the IMAC) anddiethone (acting as an AO) may provide effective protectionof mitochondria during OS Cerebrocrast has shown sometherapeutic potential for treatment of several pathologicalconditions related to cellular OS [145]
5-Acetyl(carbamoyl)-6-methylsulfanyl-14-DHP-carbo-nitriles (Figure 3) with minor differences in their molecularstructure displaying antioxidant and antiradical activitiesin vitro show different biological activities Namely 4-p-chlorophenyl derivative OSI-1146 displays AO and anti-radical activities in cardiovascular OS models whereasOSI-3701 and OSI-3761 display hepatoprotective activityThus these compounds may be potentially useful for treat-ing several pathological processes including those associatedwith OS (Fernandes et al [146]) However besides mito-chondria the cellular targets for their pharmacologicalactions have not been fully investigated [146] All these com-pounds increase the susceptibility of Mit to MPT The mostpotent is OSI-3701 although it does not affect bioenergeticparameters
Although all these compounds protected mitochondriaagainst LP induced by the oxidant pair ADPFe2+ OSI-1146was shown to be the most potent Current data point outmitochondria as potential targets for protective and toxicactions of DHPs suggesting that the potential for their use astherapeutic agents should also take into consideration theirtoxic effects on mitochondria (Fernandes et al [146])
Several structurally different DHP derivatives (antioxi-dant diludine (diethone) as a 4-unsubstituted DHP 4-substi-tuted DHPs CA foridone (bicyclic compound) and the 4-phenyldiethone compound where phenyl group is joined tothe DHP in position 4) inhibited the 1-methyl-4-phenyl-pyridinium iodide (MPP+) induced ROS production incerebellar granule cells (CGC) with a distinct potency orderforidone (26-dimethyl-35-dimethoxycarbonyl-4-(o-difluo-romethoxyphenyl)-14-dihydropyridine) gt 26-dimethyl-35-diethoxycarbonyl-4-phenyl-14-dihydropyridine gt diludineThey also reversed the MPP+-induced decrease of the mito-chondrial membrane potential in the same order (Klimavi-ciusa et al [147]) Accordingly it was postulated that theclassical two-ring (bicyclic) structure of DHP derivativesrepresents an advantage in relation to neuroprotection andROS defense and is independent on compoundrsquos propertiesrelated to calcium ions
Novel adamantane-containing 14-DHP compounds (Kli-maviciusa et al [148]) were also found to improve mitochon-drial functions (MPP+ model) (Klimaviciusa et al [148])Klusa et al [149] have discovered antineurotoxic effects of14-DHP taurine derivative tauropyrone recorded as Mitfunction improvement
Many 14-DHPs including Ca2+ antagonists and AOmodify LP processes and influencemitochondrial function invarious organs (liver heart kidney and brain) in a differentway and degree Their beneficial action oxygen or lipidfree radical scavenging antioxidative effects binding withor intercalating into phospholipid bilayer regulation of iongating and regulation of mitochondrial permeability transi-tion pores (Tirzit and Duburs [39] Zilber et al [44] andDubur et al [45]) separately or in combination with eachother depends on two strong elements (1) their individ-ual structure including nature of substituents and theirpositions and (2) the nature of the biological system Forexample the direction of LP (inhibition of promotion) wasshown to depend on structure and concentration of applied
Oxidative Medicine and Cellular Longevity 15
14-DHPs as well as stages of chain reactions Accordinglymitochondrial swelling may be prolonged (retarded) accel-erated (promoted) or inhibited (Velena et al [112])
Therefore there is a ground for 14-dihydropyridineseither Ca2+ antagonists or antioxidants to be nominated asuseful tools in development of ldquomitochondrial drugsrdquo relatedto the control of OS
(c) DHPs as AOs in Endoplasmic Reticulum (Inhibition ofNADPH-Dependent LP System) Inhibition of NADPH Oxi-dase by DHPs Elevated level of NADPH oxidase 4- (NOX4-)derived hydrogen peroxide (H
2O2) joined with concomitant
decrease of nitric oxide (NO) mediated signaling and reac-tive oxygen species scavengers are considered to be centralfactor in molecular pathogenesis of fibrosis (Sampson etal [150]) Inhibition of microsomal NADPH-dependent LPwith particular focus on NADPH oxidases (NOX1ndash5 andDUOX1) may be very important for neuro- cardio- andhepatoprotection (Velena et al [112] Leto and Geiszt [151]Griendling et al [152] and Chen et al [153]) Endoplasmicreticulum may be an important target as this is where 14-DHPs could display their antioxidative properties (Velena etal [112] Leto and Geiszt [151] Griendling et al [152] andChen et al [153])
However the initiation of LP in the NADPH-dependentmicrosomal system does not appear to involve either super-oxide or hydrogen peroxide since neither SOD nor cata-lase can inhibit it On the other hand reduced iron playsan important role in both the initiation and propaga-tion of NADPH-dependent microsomal lipid peroxidation(Hochstein and Ernster [154] and Repetto et al [111])
Many DHPs possess inhibitory activity not only towardsAsA-dependent LP in mitochondria but also towardsNADPH-dependent LP as shown in isolated rat liver micro-somes (Velena et al [112]) This means that these compoundsinteract with the shared parts (nonenzymatic and enzymatic)of LP pathways
Microcalorimetry and fluorescent probes procedureswere used for studying the interaction of alpha-tocopheroland 14-DHPs with endoplasmic reticulum membranes andmodel systems human serum albumin and phospholipidbilayers [155] Modification of microviscosity of the endo-plasmatic reticular membranes depends on localization ofantioxidants within the protein structures or phospholipidphase Increase of membrane structuralization under theinfluence of 14-DHPs blocked their antioxidant action inspontaneous and induced lipid peroxidation
Inhibition of rat heart and liver microsomal lipid perox-idation by nifedipine was observed [156] while Goncalves etal [157] found antioxidant effect of calcium antagonists onmicrosomal membranes isolated from different brain areas
Nitroaryl-14-DHPs are both calcium channel antagonistsand antioxidant agents (Letelier et al [158 159]) commonlyused for treatment of cardiovascular diseases These drugsmust be metabolized through cytochrome P450 oxidativesystem (NADPH-cytochrome P450 reductase) mainly local-ized in the hepatic endoplasmic reticulum Several lipophilicdrugs generate OS while being metabolized by this cellularsystem Thus DHP antioxidant properties may prevent the
OS associated with hepatic biotransformation of drugs Var-ious commercial and new nitro-phenyl-DHPs were studiedagainst LP using rat liver microsomes under oxidative stress[159]
Incubation of rat liver microsomes with the 41015840-nitro-4-phenyl-14-DHP compounds (26-dimethyl-4-(41015840-nitro-phenyl)-14-dihydropyridin-35-diethyl-dicarboxylate andN-ethyl-26-dimethyl-4-(41015840-nitrophenyl)-14-dihydropyri-din-35-dimethyl-dicarboxylate) results in an inhibitionof LP the UDPGT (UDP-glucuronyltransferase) oxidativeactivation and the microsomal thiol oxidation induced byFe3+ascorbate a generator system of ROS This effect wasalso produced by nitrofurantoin and naphthalene in thepresence of NADPH
Interestingly IC50
ofDHPs obtained frommicrosomal LPassays decreased to the same extent as the microsomal thiolsoxidation provoked by Fe3+ascorbate [159] Neverthelessthe AO effects of a nitrophenyl-DHP compound in whichhydrogen at position one of the DHP ring was replaced bythe ethyl groupwere significantlyweaker Authors speculatedthat DHPs can resemble NADH transferring one hydrogenatom of 4-position (Hminus) to anion superoxide and another ofthe 1-position (H+) by way of a cationic radical intermediateto generate pyridine derivatives and water [159]
The AO effects of various tested DHP derivatives (m- andp-NO
2phenyl as well as methyl or ethyl and isopropyl-DHP
35-dicarboxylate derivatives) were not significantly differentThe authors assumed that the -NH- group of the dihydropy-ridine ring could contribute both to the development ofthe calcium channel antagonism and to the antioxidativeproperties of DHPs [159]
Prevention of the membrane LP seemingly depends onthe concentration of potential antioxidants such as vitaminE or even 14-DHP in lipids However only the differencesin synthetic DHPs lipophilicity cannot explain significantvariations of DHPs concentration in microsomal membraneand cannot clarify the strength of their antioxidative activityThis work [159] has further demonstrated that 14-DHPsmay prevent the OS induced by biotransformation of somedrugs for example antibiotic nitrofurantoin Simultaneousadministration of DHPs and nitrofurantoinmay be beneficialin reducing nitrofurantoin side effects
While most of Ca antagonist 14-DHPs are metabolizedby CYP3A4 (Guengerich et al [160]) not all of them are goodinhibitors of its activity Thus nicardipine but not nifedipineand nitrendipine inhibits CYP3A4 in vitro [53] Interactionof different DHPs with various types of cytochrome P450 wasdescribed by Carosati et al [53] It was also reported thatDHP class calcium channel blockers reduce the antiplateleteffect of clopidogrel (Park et al [161])This implies themutualinteractions of both drugs with CYP3A4
(3) In Vivo Evaluation of nifedipine effects on Saccharomycescerevisiaewas recently published (Asma andReda [162]) Sur-prisingly nifedipine exercised a toxic effect on Saccharomycescerevisiae shown through measuring cellular proliferationrespiratory activity and the level of some biomarkers (CATand MDA)
16 Oxidative Medicine and Cellular Longevity
However majority of data obtained on various animalcells and tissues by other authors show the protective role ofDHPs against both LP and oxidative stress [113 163 164]
The AOA attributed to many 14-DHPs Ca2+ antag-onists and other compounds reflecting on catalytic LDLperoxidation (see Section 331 (2) and Section 35) shouldencourage their testing for treating cardiovascular diseasesandor alterations of lipid metabolism
The possibility that 14-DHP-based calcium antagonistsexert an antiatherosclerotic action (via inhibition of LDLoxidation and other mechanisms) has been proved by manyexperimental data [165] and several clinical trials Besidesantihypertensive effect nicardipine was shown to possessantioxidative and antielastase activity [165 166] These prop-erties may be useful for prevention of inflammatory reactionwhich is relevant for hypertension pathogenesis
14-DHPs administration inhibits LDL oxidation medi-ated by oxygen radicals leading to decreased carotid inti-mal media thickness and reduced progression of coronaryatherosclerosis [130] It additionally preserves Apo B-100integrity against ROS Of importance antiatherogenic mech-anisms differ between animals and humans (primarily inthe stage of conversion of aldehydes to carboxylic acids)(Parthasarathy et al [167])
For example furyl-DHP compound (FDP-1 diethyl 26-dimethyl-4-(furyl)-14-dihydropyridine-35-dicarboxylate)was shown to act as an antioxidant (decreasing MDA GOTand FFA release of ischemic myocardium and inhibiting Ca-ATPase of erythrocyte membranes) preventing against heartmyocardium ischemia-reperfusion injury and arrhythmiawhen applied (in rats) at 10mgkg (Liu et al [168])
Similarly antioxidative effects of azelnidipine andamlodipine prevented neuronal damage by CCBs aftertransient focal ischemia in rats (Lukic-Panin et al [169])
Allanore et al [170] found that both nifedipine andnicardipine significantly decrease the mean level of plasmamarkers for oxidative stress in patients suffering from sys-temic sclerosis
Antioxidants may be considered as promising neuropro-tective compounds Still while experimental data demon-strate neuroprotective effect in vitro and in animal mod-els clinical evidence is still unsatisfactory and insufficient[171]
(a) Role of Metabolism of DHPs in Their AOA Metabolicpathways and ldquobioavailabilityrdquo of the probable AOA com-pound determine antioxidant activity in vivo Antioxidantmetabolites may vary in stability and activity leading to twoopposite scenarios lack or presence of activity substantiallycontributing to the overall AOA [172] Metabolic biotransfor-mation of DHPs includes oxidation (heteroaromatization)side chain ester group cleavage (deesterification) and 4-substituent abstraction ao [160] None of the DHPs metabo-lites was shown to be more toxic than original reduced formof the compound The commonly detected metabolites ofthe DHPs do not seem to possess the AO activity (withsome exceptions as in the case of metabolites of nifedipineand its analogues including nitrosonifedipine [173 174]) (seefurther in Section 35) Due to DHPs intrinsic instability
achieving andmaintaining an adequate concentrationmay beproblematic both in vitro and in vivo
(b) Role of Concentration and Lipophilicity (MembraneWateror LipidWater Partition Coefficients) of DHPs inTheir Actionas AOs and Antiradical Compounds Antioxidative effects ofany antioxidant depend on its concentration at the site ofaction This parameter is hardly measurable especially intwo-phase systems representing one of obstacles in com-parison to AOA upon applying various compounds [172]It is often incorrectly assumed that the concentrations inthe aqueous solution and at the site of action are the sameHowever even when the concentration in the aqueous phasemay be well controlled the concentration at the site ofaction in the lipid matrix of the membranes might fluctuatebetween different test compounds depending on a differencein lipophilicity [175] The prevention of the membrane LPalso seems to be dependent on the DHP concentration in thelipidmatrix (Mason andTrumbore [46]) and its amphiphilic-ity For example AOA of diludine is associated with itslipophilicity and consequential ability to be incorporatedinto liposomes (Panasenko et al [176]) It was also foundthat diludine easily incorporates into the outer monolayer oferythrocyte membranes [176]
Membranebuffer partition coefficients (lambda) weredirectly measured in the sarcolemma and sarcoplasmicreticulum membranes for three CA DHPs The obtainedvalues were in a broad range between 5000 and 150000(Herbette et al [177])These drugs interact primarily with themembrane bilayer component but may also bind to proteinsboth nonreceptors and receptors The intrinsic forward rateconstants for DHP binding to sarcolemmal calcium channelreceptors were apparently not strongly dependent on theirmembrane partition coefficients For example nimodipine(lambda = 6300) had a forward rate constant of 68 plusmn 06 times106Ms whereas the forward rate constant for Bay P 8857
(lambda = 149000) was 14plusmn08times107Ms Since these DHPsare highly liposoluble model calculations for this bindingreaction demonstrated that these rates on lipid solubilitywould probably not be reflected in the experimental forwardrate constants In addition the intrinsic forward rate constantfor nimodipine binding to sarcolemmal calcium channelreceptors was found not to be linearly dependent on theviscosity of the buffer medium over a fivefold range The rateof drug nonspecific binding to nonreceptor protein present inhighly purified sarcoplasmic reticulum membranes appearsto be extremely fast at least 103 times faster than specificdrug binding to the receptor in the sarcolemma Authorsconcluded that partitioning into the lipid bilayer matrix ofthe sarcolemma could be a general property of CA DHPsand may be a prerequisite for their binding to sarcolemmalmembrane receptors (Herbette et al [177])
The binding of DHP calcium channel agonists and antag-onists (including those with AO properties) to receptors incardiac sarcolemmal membranes is a complex reaction thatmay involve an interaction with the lipid bilayer matrix ofthe sarcolemma (Herbette et al [178]) Belevitch et al [179]studied the binding of DHP CCBs (riodipine and nifedip-ine) and verapamil to model and biological membranes by
Oxidative Medicine and Cellular Longevity 17
fluorescence analysis The consistent location of Ca agonistBay K 8644 was determined to be within the region ofthe first few methylene segments of the fatty acyl chains ofthe membranes (Mason et al [180]) This position is nearto that observed for the DHP calcium channel antagonistsnimodipine and Bay P 8857
Themajority of studies onOSwere performedwithDHPswith various lipophilicity but only a few studies reportedamphiphilicity ofDHPderivatives AmphiphilicDHPderiva-tive K-2-11 reduced the cellular generation of ROS It alsorevealed complete reversal of multidrug resistance (MDR) ofthe resistant cells K-2-11 was more efficient than well-knownMDR inhibitor verapamil Cytotoxic effects of anticancerdrug doxorubicin were enhanced by K-2-11 in bothMDR andparental nonresistant cell line (Cindric et al [181]) K-2-11suppresses increase of ROS and consequentially prevents NF-120581B activation leading to decreased expression of MDR1 andincreased expression of antiapoptotic genes This signalingswitch is necessary for restoring the chemosensitivity ofcancer cells This phenomenon is characteristic both for14-DHPs [182] (18 novel asymmetrical DHPs bearing 3-pyridyl methyl carboxylate and alkyl carboxylate moietiesat C3 and C5 positions resp as well as nitrophenyl orheteroaromatic rings at C4) and for their oxidized formspyridine compounds (Zhou et al [183])
34 Dependence of AOA of DHPs on the Experimental SystemAO effect of DHPs depends on their structure and theexperimental system used (in vitromodel system subcellularorganelle and cells ex vivo and in vivo) Ideally for theevaluation of the profile and value of DHPs AO propertieseach compound should be tested in as many systems aspossible (Dubur et al [45])
Lipidomics studies have been traditionally explored forstudying AOA of DHPs Proteomics methods are less rep-resented and are mostly focused on the properties of DHPsrelated to scavenging of protein free radicals So far there areno studies on the role of DHPs in scavenging nitrosoperoxy-carbonate the reactive species formed out of peroxynitrite inthe presence of carbon dioxide Although it was shown thatalbumin binds diludine no studies revealed the relevance ofthis effect for the AOA of diludine
There are findings showing that dihydropyridine calciumantagonists (DHPs CA) could indirectly play a beneficialprotective role during development of atherosclerosisNamely Berkels et al [184] have studied antioxidativeproperties of four substances the DHP prototype CAnifedipine the long-acting CA lacidipine the DHP calciumchannel agonist BayK8644 and the bulkyDHPderivate BayO 5572 in three different models (1) in an in vitro superoxideanion generating system (hypoxanthinexanthine oxidase)for testing the ldquopurerdquo antioxidative effect (2) in an artificialmembrane preparation (dimyristoylphosphatidylcholine) formimicking a more physiological environment and (3) underconditions of stimulated ROS release (hyperglycemia) fromnative endothelial cells derived from porcine coronary arter-ies
The study also revealed the potential correlation betweenlipophilic and AO properties of DHPs In the first model
Bay K 8644 was significantly more effective in scavengingsuperoxide anions than lacidipine Bay O 5572 or nifedipine(micro- to millimolar concentration range) Addition of anartificial membrane preparation resulted in an enhancedAO effect with lacidipine being the most effective DHP inquenching radicals (low micromolar concentration range)In the third model mimicking hyperglycemia (30mmolL)nifedipine was significantly more potent antioxidant (ther-apeutical nanomolar concentration range) than the otherDHPs Calculated lipophilicity of these four substances(lacidipine gt Bay O 5572 gt Bay K 8644 gt nifedipine) waspositively correlated with antioxidative potential only in thesecond experimental model It has been concluded that AOproperties of DHP substances need to be tested in variousmodels for demonstrating that nifedipine exhibits ROS-quenching properties in a therapeutic concentration range[184]
341 AOA of DHPs in Isolated Cells and Cell Cultures(Comparison with Other Simplest Systems) Although DHPspossess neuromodulatory andor antimutagenic propertiesthe mechanisms of action related to these phenomena arenot entirely elucidated Borovic et al [185] have studied 14-dihydroisonicotinic acid (14-DHINA) derivatives of 14-DHP water-soluble analogues of a well-known AO diludine(diethone) 26-dimethyl-35-diethoxycarbonyl-14-dihydro-isonicotinic acid sodium 2-(26-dimethyl-35-diethoxycar-bonyl-14-dihydropyridine-4-carboxamido)glutamate gluta-pyrone and sodium 2-(26-dimethyl-35-diethoxycarbonyl-14-dihydropyridine-4-carboxamido)ethane-sulphate tauro-pyrone as AO and bioprotectors (Figure 4)
14-DHINArsquos activities were studied in comparison toTrolox by NN-diphenyl-N1015840-picrylhydrazyl (DPPH∙) deoxy-ribose degradation ABTS∙ radical scavenging and AOA(antioxidative capacity method) assays copper-induced LPof cultured rat liver cells (MDA determination by HPLCand 4-hydroxynonenal-protein conjugates by dot-blot) 3H-thymidine incorporation and trypan blue assay for liver cellsgrowth and viability Ic decreased the amount of 4-HNE-protein adducts In all assays Ia was the most potent AOable to completely abolish copper induced LP of liver cellswhile Ic only slightly decreased it Thus AOA is importantactivity principle of Ia which was even superior to Trolox intreated cell cultures Ia (and its analogues) are easily oxidizedin the Fenton system (Rubene et al [186]) exerting ARA too
35 Peculiarities Related to Antioxidative and AntiradicalActivity of Some 14-DHPs Ca Antagonists Nine commer-cialized structurally and functionally different DHPs CAwill be discussed further Their common feature is ability toprevent OS This also counts for some of their metabolitesas already discussed The comparative effects of some DHPsCA on oxidative stress-induced modification of LDL werealready reviewed in Section 331 (2)-(a) AOA of CA DHPswas discussed in Sections 331 (2)-(b) and 331 (2)-(c)
351 Nifedipine and Its Close Analogues Nifedipine vera-pamil and antiarrhythmic-antihypoxic drug stobadin wereshown to depress lipid peroxidation of phosphatidylcholine
18 Oxidative Medicine and Cellular Longevity
NH
COOH
NH
COONa
Glutapyrone
NH
Gammapyrone
NH
C 2H5OOC COOC2H5
Tauropyrone
14-DHINA
H3C H3C
H3C
H3CCH3 CH3
CH3
CH3
COOC2H5COOC2H5
COOC2H5 C2H5OOCC2H5OOCC2H5OOC
CONHCH(CH2)2COONa CONH(CH2)3COONa
CONH(CH2)2SO3Na
Figure 4 Derivatives of 14-dihydroisonicotinic acid (14-DHINA)
liposomes (Ondrias et al [187]) However data obtained insome other experimental systems are conflicting
In an in vitromodel of sarcolemmal membrane lipid per-oxidation three calcium blockers (nifedipine verapamil anddiltiazem) exhibited concentration-dependent (10ndash400 120583M)inhibitory effects [188 189] Nifedipine the most effectivecalcium blocker was more than two-fold potent compared topropranolol achieving significant effect at 10 120583M Nifedipineprotective role on LP using reduced glutathione as modelmarker was recently described (Ray et al [190]) Antiper-oxidative properties of CA nifedipine and its analogueswere explored in different systemspathogenic processesatherogenesis (Henry [165]) brain focal ischemia (Yamatoet al [191]) nephroprotection related to cyclosporine intake(Chander and Chopra [192]) and hepatoprotection relatedto intake of diethyldithiocarbamate (Gaafa et al [193])Recent data suggest that nifedipine action as protector forendothelial cells proceeds independently from its CA proper-ties
The absence of antioxidant effects of nifedipine anddiltiazemonmyocardialmembrane lipid peroxidation oppo-site to nisoldipine and propranolol was also described[194] Nisoldipine and propranolol were shown to havea concentration-dependent antiperoxidant effect with IC
50
values of 282 and 501 120583M respectively Finally nisol-dipine appeared to possess dual antiperoxidant mecha-nisms involving both preventive and chain-breaking proper-ties
These findings were confirmed in some other studiesincluding reports on the lack of antioxidative activity ofnifedipine and nicardipine even at 500120583M concentrationin heart membrane lipid peroxidation tests [134] SimilarlyROS formation in bovine aorta smooth muscle cells was notaffected by addition of amlodipine nimodipine and nife-dipine [123]
(1) Metabolites of Nifedipine and Its Analogues as Antioxidantsand Regulators of OS Antioxidant activity of nifedipine35-dimethoxycarbonyl-26-dimethyl-4-(2-nitrophenyl)-14-dihydropyridine was originally studied in vitro by Kirule etal [195] and Tirzit et al [196] According to the kinetic dataof peroxide accumulation and the ESR spectra (inhibition ofthe autoxidation of methyl oleate in presence of nifedipine)AO action was exerted by the formation of nitroso analogueof the oxidized nifedipine nitroso nifedipine 26-dimethyl-4-(2-nitrosophenyl)-35-pyridine dicarboxylate (NO-NIF)This nitroso aromatic derivative can form nitroxyl radicalsexhibiting remarkable AOA in the presence of unsaturatedfatty acids and lipids [196]
The primary species of free radicals that have beenobtained and identified were ion radicals of the nitrophenyltype (Ogle et al [76]) Such a mechanism coincides withmechanisms proposed afterwards by Nunez-Vergara et al[96] Lopez-Alarcon et al [103] Valenzuela et al [104]Fukuhara et al [174] and Yanez et al [197]
There are also data showing that nitroso compounds mayinhibit LP by direct radical trapping and subsequent forma-tion of stable nitroxide radicals It was further found that thereactivity between the synthesized 14-DHP derivatives withalkylperoxyl radicals involves electron transfer reactionsThisis documented by the presence of pyridine as a final productof the reaction and complete oxidation of the nitroso groupin the case of the nitrosoaryl 14-dihydropyridine derivatives(Valenzuela et al [104]) Tested compounds reacted fastertoward alkylperoxyl radicals and ABTS radical cation thanalkyl ones (Lopez-Alarcon et al [103])
Nitrosonifedipine a photodegradation product of nifedi-pine significantly recovers cellular damage induced by tumornecrosis factor-alpha It also prevents toxic effects of cumeneperoxide which hampers integrity of cell membranes throughoxidative stress Its positive effects are equal to Trolox-C
Oxidative Medicine and Cellular Longevity 19
As a result nitrosonifedipine was already a long time agoclaimed as a candidate for a new class of antioxidative drugs(Kirule et al [195]) cellular protectors against oxidative stressin glomerular endothelial cells [174]
Moreover Misik et al [198] Ondrias et al [199] andStasko et al [200] studied AOA of nifedipine and its oxidizednitroso analogue NO-NIF prevents the progression of type2 diabetic nephropathy associated with endothelial dysfunc-tion through selective AO effects (Ishizawa et al [201]) NO-NIF administration reduces albuminuria and proteinuriaas well as glomerular expansion without affecting glucosemetabolism or systolic blood pressure NO-NIF also sup-presses renal and systemic OS and decreases the expressionof intercellular adhesion molecule-1 (ICAM-1) a marker ofendothelial cell injury in the glomeruli of the KKAy miceSimilar effects were achieved in endothelial nitric oxide syn-thase (eNOS) knockout mice Moreover NO-NIF suppressesurinary angiotensinogen (AGT) excretion and intrarenalAGT protein expression in proximal tubular cells in theKKAy mice On the other hand hyperglycemia-inducedmitochondrial superoxide production was not attenuated byNO-NIF in cultured endothelial cells
Fujii and Berliner found EPR evidence for free radicaladducts of nifedipine in vivo [202] The nature of these rad-icals was surmised by comparing the reaction of illuminatednitrosonifedipine with polyunsaturated fatty acids Surpris-ingly identical radical spectra were detected from excisedliver doped with nonilluminated nifedipine suggesting thatthis drug can be enzymatically converted in vivo to its nitrosoanalogue without the requirement for illumination This isone of the first reports of in vivo EPR evidence for a class ofunsaturated fatty acid radical conjugates resulting from thenormal metabolism of a common drug
Dıaz-Araya et al [173] studied some 4-nitrophenyl-DHPson Fe3+ initiated LP in rat brain slices LP as measuredby MDA formation was inhibited by all the tested nitro-aryl derivatives of 14-DHP over a wide range of concen-trations On the basis of both time course and IC
50experi-
ments the tentative order of AOA on rat brain slices wasnicardipine gt nisoldipine gt (RSSR)-furnidipine gt (RRSS)-furnidipine gt nitrendipine gt nimodipine gt nifedipine14-DHP derivatives that lack a nitro group in the mole-cule (isradipine and amlodipine) also inhibited LP in ratbrain slices but at higher concentrations than that of nitro-substituted derivatives All tested compounds reduced andoxidized nitrosoaryl derivatives (26-dimethyl-4-(2-nitro-sophenyl)-35-pyridinedicarboxylic acid dimethyl ester (pho-tooxidation product of nifedipine ndash NTP) ao) and weremore potent inhibitors of LP than their parent molecules(Valenzuela et al [104])
The electrooxidation process of 4-nitrosoaromatic DHPsis a strongly pH-dependent (two-electron two-proton mech-anism) ECEC type of mechanism that is the sequenceeminusH+eminusH+ at pH gt 85 ECCE mechanism (eminusH+H+eminus)at pH lt 85 dominates Reduction reaction of nitroso groupis as follows R-NO + 2eminus + 2H+ rarr RNHOH (Bollo et al[203])
352 Lacidipine It is a generic DHP type antihypertensiveCA 35-diethyl 4-2-[(1E)-3-(tert-butoxy)-3-oxoprop-1-en-1-yl]phenyl-26-dimethyl-14-dihydropyridine-35-dicarboxy-late
Ursini [204] described redox behaviour of lacidipine andshowed its tissue protective features Cristofori et al studiedantiatherosclerotic activity in addition to lacidipinersquos CAand AO properties [205] Lacidipine reduced the extent ofatherosclerotic area in hypercholesterolemic apoE-deficientmice (these mice show widespread vascular lesions whichclosely resemble the inflammatory fibrous plaques seen inhumans in atherosclerosis) The reduction may be associatedwith the capacity of the drug to maintain endothelial NOlevels at concentrations useful to protect against vasculardamage This work suggested that DHPs modulate vascularrelaxation via increased release of NO
Herbette et al [178] remarked optimal hydrophobicity oflacidipine due to cinnamic acid substituent so membraneinteractions and facilitation of the treatment of atherosclero-sis could proceed (see also Section 331 (2)-(a))
353 Amlodipine Amlodipine (Norvasc) (RS)-3-ethyl5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-14-dihydropyridine-35-dicarboxylate (AML) hasan antioxidant effect on vessels in vitro and is a 3rd genera-tion of charged dihydropyridine CCB that is widely used forthe treatment of hypertensive patients
Amlodipine was shown to have the highest affinity(amlodipine gt verapamil ≫ diltiazem) for the membranebilayer (119870
119901= 104) It produced the significant changes in
membrane thermodynamic properties including a reductionin the thermal phase transition temperature (minus11) enthalpy(minus14) and cooperative unit size (minus59) relative to thecontrol phosphatidylcholine liposomes (Mason et al [49])
Amlodipine AOA is related to its reductant nature orhydrogen donor properties respectively Its ability for donat-ing protons and electrons to the lipid peroxide moleculesblocks the LP process
Amlodipine and even its enantiomers (Zhang et al [206])act as ROS andNOS effectors in several model systems of OSAntioxidant properties of amlodipine were recently reviewedby Vitolina et al [32] Both in vitro and in vivo studiesof amlodipine AO properties revealed inhibition of lipidsoxidative damage primarily those associated with cellularmembranes and lipoprotein particles (LDL) (Mason et al[50])
Under controlled experimental conditions in vitro amlo-dipine showed AOA and ARA by inhibition of lipid peroxideformation and trapping ROS Its scavenging activity forhydroxyl and peroxyl radicals at concentrations as low as100 nmolL (which is remarkably less compared to the classi-cal antioxidants GSH uric acid and Trolox) was shown to beindependent of the calcium channel modulation (Franzoni etal [207])
AML showed efficiency as scavenger of peroxyl radicals(TOSC assay 5945 plusmn 544 unitsmg) significantly stronger(gt50 119875 lt 0001) than GSH (2733plusmn 636 unitsmg) and 70weaker (119875 lt 00001) than uric acid (18144 plusmn 696 unitsmg)and Trolox (17522 plusmn 734 unitsmg)
20 Oxidative Medicine and Cellular Longevity
Of interest the scavenging capacity of AML towardshydroxyl radicals (1455 plusmn 154 unitsmg) was 320 higher(119875 lt 000001) than that of GSH (358 plusmn 112 unitsmg) 20higher than that of uric acid (1198plusmn121 unitsmg) and 100higher than that of Trolox (759 plusmn 143 unitsmg)
Amlodipine was shown to increase enzyme activity ofparaoxonase (PON) and glutathione peroxidase (GSH-Px)However it also decreases glutathione reductase (GSSG-R)activity and diminishes the concentration of the endogenousantioxidant 120572-tocopherol (vitamin E) Moreover AML in aconcentration of 2 ngmL decreased the content of malonicdialdehyde and activity of superoxide dismutase in the blood(Gatsura [208])
Verapamil and amlodipine produced a potent anti-ischemic effect and reduced area of myocardial infarction inrats The observed changes were accompanied by inhibitionof LP In contrast to verapamil in vitro application of AML ina dose of 50 ngmL decreased hemoglobin affinity for oxygenWhen present in a concentration of 2 ngmLAMDdecreasedthe content of MDA and activity of SOD in the blood
On the other hand amlodipine shows no activity relatedto inhibition of macrophage superoxide release and cellmigration which occurs as a consequence of decreasedTNF120572induced O
2
∙ releaseAmlodipine-induced reduction of OS in the brain is
associated with sympathoinhibitory effects in stroke-pronespontaneously hypertensive rats (SHRSP) (Hirooka et al[209]) Antihypertensive treatment with amlodipine reducedOS in all examined areas of the brain and decreased bloodpressure without a reflex increase in sympathetic nerveactivity Nicardipine another CA DHP surprisingly wassignificantly less active than amlodipine
354 Lercanidipine Tomlinson and Benzie reported AOeffect of lercanidipine [210] which is well known as anti-hypertensive drug Zanidip 2[(33-diphenylpropyl)(methyl)-amino]-11-dimethylethyl methyl 26-dimethyl-4-(3-nitro-phenyl)-14-dihydropyridine-35-dicarboxylate Compara-tive data about this drug AOA were presented in parts of thispaper about other individual CA DHPs and in the part aboutthe ex vivo DHPs effects on LDL
355 Nimodipine Nimodipine (ND) commercially knownas Nimotop is 3-(2-methoxyethyl) 5-propan-2-yl 26-dim-ethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxy-late It is centrally active CA
Treatment with glutathione blocked andwith nimodipineattenuated neuronal cell death caused by prolonged exposureof cell culture to 4-HNE (Faraqui [211])
Nascimento et al [212] found AO effect of nimodipine inyoung rats after pilocarpine- (PIL-) induced (in 400mgkg)seizures The PIL administration increased the striatal cata-lase (CAT) activity The administration of ND 30mgkg30min before PIL preserved normal value of CAT activityOn the other hand no difference was detected in the animalstreated with lower dose 10mgkg These results confirmthe neuroprotectiveantiepileptic effect of ND in young ratssuggesting that this drug acts positively on lipid peroxidation
(in both doses) Nimodipine cannot induce these effects viablockade of Ca2+ channel
Ismailoglu et al [213] studied the therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjury These beneficial effects in rats after cerebral corticalinjury seemed to be related to AOA of nimodipine
356 Benidipine Licensed in Japan and South Asia as CA(CCB) benidipine possesses AO properties Chemically it is5-methyl 3-[(3R)-1-(phenylmethyl)piperidin-3-yl] 26-dim-ethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxy-late (or its hydrochloride (4R)-rel-35-pyridinedicarboxylicacid 14-dihydro-26-dimethyl-4-(3-nitrophenyl)- 3-methyl5-[(3R)-1-(phenylmethyl)-3-piperidinyl] ester hydrochloride(1 1))
Benidipine influences processes connected with OS inseveral ways It prevents lysophosphatidylcholine- (lysoPC)-induced injury and ROS production in human aorticendothelial cells (HAECs) (Matsubara and Hasegawa [214])Matsubara et al [215] explained this effect based on stimula-tion of nitric oxide release
LysoPC is a component of oxidized low-density lipopro-teins (oxLDLs) which plays an important role in the patho-genesis of atherosclerosis Pretreatmentwith benidipine (03ndash3 120583molL) for 24 h protected against lysoPC-induced cyto-toxicity in the HAECs through inhibition of both lysoPC-stimulated ROS production and caspase-37-like activationwith a similar potency Since caspase-37 is involved inexecuting the apoptotic process the reduction of the activityof this enzyme by benidipine may explain the antiapoptoticeffect of the drug However benidipine did not suppresslysoPC-induced phosphorylation of mitogen-activated pro-tein kinases and Ca2+ influx in HAECs These results suggestthat the antioxidant properties of benidipine may be respon-sible for its ability to inhibit ROS production a possiblereason for reduced activation of caspase-37 In conclusionbenidipine suppresses lysoPC-induced endothelial dysfunc-tion through inhibition of ROS production which is due atleast in part to its antioxidant effect and not through theinhibition of L-type voltage-dependent calcium channels
Matsubara and Hasegawa [216] examined the effectsof benidipine on cytokine-induced expression of adhesionmolecules and chemokines (chemoattractants) which areimportant for the adhesion of monocytes to endotheliumPretreatment of HAECs with benidipine (03ndash10 120583molL)for 24 h significantly suppressed cytokine-induced vascularcell adhesion molecule-1 (VCAM-1) and intracellular celladhesion molecule-1 (ICAM-1) mRNA and protein expres-sion resulting in reduced adhesion of THP-1 monocytesBenidipine also suppressed induction of monocyte chemoat-tractant protein-1 (MCP-1) and interleukin-8 Benidipinealso inhibited redox-sensitive transcriptional nuclear factor-120581B (NF-120581B) pathway as determined by Western blotting ofinhibitory 120581B (I120581B) phosphorylation and luciferase reporterassay Results of analysis using optical isomers of benidip-ine and antioxidants suggest that these inhibitory effectswere dependent on pharmacological effects other than Ca2+antagonism Benidipine may thus have anti-inflammatoryproperties and benefits for the treatment of atherosclerosis
Oxidative Medicine and Cellular Longevity 21
Benidipine was also shown to inhibit ROS production inpolymorphonuclear leukocytes and oxidative stress in salt-loaded stroke-prone spontaneously hypertensive rats (Mat-subara et al [217])
It should be mentioned that other DHPs also haveendothelial AO actions [218]
357 Azelnidipine (AZL) Azelnidipine 3-[1-[di(phen-yl)methyl]azetidin-3-yl] 5-propan-2-yl 2-amino-6-methyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate(AZL) CAS number 123524-52-7 is commercially available4-nitroaryl-DHP type calcium antagonist with long-actingantihypertensive action (long-acting CA (CCB)) and a lowreported incidence of tachycardia It additionally possessesbeneficial effects in OS and diabetic conditions
Azelnidipine prevents cardiac dysfunction in strepto-zotocin-diabetic rats by reducing intracellular calcium accu-mulation (altering intracellular Ca2+ handling proteins) OSand apoptosis (Kain et al [219]) AZL can reduce the superox-ide production It exerts its protective effects by targeting theNADPH oxidase and mitochondrial redox enzymes AZL-treated diabetic rats express enhanced level of bcl-2 in thelysates of heart muscle indicating that AZL plays protectiverole in cardiac apoptosis
It has been previously observed that azelnidipine inhibitstumor necrosis factor-alpha-induced endothelial cell (EC)oxidative stress through its AO properties (Nakamura etal [220]) Azelnidipine but not nitrendipine completelyinhibits the Ang II-induced ROS generation in ECs (Matsuiet al [221])
Furthermore azelnidipine but not nitrendipine wasfound to partially restore decreased pigment epithelium-derived factor (PEDF) mRNA levels in Ang II-exposed ECsThis study suggests that AZL influence depends on its antiox-idative properties Authors concluded that upregulation ofPEDF by azelnidipine may become a therapeutic targetfor the treatment of diabetic retinopathy associated withhypertension
Antihypertensive agents with AO effects are potentiallyuseful for diabetic patients with hypertension While DHPtypeCAare among themost frequently used antihypertensivedrugs azelnidipine has been reported to have a unique AOeffect in vitro and in vivo in experimental animals (Ohmuraet al [222]) In hypertensive diabetic patients azelnidipinetreatment for 12 weeks induced a more significant decreasein erythrocyte LOOH level than amlodipine although thevalues related to blood pressure during each treatmentremained comparable These data confirm the usefulness ofLOOH level in erythrocyte membrane as a marker of OS invivo and indicate that azelnidipine has a unique antioxidativeproperty in humans
Daikuhara et al [223] reported the results of the OLCAstudy based on combination of (1) olmesartan and a calciumchannel blocker (azelnidipine) or (2) candesartan and a CCBamlodipine in two groups of diabetic hypertensive patientsPatients treated with the first combination presented highlypersistent early morning antihypertensive effect and strongerdecrease in heart rate fasting blood glucose andHbA1c levels
and microalbuminuria when compared to patients treatedwith the combination (2) Because diabetes is associated withsevere chronic OS the observed results might be at least in apart due to the AOA of azelnidipine
In favor of this are findings of Abe et al [224] who foundadditive antioxidative effects of azelnidipine on angiotensinreceptor blocker olmesartan treatment for type 2 diabeticpatients with albuminuria
Similarly the AOA of thiazolidinediones (insulin sensi-tizer) and their effect on cardiovascular function in type 2diabetic model rats and also those of some DHPs (nifedipineamlodipine or AZL commonly used antianginal and anti-hypertensive agents) in cultured human endothelial cells LPwere examined (Mizushige [225]) The AOA was evaluatedby measuring 8-iso-prostaglandine F
2120572concentration and
azelnidipine exhibited potent AOAInsulin (INS) resistance combined with hyperinsuline-
mia is involved in the generation of OS A relation-ship exists between increased production of ROS and thediverse pathogenic mechanisms involved in diabetic vascularcomplications including nephropathy Manabe et al [226]revealed that high doses of INS augmented mesangial cellproliferation through generation of intracellular ROS andactivation of redox signaling pathways Cell proliferation wasincreased in a dose-dependent manner by high doses of INS(01ndash10 120583M) but was inhibited by 01120583M AZL Namely theINS-increased phosphorylation of mitogen activated proteinkinaseextracellular signal-regulated kinase 12 (MAPKERK12) was inhibited by 01 120583MAZL The same AZL concen-tration blocked intracellular ROS production more effec-tively than 01 120583M nifedipine The NADPH oxidase inhibitorapocynin (001ndash01120583M) prevented INS-induced mesangialcell proliferation So azelnidipine inhibits insulin-inducedmesangial cell proliferation by inhibiting the productionof ROS Therefore azelnidipine may have the potential toprotect against the onset of diabetic nephropathy and slowits progression
Azelnidipine inhibited H2O2-induced cell death in
neonatal rat cardiomyocytes (Koyama et al [227]) Azelnidip-ine and nifedipine did not affect theH
2O2-induced activation
of extracellular signal-regulated protein kinases (ERK) andp38 MAPK (mitogen-activated protein kinase) In contrastazelnidipine but not nifedipine inhibited H
2O2-induced c-
Jun NH2-terminal kinases (JNK) activation Authors con-
cluded that azelnidipine has inhibited theH2O2-induced JNK
activation and cardiac cell death Therefore azelnidipine mayhave cardioprotective effects against OS
A specific atheroprotection activity of azelnidipine relatesto inhibition of TNF-120572-induced activator protein-1 activa-tion and interleukin-8 expression in human umbilical veinendothelial cells (HUVEC) through suppression of NADPHoxidase-mediated reactive oxygen species generation (Naka-mura et al [220]) TNF-120572 could play a central role in patho-genesis of insulin resistance and accelerated atherosclerosis inthe metabolic syndrome The concentration of AZL found tobe effective in these in vitro experiments is within therapeuticrange As EC do not possess voltage-operated L-type calciumchannels it is suggested that the beneficial effects of azelni-dipine are not likely due to CA property but to its unique AO
22 Oxidative Medicine and Cellular Longevity
ability Furthermore it has been recently found that serumlevels of monocyte chemoattractant protein-1 a biomarkerfor subclinical atherosclerosis were significantly decreased bythe AZL treatment in patients with essential hypertension Inthis paper [220] authors hypothesize that due to its uniqueTNF-120572 signalmodulatory activity and antioxidative propertyazelnidipine may be a promising DHP for targeting diabetesand cardiovascular diseases in hypertensive patients withmetabolic syndrome
Shinomiya et al [228] evaluated its AOA in culturedhuman arterial EC under OS Azelnidipine has shown apotent antioxidative effect that could be of significant clinicalbenefit when combined with its long-lasting antihypertensiveaction and low incidence of tachycardia
Azelnidipine inhibited TGF-1205731 and angiotensin II- (AngII-) activated 1205721(I) collagen mRNA expression in hepaticstellate cells (HSCs) (Ohyama et al [229]) FurthermoreTGF-1205731- and Ang II-induced OS and TGF-1205731-induced p38and JNK phosphorylation were reduced inHSCs treated withAZL Azelnidipine significantly decreased inflammatory cellinfiltration profibrotic genes expression HSC activation LPoxidative DNA damage and fibrosis in liver of CCl
4- or
TAA-treated mice Finally AZL prevented decrease of theexpression of some AO enzymes and accelerated regressionof liver fibrosis in CCl
4-treated mice Hence the antifibrotic
mechanism of AZL against CCl4-induced liver fibrosis in
mice may have been due to an increased level of AO defenseAs azelnidipine is widely used in clinical practice withoutserious adverse effects it may provide an effective newstrategy for antifibrotic therapy
358 Manidipine Manidipine (2-[4-(diphenylmethyl)pip-erazin-1-yl]ethyl methyl 26-dimethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate) is a DHP CCB withreported nephroprotective properties Calo et al [230] stud-ied effect of manidipine on gene expression and proteinlevel of OS related proteins p22(phox) (human neutrophilcytochrome b light chain (CYBA)) and heme oxygenase-1HO-1 Relevance for antihypertensive effects was revealedThe study assessed the effect of manidipine on normalsubjectsrsquo monocyte gene and protein expression of OS relatedproteins such as p22phox a NADPH oxidase system subunitcritical in generating O
2
∙minus and HO-1 induced by and pro-tective against OS Manidipine was compared with the ACEinhibitor captopril and the CCB nifedipine in the presenceand in the absence of sodiumarsenite (NaAsO
2) as an inducer
of OS Monocyte p22phox (CYBA) mRNA production wasreduced by both manidipine and captopril while no changeswere induced by nifedipine Manidipine increased monocyteHO-1 mRNA production while nifedipine and captoprilshowed no effect The effects of manidipine on p22phoxand HO-1 gene expression in the presence of OS were alsoconfirmed at the protein level Thus manidipine seems tosuppress p22phox and to increase the HO-1 mRNA produc-tion and protein level The manidipine-induced increase ofHO-1 gene and protein expression seems to be a peculiareffect of this drug since it is not observed with captopriland nifedipine This effect together with the reduction of
p22phoxmRNAproduction could play a role in its protectivemechanism against OS
359 Mebudipine The protective effect of mebudipine (14-dihydro-26-dimethyl-4-(3-nitrophenyl)-35-pyridinedicar-boxylic acid 3-methyl-5-tert-butyl ester BAY-n-6391) wasrevealed on OS and LP (MDA decrease SOD GPX andcatalase increase) in myocardial ischemic-reperfusion injuryin male rats (Ghyasi et al [231])
There are articles about other commercial and experi-mental DHPs on OS but we have reviewed only the mostcommonly studied compounds Effects of other commercialCA DHPs on OS are also mentioned in several parts of thisreview
36 14-DHPs Ca Agonists andTheir AOA and ARA For themost popular calcium agonist DHP Bay K 8644 no reactionwith peroxyl radicals was registered (Toniolo et al [114])However interactionwith other compounds possessing AOAand ARA (quercetin) was found
Opposite to that AON-acetylcysteine (NAC) diminishedincrease in Ca2+ transient amplitude and cell shorteninginduced by ISO and forskolin whereas NAC had no effecton the (S)-(minus)-methyl-14-dihydro-26-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylatemdash(minus)-BayK 8644-induced increases (Andersson et al [232])
Increased vasoconstriction responses to Bay K 8644 (3 times10minus7ndash3times 10minus5M)were significantly decreased by pyridoindoleantioxidant stobadine treatment in diabetes (Ceylan-Isik etal [233])
The functional interaction between two L-type Ca2+channel activators quercetin and Bay K 8644 has beeninvestigated in vascular smooth muscle cells Biological ARAcompound quercetin at nutritionally meaningful concen-trations limited the responsiveness of vascular L-type Ca2+channels to the pharmacological stimulation operated by BayK 8644 These data contribute to a better understanding ofquercetin effects on experimental in vivo cardioprotection(Saponara et al [234]) Thus these findings indicated thatalthough Bay K 8644 does not exert potent and direct AOAyet acting as calcium agonist it may affect efficiency of AOsubstances and vice versa
Interaction of grapefruit juice (containing quercetin andits analogues) with DHPs CA diminished effectiveness of CAaction of DHPs (Sica [235])
37 Interpretations of the Mechanism(s) of RadicalScavenging and AOA by DHPs
371 Molecular Mechanism(s) of Radical Scavenging andAOA of DHPs in the Model Systems 35-Dicarbonyl-14-di-hydropyridine derivatives possess powerful bis-120573-carbony-lvinyl-amino conjugation and for that reason cannot be con-sidered as ordinary amino antioxidants The electron andorH donation from DHPs ensures their reductant role andresults in AOA and ARA Oxidation reaction from DHPsresults in production of corresponding heteroaromatic pyri-dine derivatives
Oxidative Medicine and Cellular Longevity 23
Detailed studies were made about substituent in DHPring positions 14- namely 4-unsubstituted- 4-substituted4-alkyl- 4-aryl- 4-alkylaryl- ao 26- 35- (diacetyl ordialkoxycarbonyl chain ao) electronic and steric effects onAOA and ARA of DHPs [44 45 51] see Sections 331and 35 The bell-shaped dependence of DHPs AOA onthe 35-dialkoxycarbonyl- chain length was observed [4445 107 109 112] with the maximum activity at C
2H5ndash
C4H9 Decrease of AOA and incorporation into liposomes for
DHPs with alkyl chains longer than R gt C4H9further were
clarified as probable tendency to self-aggregation of thesecompounds ([51] and citation number 245 therein) Electronacceptorelectron donor properties are relevant for expres-sion of AOA or ARA of 35-disubstituted DHPs 35-Diacyl-substituted and 35-dicarbanilido- and 35-dipyridylamido-substituted DHPs are more active as AOs as their 35-dicyano-substituted analogues which have electron acceptorproperties [186]
Dubur et al [89] observed overwhelming steric influenceof substituents in position 4 of the DHP ring Gaviraghiet al [163 164] proposed that AO activity of DHPs ispartly dependent on capacity of the 14-DHP ring to donateelectrons to the propagating radical (ROO∙ or RO∙) and toreduce it to a less reactive form The abstraction (donation)of electron andor H in the oxidation and LP reactionstakes place from all 35-dicarbonyl-14-DHP systems andresults in the formation of corresponding pyridine derivatives(Augustyniak et al [51]) The physicochemical mechanism ofARA and AOA of 14-DHP has been extensively studied anddiscussed (Mulder et al [236]) but precise mechanisms oftheir activity need further clarification
The reactivity of C-4 substituted 14-DHPs possessingeither secondary or tertiary nitrogen atom in the DHP ringtoward alkyl alkylperoxyl radicals and ABTS radical cationwas determined in aqueous media at pH 74 [103] Thesecompounds reacted faster toward alkylperoxyl radicals andABTS radical cation than alkyl ones N-Ethyl-substitutedDHPs showed the lowest reactivity
The 4-methyl substituted DHP was the most reac-tive compound in previously mentioned reactions (Lopez-Alarcon et al [103]) However it was less active (068versus 10) than Trolox-C DHPs having electron-donatingsubstituents (4-Me-DHP and p-MeO-Phe-DHP) showed thehighest kinetic rate constants toward ABTS radical cation p-nitro-Phe-DHP a compound with an electron-withdrawingsubstituent showed a lower kinetic rate constant and N-alkyl-DHP compounds show kinetic rate constants lowerthan the -NH-DHP
Hydrogen at the 1-position of the DHP ring was revealedaccording to the deuteriumkinetic isotope effect studies to beinvolved in the proposedARAmechanismThis fact ismostlynoticeable in the case of alkyl radicals N-Ethyl-substitutedDHPs show the lowest reactivity when compared to Troloxor nisoldipine In all cases the respective pyridine derivativewas detected as the main product of the reaction (Lopez-Alarcon et al [103]) Authors indicate that the kinetic rateconstants toward alkyl alkylperoxyl andABTS radical cationdepend on the nature of the substituents in the C-4 positionof DHP and the presence of the secondary amine group in the
dihydropyridine ring that is the presence of the hydrogen in1-position
Yanez et al [197] have studied the reactivity of 11derivatives of 14-DHPs (including commercial CA) withalkylperoxyl radicals and ABTS radical cation The tested14-DHPs were 83-fold more reactive towards alkylperoxylradicals than to the ABTS cation radical All commercial14-DHP type CCBs were weaker than Trolox-C The par-ticipation of the hydrogen atom in the 1-position appearsto be very relevant for exhibited reactivity Hantzsch ester(diludine)was again found to be themost active compound inthe reaction with alkylperoxyl radicals 23-fold more activethan Trolox The photodegradation product of nifedipine(nitrosophenyl derivative of pyridine) also showed a highactivity Kinetic rate constants for the reaction between 14-DHP compounds and alkylperoxyl radicals exhibited a fairlygood linear correlation with the oxidation peak potentialof DHP derivatives However the activity of tested 14-DHPs towards ABTS radical cation showed an independencebetween kinetic rate constants and oxidation peak potentials
Kirule et al [195] andTirzit et al [196] studiedmechanismof AOA of 4-nitrophenyl-14-DHPs nifedipine and its ana-logues involving formation of 4-(21015840-nitrosophenyl)-pyridinederivative (as active principle) as a result of intramolecularredox reaction using chemical electrochemical and bio-chemical approaches (see Sections 331 and 351)
Nunez-Vergara et al [237] reported the electrochemicaloxidation of C4-hydroxyphenyl-substituted 14-DHP deriva-tives The oxidation proceeds via formation of the unstabledihydropyridyl radical as confirmed by controlled-potentialelectrolysis (CPE) and ESR experiments This type of 14-DHPs has significant activity towards the radicals even whencompared with commercial 14-DHP drugs with well-knownantioxidant ability
It was observed that nicardipine preferentially targets RO∙radicals and is inactive against ROO∙ Lacidipine on theother hand is equally active towards both types of radicals(Gaviraghi et al [164]) The cytoprotective effect againstexposure to H
2O2was more significant for lacidipine (ID
50=
14 nM its log119875 = 54 membrane partition = 136000 assumesposition located 7 A near to the membrane center otherless lipophilic DHPs located 12ndash16 A far from the center)as compared to amlodipine nifedipine and nicardipine insmooth muscle cell culture (Gaviraghi et al [164]) Oxidativeeffect of H
2O2shifts the Ca channel toward an open state
Thus the redox property of CCBs DHPs may augment theirCCB properties
Oxidation of pharmacologically active Hantzsch 14-dihydropyridines was found by electrogenerated superoxideusing a voltammetric approach in DMSO solutions (Ortiz etal [238] and Ortiz et al [239]) Raghuvanshi and Singh [240]have also reported oxidative aromatization of these DHPsinduced by superoxide
Chemiluminescence (CL) was used in the studies ana-lyzing the antioxidant activity of 12 various 4-flavonil-14-dihydropyridine derivatives (Kruk et al [241]) on a chemicalsystem involving a superoxide radical anion These deriva-tives showed structural similarity to flavonoids with respectto the presence of rings A B and C The results obtained in
24 Oxidative Medicine and Cellular Longevity
this study indicate that the tested derivatives may catalyzeconversion of superoxide radicals through mimicking theactivity of superoxide dismutase by delivering H+ for reac-tion
O2
minus∙+O2
minus∙+ 2H+ 997888rarr H
2O2+1O2
(3)
The enhanced emission of the light in the presence oftested compounds was significant and related to stimulatedproduction ofH
2O2and 1O
2fromO
2
∙The latter specieswereremoved from the reactionmixture by the following sequenceof reactions
H+
O2
minus∙997888rarr HO
2
∙
HO2
∙+O2
∙minus997888rarr HO
2
minus+1O2
2HO2
∙997888rarr H
2O2+1O2
2 (1O2) 997888rarr (O
2)2+ h]lowast
(4)
or to take part in spontaneous dismutation of H2O2
2H2O2997888rarr 2H
2O + 1O
2(5)
The authors have offered an original concept of action for 4-flavonil-14-dihydropyridine derivatives unrelated to that ofO2
∙ radical-trapping chain-breaking antioxidants Insteadthey showed that these compounds act similar to superoxidedismutases converting O
2
∙ to H2O2 Hydrogen peroxide
is less toxic for cells than O2
∙ because it is predominantlyremoved by peroxidases and catalases Finally AO effect ofthese DHPs differed from those mediated by flavonoids witha catechol structure of ring B which are well-known 1O
2
quenchersMulder and collaborators came to similar conclusions
especially related to molecular mechanisms of antioxidativeactivity of DHPs [236]TheAOproperties of Hantzsch 14-di-hydropyridine esters and two dibenzo-14-dihydropyridines910-dihydroacridine (DHAC) and N-methyl-910-dihydro-acridine (N-Me-DHAC) have been explored by determin-ing the autoxidation of styrene or cumene at 30∘C Theseexperiments showed that Hantzsch esters are virtually inac-tive as chain-breaking antioxidants (CB-AOs) contrary tothe findings observed by Lopez-Alarcon et al [103] whoused CB-AOA in aqueous media at pH 74 Their reactivitytoward peroxyl radicals was shown to be some 5 orders ofmagnitude lower than that of the excellent CB-AO 22578-pentamethyl-6-hydroxy-chroman (PMHC)
DHAC was found to be sim10 times less reactive thanPMHC kinetic measurements using DHAC N-deuterio-DHAC and N-Me-DHAC pointing out the abstraction ofN-H hydrogen in DHAC by peroxyl radicals despite the factthat the calculated C-H bond dissociation enthalpy (BDE) inDHAC is about 11 kcalmol lower than the N-H BDE Therates of hydrogen atom abstraction by the 22-diphenyl-1-picrylhydrazyl radical (DPPH∙) have also been determined
for the same series of compounds The trends in the peroxyl∙and DPPH∙ rate constants were found to be similar [236]
Tirzit et al [242] have observed quenching of singletoxygen by DHPs This observation paved the ground forfurther research related to reactions of DHPs with hydroxylradicals (Tirzit et al [243]) singlet oxygen (Kazush etal [94]) and mechanisms of action A series of 14-DHPderivatives in NAD-H-Cu2+-H
2O2system inhibited forming
of the hydroxyl radical (HO∙) while 14-DHP derivativeswith electron donor substituents in the molecule were shownto be capable themselves of generating HO∙ in the presenceof Cu2+ and H
2O2 Rubene et al [186] also described
interaction of 14-DHP derivatives with Fentonrsquos reagentwhich produces hydroxyl radical (HO∙) Rate constants ofthe DHPs reaction (1st order) with HO∙ radical were highin the range 109 L times mol times secminus1 close to that of NADHcysteine and thiourea 35-Diacetyl- derivatives reacted fastercompared to 35-dialkoxycarbonyl- ones The reaction ratedecrease was observed in the case of substitution at position4 as compared to 4-unsubstituted DHPs Some DHPs havingelectron donor -COOminus groups in the 35- or 26- positionsof DHP ring reacted immediately (having rate constantshigher as 109 L times mol times secminus1) Rate constants with HO
2
∙
and O2
∙minus radicals were of lower degree Thus DHPs actingas oxygen radical scavengers could effectively inhibit ROSrelated reactions of LP initiation stage
Nifedipine and nitrendipine reactivity toward singletoxygen was also studied [244] Nifedipine was shown tobe a good scavenger of excited oxygen mainly via physicaldeactivation with values of the total rate constant rangingfrom 208 times 105Mminus1 sminus1 (in dioxane) to 930 times 105Mminus1 sminus1(in propylene carbonate)The less reactive pathway generateda photooxidation product For that reason a mechanisminvolving a perepoxide-like encounter complex in the firststep of the reaction path was proposed (see [244] Figures8 and 9 therein) The dependence was observed on solventmicroscopic parameters of the total rate constant for the reac-tion between singlet oxygen and 14-DHPs These findingsshow that nifedipine possesses stronger protective activity inbiological systems than nitrendipine
Density-functional-theory (DFT) calculations made byWang et al [245] confirmed the former experimental obser-vations that Hantzsch ester diludine is potent antioxi-dant with high H atom-donating ability and relatively lowprooxidant activity Possible reaction pathways for radicalsderived from 14-dihydropyridine and the resonance modesfor radical species were given [245]
Moreover two ethoxycarbonyl (EtOCO) substituentsat C(2) and C(6) should further enhance Hantzsch esterdiludine H-atom-donating ability due to resonance effectsHowever DHPs should be used in nonpolar rather than inpolar solvents since in the latter not H-atom but electrontransfer is preferred in the radical scavenging process [245]
Mulder et al [246] proposed that quantum-thermochem-ical calculations must be used with caution to indicate ldquoapromising lead antioxidantrdquo as they criticized the density-functional-theory (DFT) calculations made by Wang et al[245]
Oxidative Medicine and Cellular Longevity 25
372 Possible Mechanisms of DHPs ARA and AOA in the Bio-logical Systems Interaction with Other OSModifiers Some ofthese mechanisms were already described (Sections 331 (2)-(b) 331 (2)-(c) 331 (3)-(b) 35)
Enzymatic sources of ROSwith confirmed functional rolein hypertension are NADPH oxidase NO synthase (NOS)xanthine oxidase and cyclooxygenase Godfraind [3] hasreviewed AO effects and protective action of calcium channelblockers (CCBs) Yao et al [247] observed antioxidant effects(as inhibition of LP) for cardio- and neuroprotective CCBs(3ndash300 120583molL) including 7 DHPs in homogenates of ratbrain IC
50values (120583M) were as follows nifedipine (515) gt
barnidipine (586) gt benidipine (712) gt nicardipine (1293)gt amlodipine (1355) gt nilvadipine (1673) gt nitrendipine(2521) gt diltiazem (gt300) = verapamil (gt300) There arealso research articles describing the AO properties of CCBsthrough direct scavenging effect or through preservationof the endogenous SOD activity These findings indicatethat CCBs may also act by reducing the production ofvasoconstrictors angiotensin and endothelin
When present in concentrations that can be achievedin plasma CCBs may inhibit LP formation [3] This AOactivity seems to be typical for high lipophilic CCBs becausetheir chemical structure facilitates proton-donating andresonance-stabilization mechanisms that quench the freeradical reaction Their insertion in the membrane nearpolyunsaturated fatty acids at relatively high concentrationspotentiates proton donation (or atomary H) to lipid peroxidemolecules thereby blocking the peroxidation process Theremaining unpaired free electron associated with the CCBmolecule can be stabilized in well-defined resonance struc-tures associated with the DHP ring (Mason et al [48])
The radical reaction (according to Godfraind [3]) thatdescribes the AO effects of a DHP CCBs is LOOlowast + DHPrarr LOOH + DHPlowast (where LOOlowast is lipid peroxide radical)which in general is reaction (7) of the LP reaction cascadeconsisting of sim10 reactions (Scheme 2) [89]
As the rate constants of in vitro interaction of 4-substituted DHPs with peroxyl radicals are three ordersof magnitude lower than that of the vitamin E derivativethese DHPs must be considered as weak AO (Ursini [204])However due to partition coefficient of DHPs in membranesand in case of specific binding high local concentration ofDHPs may be obtained
DHPs without CCB properties for instance Bay w 9798although structurally related to nifedipine inhibit TNF-120572-induced vascular cell adhesion molecule-1 expression inendothelial cells by suppressing reactive oxygen speciesgeneration [248]
Mitrega et al [249] have discovered that antiarrhythmicand hemodynamic effects of oxidized heteroaromatic DHPsoxy nifedipine oxy nimodipine oxy nitrendipine and oxynisoldipine suggest that CCB DHPs and their metabolitescould act at least in two ways targeting OS related eventsas reductants (see Section 351 (1)) andor bypassing OSrelatedmetabolic routes Authors postulated that contrary tocurrent belief NIF metabolites are pharmacologically activeATP sensitive potassium channels were mentioned as a tar-get
38 DHPs Anti- or Prooxidants Several substances (ascorbicacid being the most commonly studied) can serve either asantioxidants or as prooxidants depending on given condi-tions (Herbert [250]) Therefore Halliwell [251] has reporteddilemma related to polyphenols as possible antioxidantsand prooxidants causing experimental artifacts (about 25)by oxidation of antioxidant compounds in the cell culturemedia Nevertheless it is generally accepted opinion thatpolyphenols act as antioxidants in vivo Studies on DHPs alsoface such a dilemmaThe exact roles (anti- or prooxidative) ofany specific DHP depend on its structure appliedachievedconcentration and specificity of the targetexperimentaltesting system
This situation resembles the case of antioxidative effectsof tocopherol which depends on the fate of the secondaryradical as proposed by Winterbourn [252] The question wasldquoVitamin E - Pro- or Antioxidantrdquo
997888rarr chain termination of lipid peroxidation
(6)
Prooxidant
Toc∙ + Lipid-H 997888rarr Lipid∙ (in LDL particles) (7)
This example shows that generally speaking any AO mustfulfil several criteria to be considered as an effective com-pound physiologically
(i) It must be able to functionally interact with endoge-nous scavengers even at low concentrations
(ii) It must affect endogenous pathways of OS(iii) It should not have undesirable adverse effect(iv) It should manifest the antioxidant efficacy dependent
on the oxidant(v) It must discriminate among different strategies
needed for 1-electron and 2-electron processes(vi) Radical scavengers can be prooxidant unless linked to
a radical sink (Winterbourn [252])
According to these statements DHPs could be effective asAO under physiological conditions in vivo (Godfraind [3]and others [30 31 38]) and in vitro in various experimentalsystems (cell and tissue) (see Sections 33 34 35)
Hence calcium antagonists appeared to disrupt thefine balance between the production and scavenging ofROS Nifedipine verapamil and diltiazem were shown toinduce significant oxidative stress in the epididymal sperm(increased MDA and decreased catalase and superoxidedismutase activity) This may be the reason for the inductionof male infertility [253]
The dualism of 14-DHP effects has been recorded asinhibition or promotion of LP as quenching or initiating
26 Oxidative Medicine and Cellular Longevity
oxygen and nitrogen free radical chain reactions radiopro-tecting or radiosensitizing antagonizing or synergizing Ca2+in electromechanical coupling as well as in the membranestabilization or labilization
39 Could DHPs Be Involved in Antioxidative Stress Beforebeing applied in vivo the optimal dose and optimal timeintervals forDHPs applicationmust be knownNamely whileROS have been traditionally considered as toxic byproductsof aerobic metabolism we know nowadays that ROS may actas essential signaling molecules needed for the control ofmany different physiological processes Whether the role ofROS will be damaging protective or signaling depends onthe delicate equilibrium between time- and location-specificROS production and scavenging Accordingly the imbalanceof the increased AO potential so-called antioxidative stresscould be dangerous similar to chronic OS in particular incase of extended exposure Inappropriate interventions inthe oxidative homeostasis by excessive antioxidants especiallyin case of chronic exposure to antioxidants might havevery negative effects as was published in the ATBC studyshowing an increased cancer incidence in smokers treatedby excessive beta-carotene [254] Therefore overconsump-tion of any natural or synthetic AO including DHPs asdietary supplements or drugs must be avoided in order tosuppress oxidative damage and must not disrupt the well-integrated antioxidant defense network (Poljsak [255] andPoljsak and Milisav [256]) This is especially important whenadministrating lipid-soluble antioxidants that can be storedin biomembranes thus not only attenuating or preventing LPbut also affecting physiological effects of the natural antiox-idants in particular tocopherol The interrelationship withthe status of endogenous antioxidantsprooxidants should befollowed
DHPs primarily suppress the initiation stages of LPprocessThey do not entirely stop the LP propagation Actingsynergistically with tocopherol diludine may prevent patho-logical excess of ROS production within the lipid moiety ofthe cellular membranes and LDL However due to its lowsolubility and fast metabolism its concentration in the cellsis low For that reason it cannot cause antioxidative stresseven if used for an extended period of time Thus diludine(diethone) could be only a mild antioxidant it has potentialfor restoring the pool of natural antioxidants (as synergist of120572-tocopherol and polyphenols) in the cells
Moreover DHPs CA used for cardioprotection andvasodilatation as commercial drugs in low concentrationsare fast metabolized via CYP3A4 and for that reason theirapplication does not induce cellular AO stress [53 160]However Godfraind and Salomone [257] have postulated noevidence that allows recommending dietary supplementationwith antioxidants for the primary or secondary prevention ofcardiovascular disease
So far there are no reports on antioxidative stress causedby some DHPs diludine and its analogues Diludine andits analogues therefore could act as adaptogens supportinghormetic effects of mild oxidative stress These compoundsmay act as potential multisided modulators of Yin-Yang
cycles of redox and cell functions (the electroplasmic cycle)(Wagner et al [258])
4 Conclusions
14-Dihydropyridines (14-DHPs) have broad spectrum ofOS modulating activities DHPs have reducing and lipidperoxidation inhibitor properties act as reductants in simplechemical systems and stabilize various biological systems(LDL mitochondria microsomes cells and tissues) againstOS Examples and peculiarities and mechanisms of antiox-idant activity (AOA) and antiradical activity (ARA) as wellas stress-protective effect of DHPs including commercialcalcium antagonists (CA) were highlighted These activitiesdepend on various structural parameters related to DHPs(presence and character of substituents) lipophilicity anddepth of the incorporation in the biologicalmembranesTheyalso depend on the experimental model system for exploringthe lipid peroxidation or oxidative stress Stress-protectiveeffect of some metabolites of CA (nifedipine) is reviewedAlthough some DHPs including CA have prooxidant prop-erties (on epididymal sperm cells) they can generally beconsidered as potent antioxidants Therefore comparisonof the AOA and ARA of different DHPs (mutually andwith other AOs) was described in detail According to thedata presented the DHPs might be considered as bellwetheramong synthetic compounds targeting OS and as a kind ofpharmacological measure for respective field of organic andmedicinal chemistry
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
Authors from Latvian IOS acknowledge ESF 201300021DP1112013APIAVIAA011 and National Research Pro-gramme PUBLIC HEALTHBiomedicine of the Republicof Latvia for financial support administration of the Insti-tute for technical support and Rufus Smits PhD for con-sultations in English The support of Cooperation in Euro-pean System of Science and Technology (COST) Domain ofChemistry Molecular Sciences and Technologies (CMST)was of highest importance for preparation of this paper
[2] D J Triggle ldquo14-Dihydropyridines as calcium channel ligandsand privileged structuresrdquoCellular andMolecular Neurobiologyvol 23 no 3 pp 293ndash303 2003
[3] T Godfraind ldquoAntioxidant effects and the therapeutic modeof action of calcium channel blockers in hypertension andatherosclerosisrdquo Philosophical Transactions of the Royal SocietyB Biological Sciences vol 360 no 1464 pp 2259ndash2272 2005
[4] E Cadenas ldquoMitochondrial free radical production and cellsignalingrdquoMolecular Aspects of Medicine vol 25 no 1-2 pp 17ndash26 2004
[5] E Cadenas ldquoFree radicals oxidative stress and diseasesrdquo inLecture PSC 616 p 38 Missouri University of Science andTechnology Rolla Mo USA httpwwwcarnicominstituteorgarticlesenrique cadenaspdf
[6] K Rahman ldquoStudies on free radicals antioxidants and co-fac-torsrdquo Clinical Interventions in Aging vol 2 no 2 pp 219ndash2362007
[7] V Bocci and G Valacchi ldquoFree radicals and antioxidants howto reestablish redox homeostasis in chronic diseasesrdquo CurrentMedicinal Chemistry vol 20 no 27 pp 3397ndash3415 2013
[8] M Valko C J Rhodes J Moncol M Izakovic and M MazurldquoFree radicals metals and antioxidants in oxidative stress-induced cancerrdquo Chemico-Biological Interactions vol 160 no 1pp 1ndash40 2006
[9] G Bartosz ldquoReactive oxygen species destroyers or messen-gersrdquo Biochemical Pharmacology vol 77 no 8 pp 1303ndash13152009
[10] R Visconti and D Grieco ldquoNew insights on oxidative stress incancerrdquo Current Opinion in Drug Discovery and Developmentvol 12 no 2 pp 240ndash245 2009
[11] R N Kujundzic N Zarkovic and K G Troselj ldquoPyridinenucleotides in regulation of cell death and survival by redoxand non-redox reactionsrdquo Critical Reviews in Eukaryotic GeneExpression vol 24 no 4 pp 287ndash309 2014
[12] B Halliwell and J M C Gutteridge ldquoThe definition and mea-surement of antioxidants in biological systemsrdquo Free RadicalBiology and Medicine vol 18 no 1 pp 125ndash126 1995
[13] V D Kancheva and O T Kasaikina ldquoBio-antioxidantsmdashachemical base of their antioxidant activity and beneficial effect
on human healthrdquo Current Medicinal Chemistry vol 20 no 37pp 4784ndash4805 2013
[14] H V Panglossi Ed Frontiers in Antioxidants Research NovaScience Publishers New York NY USA 2006
[15] E B Burlakova E M Molochkina and G A NikiforovldquoHybrid antioxidantsrdquo Oxidation Communications vol 31 no4 pp 739ndash757 2008 httpmembraneustceducnpaperpdfHybrid20Antioxidantspdf
[16] A Bast and G R M M Haenen ldquoTen misconceptions aboutantioxidantsrdquo Trends in Pharmacological Sciences vol 34 no 8pp 430ndash436 2013
[17] E B Burlakova A V 0lesenko E M Molochkina N PPalmina and N G Khrapova Bioantioxidants for RadiationDamage and Malignant Growth Nauka Moscow Russia 1975(Russian)
[18] J Fang T Seki and H Maeda ldquoTherapeutic strategies by mod-ulating oxygen stress in cancer and inflammationrdquo AdvancedDrug Delivery Reviews vol 61 no 4 pp 290ndash302 2009
[19] M Valko D Leibfritz J Moncol M T D Cronin M Mazurand J Telser ldquoFree radicals and antioxidants in normal physi-ological functions and human diseaserdquo International Journal ofBiochemistry and Cell Biology vol 39 no 1 pp 44ndash84 2007
[20] M Jimenez-Del-Rio and C Velez-Pardo ldquoThe bad the goodand the ugly about oxidative stressrdquo Oxidative Medicine andCellular Longevity vol 2012 Article ID 163913 13 pages 2012
[21] C D Kamat S Gadal M Mhatre K S Williamson Q N Pyeand K Hensley ldquoAntioxidants in central nervous system dis-eases preclinical promise and translational challengesrdquo Journalof Alzheimerrsquos Disease vol 15 no 3 pp 473ndash493 2008
[22] A Pompella H Sies R Wacker et al ldquoThe use of totalantioxidant capacity as surrogate marker for food quality andits effect on health is to be discouragedrdquo Nutrition vol 30 no7-8 pp 791ndash793 2014
[23] Z Ye and H Song ldquoAntioxidant vitamins intake and the risk ofcoronary heart disease meta-analysis of cohort studiesrdquo Euro-pean Journal of Cardiovascular Prevention and Rehabilitationvol 15 no 1 pp 26ndash34 2008
[24] P Knekt J Ritz M A Pereira et al ldquoAntioxidant vitamins andcoronary heart disease risk a pooled analysis of 9 cohortsrdquoTheAmerican Journal of Clinical Nutrition vol 80 no 6 pp 1508ndash1520 2004
[25] A C Carr and M C M Vissers ldquoSynthetic or food-derivedvitamin Cmdashare they equally bioavailablerdquo Nutrients vol 5 no11 pp 4284ndash4304 2013
[26] R Tabrizchi ldquoEdaravoneMitsubishi-TokyordquoCurrentOpinion inInvestigational Drugs vol 1 no 3 pp 347ndash354 2000
[27] K Kikuchi S Tancharoen N Takeshige et al ldquoThe efficacy ofedaravone (radicut) a free radical scavenger for cardiovasculardiseaserdquo International Journal of Molecular Sciences vol 14 no7 pp 13909ndash13930 2013
[28] D Mauzerall and F H Westheimer ldquo1-Benzyldihydronicoti-namidemdasha model for reduced DPNrdquo Journal of the AmericanChemical Society vol 77 no 8 pp 2261ndash2264 1955 ChemicalAbstracts vol 50 Article ID 2588i 1956
[29] F Bossert and W Vater ldquo14-Dihydropyridinesmdasha basis fordeveloping new drugsrdquo Medicinal Research Reviews vol 9 no3 pp 291ndash324 1989
[30] G Swarnalatha G Prasanthi N Sirisha and CMadhusudhanaChetty ldquo14-Dihydropyridines a multtifunctional moleculemdash areviewrdquo International Journal of ChemTech Research vol 3 no1 pp 75ndash89 2011
28 Oxidative Medicine and Cellular Longevity
[31] M Cataldi and F Bruno ldquo14-Dihydropyridines the multiplepersonalities of a blockbuster drug familyrdquo Translational Medi-cine UniSa vol 4 no 2 pp 12ndash26 2012 httpwwwncbinlmnihgovpmcarticlesPMC3728803
[32] R Vitolina A Krauze G Duburs and A Velena ldquoAspects ofthe amlodipine pleiotropy in biochemistry pharmacology andclinicsrdquo International Journal of Pharmaceutical Sciences andResearch vol 3 no 5 pp 1215ndash1232 2012
[33] D Grover S N Mokale and M T Shete ldquoDihydropyridinea novel pharmacophorerdquo International Journal of Pharmaceu-tical Erudition vol 1 no 2 pp 16ndash29 2011 httppharmaeru-ditionorgContentPaper20111-RV-320Final2016-29pdf
[34] A M Vijesh A M Isloor S K Peethambar K N ShivanandaT Arulmoli and N A Isloor ldquoHantzsch reaction synthesis andcharacterization of somenew 14-dihydropyridine derivatives aspotent antimicrobial and antioxidant agentsrdquo European Journalof Medicinal Chemistry vol 46 no 11 pp 5591ndash5597 2011
[35] P Mehta and P Verma ldquoAntimicrobial activity of some deriva-tives of 14-dihydropyridinesrdquo Journal of Chemistry vol 2013Article ID 865128 4 pages 2013
[36] P Olejnıkova L Svorc D Olsovska et al ldquoAntimicrobialactivity of novel C2-substituted 14-dihydropyridine analoguesrdquoScientia Pharmaceutica vol 82 no 2 pp 221ndash232 2014
[37] S Sepehri H Perez Sanchez and A Fassihi ldquoHantzsch-typedihydropyridines and biginelli-type tetra-hydropyrimidinesa review of their chemotherapeutic activitiesrdquo Journal of Phar-macy amp Pharmaceutical Sciences vol 18 no 1 pp 1ndash52 2015httpsejournalslibraryualbertacaindexphpJPPSarticleview2383617863
[38] S A Khedkar and P B Auti ldquo14-Dihydropyridines a classof pharmacologically important moleculesrdquo Mini-Reviews inMedicinal Chemistry vol 14 no 3 pp 282ndash290 2014
[39] G D Tirzit and G Ya Duburs ldquo14-dihydropyridines as inhi-bitors of free-radical reactionsrdquo Chemistry of Heterocyclic Com-pounds vol 8 no 1 pp 126ndash127 1972 Translated from KhimiyaGeterotsiklicheskikh Soedinenii no1 pp 133ndash134 1972 (Rus-sian)
[40] I Bogeski R Kappl C Kummerow R Gulaboski M Hothand B A Niemeyer ldquoRedox regulation of calcium ion channelschemical and physiological aspectsrdquoCell Calcium vol 50 no 5pp 407ndash423 2011
[41] S A Giller G Y Dubur Y R Uldrikis et al ldquoDiludine [Themethod to obtain 35-dicarbonylderivatives of 26-dimethyl-14-dihydropyridines]rdquo Authors certificate of USSR no 3004651971 [Byull Izobret no13 p 95 1971] and following patentsPatent of England no 1294650 1973 Patent of France no2055458 1971 Patent of Japan no 702883 1973 Patent ofHolland no 149787 1976 Patent of Italy no 969022 1974 Patentof FRG no 2036403 1978 US Patent no 3883673 1975 USPatent no 3948924 1976
[42] S A Giller G Y Dubur Y R Uldrikis et al ldquoImprovementsin or relating to the stabilization of carotenerdquo GB Patent no1294650 1972
[43] S A Giller G Y Dubur Y R Uldrikis et al ldquoStabilization ofcarotenerdquo US Patent no 3883673 1975 Chemical Abstracts vol83 Article ID 95193 1975
[44] Yu A Zilber G Ya Dubur K K Kumsar and A Kh VelenaldquoThe effect of antioxidants on the peroxidation of bimole-cular phospholipid membranesrdquo Latvijas PSR ZA Vestis Izves-tia Akademii Nauk Latviyskoy SSR vol 6 pp 80ndash82 1971(Russian) translated from the original Russian Doc Accesion
No AD0771751 distributed by NTIS US Department of Com-merce httpwwwdticmildtictrfulltextu2771751pdf
[45] G Ya Dubur Yu A Zilbers A Kh Velena A O Kumerovaand G D Tirzitis ldquoMultistage study of regulation of peroxida-tion processes in biological membranes by antioxidants of 14-dihydropyridine grouprdquo Izvestiya Akademii Nauk LatviyskoySSR vol 336 no 7 pp 65ndash68 1975 (Russian)
[46] R P Mason and M W Trumbore ldquoDifferential membraneinteractions of calcium channel blockers Implications forantioxidant activityrdquo Biochemical Pharmacology vol 51 no 5pp 653ndash660 1996
[47] R P Mason M F Walter M W Trumbore E G Olmstead Jrand P E Mason ldquoMembrane antioxidant effects of the chargeddihydropyridine calcium antagonist amlodipinerdquo Journal ofMolecular and Cellular Cardiology vol 31 no 1 pp 275ndash2811999
[48] R PMason I T MakMW Trumbore and P EMason ldquoAnti-oxidant properties of calcium antagonists related to membranebiophysical interactionsrdquo American Journal of Cardiology vol84 no 4 pp 16ndash22 1999
[49] R PMasonMW Trumbore and P EMason ldquoMembrane bio-physical interaction of amlodipine and antioxidant propertiesrdquoDrugs vol 59 no 2 pp 9ndash16 2000 (French)
[50] R P Mason P Marche and T H Hintze ldquoNovel vascularbiology of third-generation L-type calcium channel antagonistsAncillary actions of amlodipinerdquo Arteriosclerosis Thrombosisand Vascular Biology vol 23 no 12 pp 2155ndash2163 2003
[51] A Augustyniak G Bartosz A Cipak et al ldquoNatural andsynthetic antioxidants an updated overviewrdquo Free RadicalResearch vol 44 no 10 pp 1216ndash1262 2010
[52] T Grune N Zarkovic and K Kostelidou ldquoLipid peroxidationresearch in Europe and the COST B35 action lsquoLipid Peroxida-tion Associated Disordersrsquordquo Free Radical Research vol 44 no10 pp 1095ndash1097 2010
[53] E Carosati P Ioan M Micucci et al ldquo14-Dihydropyridinescaffold in medicinal chemistry the story so far and perspec-tives (part 2) action in other targets and antitargetsrdquo CurrentMedicinal Chemistry vol 19 no 25 pp 4306ndash4323 2012
[54] U Eisner and J Kuthan ldquoThe chemistry of dihydropyridinesrdquoChemical Reviews vol 72 no 1 pp 1ndash42 1972 httpwwwsci-encemadnessorgtalkfilesphppid=138742ampaid=6475
[55] J Kuthan and A Kurfurst ldquoDevelopment in dihydropyri-dine chemistryrdquo Industrial amp Engineering Chemistry ProductResearch and Development vol 21 no 2 pp 191ndash261 1982
[56] A Sausins and G Duburs ldquoSynthesis of 14-dihydropyridinesby cyclocondensation reactionsrdquo Heterocycles vol 27 no 1 pp269ndash289 1988
[57] A E Sausins and G Y Duburs ldquoSynthesis of 14-dihydro-pyridines in cyclocondensation reactions (review)rdquo Chemistryof Heterocyclic Compounds vol 28 no 4 pp 363ndash391 1992Translated from Khimiya Geterotsiklicheskikh Soedinenii no 4pp 435ndash467 1992 (Russian)
[58] S Kazda ldquoTwenty years of dihydropyridinesrdquo in Dihydropy-ridines Progress in Pharmacology and Therapy W-D Busse BGarthoff and F Seuter Eds pp 1ndash12 Springer Verlag BerlinGermany 1993
[59] J-P Wan and Y Liu ldquoRecent advances in new multicomponentsynthesis of structurally diversified 14-dihydropyridinesrdquo RSCAdvances vol 2 no 26 pp 9763ndash9777 2012
[61] Reaxys Database[62] J Tuttle ldquoStructure mechanism and reactivity of hantzsch
estersrdquo in MacMillan Lab Group Meeting (082504) p 332004 httpwwwprincetoneduchemistrymacmillangroup-meetingsJBT20Hantzschpdf
[63] A Saini S Kumar and J S Sandhu ldquoHantzsch reaction recentadvances in Hantzsch 14-dihydropyridinesrdquo Journal of Sci-entific amp Industrial Research vol 67 pp 95ndash111 2008
[64] L LW Cheung S A Styler and A P Dicks ldquoRapid and conve-nient synthesis of the 14-dihydropyridine privileged structurerdquoJournal of Chemical Education vol 87 no 6 pp 628ndash630 2010
[65] A Kumar R A Maurya S Sharma M Kumar and G BhatialdquoSynthesis and biological evaluation of N-aryl-14-dihydro-pyridines as novel antidyslipidemic and antioxidant agentsrdquoEuropean Journal of Medicinal Chemistry vol 45 no 2 pp 501ndash509 2010
[66] R S Kumar A Idhayadhulla A J Abdul Nasser and J SelvinldquoSynthesis and anticoagulant activity of a new series of 14-dihydropyridine derivativesrdquo European Journal of MedicinalChemistry vol 46 no 2 pp 804ndash810 2011
[67] H A Stefani C B Oliveira R B Almeida et al ldquoDihydro-pyrimidin-(2H)-ones obtained by ultrasound irradiation anew class of potential antioxidant agentsrdquo European Journal ofMedicinal Chemistry vol 41 no 4 pp 513ndash518 2006
[68] H Sun C Shang L Jin and J Zhang ldquoSynthesis and antiox-idant activity of a series of novel 3-chalcone-substituted 14-dihydropyridine derivativesrdquoHeterocyclic Communications vol18 no 5-6 pp 239ndash243 2012
[69] D B Tikhonov and B S Zhorov ldquoStructural model for dihy-dropyridine binding to L-type calcium channelsrdquo The Journalof Biological Chemistry vol 284 no 28 pp 19006ndash19017 2009
[70] G Y Dubur and Y R Uldrikis ldquoThe oxidation of 14-dihydro-pyridinesrdquo Chemistry of Heterocyclic Compounds vol 6 no 1pp 80ndash84 1970 Translated from Khimiya GeterotsiklicheskikhSoedinenii no 1 pp 83ndash88 1970 (Russian)
[71] G Ya Duburs A O Kumerova and Ya R Uldrikis ldquoEnzymicoxidation of hydrogenated pyridines with peroxidase-hydrogenperoxide systemrdquoLatvijas PSRZAVestis vol 73 no 7 pp 73ndash771970 (Russian) Chemical Abstracts vol 73 Article ID 94913g1970
[72] K Xie Y-C Liu Y Cui J-GWang Y Fu andT CWMak ldquoN-methyl-(R)-3-(tert-butyl)-sulfinyl-14-dihydropyridine a novelNADHmodel compoundrdquoMolecules vol 12 no 3 pp 415ndash4222007
[73] S Tamagaki T Mimura and W Tagaki ldquoMetal-ion-facilitatedoxidations of dihydropyridines with molecular oxygen andhydrogen peroxiderdquo Journal of the Chemical Society PerkinTransactions 2 no 10 pp 1645ndash1650 1990
[74] D Tirzite G Tirzitis andD Antipova ldquoReductive ability of 14-dihydropyridine derivatives in relation to ions of trivalent ironrdquoChemistry of Heterocyclic Compounds vol 35 no 5 pp 592ndash594 1999
[76] J Ogle J Stradins and L Baumane ldquoFormation and decay offree cation-radicals in the course of electro-oxidation of 12- and14-dihydropyridines (Hantzsch esters)rdquo Electrochimica Actavol 39 no 1 pp 73ndash79 1994
[77] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for the
synthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts C Wittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Berlin Germany 2010
[78] WDu and Zh Yu ldquoBiomimetic in situ regeneration of cofactorsNAD(P)+ and NAD(P)H models hantzsch esters and dihy-drophenanthridinerdquo Synlett vol 23 no 9 pp 1300ndash1304 2012
[79] H K Chenault and G M Whitesides ldquoRegeneration ofnicotinamide cofactors for use in organic synthesisrdquo AppliedBiochemistry and Biotechnology vol 14 no 2 pp 147ndash197 1987
[80] Y R Uldrikis A A Zidermane E A Biseniex I E Preisa GY Dubur and G D Tirzit ldquoEsters of 26-dimethyl-14-dihydro-pyridine-35-dicarboxylic acid and method of obtainingthereofrdquo WO 8000345 A1 1978 httpworldwideespacenetcompublicationDetailsbiblioDB=EPODOCampII=1ampND=3ampadjacent=trueamplocale=en EPampFT=Dampdate=19800306ampCC=WOampNR=8000345A1ampKC=A1
[81] Y Sambongi H Nitta K Ichihashi M Futai and I Ueda ldquoAnovel water-soluble Hantzsch 14-dihydropyridine compoundthat functions in biological processes through NADH regener-ationrdquo Journal of Organic Chemistry vol 67 no 10 pp 3499ndash3501 2002
[82] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for thesynthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts ChWittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Verlag Berlin Germany 2010
[83] T Okamura T Kikuchi A Nagamine et al ldquoAn approach formeasuring in vivo cerebral redox states using the oxidative con-version of dihydropyridine to pyridinium ion and themetabolictrapping principlerdquo Free Radical Biology and Medicine vol 38no 9 pp 1197ndash1205 2005
[84] K A Schellenberg and F H Westheimer ldquoA free-radicaloxidation of a dihydropyridine1ardquo The Journal of OrganicChemistry vol 30 no 6 pp 1859ndash1862 1965
[85] K A Schellenberg ldquoReaction of hydroxyl radical with thymi-dine Scavenging by a dihydropyridinerdquo Federation Proceedingsvol 38 no 3 I p 1433 1979
[86] E S Huyser J A K Harmony and F L McMillian ldquoPeroxideoxidations of dihydropyridine derivativesrdquo Journal of the Amer-ican Chemical Society vol 94 no 9 pp 3176ndash3180 1972
[87] A Sakamoto S T Ohnishi and R Ogawa ldquoInhibition of lipidperoxidation by some dihydropyridine derivativesrdquo Journal ofAnesthesia vol 7 no 2 pp 193ndash197 1993
[88] R Hardeland ldquoReview Neuroprotection by radical avoidancesearch for suitable agentsrdquo Molecules vol 14 no 12 pp 5054ndash5102 2009
[89] G Ya Dubur A Kh Velena V M Gukasov and Yu AVladimirov ldquoRegulation of peroxidation of mitochondrialmembrane lipids initiated by Fe2+ ions by antoxidants of the14-dihydropyridine series in experiments in vitrordquo Biomed-itsinskaya Khimiya vol 22 no 5 pp 665ndash673 1976 (Russian)Chemical Abstracts vol 88 Article ID 2640 1977
[90] G RMMHaenenM J T J Arts A Bast andMD ColemanldquoStructure and activity in assessing antioxidant activity in vitroand in vivo a critical appraisal illustrated with the flavonoidsrdquoEnvironmental Toxicology and Pharmacology vol 21 no 2 pp191ndash198 2006
[91] G Tirzitis and G Bartosz ldquoDetermination of antiradical andantioxidant activity basic principles and new insightsrdquo ActaBiochimica Polonica vol 57 no 2 pp 139ndash142 2010
30 Oxidative Medicine and Cellular Longevity
[92] G R Buettner and R P Mason ldquoSpin-trapping methods fordetecting superoxide and hydroxyl free radicals in vitro and invivordquo inCritical Reviews of Oxidative Stress and Aging Advancesin Basic Science Diagnostics and Intervention R G Cutler andH Rodriguez Eds vol 1 chapter 2 pp 27ndash38World ScientificLondon UK 2003
[93] M M Tarpey and I Fridovich ldquoMethods of detection ofvascular reactive species Nitric oxide superoxide hydrogenperoxide and peroxynitriterdquo Circulation Research vol 89 no3 pp 224ndash236 2001
[94] E Y Kazush E I Sagun G D Tirzit and G Y DaburldquoQuenching of singlet oxygen by electron donating derivativesof 14-dihydropyridinerdquo Chemistry of Heterocyclic Compoundsvol 30 no 5 pp 562ndash563 1994
[95] G Tirzitis E Kazush and G Duburs ldquoReaction of 14-dihydropyridine derivatives with peroxynitrite anionrdquo Chem-istry of Heterocyclic Compounds vol 34 no 3 pp 321ndash3231998 (Russian) Translated from Khimiya GeterotsiklicheskikhSoedinenii no 3 pp 355ndash357 1998
[96] L J Nunez-Vergara C Lopez-Alarcon P A Navarrete-EncinaA M Atria C Camargo and J A Squella ldquoElectrochemicaland EPR characterization of 14-dihydropyridines Reactivitytowards alkyl radicalsrdquo Free Radical Research vol 37 no 1 pp109ndash120 2003
[97] D Tirzite A Krauze A Zubareva G Tirzitis and G DubursldquoSynthesis and antiradical activity of 5-acetyl-2-alkylthio-4-aryl-6-methyl-14-dihydropyridine-3-carboxylic acid nitrilesrdquoChemistry of Heterocyclic Compounds vol 38 no 7 pp 795ndash800 2002
[98] H Ohkawa N Ohishi and K Yagi ldquoAssay for lipid peroxidesin animal tissues by thiobarbituric acid reactionrdquo AnalyticalBiochemistry vol 95 no 2 pp 351ndash358 1979
[99] N Zarkovic ldquo4-Hydroxynonenal as a bioactive marker ofpathophysiological processesrdquo Molecular Aspects of Medicinevol 24 no 4-5 pp 281ndash291 2003
[100] M Parola G Bellomo G Robino G Barrera and M UDianzani ldquo4-Hydroxynonenal as a biological signal molecularbasis and pathophysiological implicationsrdquo Antioxidants andRedox Signaling vol 1 no 3 pp 255ndash284 1999
[101] T Lovakovic M Poljak-Blazi G Duburs et al ldquoGrowthmodulation of human cells in vitro by mild oxidative stressand 14-dihydropyridine derivative antioxidantsrdquo CollegiumAntropologicum vol 35 no 1 pp 137ndash141 2011
[102] R van den Berg G R M M Haenen H van den Bergand A Bast ldquoApplicability of an improved Trolox equivalentantioxidant capacity (TEAC) assay for evaluation of antioxidantcapacity measurements of mixturesrdquo Food Chemistry vol 66no 4 pp 511ndash517 1999
[103] C Lopez-Alarcon P Navarrete C Camargo J A Squella andL J Nunez-Vergara ldquoReactivity of 14-dihydropyridines towardalkyl alkylperoxyl radicals and ABTS radical cationrdquo ChemicalResearch in Toxicology vol 16 no 2 pp 208ndash215 2003
[104] V Valenzuela P Santander C Camargo J A Squella C Lopez-Alarcon and L J Nunez-Vergara ldquo14-Dihydropyridines reac-tivity of nitrosoaryl and nitroaryl derivatives with alkylperoxylradicals andABTS radical cationrdquo Free Radical Research vol 38no 7 pp 715ndash727 2004
[105] L G Tsetlin N A Chebotareva B I Kurganov A K VelenaG Y Dubur and V Z Lankin ldquoStudy of 14-dihydropyridinesas lipoxygenase inhibitors with the use of hydrated reversedmicellesrdquo Pharmaceutical Chemistry Journal vol 22 no 6 pp425ndash428 1988 (Russian)
[106] J Panek Z Reblova L Kocirkova et al ldquoAntioxidant activityof dihydropyridine derivativesrdquo Czech Journal of Food Sciencesvol 18 pp 144ndash145 2000
[107] G Tirzitis I Kirule and G Duburs ldquoAntioxidationsaktivitatder 35-dicarbonylderivate des 26-demethyl-14-dihydropyri-dinsrdquo Fett Wissenschaft TechnologieFat Science Technology vol90 no 10 pp 411ndash413 1988
[108] M Plotniece G Tirzitis Y Uldrikis et al ldquoSynthesis of 14-dihydropyridine derivatives having an oxy- alkoxy- or dimeth-ylaminophenyl substituent in the 4 position their antioxidantactivity and their binding to phospholipid membranesrdquo Chem-istry of Heterocyclic Compounds vol 32 no 10 pp 1166ndash11721996 Translated from Khimiya Geterotsiklicheskikh Soedineniino 10(352) pp 1358ndash1365 1996 (Russian)
[109] D Y Rubene V S Sharov V I Olenev G D Tirzit G Y Duburand Y A Vladimirov ldquoUse of chemiluminescent method forthe evaluation of antioxidant activity of some derivatives of 14-dihydropyridinerdquo Russian Journal of Physical Chemistry A vol55 no 2 pp 511ndash512 1981 (Russian)
[110] M C R Symons and JM C Gutteridge Free Radicals and IronChemistry Biology and Medicine Oxford Science PublicationsOxford University Press Oxford UK 1998
[111] M Repetto J Semprine and A Boveris ldquoLipid peroxidationchemical mechanism biological implications and analyticaldeterminationrdquo in Lipid Peroxidation A Catala Ed Section ILipid Peroxidation Chemical Mechanisms Antioxidants Bio-logical Implications of Biochemistry Genetics and MolecularBiology chapter 1 pp 3ndash30 InTech Rijeka Croatia 2012
[112] A Velena J Zilbers and G Duburs ldquoDerivatives of 14-dihydropyridines asmodulators of ascorbate-induced lipid per-oxidation and high-amplitude swelling ofmitochondria causedby ascorbate sodium linoleate and sodiumpyrophosphaterdquoCellBiochemistry and Function vol 17 no 4 pp 237ndash252 1999
[113] M V Bilenko L N Shelenkova G Y Dubur and A K VelenaldquoUse of antioxidants to prevent renal damage during acuteischemia and reperfusionrdquo Bulletin of Experimental Biology andMedicine vol 96 no 3 pp 1195ndash1198 1983 Translated fromByulletenrsquo Eksperimentalrsquonoi Biologii i Meditsiny vol 96 no 9pp 8ndash11 1983 (Russian)
[114] R Toniolo F Tubaro F Ursini and G Bontempelli ldquoAn elec-troanalytical investigation on the redox properties of calciumantagonist dihydropyridinesrdquo Electroanalysis vol 15 no 10 pp855ndash861 2003
[115] L Kourimska J Pokorny and G Tirzitis ldquoThe antioxidant aci-tivity of 26-dimethyl-35-diethoxycarbonyl-14-dihydropyri-dine in edible oilsrdquo Nahrung vol 37 no 1 pp 91ndash93 1993
[116] C Lopez-Alarcon H Speisky J A Squella C Olea-Azar CCamargo and L J Nunez-Vergara ldquoReactivity of 14-dihydro-pyridines toward SIN-1-derived peroxynitriterdquo PharmaceuticalResearch vol 21 no 10 pp 1750ndash1757 2004
[117] R A Olek W Ziolkowski J J Kaczor L Greci J Popinigisand J Antosiewicz ldquoAntioxidant activity of NADH and its ana-loguemdashan in vitro studyrdquo Journal of Biochemistry andMolecularBiology vol 37 no 4 pp 416ndash421 2004
[118] E Niki N Noguchi and N Gotoh ldquoInhibition of oxidativemodification of low density lipoprotein by antioxidantsrdquo Jour-nal of Nutritional Science andVitaminology vol 39 supplementpp S1ndashS8 1993
[119] N Rojstaczer and D J Triggle ldquoStructure-function relation-ships of calcium antagonists effect on oxidative modificationof low density lipoproteinrdquo Biochemical Pharmacology vol 51no 2 pp 141ndash150 1996
Oxidative Medicine and Cellular Longevity 31
[120] A Sevanian L Shen and FUrsini ldquoInhibition of LDLoxidationand oxidized LDL-induced cytotoxicity by dihydropyridinecalcium antagonistsrdquo Pharmaceutical Research vol 17 no 8 pp999ndash1006 2000
[121] A Negre-Salvayre and R Salvayre ldquoProtection by Ca2+ channelblockers (nifedipine diltiazem and verapamil) against the tox-icity of oxidized low density lipoprotein to cultured lymphoidcellsrdquo British Journal of Pharmacology vol 107 no 3 pp 738ndash744 1992
[122] A Negre-Salvayre G FitoussiM Troly and R Salvayre ldquoCom-parative cytoprotective effect of dihydropyridine calcium chan-nel blockers against the toxicity of oxidized low density lipopro-tein for cultured lymphoid cellsrdquo Biochemical Pharmacologyvol 44 no 12 pp 2379ndash2386 1992
[123] L Cominacini A F Pasini U Garbin et al ldquoAntioxidant activ-ity of different dihydropyridinesrdquo Biochemical and BiophysicalResearch Communications vol 302 no 4 pp 679ndash684 2003
[124] L Cominacini U Garbin A Fratta Pasini et al ldquoOxidized low-density lipoprotein increases the production of intracellularreactive oxygen species in endothelial cells inhibitory effect oflacidipinerdquo Journal of Hypertension vol 16 no 12 part 2 pp1913ndash1919 1998
[125] H M Lander ldquoAn essential role for free radicals and derivedspecies in signal transductionrdquo The FASEB Journal vol 11 no2 pp 118ndash124 1997
[126] M L L Martinez E Rizzi M M Castro et al ldquoLercanidipinedecreases vascular matrix metalloproteinase-2 activity andprotects against vascular dysfunction in diabetic ratsrdquo EuropeanJournal of Pharmacology vol 599 no 1ndash3 pp 110ndash116 2008
[127] P Lesnik C Dachet L Petit et al ldquoImpact of a combinationof a calcium antagonist and a 120573-blocker on cell- and copper-mediated oxidation of LDL and on the accumulation and effluxof cholesterol in human macrophages and murine J774 cellsrdquoArteriosclerosis Thrombosis and Vascular Biology vol 17 no 5pp 979ndash988 1997
[128] G Sobal E J Menzel and H Sinzinger ldquoCalcium antagonistsas inhibitors of in vitro low density lipoprotein oxidation andglycationrdquoBiochemical Pharmacology vol 61 no 3 pp 373ndash3792001
[129] E Lupo R Locher B Weisser and W Vetter ldquoIn vitro antiox-idant activity of calcium antagonists against LDL oxidationcompared with 120572-tocopherolrdquo Biochemical and BiophysicalResearch Communications vol 203 no 3 pp 1803ndash1808 1994
[130] J Zou Y Li H-Q Fan and J-G Wang ldquoEffects of dihydropy-ridine calcium channel blockers on oxidized low-density lipo-protein induced proliferation and oxidative stress of vascularsmooth muscle cellsrdquo BMC Research Notes vol 5 article 1682012
[131] C Napoli S Salomone T Godfraind et al ldquo14-Dihydro-pyridine calcium channel blockers inhibit plasma and LDL oxi-dation and formation of oxidation-specific epitopes in the arte-rial wall and prolong survival in stroke-prone spontaneouslyhypertensive ratsrdquo Stroke vol 30 no 9 pp 1907ndash1915 1999
[132] G Zernig I Graziadei T Moshammer C Zech N Reider andH Glossmann ldquoMitochondrial Ca2+ antagonist binding sitesare associated with an inner mitochondrial membrane anionchannelrdquo Molecular Pharmacology vol 38 no 3 pp 362ndash3691990
[133] F E Hunter Jr A Scott P E Hochstein et al ldquoStudies of themechanism of ascorbate-induced swelling and lysis of isolatedliver mitochondriardquo The Journal of Biological Chemistry vol239 pp 604ndash613 1964
[134] D R Janero B Burghardt and R Lopez ldquoProtection of cardiacmembrane phospholipid against oxidative injury by calciumantagonistsrdquoBiochemical Pharmacology vol 37 no 21 pp 4197ndash4203 1988
[135] A Karadag B Ozcelik and S S Saner ldquoReview of methods todetermine antioxidant capacitiesrdquo FoodAnalyticalMethods vol2 no 1 pp 41ndash60 2009
[136] Y I Gubskiı N V Litvinova and E V Shnurko-TabakovaldquoAntioxidant and antiradical activity of various classes of antiox-idantsrdquo Ukrainskiı Biokhimicheskiı Zhurnal vol 66 no 4 pp114ndash116 1994 (Russian)
[137] M Takei M Hiramatsu and A Mori ldquoInhibitory effects ofcalcium antagonists onmitochondrial swelling induced by lipidperoxidation or arachidonic acid in the rat brain in vitrordquoNeurochemical Research vol 19 no 9 pp 1199ndash1206 1994
[138] M Takei M Hiramatsu R Edamatsu and A Mori ldquoFreeradical scavenging by calcium antagonistsrdquo Neurosciences vol20 no 2 pp 75ndash82 1994
[139] Ya P Stradin G Ya Dubur Yu A Beilis Ya R Uldrikis andA F Korotkova ldquoVoltammetry of 14-dihydropyridine deriva-tives I Potentials of electrochemical oxidation of 35-diacyl-and 35-di(alkoxycarbonyl)-14-dihydropyridines in acetoni-trilerdquo Chemistry of Heterocyclic Compounds no 1 pp 84ndash871972 (Russian)
[140] E V Ivanov T V Ponomarjova G N Merkusev et al ldquoEinneuer Haut-Radioprotektor Diethon (experimentelle Unter-suchung)rdquo Radiobiologia Radiotherapia vol 31 no 1 pp 69ndash78 1990
[141] E V Ivanov T V Ponomareva G N Merkushev et al ldquoRadia-tion modulating properties of derivates of 14-dihydropyridineand 12345678910-decahydroacridine-18 dionerdquo Radiat-sionnaia Biologiia Radioecologiia vol 44 no 5 pp 550ndash5592004 (Russian)
[142] R O Vitolinia D A Berzinia A K Velena I A Vutsina A AKimenis and G Y Duburs ldquoThe protective effects of the cal-cium antagonist foridon in acute myocardial ischaemiardquo Kardi-ologiya vol 27 no 3 pp 90ndash93 1987 (Russian)
[143] A H Velena G Ya Duburs R O Vitolina et al ldquoEffect ofryodipine on electromechanical parameters of heart and vesselscAMP phosphodiesterase activity and swelling-contractioncycle of mitochondriardquo Arzneimittelforschung vol 35 no 6 pp907ndash914 1985
[144] L I Utno Z E Lipsberga A A Silova M I Girgensone EA Bisenieks and G I Ia ldquoCardioprotective properties of a 14-dihydropyridine derivative glutapyrone in deep hypothermiardquoBiulletenrsquo Eksperimentalrsquonoı Biologii i Meditsiny vol 108 no 11pp 558ndash561 1989 (Russian)
[145] M A S FernandesM S Santos J A F Vicente et al ldquoEffects of14-dihydropyridine derivatives (cerebrocrast gammapyroneglutapyrone and diethone) onmitochondrial bioenergetics andoxidative stress a comparative studyrdquoMitochondrion vol 3 no1 pp 47ndash59 2003
[146] M A S Fernandes M S Santos A J M Moreno et al ldquoEffectsof 5-acetyl(carbamoyl)-6-methylsulfanyl-14-dihydropyridine-5-carbonitriles on rat liver mitochondrial functionrdquo Toxicologyin Vitro vol 23 no 7 pp 1333ndash1341 2009
[147] L Klimaviciusa A Kalda A Kaasik et al ldquoNeuroprotectiveactivity of 14-dihydropyridine derivatives structure determi-nantsrdquo Proceedings of the Latvian Academy of Sciences BNatural Exact and Applied Sciences vol 61 no 1-2 pp 33ndash372007
32 Oxidative Medicine and Cellular Longevity
[148] L Klimaviciusa M A S Fernandes N Lencberga et alldquoTargeting the mitochondria by novel adamantane-containing14-dihydropyridine compoundsrdquo in Bioenergetics K B ClarkEd pp 257ndash272 InTech 2012
[149] V Klusa L Klimaviciusa G Duburs J Poikans and AZharkovsky ldquoAnti-neurotoxic effects of tauropyrone a taurineanaloguerdquo Advances in Experimental Medicine and Biology vol583 pp 499ndash508 2006
[150] N Sampson P Berger and Ch Zenzmaier ldquoRedox signalingas a therapeutic target to inhibit myofibroblast activation indegenerative fibrotic diseaserdquo BioMed Research Internationalvol 2014 Article ID 131737 14 pages 2014
[151] T L Leto and M Geiszt ldquoRole of Nox family NADPH oxidasesin host defenserdquoAntioxidantsampRedox Signaling vol 8 no 9-10pp 1549ndash1561 2006
[152] K K Griendling D Sorescu and M Ushio-Fukai ldquoNAD(P)Hoxidase role in cardiovascular biology and diseaserdquo CirculationResearch vol 86 no 5 pp 494ndash501 2000
[153] H Chen Y S Song and P H Chan ldquoInhibition of NADPHoxi-dase is neuroprotective after ischemia-reperfusionrdquo Journal ofCerebral Blood Flow and Metabolism vol 29 no 7 pp 1262ndash1272 2009
[154] P Hochstein and L Ernster ldquoADP-activated lipid peroxidationcoupled to the TPNH oxidase system of microsomesrdquo Biochem-ical and Biophysical Research Communications vol 12 no 5 pp388ndash394 1963
[155] I I Gubskiı AGGoriushkoNV Litvinova et al ldquoAntioxidantproperties and membranotropic effect of certain derivatives of14-dihydropyridinerdquo Ukrainskiı Biokhimicheskiı Zhurnal vol71 no 4 pp 35ndash39 1999 (Russian)
[156] F Engineer and R Sridhar ldquoInhibition of rat heart andliver microsomal lipid peroxidation by nifedipinerdquo BiochemicalPharmacology vol 38 no 8 pp 1279ndash1285 1989
[157] T Goncalves A P Carvalho and C R Oliveira ldquoAntioxidanteffect of calcium antagonists on microsomai membranes iso-lated from different brain areasrdquo European Journal of Pharma-cology vol 204 no 3 pp 315ndash322 1991
[158] M E Letelier P Izquierdo L Godoy A M Lepe and MFaundez ldquoLiver microsomal biotransformation of nitro-aryldrugs mechanism for potential oxidative stress inductionrdquoJournal of Applied Toxicology vol 24 no 6 pp 519ndash525 2004
[159] M E Letelier P Entrala C Lopez-Alarcon et al ldquoNitroaryl-14-dihydropyridines as antioxidants against rat liver microsomesoxidation induced by ironascorbate Nitrofurantoin and naph-thalenerdquo Toxicology in Vitro vol 21 no 8 pp 1610ndash1618 2007
[160] F P Guengerich W R Brian M Iwasaki M-A Sari CBaarnhielm and P Berntsson ldquoOxidation of dihydropyridinecalcium channel blockers and analogues by human liver cyto-chrome P-450 IIIA4rdquo Journal of Medicinal Chemistry vol 34no 6 pp 1838ndash1844 1991
[161] S H Park S-W RhaW-Y Shin et al ldquoAS-160 Calcium channelblockers of dihydropyridine class reduce the antiplatelet effectof Clopidogrel what is clinical impactrdquo The American Journalof Cardiology vol 107 no 8 supplement p 47A 2011
[162] C Asma and D M Reda ldquoEvaluation of dihydropyridinecalcium antagonist effects on the stress bioindicator orga-nism Saccharomyces cerevisiaerdquo Annals of Biological Researchvol 4 no 10 pp 40ndash46 2013 httpscholarsresearchlibrarycomABR-vol4-iss10ABR-2013-4-10-40-46pdf
[163] G Gaviraghi A M Pastorino E Ratti and D G TristldquoCalcium channel blockers with antioxidant activityrdquo in Free
Radicals Lipoprotein Oxidation andAtherosclerosis G BellomoG Finardi E Maggi and E Rice-Evans Eds pp 431ndash456Richelieu Press London UK 1995
[164] G Gaviraghi AM Pastorino E Ratti and D G Trist ldquoAntiox-idant dihydropyridines a new and comprehensive therapy forfree radical-induced cardiovascular diseasesrdquo in Free Radicalsin Biology and Environment F Minisci Ed vol 27 of NATOASI Series pp 193ndash221 Springer Dordrecht The Netherlands1997
[165] P D Henry ldquoAntiperoxidative actions of calcium antagonistsand atherogenesisrdquo Journal of Cardiovascular Pharmacologyvol 18 supplement 1 pp S6ndashS10 1991
[166] F Kouoh B Gressier T Dine et al ldquoAntioxidant effects andanti-elastase activity of the calcium antagonist nicardipine onactivated human and rabbit neutrophilsmdasha potential antiath-erosclerotic property of calcium antagonistsrdquo CardiovascularDrugs andTherapy vol 16 no 6 pp 515ndash520 2002
[167] S Parthasarathy D Litvinov K Selvarajan and M GarelnabildquoLipid peroxidation and decompositionmdashconflicting roles inplaque vulnerability and stabilityrdquo Biochimica et BiophysicaActa vol 1781 no 5 pp 221ndash231 2008
[168] D-Q Liu Z-Q Pang D-H Zhao and B-H Sheng ldquoEffects offuryl-dihydropyridines I on lipid peroxides of ischemic myo-cardium and ATPases activity of erythrocyte membranes inratsrdquo Acta Pharmacologica Sinica vol 12 no 3 pp 253ndash2561991
[169] V Lukic-Panin T Kamiya H Zhang et al ldquoPrevention of neu-ronal damage by calcium channel blockers with antioxidativeeffects after transient focal ischemia in ratsrdquo Brain Research vol1176 no 1 pp 143ndash150 2007
[170] Y Allanore D Borderie H Lemarechal O G Ekindjian andA Kahan ldquoAcute and sustained effects of dihydropyridine-typecalcium channel antagonists on oxidative stress in systemicsclerosisrdquo American Journal of Medicine vol 116 no 9 pp 595ndash600 2004
[171] I Casetta V Govoni and E Granieri ldquoOxidative stress antioxi-dants and neurodegenerative diseasesrdquo Current PharmaceuticalDesign vol 11 no 16 pp 2033ndash2052 2005
[172] M J T J Arts Assessing antioxidant activity [PhD the-sis] Maastricht University Maastricht The Netherlands 2007httparnounimaasnlshowcgifid=8676
[173] G Dıaz-Araya L Godoy L Naranjo A Squella M E Letelierand L J Nunez-Vergara ldquoAntioxidant effects of 14-dihydro-pyridine and nitroso aryl derivatives on the Fe+3ascorbate-stimulated lipid peroxidation in rat brain slicesrdquo General Phar-macology The Vascular System vol 31 no 3 pp 385ndash391 1998
[174] Y Fukuhara K Tsuchiya Y Horinouchi et al ldquoProtectiveeffect of photodegradation product of nifedipine against tumornecrosis factor 120572-induced oxidative stress in human glomerularendothelial cellsrdquo Journal of Medical Investigation vol 58 no1-2 pp 118ndash126 2011
[175] W Stengel M Jainz and K Andreas ldquoDifferent potencies ofdihydropyridine derivatives in blocking T-type but not L-typeCa2+ channels in neuroblastoma-glioma hybrid cellsrdquo EuropeanJournal of Pharmacology vol 342 no 2-3 pp 339ndash345 1998
[176] O M Panasenko D J Tirzite G D Tirzitis and G J DubursldquoEffect of some 14-dihydropyridine derivatives on structuralorganization of erythrocyte membranesrdquo Biologicheskie Mem-brany (Biochemistry (Moscow) Series A Membrane and CellBiology) vol 1 pp 919ndash925 1984 (Russian)
[177] L G Herbette Y M H Vant Erve and D G Rhodes ldquoInter-action of 14 dihydropyridine calcium channel antagonists with
Oxidative Medicine and Cellular Longevity 33
biological membranes lipid bilayer partitioning could occurbefore drug binding to receptorsrdquo Journal of Molecular andCellular Cardiology vol 21 no 2 pp 187ndash201 1989
[178] L G Herbette P E Mason G Gaviraghi T N Tulenko andR P Mason ldquoThe molecular basis for lacidipinersquos unique phar-macokinetics optimal hydrophobicity results in membraneinteractions that may facilitate the treatment of atherosclerosisrdquoJournal of Cardiovascular Pharmacology vol 23 supplement 5pp S16ndashS25 1994
[179] G V Belevitch G Y Dubur G E Dobretsov N K Kurek andM M Spirin ldquoCalcium antagonists riodipine nifedipine andverapamil binding to model and biological membranes fluore-scence analysisrdquo Biologicheskie Membrany (Biochemistry(Moscow) Series A Membrane and Cell Biology) vol 5 pp768ndash776 1988 (Russian)
[180] R P Mason G E Gonye D W Chester and L G HerbetteldquoPartitioning and location of Bay K 8644 14-dihydropyridinecalcium channel agonist in model and biological membranesrdquoBiophysical Journal vol 55 no 4 pp 769ndash778 1989
[181] M Cindric A Cipak J Serly et al ldquoReversal of multidrugresistance inmurine lymphoma cells by amphiphilic dihydropy-ridine antioxidant derivativerdquo Anticancer Research vol 30 no10 pp 4063ndash4070 2010
[182] F Shekari H Sadeghpour K Javidnia et al ldquoCytotoxic andmultidrug resistance reversal activities of novel 14-dihydro-pyridines against human cancer cellsrdquo European Journal ofPharmacology vol 746 no 1 pp 233ndash244 2015
[183] X-F Zhou Q Shao R A Coburn and M E Morris ldquoQuanti-tative structure-activity relationship and quantitative structure-pharmacokinetics relationship of 14-dihydropyridines andpyridines as multidrug resistance modulatorsrdquo PharmaceuticalResearch vol 22 no 12 pp 1989ndash1996 2005
[184] R Berkels T Breitenbach H Bartels et al ldquoDifferent antioxida-tive potencies of dihydropyridine calcium channel modulatorsin various modelsrdquo Vascular Pharmacology vol 42 no 4 pp145ndash152 2005
[185] S Borovic G Tirzitis D Tirzite et al ldquoBioactive 14-dihydro-isonicotinic acid derivatives prevent oxidative damage of livercellsrdquo European Journal of Pharmacology vol 537 no 1ndash3 pp12ndash19 2006
[186] D Ya Rubene G D Tirzitis and G Ya Duburs ldquoInteractionof some 14-dihydropyridine derivatives with Fentonrsquos reagentrdquoLatvijas PSRZinatnuAkademijas Vestis Kimijas Serija Proceed-ings of the Latvian SSR Academy of Sciences Chemistry Seriespp 212ndash216 1982 (Russian)
[187] K Ondrias V Misık D Gergel and A Stasko ldquoLipid per-oxidation of phosphatidylcholine liposomes depressed by thecalcium channel blockers nifedipine and verapamil and bythe antiarrhythmic-antihypoxic drug stobadinerdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1003 no 3pp 238ndash245 1989
[188] I T Mak and W B Weglicki ldquoComparative antioxidant acti-vities of propranolol nifedipine verapamil and diltiazemagainst sarcolemmal membrane lipid peroxidationrdquoCirculationResearch vol 66 no 5 pp 1449ndash1452 1990
[189] I T Mak P Boehme and W B Weglicki ldquoProtective effects ofcalcium channel blockers against free radical-impaired endo-thelial cell proliferationrdquo Biochemical Pharmacology vol 50 no9 pp 1531ndash1534 1995
[190] S Ray S Mondal and N Dana ldquoEvaluation of protective roleof nifedipine on lipid peroxidation using reduced glutathione as
model markerrdquo Oxidants and Antioxidants in Medical Sciencevol 1 no 2 pp 97ndash100 2012
[191] M Yamato T Shiba T Ide Y Honda K-I Yamada andH Tsutsui ldquoNifedipine treatment reduces brain damage aftertransient focal ischemia possibly through its antioxidativeeffectsrdquoHypertension Research vol 34 no 7 pp 840ndash845 2011
[192] V Chander and K Chopra ldquoNifedipine attenuates changes innitric oxide levels renal oxidative stress and nephrotoxicityinduced by cyclosporinerdquo Renal Failure vol 27 no 4 pp 441ndash450 2005
[193] K M Gaafa M M Badawy and A A Hamza ldquoThe protectiveeffects of ascorbic acid cimetidine and nifedipine on diethyl-dithiocarbamate-induced hepatic toxicity in albino ratsrdquo Drugand Chemical Toxicology vol 34 no 4 pp 405ndash419 2011
[194] H Sugawara K Tobise and S Onodera ldquoAbsence of antiox-idant effects of nifedipine and diltiazem on myocardial mem-brane lipid peroxidation in contrast with those of nisoldipineand propranololrdquo Biochemical Pharmacology vol 47 no 5 pp887ndash892 1994
[195] I E Kirule D Y Rubene E A Bisenieks G D Tirzit and GY Dubur ldquo4-Nitrophenyl-14-dihydropyridinesmdasha new groupof inhibitors of peroxide oxidationrdquo Chemistry of HeterocyclicCompounds vol 18 no 3 p 316 1982
[196] G D Tirzit I E Kirule L K Baumane R A Gavar Y PStradynrsquo andG YDubur ldquoMechanism of the antioxidant actionof 26-dimethyl-35-dimethoxy-carbonyl-4-(2-nitrophenyl)14-dihydropyridinerdquoChemistry ofHeterocyclic Compounds vol 20no 8 pp 915ndash918 1984
[197] C Yanez C Lopez-Alarcon C Camargo V Valenzuela J ASquella and L J Nunez-Vergara ldquoStructural effects on thereactivity 14-dihydropyridines with alkylperoxyl radicals andABTS radical cationrdquo Bioorganic and Medicinal Chemistry vol12 no 9 pp 2459ndash2468 2004
[198] VMisik A J Stasko D Gergel and K Ondrias ldquoSpin-trappingand antioxidant properties of illuminated and nonilluminatednifedipine and nimodipine in heart homogenate and modelsystemrdquo Molecular Pharmacology vol 40 no 3 pp 435ndash4391991
[199] K Ondrias V Misık A Stasko D Gergelrsquo and M HromadovaldquoComparison of antioxidant properties of nifedipine and illu-minated nifedipine with nitroso spin traps in low densitylipoproteins and phosphatidylcholine liposomesrdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1211 no 1pp 114ndash119 1994
[200] A Stasko V Brezova S Biskupic K Ondrias and V MisıkldquoReactive radical intermediates formed from illuminated nife-dipinerdquoFree Radical Biology andMedicine vol 17 no 6 pp 545ndash556 1994
[201] K Ishizawa Y Izawa-Ishizawa N Yamano et al ldquoNitrosoni-fedipine ameliorates the progression of type 2 diabetic nephro-pathy by exerting antioxidative effectsrdquo PLoS ONE vol 9 no 1Article ID e86335 2014
[202] H Fujii and L J Berliner ldquoIn vivo EPR evidence for free radicaladducts of nifedipinerdquoMagnetic Resonance in Medicine vol 42no 4 pp 691ndash694 1999
[203] S Bollo S Finger J C Sturm L J Nunez-Vergara and JA Squella ldquoCyclic voltammetry and scanning electrochemicalmicroscopy studies of the heterogeneous electron transferreaction of some nitrosoaromatic compoundsrdquo ElectrochimicaActa vol 52 no 15 pp 4892ndash4898 2007
34 Oxidative Medicine and Cellular Longevity
[204] F Ursini ldquoTissue protection by lacidipine insight from redoxbehaviorrdquo Journal of Cardiovascular Pharmacology vol 30supplement 2 pp S28ndashS30 1997
[205] P G Cristofori F A Crivellente I Faustinelli et al ldquoInvolve-ment of the nitric oxide system in the anti-atheroscleroticpotential of lacidipine in the apoE-deficient mouse a mor-phological functional and electrochemical studyrdquo ToxicologicPathology vol 32 no 4 pp 493ndash499 2004
[206] X-P Zhang E L Kit S Mital S Chahwala and T HHintze ldquoParadoxical release of nitric oxide by an L-type calciumchannel antagonist the R+ enantiomer of amlodipinerdquo Journalof Cardiovascular Pharmacology vol 39 no 2 pp 208ndash2142002
[207] F Franzoni G Santoro F Regoli et al ldquoAn in vitro study of theperoxyl and hydroxyl radical scavenging capacity of the calciumantagonist amlodipinerdquo Biomedicine and Pharmacotherapy vol58 no 8 pp 423ndash426 2004
[208] S V Gatsura ldquoOxygen-dependent mechanisms underlying theantiischemic effect of verapamil and amlodipinerdquo Bulletin ofExperimental Biology and Medicine vol 137 no 1 pp 40ndash422004
[209] Y Hirooka Y Kimura M Nozoe Y Sagara K Ito and KSunagawa ldquoAmlodipine-induced reduction of oxidative stressin the brain is associated with sympatho-inhibitory effects instroke-prone spontaneously hypertensive ratsrdquo HypertensionResearch vol 29 no 1 pp 49ndash56 2006
[210] B Tomlinson and I F F Benzie ldquoAntioxidant effect of lercani-dipine (note)rdquo Hypertension vol 42 no 4 pp e10ndashe11 2003
[211] A A Faraqui ldquoNeurochemical aspects of 4-hydroxynonenalrdquoin Lipid Mediators and Their Metabolism in the Brain A AFaraqui Ed chapter 6 pp 159ndash191 Springer New York NYUSA 2011
[212] V S NascimentoM S DrsquoAlva A AOliveira et al ldquoAntioxidanteffect of nimodipine in young rats after pilocarpine-inducedseizuresrdquo Pharmacology Biochemistry and Behavior vol 82 no1 pp 11ndash16 2005
[213] O Ismailoglu P Atilla S Palaoglu et al ldquoThe therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjuryrdquo Turkish Neurosurgery vol 22 no 6 pp 740ndash746 2012
[214] M Matsubara and K Hasegawa ldquoBenidipine a dihydropy-ridine-calcium channel blocker prevents lysophosphatidyl-choline-induced injury and reactive oxygen species productionin human aortic endothelial cellsrdquo Atherosclerosis vol 178 no1 pp 57ndash66 2005
[215] M Matsubara K Yao and K Hasegawa ldquoBenidipine adihydropyridine-calcium channel blocker inhibits lysophos-phatidylcholine-induced endothelial injury via stimulation ofnitric oxide releaserdquo Pharmacological Research vol 53 no 1 pp35ndash43 2006
[216] MMatsubara and K Hasegawa ldquoEffects of benidipine a dihyd-ropyridine-Ca2+ channel blocker on expression of cytokine-induced adhesion molecules and chemoattractants in humanaortic endothelial cellsrdquo European Journal of Pharmacology vol498 no 1ndash3 pp 303ndash314 2004
[217] M Matsubara O Akizuki J-I Ikeda K Saeki K Yao and KSasaki ldquoBenidipine an anti-hypertensive drug inhibits reactiveoxygen species production in polymorphonuclear leukocytesand oxidative stress in salt-loaded stroke-prone spontaneouslyhypertensive ratsrdquo European Journal of Pharmacology vol 580no 1-2 pp 201ndash213 2008
[218] A C Rosenkranz H Lob T Breitenbach R Berkels and RRoesen ldquoEndothelial antioxidant actions of dihydropyridines
and angiotensin converting enzyme inhibitorsrdquo European Jour-nal of Pharmacology vol 529 no 1ndash3 pp 55ndash62 2006
[219] V Kain S Kumar and S L Sitasawad ldquoAzelnidipine preventscardiac dysfunction in streptozotocin-diabetic rats by reducingintracellular calcium accumulation oxidative stress and apop-tosisrdquo Cardiovascular Diabetology vol 10 article 97 2011
[220] K Nakamura S Yamagishi and H Inoue ldquoUnique atheropro-tective property of azelnidipine a dihydropyridine-based cal-cium antagonistrdquoMedical Hypotheses vol 65 no 1 pp 155ndash1572005
[221] TMatsui S Yamagishi K Nakamura S Kikuchi andH InoueldquoAzelnidipine a dihydropyridine-based calcium antagonistinhibits angiotensin II-induced oxidative stress generation anddownregulation of pigment epithelium-derived factor mRNAlevels in microvascular endothelial cellsrdquo Drugs under Experi-mental and Clinical Research vol 31 no 5-6 pp 215ndash219 2005
[222] C Ohmura H Watada T Shimizu et al ldquoCalcium channelblocker azelnidipine reduces lipid hydroperoxides in patientswith type 2 diabetes independent of blood pressurerdquo EndocrineJournal vol 54 no 5 pp 805ndash811 2007
[223] H Daikuhara F Kikuchi and T Ishida ldquoThe combination ofOLmesartan and a CAlcium channel blocker (azelnidipine) orcandesartan and a calcium channel blocker (amlodipine) intype 2 diabetic hypertensive patients theOLCA studyrdquoDiabetesand Vascular Disease Research vol 9 no 4 pp 280ndash286 2012
[224] MAbe NMaruyama KOkada SMatsumoto KMatsumotoand M Soma ldquoAdditive antioxidative effects of azelnidipine onangiotensin receptor blocker olmesartan treatment for type 2diabetic patients with albuminuriardquoHypertension Research vol34 no 8 pp 935ndash941 2011
[225] K Mizushige ldquoAntioxidative activities of thiazolidinedionesand dihydropyridine-type calcium antagonistsrdquo IRYOmdashJapa-nese Journal of National Medical Services vol 59 no 11 pp 581ndash592 2005
[226] S Manabe T Okura T Fukuoka and J Higaki ldquoAntioxidativeeffects of azelnidipine on mesangial cell proliferation inducedby highly concentrated insulinrdquo European Journal of Pharma-cology vol 567 no 3 pp 252ndash257 2007
[227] Y Koyama Y Takeishi H Takahashi et al ldquoAzelnidipine inhi-bits H
2O2-induced cell death in neonatal rat cardiomyocytesrdquo
CardiovascularDrugs andTherapy vol 21 no 1 pp 69ndash72 2007[228] K Shinomiya K Mizushige M Fukunaga et al ldquoAntioxidant
effect of a new calcium antagonist azelnipidine in culturedhuman arterial endothelial cellsrdquo Journal of International Med-ical Research vol 32 no 2 pp 170ndash175 2004
[229] T Ohyama K Sato K Kishimoto et al ldquoAzelnidipine is acalcium blocker that attenuates liver fibrosis and may increaseantioxidant defencerdquo British Journal of Pharmacology vol 165no 4 pp 1173ndash1187 2012
[230] L A Calo F Zaghetto E Pagnin P A Davis A Sempliciniand A C Pessina ldquoEffect of manidipine on gene expressionand protein level of oxidative stress-related proteins p22phoxand HO-1 Relevance for antihypertensive and anti-remodelingeffectsrdquo Journal of Cardiovascular Pharmacology vol 43 no 4pp 531ndash538 2004
[231] R Ghyasi G Sepehri M Mohammadi R Badalzadeh and AGhyasi ldquoEffect of mebudipine on oxidative stress and lipid per-oxidation in myocardial ischemic-reperfusion injury in maleratrdquo Journal of Research in Medical Sciences vol 17 no 12 pp1150ndash1155 2012
Oxidative Medicine and Cellular Longevity 35
[232] DCAndersson J Fauconnier T Yamada et al ldquoMitochondrialproduction of reactive oxygen species contributes to the 120573-adrenergic stimulation of mouse cardiomycytesrdquoThe Journal ofPhysiology vol 589 no 7 pp 1791ndash1801 2011
[233] A F Ceylan-Isik N Ari M Stefek et al ldquoEffects of a long-term treatment with an antioxidant pyridoindole on vascularresponsiveness in diabetes-induced aging ratsrdquo Current AgingScience vol 4 no 2 pp 150ndash157 2011
[234] S Saponara G Sgaragli and F Fusi ldquoQuercetin antagonismof Bay K 8644 effects on rat tail artery L-type Ca2+ channelsrdquoEuropean Journal of Pharmacology vol 598 no 1ndash3 pp 75ndash802008
[235] D A Sica ldquoInteraction of grapefruit juice and calcium channelblockersrdquo American Journal of Hypertension vol 19 no 7 pp768ndash773 2006
[236] P Mulder G Litwinienko S Lin P D MacLean L R CBarclay and K U Ingold ldquoThe L-type calcium channel block-ers Hantzsch 14-dihydropyridines are not peroxyl radical-trapping chain-breaking antioxidantsrdquo Chemical Research inToxicology vol 19 no 1 pp 79ndash85 2006
[237] L J Nunez-Vergara R Salazar C Camargo et al ldquoOxidation ofC4-hydroxyphenyl 14-dihydropyridines in dimethylsulfoxideand its reactivity towards alkylperoxyl radicals in aqueousmediumrdquo Bioorganic and Medicinal Chemistry vol 15 no 12pp 4318ndash4326 2007
[238] M E Ortiz L J Nunez-Vergara and J A Squella ldquoRelativereactivity of dihydropyridine derivatives to electrogeneratedsuperoxide ion in DMSO solutions a voltammetric approachrdquoPharmaceutical Research vol 20 no 2 pp 292ndash296 2003
[239] M E Ortiz L J Nunez-Vergara C Camargo and J A SquellaldquoOxidation of Hantzsch 14-dihydropyridines of pharmacolog-ical significance by electrogenerated superoxiderdquo Pharmaceuti-cal Research vol 21 no 3 pp 428ndash435 2004
[240] R S Raghuvanshi and K N Singh ldquoSuperoxide induced oxida-tive aromatization of Hantzsch 14-dihydropyridinesrdquo IndianJournal of Chemistry Section B Organic and Medicinal Chem-istry vol 47 no 11 pp 1735ndash1738 2008
[241] I Kruk A Kladna K Lichszteld et al ldquoAntioxidant activityof 4-flavonil-14-dihydropyridine derivativesrdquo Biopolymers vol62 no 3 pp 163ndash167 2001
[242] G D Tirzit I M Byteva K I Salokhiddinov G P Gurinovichand G Y Dubur ldquo14-Dihydropyridine derivatives as deactiva-tors of singlet oxygenrdquo Chemistry of Heterocyclic Compoundsvol 17 no 7 pp 682ndash684 1981
[243] G D Tirzit E Y Kazush and G Y Dubur ldquoInfluence of14-dihydropyridine derivatives on the generation of hydroxylradicalsrdquo Chemistry of Heterocyclic Compounds vol 28 no 4pp 435ndash437 1992
[244] N A Pizarro-Urzua and L J Nunez-Vergara ldquoNifedipine andnitrendipine reactivity toward singlet oxygenrdquo Journal of Photo-chemistry and Photobiology A Chemistry vol 175 no 2-3 pp129ndash137 2005
[245] L-F Wang H-Y Zhang L Konga Z-W Chena and J-G ShildquoDFT calculations indicate that 14-dihydropyridine is a promis-ing lead antioxidantrdquo Helvetica Chimica Acta vol 87 no 6 pp1515ndash1521 2004
[246] P Mulder H-G Korth and K U Ingold ldquoWhy quantum-thermochemical calculations must be used with caution toindicate lsquoa promising lead antioxidantrsquordquoHelvetica Chimica Actavol 88 no 2 pp 370ndash374 2005
[247] K Yao Y Ina K Nagashima K Ohmori and T Ohno ldquoAntiox-idant effects of calcium antagonists in rat brain homogenatesrdquo
Biological and Pharmaceutical Bulletin vol 23 no 6 pp 766ndash769 2000
[248] T Matsui S-I Yamagishi K Nakamura and H Inoue ldquoBayw 9798 a dihydropyridine structurally related to nifedipinewith no calcium channel-blocking properties inhibits tumournecrosis factor-120572-induced vascular cell adhesion molecule-1expression in endothelial cells by suppressing reactive oxygenspecies generationrdquo Journal of International Medical Researchvol 35 no 6 pp 886ndash891 2007
[249] K AMitrega B VargheseM Porc and T F Krzeminski ldquoAnti-arrhythmic and hemodynamic effects of oxy nifedipine oxynimodipine oxy nitrendipine and oxy nisoldipinerdquo Pharmaco-logical Research vol 66 no 4 pp 300ndash308 2012
[250] V Herbert ldquoSymposium prooxidant effects of antioxidantvitamins Introductionrdquo The Journal of Nutrition vol 126 no4 supplement pp 1197Sndash1200S 1996 httpjnnutritionorgcontent1264 Suppl1197Sfullpdf
[251] B Halliwell ldquoAre polyphenols antioxidants or pro-oxidantsWhat do we learn from cell culture and in vivo studiesrdquoArchives of Biochemistry and Biophysics vol 476 no 2 pp 107ndash112 2008
[252] C Winterbourn Pro-Oxidants or Antioxidants ChristchurchSchool of Medicine Depatment of Pathology Free RadicalSchool SFRBMUniversity of Otago San Francisco Calif USA2009 httpwwwsfrbmorgfrsWinterbournpdf
[253] A Morakinyo B Iranloye and O Adegoke ldquoCalcium antag-onists modulate oxidative stress and acrosomal reaction in ratspermatozoardquo Archives of Medical Science vol 7 no 4 pp 613ndash618 2011
[254] The Alpha-Tocopherol Beta Carotene Cancer Prevention StudyGroup ldquoThe effect of vitamin E and beta carotene on theincidence of lung cancer and other cancers in male smokersrdquoTheNew England Journal of Medicine vol 330 no 15 pp 1029ndash1035 1994
[255] B Poljsak ldquoStrategies for reducing or preventing the generationof oxidative stressrdquo Oxidative Medicine and Cellular Longevityvol 2011 Article ID 194586 15 pages 2011
[256] B Poljsak and I Milisav ldquoThe neglected significance of lsquoanti-oxidative stressrsquordquoOxidativeMedicine and Cellular Longevity vol2012 Article ID 480895 12 pages 2012
[257] T Godfraind and S Salomone ldquoAmbiguities in dietary antiox-idant supplementation compared to calcium channel blockerstherapyrdquo Frontiers in Pharmacology vol 6 article 10 2015
[258] H Wagner H Norr and H Winterhoff ldquoDrugs with adap-togenic effects for strengthening the powers of resistancerdquoZeitschrift fur Phytotherapie vol 13 no 2 pp 42ndash54 1992
2 Oxidative Medicine and Cellular Longevity
antioxidative effect may be direct resulting from direct ROSscavenging or indirect from the influence on various signal-ing pathways related to cellular defense that is stress res-ponses In relation to human physiology antioxidants are tra-ditionally classified as exogenous (supplied mostly throughfood) and endogenous and are further subclassified as enzy-matic (ie superoxide dismutase (SOD) and catalase (CAT))and nonenzymatic (ie glutathione vitamins A C and Eetc) [3]
DHPs could be classified as the separate group of syn-thetic nonenzymatic however biomimetic AOs
2 Oxidative Stress andIts Prevention Wavy Scientific ProcessDevelopmentmdashPro et Contra
There are opposite views both towards the role of oxidativestress and about potential applications of exogenous antioxi-dants in onset of OS [14ndash16]
Herewith we need to mention that antioxidants havebeen studied for decades (starting from 1970s) as the toolsfor the treatment of various disorders The role of native andsynthetic antioxidants (acting on lipid peroxidation (LP) inbiological membranes) in radiation damage and malignantgrowth was seriously evaluated [17] The overall conclusionspoint out antioxidants role in decreasing the damage ofcells by reducing oxidants before the occurrence of cellulardamage [14] It was elicited and accented (Burlakova et al[15]) that
(i) antioxidants nontoxic inhibitors of free radical pro-cesses exhibit a wide gamut (pleiotropy) of biologicalactivity (as further will be reported this phenomenonis also characteristic for theDHP antioxidants group)
(ii) the biological effectiveness of AOs correlates withtheir antioxidant activity (AOA)
(iii) depending on dose AOs may either increase ordecrease the AOA
(iv) the efficacy of AO depends on the time of introduc-tion in the course of medical treatment because thedevelopment of the disease may be accompanied bystages of changing the AOA
In relation to dose-effect dependence Burlakova et al [15]have found the nonlinear pattern after addition of an AOthere is an initial increase of AOA followed by returning tonormal and finally decreasing drastically below the normalvalue Therefore antioxidants may produce a specific effectby decreasing (at low doses) or increasing (at high doses)the rate of free radical reactions Hence the compound maybe efficient AO only if it is introduced in a low dose atthe stage of reduced AOA or in a high dose at the stage ofAOA elevation The widespread opinion of opponents wasthat the antioxidant function even that of tocopherol wasa side effect of its activity and important only for in vitroprocesses andwithout any role in bioobjects lifeThis opinionwas supported by the fact that the deficiency of natural AOtocopherol (E-avitaminosis) cannot be cured completely by
applying synthetic AO Eventually it was not certain alsothat detected lipid peroxides have been generated in vivoin the intact organs and were not artificially formed duringthe isolation [15] All these objections and skepticism wererejected in due time
However some other research directions were suggestedFang et al [18] reported two different therapeutic strate-
gies for modulating OS in cancer and inflammation includ-ing (1) antioxidant therapy and (2) ldquooxidation therapyrdquo
For (1) polymeric superoxide dismutase (eg pyrancopolymer-SOD) xanthine oxidase (XO) inhibitor devel-oped water-soluble form of 4-amino-6-hydroxypyrazolo[34-d]pyrimidine (AHPP) heme oxygenase-1 (HO-1) inducers(eg hemin and its polymeric form) and other antioxidantsor radical scavengers (eg phenolic compound canolol 4-vinyl-26-dimethoxyphenol) were used
About (2) besides neurodegenerative diseases cancermay represent yet another very interesting field for exploringantioxidants and prooxidants as therapeutic substances dueto their cytotoxic effects (including overproduction of ROS)that if achieving proper selectivity may be used for cancercells destruction (Fang et al [18]) To achieve this goal aunique therapeutic strategy was developed named as ldquooxida-tion therapyrdquo by delivering cytotoxic ROSdirectly to the solidtumor or alternatively inhibiting the antioxidative enzymesystem such as HO-1 in tumor This anticancer strategywas examined by use of O
2
∙minus or H2O2-generating enzymes
(ie XO and d-amino acid oxidase [DAO] resp) and bydiscovering the inhibitor of HO-1 (ie zinc protoporphyrin[ZnPP] and its polymeric derivatives)
While deleterious when present at high concentra-tions low concentrations of ROS exhibit beneficial proper-ties needed for controlling physiological cellular processes(reviewed in Valko et al 2007 [19])
Jimenez-Del-Rio and Velez-Pardo [20] have discussedoxidative stress as an important etiopathogenic factor foroccurrence and development of neurodegenerative diseases(notably Alzheimerrsquos disease and Parkinsonrsquos disease) andcancer As an extension possible preventive and therapeuticvalues of antioxidants were also discussed Indeed if con-sidered within a narrow context of oxidative homeostasisantioxidants may seem to be ideal weapon in preventingand fighting these diseases However the context of humanpathology is very broad and so far there was little benefitof exogenous antioxidants in human intervention studies orclinical trials There are numerous reasons for these failuresMaybe themost important one is the design of the preclinicalstudies especially related to concentration of the antioxidantused and time parameters relevant to the clinical setting(Kamat et al 2008 [21]) The imbalance between uncriticalacceptance of antioxidants as powerful ldquodrugsrdquo for variouspathological conditions and disappointing results obtainedin clinical studies has made a sort of confusion This issuewas addressed by Bast and Haenen [16] through listing tenmisconceptions related to commercialized applications ofantioxidants (a) ldquoprosrdquo (1) antioxidants can cure any disease(2) the more the better (3) any AO will do (the trick) (4)AO status measures the level of health (5) natural AOs aresuperior (over synthesized ones) and (b) ldquocontrasrdquo (1) AOs
Oxidative Medicine and Cellular Longevity 3
increase mortality (2) when present at high doses antioxi-dants become prooxidant (3) theoretically antioxidants can-not behave as such (4) once used antioxidants are inactive(5) antioxidant drugs do not work
The first three ldquoprosrdquo clearly cross the line of realistic wayof thinking and cannot be considered seriously The ldquoprordquo4 was very informatively discussed by Pompella et al [22]who comprehensively presented current problems with themethods (ORAC oxygen radical absorbance capacity ferric-reducing ability of plasma and TEAC Trolox equivalentantioxidant capacity) routinely used formeasurement of totalantioxidant capacity (TAC) in plasma (Pompella et al 2014[22]) These include lack of needed specificity especially rel-evant for ORAC related measurements Instead precise mea-surement of specific compounds is recommended Regardingthe ldquoprordquo 5 the situation does not seem entirely clearas some published metastudies related to protective role ofvitamin C in coronary heart disease showed some contra-dictions (better protection with dietary vitamin C versussynthetic vitamin C) (Ye and Song [23] Knekt et al [24])In any event this kind of research is anything but simple asobserved health effects of fruit and vegetable ingestion arecertainly related not only to the content of vitamin C butalso to other macro- and micronutrients and phytochemi-cals proven to confer additional health benefits (Carr andVissers [25]) Similar to ldquoprosrdquo stated ldquocontrasrdquo seem to bea common misconcept related to the design of the study (thisis especially relevant for epidemiological studies) relevanceof a specific pathological condition and measurement of itsoutcomes and finally complexity of a living organism Forall these reasons there is the realistic need for well-designedepidemiological clinical and molecular studies that wouldoffer firm evidence and undoubtful conclusions on the role ofantioxidants on human health (see also Sections 38 and 39)
There are still unanswered questions related to oxidativestress and its mediators in pathogenesis of OS-associateddiseases However it is clear that overproduction of ROShas harmful cellular effects For that reason small syntheticantioxidants molecular scavengers have been developed tobe used in various pathological conditions The first oneimplemented in the clinic for acute brain infarction was3-methyl-1-phenyl-2-pyrazolin-5-one (MCI-186 EdaravoneRadicut norphenazone) approved until now only in Japan(Tabrizchi 2000 [26]) So far its free radical scavengingproperties were revealed by various biological effects (antiox-idant attenuation of cytokine production antiapoptoticantinecrotic and some other effects) as recently reviewed(Kikuchi et al [27])
3 14-Dihydropyridines A SeparateGroup of Bioantioxidants
14-Dihydropyridines could be used as model compounds forstudying molecular mechanisms of action modulated by cel-lular enzymes NADH and NAD(P)H due to their structuralanalogy to 14-dihydronicotinamide [28] This structure rep-resents the active part of these reduced coenzymes which areimportant modulators of various enzymatic redox reactionsand are involved in electron transfer
Chemically 14-dihydropyridines are synthetic hydro-genated N-heteroaromatic compounds They may have var-ious substituents at positions 26- 35- and 14- (Figures1ndash3) Their derivatives can be obtained synthetically in theHantzsch type cyclic condensation reactions
Bossert and Vater [29] postulated DHPs as a basis fordevelopment of new cardiovascular drugs Today there aremany marketed drugs which contain 14-DHP ring as basicscaffold [30ndash32] (Figures 1 and 2)
Grover et al [33] classified dihydropyridine nucleus (skel-eton) as a novel pharmacophore and offered some examplesrelated to DHPs pleiotropy So far AOAs have been revealedfor several groups of DHP compounds andDHP-based drugs[34ndash36] contributing to their well-known pleiotropic ways ofaction (antiaging neuroprotective anticancer antibacterial[37] and many more) These features are promising fordevelopment of novel drugs in the future [32 38]
It is well known that hydrogen donors such as aminesthiols (aminothiols) or phenols (plant phenols and polyphe-nols aswell as synthetic hindered phenols) act as antioxidantsprimarily through inhibition of oxidation reactions of variouschemical targetssubstrates Similarly depending on theirparticular chemical structure 14-dihydropyridines have sig-nificant hydrogen donor ability (see further in Section 32)This feature allows them to act as direct inhibitors of freeradical reactions It further classifies them as specific group ofdihydropyridine type of antioxidantsHowever under certainconditions primarily dependent on individual structure andapplied dose DHPs can act as prooxidants (see further inSection 38)
On the other hand some DHPs may exert synergisticeffects when applied together with other types of AOs [39]They can also be involved in the redox regulation of Ca2+ion channels [40] Namely oxidative stress characterized bysignificant increase of ROS closely relates to cellular imbal-ance of Ca2+ ions Such a CA activity of DHPs can also resultin the indirect OS modulation as an additional positive sideeffect Accordingly DHPs acting as CA and as antioxidantsmay modify various OS-associated pathological processes byinfluencing cellular redox signaling potential Additionallymultiple biological effects of DHPs attenuating OS could beimportant at drug-drug interactions by combination therapyusing DHPs and other CA andor antioxidants
It should be mentioned that the studies on the possibleAOA of 14-DHPs have begun due to the assumption thatthese substances could be useful for the design for novelantioxidants intended to be used primarily in the food tech-nology notably as animal chow stabilizers [41ndash43]TheAOAsof 14-dihydropyridine derivatives 26-dimethyl-35-dieth-oxycarbonyl-14-dihydropyridine (Hantzsch ester (HEH)diludine) and its close analogues 4-unsubstituted 14-DHPswere discovered by Latvian scientists that intended to usethem for the termination of the lipid peroxidation (LPO) invarious chemical lipid substratesmixtures target (solutionsemulsions and liposomes) [44 45] Afterwards antioxi-dant properties of several calcium antagonists DHPs werediscovered [31 46ndash53] Interestingly research on the AOAof DHPs on LPO continues nowadays including several
Figure 1 Structures of the most known 14-dihydropyridine derivatives and some non-DHP Ca2+ antagonists
interdisciplinary projects funded by EU in particular theCOST B35 action [51 52]
31 Synthesis of 14-Dihydropyridines Routes and ApproachesClassical 3-component Hantzsch synthesis of DHP com-pounds [54ndash57] is usually performed in solutions (includingionic liquids) by heating Discoveries related to this process
and published between 1986 and 1990 are summarized in thereview of Sausins and Duburs [57] In 1993 Kazda [58] hasreviewed ldquotwenty years of dihydropyridinesrdquo including theirsynthesis chemistry progress in pharmacology and therapyand some other applications Since then there were manyimportant discoveries in this field and there is a time fora review on ldquoanother twenty years of DHPsrdquo It has to be
Oxidative Medicine and Cellular Longevity 5
NH
Lercanidipine
NH
Cl
Felodipine
Cl
NH
Lacidipine
NH
Nicardipine
NH
Isradipine
NO
N
NH
COO
Azelnidipine
N
NH
Bay O 5572
NH
COO
Benidipine
N
NH
Manidipine
N N
NH
NC
Nivaldipine
NH
COOC(CH3)3
COOCH(CH3)2
Mebudipine
N
S
O
Diltiazem
N
S
O
O
H
O
Semotiadil
NH
COO
Barnidipine
N
H3C
H3C H3C
H3C
H3C
H3C
H3C
H3CO
H3C
H3C
H3C
H3CCH3
CH3 CH3CH3
CH3
CH3
OCH3
OCOCH3
CH3
CH3
CH3
CH3CH3
NH2
CH3
NO2NO2
H3COOC
H3COOC H3COOC
H3COOC
H3COOC
H3COOC
H3COOC
H3COOC H3COOC
H3COOCCOOC(CH3)2CH2N(CH3)CH2CH2CHPh2
COOCH(CH3)2
N(CH3)COOCH2 CH2CH2 Ph
COOC2H5 COOC2H5C2H5OOC
COOC(CH3)3
NO2NO2
NO2NO2
NO2
NO2
NO2
CH2Ph
CH2Ph
CH 2Ph
CH 2Ph
COO(CH2)7CH3(H3C)2HCOOC
COOCH2CH2
O(CH2)3N(CH3)CH2CH2O
N(CH3CH )2 2CH2
Figure 2 Structures of the most known 14-dihydropyridine derivatives and some non-DHP Ca2+ antagonists
mentioned that nearby this classical multicomponent synthe-sis also a process to obtain structurally diversified 14-dihyd-ropyridines at sophisticated conditions was recently reviewedby Wan and Liu [59]
Many discoveries relevant for novel routes in DHPdesigning and synthesis were published and deposited in
various databases (see httpwwworganic-chemistryorgnamedreactionshantzsch-dihydropyridine-synthesisshtm[60]) For example httpwwwscifindercom [1] databaselists approximately 1000 citations on the simple DHP com-pound diludine Reaxys database [61] contains data relatedto variations in starting materials intermediates as building
6 Oxidative Medicine and Cellular Longevity
NH
SCH3
CN
Cl
O
NH
SCH3 SCH3 SCH3
CN
O
NH
CN
O
NH
CN
OCl OCHF2 OCHF2
OSI-3701OSI-9642OSI-3761OSI-1146
H3C
H3C H3C
H3C H3C H2N
H3C H3C
Figure 3 Molecular structures of OSI-1146 OSI-3701 OSI-3761 and OSI-9642 (according to [146])
blocks media and reactions routes Water and ionic liquidsas reaction media microwave and infrared irradiation newcatalysts solid phase synthesis and biotechnology based andgreen chemistry approaches were also proposed as attractiveoptions for syntheses of DHPs [62ndash66]
Furthermore several new dihydropyrimidin-(2H)-ones(DHPMs) close analogues of DHPs were prepared in theBiginelli reaction under ultrasound irradiation and in thepresence of NH
4Cl Some of these compounds when tested
in vitro at concentrations higher than 100 120583M [67] showedAOAs manifested as inhibition of LPO induced by complexFe + EDTA and reduction of ROS levels
Recently Sun et al [68] reported about the synthesis andantioxidant activity of a series of novel 3-chalcone-substituted14-dihydropyridine derivatives based on dimethyl or diethyl26-dimethyl-4-phenyl-14-DHP-35-dicarboxylate
32 14-Dihydropyridines as Hydrogen Donors Steric elec-trostatic and hydrophobic descriptors in DHP moleculecould serve as its potential pharmacophores [2] In caseof Hantzsch ester this implies partly hydrogenated N-heteroaromatic DHP nucleus itself or its fragments that isNH group or C-4 H- atom as hydrogen donors necessaryfor the AO activity andor carboxylic ester side groups (itsC=O group and O atom as hydrogen bond acceptors) inpositions 3- and 5- and alkyl side groups in positions 2-and 6- (as hydrophobic features) (Grover et al [33] andTikhonov and Zhorov [69]) The presence of labile hydrogenatoms (mainly in positions 14-) in DHPs molecule assignssignificant hydrogen donating ability to these compounds
DHPs (26-dimethyl-14-dihydropyridine-35-dicarboxy-lic acid esters) can be oxidized in chemical (Dubur andUldrikis [70]) electrochemical enzymatic (Duburs et al[71]) and biological (including metabolism and biotransfor-mation) systems As already stated dihydropyridines (espe-cially unsubstituted in position 4) may transfer the hydro-gen similar to the reduced diphosphopyridine nucleotidesNADH and NADPH (Scheme 1) (Mauzerall and Westheimer[28]) while HEH hydrogen transfer studies and search fornovel NADHmodel compounds are continuously developing(Xie et al [72])
Tamagaki et al [73] observedmetal-ion-facilitated oxida-tions ofDHPswithmolecular oxygen andhydrogenperoxideOn the other side Tirzite et al [74] studied some 14-DHP derivatives as reductants in relation to trivalent iron
Hantzsch esters have been extensively utilized as stoichio-metric biomimetic reducing agents Recent summarized lit-erature about DHPs as reducing agents including referenceson diludine may be found on specialized websites httpwwworganic-chemistryorgchemicalsreductions [75]
DHPs form free radicals in chemical electrochemicaland biological oxidation processes The kinetic parametersand pathways of decay of the cationic radicals formed asprimary products in the course of electrooxidation of theesters of 12- and 14-dihydropyridine have been extensivelystudied [76]
The regenerative system of nicotinamide cofactors mayinvolve oxidizing or reducing reagents regulating enzymesand photochemical reactions Thus in situ regenerationof the consumed cofactors was observed in the biosys-tems engineering which create superior biocatalysts by thereduction of NAD(P)+ which can lead to the 14-DHPproduct (which is the only active form) and to the 16-DHP compound [77] The NADPH models of HEHs can beregenerated in situ as biomimetic hydrogen sources bymeansof transition metalBroslashnsted acid catalyzed relay asymmetrichydrogenation [78] General regeneration strategies werereviewed by Chenault and Whitesides [79] Based on thesestrategies particularly related to methods of preparation andpractical use of esters of 26-dimethyl-14-dihydropyridine-35-dicarboxylic acid as antioxidants that might be probablyapplicable for radioprotection and adjuvant treatment againstmetastases several patents were prepared [80]
Sambongi et al [81] have found that the novel water-soluble Hantzsch 14-dihydropyridine compound (the potas-sium salt of 26-dimethyl-14-dihydropyridine-35-dicar-boxylic acid monomethyl ester) functions in biological pro-cesses through regeneration of NADH Various parametersrelated to nicotinamide coenzymes regeneration especiallyin a light of chiral compounds have been published recently[82] while Okamura et al [83] reported the use of theoxidative conversion of dihydropyridine to pyridinium ionand the metabolic trapping principle as an approach formeasuring in vivo cerebral redox states
33 Antioxidant Activity (AOA) and Antiradical Activity(ARA) of 14-Dihydropyridines Antioxidative activity of 14-DHPs was first evaluated and studied in the Latvian IOS(Tirzit and Duburs [39] Zilber et al [44] and Dubur et al[45])
Oxidative Medicine and Cellular Longevity 7
N
O O
N
O O
R R
N
O Ominuseminus minuseminusminuseminus
minusH+
minusH+minusHminus
minusH∙
R998400(H)R998400H R998400(H)
oplus
R=H
Scheme 1 Reactions of 14-dihydropyridines leading to the formation of pyridine derivatives
In the field of ARA pioneering work was made by Schel-lenberg and Westheimer [84] in 1965 In 1979 Schellenberg[85] revealed the free radical oxidation of a dihydropyridinefollowing Huyser et al [86] who reported hydroxyl radicalquenching by DHPs especially Hantzsch ester studying freeradical oxidation of DHPs in vitro in the Fenton system
AOA and ARA of various 14-DHPs were further studiedby several different methods in both in vitro and ex vivoinvivo systems [3 31 44ndash53] CA nisoldipine nimodipinenitrendipine nifedipine and nicardipine have AOA thatcorrelates with their lipophilicity (modified Buege and Austrsquosmethod of TBA determination applied in model of rat braincortex ischemiareperfusion) [87]
N-Aryl-DHPs designed as sirtuin activators were furtherreported as suitable agents for neuroprotection due to theirradical avoidance properties (Hardeland [88])
14-DHPs inhibit free radicals and consequentially thecascade of events related to lipid peroxidation They mayinfluence several stages (initiation andor propagation) of thelipid peroxidation cascade which consist of sim10 reactions[89] (detailed discussion in Section 331 (2)-(b) Scheme 2)
However considering the great number of AO com-pounds (including DHPs) and the diversity in their actionmechanisms [90] in vivo studies are not always convincingand conclusive Therefore concise in vitro models are neces-sary to screen each compound with antioxidative propertiesAntioxidants are designed to react readily with oxidizingspecies and are often extensively oxidized already duringincubations at atmospheric oxygen tension (oxidation ofsome water-soluble DHPs in water (buffer) solutions is veryfast especially in the presence of light) Even during arelatively short incubation period the concentration can dropdrastically and the real potency of the compound could beunderestimated [90]
331 Common AOA and ARA Features of Some DHPs
(1) In Vitro (in Solutions Emulsions and Liposomes) Basicmolecular principles related to antioxidative and antiradi-cal activity of various antioxidants including DHPs werepublished recently [91] These data show that DHPs reactwith various types of free radical species stable free radicals(DPPH ao) and alkyl radicals and with oxygen and nitrogenfree radicals Some derivatives of DHPs may quench a singletoxygen and may react with peroxynitrite anion [92ndash95]
Reactivity of DHPs toward alkyl radicals was studiedelectrochemically [96]
The activity against DPPH radical was found for the5-acetyl-2-alkylthio-4-aryl-6-methyl-14-dihydropyridine-3-carboxylic acid nitriles [97] structural analogues of the5-acetyl(carbamoyl)-6-methylsulfanyl-14-DHP-carbonitrile(studied as mitochondriotropic compounds see further inthe text Section 331 (2)-(b))The highest antiradical activityoccurred for a compound which contains two hydroxylgroups in the 4-phenyl substituent
DHPs were proved to decrease oxygen uptake (2-3-fold) in the heme (methemoglobin hematin hemin andcytochrome C) catalysis by oxidation of emulsions of estersof unsaturated fatty acids and liposomes of phospholipidphosphatidylcholine (Zilber et al [44] and Dubur et al [45])
Reactivity of nitrosoaryl and nitroaryl derivatives of 14-DHPs toward alkyl alkylperoxyl radicals and ABTS radicalcation was found in various LP modeling systems suitablefor determination of DHPs AOA and ARE features [98ndash104] Diludine and foridone and its analogues were shown toinhibit lipid peroxidation through inhibitory effect on lipoxy-genase in emulsions and in reversed micelles (Tsetlin et al[105] and Panek et al [106]) In addition to inhibition of ther-mally initiated oxidation of methyloleate in the solution [107](where AOA of 4-unsubstituted 35-dicarbonylderivativesof 26-dimethyl-14-DHPs is not linearly dependent onthe inhibitor concentration) DHPs derivatives containinghydroxy alkoxy or dimethylaminophenyl substituents inposition 4 were shown to prevent loss of 120573-carotene in thedisperse system of 120573-carotene and methyllinoleate (Plotnieceet al [108])
The AOA of DHPs has been detected using differentmethods in various systems where lipid free radical gen-eration (nonenzymatic Fe2+-dependent andor enzymaticNADPH-dependent) took the place [109ndash112] This activitywas further confirmed in vivo through prevention of damagecaused by renal ischemia and reperfusion as shown fordiludine [113]
Some redox properties of calcium antagonist dihydropy-ridines were revealed through electroanalytical studies [114]Competitive kinetic procedure was used for exploring theAO capacity of five (four 14-DHPs lacidipine felodipinenifedipine and amlodipine and one 12-DHP compoundGR44966) CA and one calcium ion agonist (Bay K 8644) Allbut one (amlodipine) antagonist displayed an unambiguousAO capacity (crocin test) The calcium agonist DHP revealedno reaction with peroxyl radicals Lacidipine was the mosteffective A calcium agonist Bay K 8644 is quite resistant tooxidation and does not bind H+ This could be important
8 Oxidative Medicine and Cellular Longevity
fact in the interaction with the target proteins (it should bementioned that there are no studies on LP with other Ca2+agonists)
The decreased oxidation potential correlates with AOcapacity and increased basic characterThese findings suggestthe relevance of the electron density on the DHP ring
For all the DHP compounds investigated the overalloxidation process proceeds through two consecutive one-electron releases a primary one-electron step accompaniedby a fast proton release and the formation of a neutral radical(PyH∙) undergoing a second much easier one-electron step[114]
The final product is the protonated form of the parentpyridine derivative This pattern is relevant for the antioxida-tive activity since the radical intermediate is far less prone tobe reduced than oxidized
In the case of CA DHPs the release of protons compli-cates the overall oxidation process by introducing a ldquopara-siticrdquo side reaction where a coupling between protons and thestarting species takes place
This DHP self-protonation subtracts part of the originalspecies from the electrode process because the parent cationicspecies are no longer electroactive
Conversely the calcium agonist DHP which is less proneto be oxidized turned out to be so weak base to be evenunable to undergo the self-protonation reaction
Thus the combined effect of oxidation potentials andproton binding capacity of DHPs is a key element for theredox transition relevant for their AO activity Yet opposingeffects (antagonistic versus agonistic) on protein targets ascalcium ion channels connected with protein thiol oxidationto disulfide should be also considered [114]
Kourimska et al [115] found AO effect of diludine (HEH)in edible oil Reactivity of 14-DHPs toward SIN-1-derivedperoxynitrite was shown by Lopez-Alarcon et al [116] Oleket al [117] discovered antioxidative activity of NADH and itsanalogue in vitro
Further see as referred in several subparts below Sections34 35 and 37
(2) Ex Vivo (on Lipid Peroxidation in LDL MitochondriaMicrosomes and Cells) Main chemical structures of DHPsexamined in numerous studies and reviewed in this paper arepresented in Figures 1 and 2
(a) Various DHPs Calcium Antagonists as Inhibitors of LDLPeroxidation Free radicals induce peroxidation of LDLThis process proceeds by a chain mechanism which revealsphosphatidylcholine hydroperoxides and cholesteryl esterhydroperoxides as themajor primary products [118] Calciumantagonist DHPs could act as antioxidants on LDL at leastin three ways (1) as inhibitors of isolated LDL peroxi-dation caused by various inducers (Cu2+ ions UV lightand xanthinexanthine oxidase system) (2) if preincubatedwith cells preventing against intracellular LDL oxidation (3)preventing against the harmful effect of oxidized LDL on cellsand decreasing cytotoxicity [119ndash131]
Combined application of ascorbic acid and CA DHPs(amlodipine and felodipine) has an additive (cytoprotective
and LDL antioxidant activity) effect [120] It includes acombination of peroxide-degrading and peroxyl radical scav-enging reactions thus demonstrating the importance of LPduring LDL oxidation and cytotoxicity induced by oxidizedLDL Cytoprotection is associated with inhibition of oxidant-induced increases in intracellular free calcium
Similar to the othermodel systems the recorded values ofthe tested DHPs related to AO activity on LDL LP and relatedevents [119ndash131] depend on the prooxidant model system andmethods used for activity measuring (see Tables 1ndash5)
Commercial Ca2+ antagonists (including 14-DHP deri-vatives) as well as some other 14-DHPs with less CA activitywere shown to decrease the rate of oxidation (detected asTBARS) of low-density lipoprotein (LDL) induced by Cu2+ions (CuSO
4) in two different cell lines U937 human mono-
cyte-like and J774A1 murine monocyte-macrophage cellline (Rojstaczer and Triggle [119]) The strongest effect wasrecorded for vitamin E followed by felodipine 2-Cl analogueof nifedipine nifedipine amlodipine nitrendipine vera-pamil and diltiazem
Rojstaczer and Triggle [119] found that CA from differentchemical groups had a concentration-dependent effect asantioxidants against LDL oxidation (see Table 1) Howeverthe order of potency (activity rank order ARO) of the drug(s)again depends on the oxidation system and the antioxidantassay Both CA and antioxidative effects relate to the 2- (or o-orto-) substituent of the 4-phenyl ring in the same potencyorder 119900 gt 119898 ≫ 119901 [119] On the other hand the require-ment for the 14-DHP ring is essential for both AOA andCa2+channel antagonism A charged substituent at the position C-2 of the 14-DHP ring influences the AO activity (analogousto [46ndash53]) However some other factors should not beneglected for example although amlodipine has a positivelycharged amine at this position this modificationmakes it lesslipophilic and indirectly less potent antioxidant
Similar results were obtained when testing antioxidanteffect of CA on LDL peroxidation in bovine aortic endothelialcells (BAECs) (Cominacini et al [123] see Tables 2 and 3) aswell as in HUVECs (Lupo et al [129]) (see Table 4)
Cominacini et al [123] observed antioxidant effect ofCCBs and 120572-tocopherol in BAECs The order of potency(see Tables 2 and 3) [123] was however different than inU937 human monocyte-like and J774A1 murine monocyte-macrophage cells (see Rojstaczer and Triggle [119] Table 1)The tested DHPs were lacidipine amlodipine lercanidipinenimodipine and nifedipine (in two different intracellularconcentrations 2 and 4 fmol) ROS production was signif-icantly lowered only by lacidipine (which is the compoundwith the highest lipophilicity) and lercanidipine the effectof lacidipine was much more evident than lercanidipineSurprisingly amlodipine nimodipine and nifedipine had noeffect on ROS formation suggesting that the positive effectson the earliest events of atherosclerosis are a peculiarity oflacidipine molecule through its antioxidant activity
The strong AO action of lacidipine may be related tothe lipophilic cinnamic acid side chain which favors a drugpartitioning in the membrane due to favorable physicochem-ical (hydrophobic) interactions of drug hydrophobic residues
Oxidative Medicine and Cellular Longevity 9
Table 1 Relative structure-function relationships of calcium antagonists (DHPs verapamil and diltiazem) and vitamin E Effect on oxidativemodification of isolated ex vivo human low-density lipoprotein using two various oxidation systems (copper (II) ions induced and monocyteinduced) Compiled according to data presented by Rojstaczer and Triggle [119]
Compound
Systems of LDL oxidation
Copper (II) ions induced system (comparison of three methods) Monocyte induced celloxidation system
Methods
Reduction of TBARS level of LDL(relative efficacy)
Degradation of oxidized[125I] LDL by J774
macrophages
Relative electrophoreticmobility of LDL on
agarose gel
TBARS content of LDL(in )
Relative efficacy (activity rank order (ARO) ARO = I for the most effective) effective inhibitor concentration [IC] in120583M
with polyunsaturated groups of membrane phospholipidsHowever DHPs can also reduce the oxLDL-induced ROSconcentration by affecting some intracellular ROS producerssuch as NADPH oxidases xanthine oxidase and cyclooxyge-nase enzymes The activity of these enzymes contributes tointracellular ROS elevation [125]
Preincubation of HUVECs with lacidipine inhibited anincrease of intracellular ROS caused by oxidized LDL [124]
Lupo et al [129] have studied the dose-dependent (1 510 and 50 120583M) AOA of various CA (verapamil diltiazemand DHPs nifedipine amlodipine isradipine or lacidipine)
Table 3Modulation of ROS formation in BAECs by CA (DHPs andverapamil) and vitamin E Compiled according to data presented byCominacini et al [123]
Compound
Method of flow cytometry (reduced2101584071015840-dichlorofluorescein diacetate(DCFH-DA) oxidation by ROS)
Activity rank order(ARO = I for the highest activity ARO = III for
the mindest activity)(Effective [IC] 1 5 10 50 120583M)
Lacidipine + + + (ARO = I)Lercanidipine + + (ARO = II)Amlodipine No effectNifedipine No effectNimodipine No effectVerapamil + (ARO = III)120572-Tocopherol + + + (ARO = I)
against normolipidemic human blood LDL oxidation com-pared with 120572-tocopherol by measuring the content of TBARSand the diene formation (see Table 4)
10 Oxidative Medicine and Cellular Longevity
Table 4 Normolipidemic human blood LDL (025mgmL) in vitro oxidation in the presence of 5 120583M CuSO4and CA of 3 types (DHPs
verapamil and diltiazem) and vitamin E Compiled according to Lupo et al [129]
Compound
MethodsTBARS method (fluorimetry at 515 nm533 nm 4 hours
preincubation of LDL with compounds and copper (II)ions 320 TBARS increase in control during 4 h
period)
Inhibition of conjugated diene formation (at 234 nm)expressed as prolongation of induction period (in
of control) 119905contr = 368min
Effective [IC] (in 120583M)1 120583M 10120583M 50 120583M
Activity rank order (ARO= I for the highest activity
ARO = VII for themindest activity)
Effective [IC] (in 120583M)1 120583M 5 120583M 10120583M 50 120583M
Activity rank order (ARO= I for the highest activity
ARO = VII for themindest activity)
Nifedipine 10120583M50 120583M ARO = III
5 120583M10120583M 15050 120583M 213
ARO = III
Amlodipine 50 120583M ARO = IV5 120583M
10120583M 12250120583M 138
ARO = IVndashVI
Isradipine 50 120583M ARO = VI 10120583M 15050 120583M 183 ARO = IVndashVI
Lacidipine1 120583M10120583M50 120583M
ARO = II5 120583M
10120583M 19250 120583M 283
ARO = II
Verapamil 50 120583M ARO = V 10120583M 15050 120583M 178 ARO = IVndashVI
Diltiazem No effect No effect (ARO = VII) No effect No effect (ARO = VII)
Vitamin E1 120583M
10120583M (IC50)
50 120583M (20 of control)ARO = I
5 120583M10 120583M 23050 120583M 370
ARO = I
Table 5 Antiproliferative effect (oxLDL-induced HUVSMCs proliferation) of CA DHPs and simultaneous oxLDL-induced ROS productionscavenging Comparison with N-acetyl-L-cysteine NAC (intracellular ROS scavenger) Compiled according to data presented by Zou et al2012 [130]
DHP compound
MethodsAntiproliferative effect against proproliferative effectinduced by oxLDL (50 120583gmL) (UV detection of
formazan production from tetrazolium salt)
oxLDL-induced ROS production (fluorescent DCF(2101584071015840-dichlorofluorescein) production)
Effective [IC] in120583M and I in
Amlodipine 3 120583M I = 18 3 120583M 10 120583M No effectI = 20
S(minus)-Amlodipine No effect No effect
Lacidipine 10 120583M30 120583M
I = 21I = 27 10120583M Isim23 of control
N-Acetyl-L-cysteineNAC
mdash 5000 120583M(5mM) I = 28
As presented (Table 4 according to [129]) for diltiazem(poor lipid solubility) noAOwas detected whereas the otherCA and 120572-tocopherol have demonstrated AOA at least atconcentrations of 10 and 50120583M 120572-tocopherol gt lacidipinegt nifedipine gt isradipine verapamil and amlodipine Addi-tionally120572-tocopherol and lacidipinewere able to significantlyattenuate in vitro LDL oxidation at 1 and 5120583M Theseresults have confirmed the highest activity for the stronglylipophilic DHP type CA compound lacidipine This might be
a possible antiatherogenic mechanism of CA since oxidativemodification enhances the atherogenic potential of LDL
The lipid peroxidation of LDL promoted either by UVradiation or by copper ions was inhibited (antioxidant effect)by nisoldipine in a dose-dependentmanner (IC
50values were
evaluated at around 10 120583M) nimodipine was less potent (IC50
around 50ndash100 120583M) and nicardipine almost inactive In addi-tion to this indirect protective effect CA DHPs nisoldipineand nimodipine exerted direct protective effect on lymphoid
Oxidative Medicine and Cellular Longevity 11
cells against toxicity of previously oxidized LDL The IC50
values were 6 plusmn 2 and 80 plusmn 20 120583M respectively [122] Theinhibition of the cytotoxic effect of LDL oxidized in thepresence of DHP type Ca2+ channel blockers correlated wellwith protection from oxidation by these compounds Com-plete protection cannot be obtained because the DHPs arecytotoxic themselves The potential relevance to the preven-tion of atherogenesis is envisaged
DHP typeCCBnifedipinewas themost effective inhibitorof oxidation promoted either by UV radiation or by copperions in experiments with cultured lymphoid cells LDL (2mgapoBmL) CCBs from other two CCB classes diltiazem andverapamil were only poorly active or completely ineffective[121] The protective effect of nifedipine occurs at two levelsbesides its direct antioxidant effect by inhibition of LDLoxidation it also exhibits a direct cytoprotective effect againstcytotoxicity of oxidized LDL by yet unknown mechanismsThe protective effect of CCBs was not due to an inhibitionof LDL uptake This effect seems to be independent of theinhibition of LDL oxidation per se since LDL was oxidizedin the absence of the drug before the incubation withcells Moreover this direct protective effect was observedat lower concentrations (IC
50of 1 plusmn 02 120583M) compared to
the antioxidant effect (IC50
of TBARS inhibition is around10 plusmn 2 120583M at UV promoted and 4 plusmn 05 120583M by Cu2+ ionsinitiated) The AO effect of nifedipine is also correlated withthe protection of endogenous tocopherols (IC
50= 50 120583M)
It was suggested that the AO effect of CCBs protected cellsindirectly from the cytotoxic effect of oxidized LDL [121]
A recent study has reported that beneficial vascular effectsof lercanidipine in diabetic rats depend on its antioxidantactivity related to attenuating the increase in oxidativestress and in vascular matrix metalloproteinase-2 (MMP-2) (Martinez et al [126]) Lesnik et al [127] studied theimpact of a combination of this calcium antagonist and a120573-blocker atenolol on cell- and copper-mediated oxidationof LDL and on the accumulation and efflux of cholesterolin human macrophages and murine J774 cells They realizedthat lercanidipine reduced the oxidative modification of LDLrather than diminished cholesterol accumulation in humanfoam cells
Comparing the antioxidative action of CA (DHPs amlo-dipine lacidipine nifedipine and isradipine as well as diltia-zem and semotiadil) in the copper-catalyzed oxidation oflow-density lipoprotein (LDL) with that of glycated (g)gly-coxidated (go) LDL demonstrated that the strongest AOeffects during long-term LDL glycation are seen for isradip-ine lacidipine nifedipine and semotiadil [128] Inhibitoryeffects were in the range 10minus5ndash10minus3MAuthors suggested thatdue to the increased generation of ROS by glucose-modifiedLDL the chain-breaking capacity of CA may be overriddenThe AOA of CA depends on their lipophilicity and theirability to incorporate into the LDL particle that is to reachthe site of peroxidation CA like other AOs significantlyretards advanced glycation end products (AGE) formationwhereas initial glycation reactions such as Amadori productformation are only weakly inhibited The observation thatboth oxidative changes and at least long-termglycation effectsare indeed drastically reduced by CA is corroborated by
fluorescence analysis AGE-ELISA quantitation of lipid per-oxidation and TBARS measurement of long-term ggo LDL
The effects of lipophilic DHP calcium channel blockerson oxidized LDL-induced proliferation and oxidative stressof vascular smooth muscle cells were also studied [130] (seeTable 5)
Lacidipine and amlodipine reduced carotid intima-media thickness by decreasing proliferative effect of oxLDLwhereas (S-)-amlodipine had no antiproliferative effect ROS-MAPKs (mitogen-activated protein kinases) pathway mightbe involved in the mechanism
Both 14-DHP CCBs lacidipine and nifedipine reduceplasma and LDL oxidation and formation of oxidation-specific epitopes Their application may also relate to pro-longed survival of rats independently of blood pressuremod-ifications (in the SPSHR model 1mgkg per day lacidipineand 80mgkg per day nifedipine) These results suggestedthat the protective effect of these two 14-DHP drugs invivo as shown in cerebral ischemia and stroke may in partresult from inhibition of LDL oxidative process althoughthese two drugs possess different lipophilic properties [131]Both lacidipine (03 and 10mgkg) andnifedipine (80mgkg)prolonged lag time of the conjugated diene formation inLDL isolated from arterial wall and 119905max These drugssignificantly reduced electrophoreticmobility of oxLDL fromSPSHR subjected to XXO oxidation system 14-DHP CCBsalso protected apolipoprotein B which is important for thebinding with macrophage LDL receptor lysine residues Thedoses used (gt10minus6molL for SPSHR and normotensive WKYrats) however are 2 to 3 orders of magnitude higher thanthose inhibiting vascular smooth muscle contraction in vitroand in vivo They also exceed values that are commonlyused in clinical practice The daily dose of lacidipine forhypertensive patients is 007mgkg asymp4- to 14-fold lower thanthe 2 doses used in SPSHR The maximum daily dose ofnifedipine given to hypertensive patients is 20mgkg asymp40-fold lower thanwhatwere used [131]These discrepanciesmaybe related to differences in bioavailability of CA between ratsand humans [131]
Accordingly in routine clinical use 14-DHPCCBs donotreach the concentrations required for antioxidant activity invitro [131]
Another data concerning the effect of CA DHPs on OSrelated to LDL is presented under Section 35
(b) Effect of DHPs on Isolated Rat Liver and Heart Mitochon-dria As a major cellular source of oxygen radicals (Cadenas[4 5]) mitochondria are promising targets for pharmaco-logical and toxicological actions of various membrane-activecompounds including several 14-DHP derivatives Zernig etal [132] have discovered CA binding sites associated with aninner mitochondrial membrane anion channel
More than 40-year long research onmitochondrial effectsof the DHPs (on their bioenergetics chemiosmotic proper-ties and ion fluxes) clearly points them out as mitochondri-otropic compounds
The activity of the first 35 synthesized compounds(derivatives of 14-DHP their heteroaromatic analogues
12 Oxidative Medicine and Cellular Longevity
NAD-H+ and butylated hydroxytoluene (BHT BOT)) orig-inally was examined in rat liver mitochondrial LP system inthe presence of Fe2+ ions and using the ultraweak chemilu-minescence method (Dubur et al [89])
Several 14-DHP derivatives Hantzsch ester diludine andits analogues were found to be effective antioxidants in thisexperimental system changing the kinetics of LP lengtheningthe time of the appearance of the maximum of the slowburst of the chemiluminescence (latency latent period) anddiminishing the reaction rate (the tangent of the slope angleduring the time in which the amplitude of the slow burstcharacterizing LP rate increases) and its peak value Theirpresence has influenced the reaction constant 119870
6 in relation
to a very significant reduction of lipid hydroperoxides andorinactivation of free radicals as follows
ROO∙ + ROO∙ 997888rarr P + h]lowast termination (1)
(P = molecular products) or
ROO∙ + ROO∙ +H2O 997888rarr ROH + RO∙ + 1O
2
lowast (2)
In this study diludine was one of themost active compoundsDHPs had activity similar to the standard synthetic AO-BHT(ionol) However when plotted against applied concentrationand time window diludinersquos activity profile differed from thatof BHT
There were also similar studies (using different LP rateexperimental detection system and method Hunter et al[133]) based on exploring a group of 26 26-dimethyl-35-disubstituted- and 26-dimethyl-345-trisubstituted-14-dihydropyridines (14-H
2Py=14-DHPs) and five related pyri-
dines as inhibitors of rat liver Mit swelling (Δ119860520119905) and O
2
uptake by ascorbic acid- (AsA-) dependent lipid peroxidationand as modulators of Mit swelling induced by Na+-linoleateor Na+-pyrophosphate (Velena et al [112])
Some of tested 4-DHPs (4-unsubstituted 35-dialkoxy-carbonyl-26-dimethyl-14-DHPs and 35-diamido-26-dim-ethyl-14-DHPs both 4-unsubstituted or those possessinglipophilic 4-aryl- groups) have shown significant AO andmembrane stabilizing activity These studies further revealedthat 14-DHPs preferably act as AO during the stages ofinitiation and prolongation of LP chain reactions at lowconcentrations The studied 14-DHPs had IC
50(when 119881
0119881
or 1205911205910= 2) 01 120583M to 100 120583M and the minimal activity was
scored for oxidized (heteroaromatized) derivativesAt the concentration of 100120583M 35-di-n-butyloxycarbo-
nyl-26-dimethyl-14-DHP entirely stops mitochondrialswelling in the presence of 08mM Na+-pyrophosphateAt the same concentration the following compoundsalter the mitochondrial swelling rate in the presence ofnatural protonophore Na+-linoleate 35-di-p-hydroxyphen-oxycarbonyl- and 35-di-p-tolyloxycarbonyl-26-dimethyl-14-DHPs 35-diethoxycarbonyl-26-dimethyl-pyridine (oxi-dized form of Hantzsch ester) and more lipophilic 35-diamyloxycarbonyl-26-dimethyl-pyridine The alteration ofswelling may be scored as prolonged promoted acceleratedor inhibited The type of alteration depends on the structureand concentration of 14-DHPs the type of initiators of theswelling process and the medium composition
In accord with previously published Janerorsquos results (lackof AO for Ca2+ antagonists nifedipine and nicardipine evenat 500120583M concentration in LP tests performed on heartmembrane [134]) no antioxidative activity for 4-phenyl sub-stituted derivatives of 35-dialkoxycarbonyl 14-DHP (closeanalogues of Ca2+ antagonists) was found contrary to various4-nitrophenyl 14-DHP derivatives calcium antagonists forwhich the significant antioxidant activity was reported [3146ndash53]
Studies made on phosphatidylcholine liposomes (ourunpublished data) suggest approximately three and twotimes more antioxidative activity for 100 120583M 4-unsubstitutedDHP compound diludine when compared to 4-substitutedDHPs riodipinenifedipine and nicardipine respectively atmethemoglobin-induced LP (oxygraphy)
Inhibition of mitochondrial AsA-dependent LP and sta-bilization ofmitochondriawere shown to be characteristic fora large group of 14-DHP compounds [112] showing to pos-sess the AOA in simplest in vitro systems (Tirzit andDuburs [39] Zilber et al [44] and Dubur et al [45])based on reactions with the stable free radical 11-diphenyl-2-picrylhydrazyl (DPPH) LP of fatty acid ester (linethole andmethyloleate) emulsions and phospholipid (phosphatidyl-choline) liposomes Generally these properties did not coin-cide with Ca2+ antagonism Depending on DHP structure itseems that AOA properties are less specific than Ca2+ antago-nist properties Both properties may be interrelated but notinterdependent
These data show that the presence and the nature ofa substituent in position 4 as well as 35-substituentsare important factors for 14-DHP antioxidant effects invarious systems that is AsA-dependent nonenzymatic aswell as enzymatic NADPH-dependent lipid peroxidationSometimes the efficacy of inhibition of nonenzymatic LPby 14-DHPs is higher than the inhibition of the enzymaticLP However the action may be opposite stimulation of theLP Hantzsch ester (HEH diludine) and its close analoguesexhibited significant AOA and membrane stabilizing prop-erties in both AsA-dependent nonenzymatic peroxidationof mitochondria and NADPH-dependent enzymatic LP ofmicrosomes usually at similar 10 to 100120583M concentrations[112]
The order of AOpotency (IC50
values) in vitro depends ondrug structure as well as on the experimental conditions andspecificity of the biological system Eachmethod for determi-nation of AOA and ARA has advantages and disadvantages(Karadag et al [135])
Accordingly as reported by Gubskiı et al [136] IC50
forthe AsA-dependent LP was 025 120583M and 20 120583M for 14-DHPCa2+ antagonists nitrepine (nitrendipine) and nifedipinerespectively Takei et alrsquos [137 138] studies on mitochondrialswelling induced by LP or arachidonic acid in the rat braindetermined the IC
50values of 127 105 1568 and 384 120583Mfor
efonidipine nicardipine nifedipine and nimodipine respec-tively For LDL in the copper-induced oxidation system theorder of potencywas vitamin Egt felodipinegt 2-chlorophenylanalogue of nifedipine gt nifedipine gt amlodipine nitrendip-ine verapamil and diltiazem (Rojstaczer and Triggle [119])
Oxidative Medicine and Cellular Longevity 13
It was interesting to compare the AOAofDHPswith theirsusceptibility to oxidation that is electron and hydrogendonating properties
It has been estimated that electron donor substituentsin positions 2 and 6 of 14-DHP cycle usually promoteoxidation while electron acceptor substituents promotequench oxidation Stronger electron acceptors in positions 3and 5 also significantly quench oxidation These estimationsare based on studies including chemical enzymatic andelectrochemical oxidation of 14-DHPderivatives (Dubur andUldrikis [70] Duburs et al [71] and Stradin et al [139])
On the other hand diminished AOA of 14-DHP relatesto presence of substituents in position 4 (both electron donorand electron acceptor) (Velena et al [112])
35-Dicarbamoyl substituents possess minimal quench-ing feature and are followed by benzoyl- acetyl- andalkoxycarbonyl- groups Maximal decrease was obtainedwith condensed substituents (ie oxoindeno- or oxocyclo-hexeno- groups) and a CN-group 4-Unsubstituted 35-dicar-bamoyl derivatives can be easily oxidized and consequen-tially inactivated whereas 4-substituted 35-dicarbamoyl-14-DHPs possess an oxidation potential analogous to the 4-unsubstituted 35-COOR derivatives Therefore they haveadequate electron donor properties and are considerablystableThismay be the reason for significantmembrane stabi-lization upon exposure to 4-substituted derivatives Ofimportance their AOA was usually more pronounced incomparison to 4-unsubstituted derivatives
Among them 26-dimethyl-35-difurfuryloxycarbonyl-14-DHP showed the highest antioxidative activity In thegroup of 35-dialkoxycarbonyl derivatives the strongestactivity was attributed to compounds with medium lengthalkyl chains (i-butyl- t-butyl- and i-amyl- substituents) highlevel of lipophilicity minimal electron acceptor propertiesand moderate steric hindrance as contrasted to short or longalkyl chain ester derivatives (35-dimethoxycarbonyl- 35-diethoxycarbonyl derivatives and 35-didodecyloxycarbonylderivative) These data demonstrate the bell-shaped depen-dence of AOA on alkyl chain length [112] and are in accordwith results obtained in liposomes However these datadiffer from those obtained in emulsions where diludine wasthe most active compound Finally oxidized heteroaromaticderivatives showed only minimal activity
In both LP systems studied (AsA-dependent in mito-chondria and NADPH-dependent in microsomes) some of14-DHPs showed activity similar to classical antioxidantbutylated hydroxytoluene (ionol BHT) (Velena et al [112])However there was a significant difference related to con-centration and incubation time It allowed us to postu-late that 14-dihydropyridines (InH) acting as antioxidants-reductants and scavengers of reactive oxygen species and lipidfree radicals preferably influence initiation and propagation(prolongation) of lipid peroxidation chain reactions (1)ndash(5) according to Scheme 2 The phenomenon is particularlyprominent in the presence of Fe2+ and other ions of variablevalency
Chain break and termination reactions (6)ndash(10) of theLP reaction cascade [89] were influenced by 14-DHPs in alesser degree than were initiation and propagation steps This
may be important for their therapeutic effects even in theadvanced stages of LP
Scheme 2 (stages of initiation propagation and terminationof lipid peroxidation chain reactions (1ndash10)) Initiation andpropagation reactions are as follows
(8) RO∙ + In∙minus rarr Y (Y = molecular products)(9) ROO∙ + Fe2+ rarr Fe3+ + X (X = molecular products)(10) RO∙ + RO∙minus rarr Y (Y = molecular products)
In the reversible swelling of mitochondria accompanyingLP (initiated by mixture of 5mM GSSG1mM GSH) several14-DHPs showed low or no activity manifested only as adecrease of the swelling amplitude without a rate decreaseAn addition of GSH (4mM) or ATP to swollenmitochondriacaused their contraction in both control and tested systemIt may be suggested that 14-DHPs acting as antioxidantsin mitochondria preferably influence LP reactions initiatedby ions with variable valency or their complexes with hemetype compounds methemoglobin hemin hematin and soforth (Velena et al [112]) If the peroxidation process has amaximal velocity and 50 percent of initial O
2were consumed
14-DHPs cannot completely break the chain reactions andprevent subsequent membrane damage by addition of DHPsubstance at 10 120583M concentration at the moment of 50percent oxygen consumption the subsequent oxygen uptakeproceeded unchanged This observation is important for theapplication of DHPs as inhibitors of initiation and to a lesserdegree propagation stages of LP chain reactions
The influence of 14-DHPs on Mit swelling is not strictlyassociated with their own oxidation There is the possibilitythat the labilizing (or stabilizing) effect relates to surfaceactivity (connected with substituent lipophilicity) or may bethe consequence of complexation with some -OH (or -CH
3)
group sensitive receptors at the mitochondrial membraneNamely a bathochromic shift of the absorption band maxi-mum (about 10 nm) was observed in the visible region beforeswelling However after swelling in the presence of Na+linoleate the spectrum returns to its initial value [112]
Some 14-DHPs not only protect mitochondria againstswelling caused by AsA-dependent LP salts of fatty acids
14 Oxidative Medicine and Cellular Longevity
in vitro [112] but also have beneficial effects on repairingtheir integrity in vivo after exposure to irradiation hepato-toxins ischemia hypoxia or hypothermia Some of themwere shown to normalize the process of intracellular repara-tion and physiological regeneration of ultrastructures Theywere also shown to stimulate reparative processes If pre-treated with 14-DHPs irradiatedmitochondria will not swell(Ivanov et al [140 141])
Diludine ionol and some other AOs mitochondria pro-tectors act as anti-ischemic agents If applied prophylacticallyin vivo they may prevent ischemic and reperfusion lesionsin heart kidney and other organs (Bilenko et al [113]) Theeffect is dependent on applied dose timing and way ofapplicationWhen added onto the cryoconservationmediumfor mitochondria preservation 14-DHPs prevented decreaseof membrane potential normalized facilitated respirationand prevented loss of mitochondrial Na+ and Ca2+ ionsafter thawing ([112] see citation number 36 (Subbota et alKharkov 1984) therein) Diludine was stronger protectorwhen compared to ionol
CA drug foridone (riodipine) was shown to possesscardioprotective features primarily due to is protective effecton mitochondria exposed to OS [142 143]
Similarly the DHP water-soluble antiarrhythmic com-pound glutapyrone inhibits initiation of LP by free radicalsin erythrocytes and heart mitochondria Its cardioprotectiveeffect has been experimentally shown in heart mitochondrialmembranes especially during deep hypothermia (Utno et al[144])
Cerebrocrast was effective in several translation modelsmimicking pathological situations known to be associatedwith cellular OS The potential protective action of 14-DHP derivatives (4-substituted compounds cerebrocrastgammapyrone glutapyrone and 4-unsubstituted drug dieth-one) has been studied in rat liver in experimental modelsrelevant for oxidative stress and mitochondrial bioenergetics(Fernandes et al [145]) When succinate was used as therespiratory substrate higher concentrations (gt25 120583M) ofcerebrocrast depressed respiratory control ratio (RCR) ADPto oxygen ratio (ADPO) state 3 and uncoupled respirationrates transmembrane potential (deltapsi) and the phosphatecarrier rate At the same time state 4 respiration rate wasthree times increased At concentrations lower than 25120583Mcerebrocrast inhibited mitochondrial IMAC and partiallyprevented Ca2+-induced opening of the mitochondrial PTPGammapyrone glutapyrone and diethone did not inducethese phenomena When applied at concentrations up to100 120583M cerebrocrast gammapyrone and glutapyrone didnot affect ADPFe2+-induced LP of mitochondria in rat liver(as measured by oxygen consumption and TBARS forma-tion) On the other hand low diethone concentrations (upto 5 120583M) inhibited it in a dose-dependent manner Diethonealso prevented against deltapsi dissipation induced by LPinitiated by ADPFe2+ Based on these data it may bespeculated that cerebrocrast (inhibition of the IMAC) anddiethone (acting as an AO) may provide effective protectionof mitochondria during OS Cerebrocrast has shown sometherapeutic potential for treatment of several pathologicalconditions related to cellular OS [145]
5-Acetyl(carbamoyl)-6-methylsulfanyl-14-DHP-carbo-nitriles (Figure 3) with minor differences in their molecularstructure displaying antioxidant and antiradical activitiesin vitro show different biological activities Namely 4-p-chlorophenyl derivative OSI-1146 displays AO and anti-radical activities in cardiovascular OS models whereasOSI-3701 and OSI-3761 display hepatoprotective activityThus these compounds may be potentially useful for treat-ing several pathological processes including those associatedwith OS (Fernandes et al [146]) However besides mito-chondria the cellular targets for their pharmacologicalactions have not been fully investigated [146] All these com-pounds increase the susceptibility of Mit to MPT The mostpotent is OSI-3701 although it does not affect bioenergeticparameters
Although all these compounds protected mitochondriaagainst LP induced by the oxidant pair ADPFe2+ OSI-1146was shown to be the most potent Current data point outmitochondria as potential targets for protective and toxicactions of DHPs suggesting that the potential for their use astherapeutic agents should also take into consideration theirtoxic effects on mitochondria (Fernandes et al [146])
Several structurally different DHP derivatives (antioxi-dant diludine (diethone) as a 4-unsubstituted DHP 4-substi-tuted DHPs CA foridone (bicyclic compound) and the 4-phenyldiethone compound where phenyl group is joined tothe DHP in position 4) inhibited the 1-methyl-4-phenyl-pyridinium iodide (MPP+) induced ROS production incerebellar granule cells (CGC) with a distinct potency orderforidone (26-dimethyl-35-dimethoxycarbonyl-4-(o-difluo-romethoxyphenyl)-14-dihydropyridine) gt 26-dimethyl-35-diethoxycarbonyl-4-phenyl-14-dihydropyridine gt diludineThey also reversed the MPP+-induced decrease of the mito-chondrial membrane potential in the same order (Klimavi-ciusa et al [147]) Accordingly it was postulated that theclassical two-ring (bicyclic) structure of DHP derivativesrepresents an advantage in relation to neuroprotection andROS defense and is independent on compoundrsquos propertiesrelated to calcium ions
Novel adamantane-containing 14-DHP compounds (Kli-maviciusa et al [148]) were also found to improve mitochon-drial functions (MPP+ model) (Klimaviciusa et al [148])Klusa et al [149] have discovered antineurotoxic effects of14-DHP taurine derivative tauropyrone recorded as Mitfunction improvement
Many 14-DHPs including Ca2+ antagonists and AOmodify LP processes and influencemitochondrial function invarious organs (liver heart kidney and brain) in a differentway and degree Their beneficial action oxygen or lipidfree radical scavenging antioxidative effects binding withor intercalating into phospholipid bilayer regulation of iongating and regulation of mitochondrial permeability transi-tion pores (Tirzit and Duburs [39] Zilber et al [44] andDubur et al [45]) separately or in combination with eachother depends on two strong elements (1) their individ-ual structure including nature of substituents and theirpositions and (2) the nature of the biological system Forexample the direction of LP (inhibition of promotion) wasshown to depend on structure and concentration of applied
Oxidative Medicine and Cellular Longevity 15
14-DHPs as well as stages of chain reactions Accordinglymitochondrial swelling may be prolonged (retarded) accel-erated (promoted) or inhibited (Velena et al [112])
Therefore there is a ground for 14-dihydropyridineseither Ca2+ antagonists or antioxidants to be nominated asuseful tools in development of ldquomitochondrial drugsrdquo relatedto the control of OS
(c) DHPs as AOs in Endoplasmic Reticulum (Inhibition ofNADPH-Dependent LP System) Inhibition of NADPH Oxi-dase by DHPs Elevated level of NADPH oxidase 4- (NOX4-)derived hydrogen peroxide (H
2O2) joined with concomitant
decrease of nitric oxide (NO) mediated signaling and reac-tive oxygen species scavengers are considered to be centralfactor in molecular pathogenesis of fibrosis (Sampson etal [150]) Inhibition of microsomal NADPH-dependent LPwith particular focus on NADPH oxidases (NOX1ndash5 andDUOX1) may be very important for neuro- cardio- andhepatoprotection (Velena et al [112] Leto and Geiszt [151]Griendling et al [152] and Chen et al [153]) Endoplasmicreticulum may be an important target as this is where 14-DHPs could display their antioxidative properties (Velena etal [112] Leto and Geiszt [151] Griendling et al [152] andChen et al [153])
However the initiation of LP in the NADPH-dependentmicrosomal system does not appear to involve either super-oxide or hydrogen peroxide since neither SOD nor cata-lase can inhibit it On the other hand reduced iron playsan important role in both the initiation and propaga-tion of NADPH-dependent microsomal lipid peroxidation(Hochstein and Ernster [154] and Repetto et al [111])
Many DHPs possess inhibitory activity not only towardsAsA-dependent LP in mitochondria but also towardsNADPH-dependent LP as shown in isolated rat liver micro-somes (Velena et al [112]) This means that these compoundsinteract with the shared parts (nonenzymatic and enzymatic)of LP pathways
Microcalorimetry and fluorescent probes procedureswere used for studying the interaction of alpha-tocopheroland 14-DHPs with endoplasmic reticulum membranes andmodel systems human serum albumin and phospholipidbilayers [155] Modification of microviscosity of the endo-plasmatic reticular membranes depends on localization ofantioxidants within the protein structures or phospholipidphase Increase of membrane structuralization under theinfluence of 14-DHPs blocked their antioxidant action inspontaneous and induced lipid peroxidation
Inhibition of rat heart and liver microsomal lipid perox-idation by nifedipine was observed [156] while Goncalves etal [157] found antioxidant effect of calcium antagonists onmicrosomal membranes isolated from different brain areas
Nitroaryl-14-DHPs are both calcium channel antagonistsand antioxidant agents (Letelier et al [158 159]) commonlyused for treatment of cardiovascular diseases These drugsmust be metabolized through cytochrome P450 oxidativesystem (NADPH-cytochrome P450 reductase) mainly local-ized in the hepatic endoplasmic reticulum Several lipophilicdrugs generate OS while being metabolized by this cellularsystem Thus DHP antioxidant properties may prevent the
OS associated with hepatic biotransformation of drugs Var-ious commercial and new nitro-phenyl-DHPs were studiedagainst LP using rat liver microsomes under oxidative stress[159]
Incubation of rat liver microsomes with the 41015840-nitro-4-phenyl-14-DHP compounds (26-dimethyl-4-(41015840-nitro-phenyl)-14-dihydropyridin-35-diethyl-dicarboxylate andN-ethyl-26-dimethyl-4-(41015840-nitrophenyl)-14-dihydropyri-din-35-dimethyl-dicarboxylate) results in an inhibitionof LP the UDPGT (UDP-glucuronyltransferase) oxidativeactivation and the microsomal thiol oxidation induced byFe3+ascorbate a generator system of ROS This effect wasalso produced by nitrofurantoin and naphthalene in thepresence of NADPH
Interestingly IC50
ofDHPs obtained frommicrosomal LPassays decreased to the same extent as the microsomal thiolsoxidation provoked by Fe3+ascorbate [159] Neverthelessthe AO effects of a nitrophenyl-DHP compound in whichhydrogen at position one of the DHP ring was replaced bythe ethyl groupwere significantlyweaker Authors speculatedthat DHPs can resemble NADH transferring one hydrogenatom of 4-position (Hminus) to anion superoxide and another ofthe 1-position (H+) by way of a cationic radical intermediateto generate pyridine derivatives and water [159]
The AO effects of various tested DHP derivatives (m- andp-NO
2phenyl as well as methyl or ethyl and isopropyl-DHP
35-dicarboxylate derivatives) were not significantly differentThe authors assumed that the -NH- group of the dihydropy-ridine ring could contribute both to the development ofthe calcium channel antagonism and to the antioxidativeproperties of DHPs [159]
Prevention of the membrane LP seemingly depends onthe concentration of potential antioxidants such as vitaminE or even 14-DHP in lipids However only the differencesin synthetic DHPs lipophilicity cannot explain significantvariations of DHPs concentration in microsomal membraneand cannot clarify the strength of their antioxidative activityThis work [159] has further demonstrated that 14-DHPsmay prevent the OS induced by biotransformation of somedrugs for example antibiotic nitrofurantoin Simultaneousadministration of DHPs and nitrofurantoinmay be beneficialin reducing nitrofurantoin side effects
While most of Ca antagonist 14-DHPs are metabolizedby CYP3A4 (Guengerich et al [160]) not all of them are goodinhibitors of its activity Thus nicardipine but not nifedipineand nitrendipine inhibits CYP3A4 in vitro [53] Interactionof different DHPs with various types of cytochrome P450 wasdescribed by Carosati et al [53] It was also reported thatDHP class calcium channel blockers reduce the antiplateleteffect of clopidogrel (Park et al [161])This implies themutualinteractions of both drugs with CYP3A4
(3) In Vivo Evaluation of nifedipine effects on Saccharomycescerevisiaewas recently published (Asma andReda [162]) Sur-prisingly nifedipine exercised a toxic effect on Saccharomycescerevisiae shown through measuring cellular proliferationrespiratory activity and the level of some biomarkers (CATand MDA)
16 Oxidative Medicine and Cellular Longevity
However majority of data obtained on various animalcells and tissues by other authors show the protective role ofDHPs against both LP and oxidative stress [113 163 164]
The AOA attributed to many 14-DHPs Ca2+ antag-onists and other compounds reflecting on catalytic LDLperoxidation (see Section 331 (2) and Section 35) shouldencourage their testing for treating cardiovascular diseasesandor alterations of lipid metabolism
The possibility that 14-DHP-based calcium antagonistsexert an antiatherosclerotic action (via inhibition of LDLoxidation and other mechanisms) has been proved by manyexperimental data [165] and several clinical trials Besidesantihypertensive effect nicardipine was shown to possessantioxidative and antielastase activity [165 166] These prop-erties may be useful for prevention of inflammatory reactionwhich is relevant for hypertension pathogenesis
14-DHPs administration inhibits LDL oxidation medi-ated by oxygen radicals leading to decreased carotid inti-mal media thickness and reduced progression of coronaryatherosclerosis [130] It additionally preserves Apo B-100integrity against ROS Of importance antiatherogenic mech-anisms differ between animals and humans (primarily inthe stage of conversion of aldehydes to carboxylic acids)(Parthasarathy et al [167])
For example furyl-DHP compound (FDP-1 diethyl 26-dimethyl-4-(furyl)-14-dihydropyridine-35-dicarboxylate)was shown to act as an antioxidant (decreasing MDA GOTand FFA release of ischemic myocardium and inhibiting Ca-ATPase of erythrocyte membranes) preventing against heartmyocardium ischemia-reperfusion injury and arrhythmiawhen applied (in rats) at 10mgkg (Liu et al [168])
Similarly antioxidative effects of azelnidipine andamlodipine prevented neuronal damage by CCBs aftertransient focal ischemia in rats (Lukic-Panin et al [169])
Allanore et al [170] found that both nifedipine andnicardipine significantly decrease the mean level of plasmamarkers for oxidative stress in patients suffering from sys-temic sclerosis
Antioxidants may be considered as promising neuropro-tective compounds Still while experimental data demon-strate neuroprotective effect in vitro and in animal mod-els clinical evidence is still unsatisfactory and insufficient[171]
(a) Role of Metabolism of DHPs in Their AOA Metabolicpathways and ldquobioavailabilityrdquo of the probable AOA com-pound determine antioxidant activity in vivo Antioxidantmetabolites may vary in stability and activity leading to twoopposite scenarios lack or presence of activity substantiallycontributing to the overall AOA [172] Metabolic biotransfor-mation of DHPs includes oxidation (heteroaromatization)side chain ester group cleavage (deesterification) and 4-substituent abstraction ao [160] None of the DHPs metabo-lites was shown to be more toxic than original reduced formof the compound The commonly detected metabolites ofthe DHPs do not seem to possess the AO activity (withsome exceptions as in the case of metabolites of nifedipineand its analogues including nitrosonifedipine [173 174]) (seefurther in Section 35) Due to DHPs intrinsic instability
achieving andmaintaining an adequate concentrationmay beproblematic both in vitro and in vivo
(b) Role of Concentration and Lipophilicity (MembraneWateror LipidWater Partition Coefficients) of DHPs inTheir Actionas AOs and Antiradical Compounds Antioxidative effects ofany antioxidant depend on its concentration at the site ofaction This parameter is hardly measurable especially intwo-phase systems representing one of obstacles in com-parison to AOA upon applying various compounds [172]It is often incorrectly assumed that the concentrations inthe aqueous solution and at the site of action are the sameHowever even when the concentration in the aqueous phasemay be well controlled the concentration at the site ofaction in the lipid matrix of the membranes might fluctuatebetween different test compounds depending on a differencein lipophilicity [175] The prevention of the membrane LPalso seems to be dependent on the DHP concentration in thelipidmatrix (Mason andTrumbore [46]) and its amphiphilic-ity For example AOA of diludine is associated with itslipophilicity and consequential ability to be incorporatedinto liposomes (Panasenko et al [176]) It was also foundthat diludine easily incorporates into the outer monolayer oferythrocyte membranes [176]
Membranebuffer partition coefficients (lambda) weredirectly measured in the sarcolemma and sarcoplasmicreticulum membranes for three CA DHPs The obtainedvalues were in a broad range between 5000 and 150000(Herbette et al [177])These drugs interact primarily with themembrane bilayer component but may also bind to proteinsboth nonreceptors and receptors The intrinsic forward rateconstants for DHP binding to sarcolemmal calcium channelreceptors were apparently not strongly dependent on theirmembrane partition coefficients For example nimodipine(lambda = 6300) had a forward rate constant of 68 plusmn 06 times106Ms whereas the forward rate constant for Bay P 8857
(lambda = 149000) was 14plusmn08times107Ms Since these DHPsare highly liposoluble model calculations for this bindingreaction demonstrated that these rates on lipid solubilitywould probably not be reflected in the experimental forwardrate constants In addition the intrinsic forward rate constantfor nimodipine binding to sarcolemmal calcium channelreceptors was found not to be linearly dependent on theviscosity of the buffer medium over a fivefold range The rateof drug nonspecific binding to nonreceptor protein present inhighly purified sarcoplasmic reticulum membranes appearsto be extremely fast at least 103 times faster than specificdrug binding to the receptor in the sarcolemma Authorsconcluded that partitioning into the lipid bilayer matrix ofthe sarcolemma could be a general property of CA DHPsand may be a prerequisite for their binding to sarcolemmalmembrane receptors (Herbette et al [177])
The binding of DHP calcium channel agonists and antag-onists (including those with AO properties) to receptors incardiac sarcolemmal membranes is a complex reaction thatmay involve an interaction with the lipid bilayer matrix ofthe sarcolemma (Herbette et al [178]) Belevitch et al [179]studied the binding of DHP CCBs (riodipine and nifedip-ine) and verapamil to model and biological membranes by
Oxidative Medicine and Cellular Longevity 17
fluorescence analysis The consistent location of Ca agonistBay K 8644 was determined to be within the region ofthe first few methylene segments of the fatty acyl chains ofthe membranes (Mason et al [180]) This position is nearto that observed for the DHP calcium channel antagonistsnimodipine and Bay P 8857
Themajority of studies onOSwere performedwithDHPswith various lipophilicity but only a few studies reportedamphiphilicity ofDHPderivatives AmphiphilicDHPderiva-tive K-2-11 reduced the cellular generation of ROS It alsorevealed complete reversal of multidrug resistance (MDR) ofthe resistant cells K-2-11 was more efficient than well-knownMDR inhibitor verapamil Cytotoxic effects of anticancerdrug doxorubicin were enhanced by K-2-11 in bothMDR andparental nonresistant cell line (Cindric et al [181]) K-2-11suppresses increase of ROS and consequentially prevents NF-120581B activation leading to decreased expression of MDR1 andincreased expression of antiapoptotic genes This signalingswitch is necessary for restoring the chemosensitivity ofcancer cells This phenomenon is characteristic both for14-DHPs [182] (18 novel asymmetrical DHPs bearing 3-pyridyl methyl carboxylate and alkyl carboxylate moietiesat C3 and C5 positions resp as well as nitrophenyl orheteroaromatic rings at C4) and for their oxidized formspyridine compounds (Zhou et al [183])
34 Dependence of AOA of DHPs on the Experimental SystemAO effect of DHPs depends on their structure and theexperimental system used (in vitromodel system subcellularorganelle and cells ex vivo and in vivo) Ideally for theevaluation of the profile and value of DHPs AO propertieseach compound should be tested in as many systems aspossible (Dubur et al [45])
Lipidomics studies have been traditionally explored forstudying AOA of DHPs Proteomics methods are less rep-resented and are mostly focused on the properties of DHPsrelated to scavenging of protein free radicals So far there areno studies on the role of DHPs in scavenging nitrosoperoxy-carbonate the reactive species formed out of peroxynitrite inthe presence of carbon dioxide Although it was shown thatalbumin binds diludine no studies revealed the relevance ofthis effect for the AOA of diludine
There are findings showing that dihydropyridine calciumantagonists (DHPs CA) could indirectly play a beneficialprotective role during development of atherosclerosisNamely Berkels et al [184] have studied antioxidativeproperties of four substances the DHP prototype CAnifedipine the long-acting CA lacidipine the DHP calciumchannel agonist BayK8644 and the bulkyDHPderivate BayO 5572 in three different models (1) in an in vitro superoxideanion generating system (hypoxanthinexanthine oxidase)for testing the ldquopurerdquo antioxidative effect (2) in an artificialmembrane preparation (dimyristoylphosphatidylcholine) formimicking a more physiological environment and (3) underconditions of stimulated ROS release (hyperglycemia) fromnative endothelial cells derived from porcine coronary arter-ies
The study also revealed the potential correlation betweenlipophilic and AO properties of DHPs In the first model
Bay K 8644 was significantly more effective in scavengingsuperoxide anions than lacidipine Bay O 5572 or nifedipine(micro- to millimolar concentration range) Addition of anartificial membrane preparation resulted in an enhancedAO effect with lacidipine being the most effective DHP inquenching radicals (low micromolar concentration range)In the third model mimicking hyperglycemia (30mmolL)nifedipine was significantly more potent antioxidant (ther-apeutical nanomolar concentration range) than the otherDHPs Calculated lipophilicity of these four substances(lacidipine gt Bay O 5572 gt Bay K 8644 gt nifedipine) waspositively correlated with antioxidative potential only in thesecond experimental model It has been concluded that AOproperties of DHP substances need to be tested in variousmodels for demonstrating that nifedipine exhibits ROS-quenching properties in a therapeutic concentration range[184]
341 AOA of DHPs in Isolated Cells and Cell Cultures(Comparison with Other Simplest Systems) Although DHPspossess neuromodulatory andor antimutagenic propertiesthe mechanisms of action related to these phenomena arenot entirely elucidated Borovic et al [185] have studied 14-dihydroisonicotinic acid (14-DHINA) derivatives of 14-DHP water-soluble analogues of a well-known AO diludine(diethone) 26-dimethyl-35-diethoxycarbonyl-14-dihydro-isonicotinic acid sodium 2-(26-dimethyl-35-diethoxycar-bonyl-14-dihydropyridine-4-carboxamido)glutamate gluta-pyrone and sodium 2-(26-dimethyl-35-diethoxycarbonyl-14-dihydropyridine-4-carboxamido)ethane-sulphate tauro-pyrone as AO and bioprotectors (Figure 4)
14-DHINArsquos activities were studied in comparison toTrolox by NN-diphenyl-N1015840-picrylhydrazyl (DPPH∙) deoxy-ribose degradation ABTS∙ radical scavenging and AOA(antioxidative capacity method) assays copper-induced LPof cultured rat liver cells (MDA determination by HPLCand 4-hydroxynonenal-protein conjugates by dot-blot) 3H-thymidine incorporation and trypan blue assay for liver cellsgrowth and viability Ic decreased the amount of 4-HNE-protein adducts In all assays Ia was the most potent AOable to completely abolish copper induced LP of liver cellswhile Ic only slightly decreased it Thus AOA is importantactivity principle of Ia which was even superior to Trolox intreated cell cultures Ia (and its analogues) are easily oxidizedin the Fenton system (Rubene et al [186]) exerting ARA too
35 Peculiarities Related to Antioxidative and AntiradicalActivity of Some 14-DHPs Ca Antagonists Nine commer-cialized structurally and functionally different DHPs CAwill be discussed further Their common feature is ability toprevent OS This also counts for some of their metabolitesas already discussed The comparative effects of some DHPsCA on oxidative stress-induced modification of LDL werealready reviewed in Section 331 (2)-(a) AOA of CA DHPswas discussed in Sections 331 (2)-(b) and 331 (2)-(c)
351 Nifedipine and Its Close Analogues Nifedipine vera-pamil and antiarrhythmic-antihypoxic drug stobadin wereshown to depress lipid peroxidation of phosphatidylcholine
18 Oxidative Medicine and Cellular Longevity
NH
COOH
NH
COONa
Glutapyrone
NH
Gammapyrone
NH
C 2H5OOC COOC2H5
Tauropyrone
14-DHINA
H3C H3C
H3C
H3CCH3 CH3
CH3
CH3
COOC2H5COOC2H5
COOC2H5 C2H5OOCC2H5OOCC2H5OOC
CONHCH(CH2)2COONa CONH(CH2)3COONa
CONH(CH2)2SO3Na
Figure 4 Derivatives of 14-dihydroisonicotinic acid (14-DHINA)
liposomes (Ondrias et al [187]) However data obtained insome other experimental systems are conflicting
In an in vitromodel of sarcolemmal membrane lipid per-oxidation three calcium blockers (nifedipine verapamil anddiltiazem) exhibited concentration-dependent (10ndash400 120583M)inhibitory effects [188 189] Nifedipine the most effectivecalcium blocker was more than two-fold potent compared topropranolol achieving significant effect at 10 120583M Nifedipineprotective role on LP using reduced glutathione as modelmarker was recently described (Ray et al [190]) Antiper-oxidative properties of CA nifedipine and its analogueswere explored in different systemspathogenic processesatherogenesis (Henry [165]) brain focal ischemia (Yamatoet al [191]) nephroprotection related to cyclosporine intake(Chander and Chopra [192]) and hepatoprotection relatedto intake of diethyldithiocarbamate (Gaafa et al [193])Recent data suggest that nifedipine action as protector forendothelial cells proceeds independently from its CA proper-ties
The absence of antioxidant effects of nifedipine anddiltiazemonmyocardialmembrane lipid peroxidation oppo-site to nisoldipine and propranolol was also described[194] Nisoldipine and propranolol were shown to havea concentration-dependent antiperoxidant effect with IC
50
values of 282 and 501 120583M respectively Finally nisol-dipine appeared to possess dual antiperoxidant mecha-nisms involving both preventive and chain-breaking proper-ties
These findings were confirmed in some other studiesincluding reports on the lack of antioxidative activity ofnifedipine and nicardipine even at 500120583M concentrationin heart membrane lipid peroxidation tests [134] SimilarlyROS formation in bovine aorta smooth muscle cells was notaffected by addition of amlodipine nimodipine and nife-dipine [123]
(1) Metabolites of Nifedipine and Its Analogues as Antioxidantsand Regulators of OS Antioxidant activity of nifedipine35-dimethoxycarbonyl-26-dimethyl-4-(2-nitrophenyl)-14-dihydropyridine was originally studied in vitro by Kirule etal [195] and Tirzit et al [196] According to the kinetic dataof peroxide accumulation and the ESR spectra (inhibition ofthe autoxidation of methyl oleate in presence of nifedipine)AO action was exerted by the formation of nitroso analogueof the oxidized nifedipine nitroso nifedipine 26-dimethyl-4-(2-nitrosophenyl)-35-pyridine dicarboxylate (NO-NIF)This nitroso aromatic derivative can form nitroxyl radicalsexhibiting remarkable AOA in the presence of unsaturatedfatty acids and lipids [196]
The primary species of free radicals that have beenobtained and identified were ion radicals of the nitrophenyltype (Ogle et al [76]) Such a mechanism coincides withmechanisms proposed afterwards by Nunez-Vergara et al[96] Lopez-Alarcon et al [103] Valenzuela et al [104]Fukuhara et al [174] and Yanez et al [197]
There are also data showing that nitroso compounds mayinhibit LP by direct radical trapping and subsequent forma-tion of stable nitroxide radicals It was further found that thereactivity between the synthesized 14-DHP derivatives withalkylperoxyl radicals involves electron transfer reactionsThisis documented by the presence of pyridine as a final productof the reaction and complete oxidation of the nitroso groupin the case of the nitrosoaryl 14-dihydropyridine derivatives(Valenzuela et al [104]) Tested compounds reacted fastertoward alkylperoxyl radicals and ABTS radical cation thanalkyl ones (Lopez-Alarcon et al [103])
Nitrosonifedipine a photodegradation product of nifedi-pine significantly recovers cellular damage induced by tumornecrosis factor-alpha It also prevents toxic effects of cumeneperoxide which hampers integrity of cell membranes throughoxidative stress Its positive effects are equal to Trolox-C
Oxidative Medicine and Cellular Longevity 19
As a result nitrosonifedipine was already a long time agoclaimed as a candidate for a new class of antioxidative drugs(Kirule et al [195]) cellular protectors against oxidative stressin glomerular endothelial cells [174]
Moreover Misik et al [198] Ondrias et al [199] andStasko et al [200] studied AOA of nifedipine and its oxidizednitroso analogue NO-NIF prevents the progression of type2 diabetic nephropathy associated with endothelial dysfunc-tion through selective AO effects (Ishizawa et al [201]) NO-NIF administration reduces albuminuria and proteinuriaas well as glomerular expansion without affecting glucosemetabolism or systolic blood pressure NO-NIF also sup-presses renal and systemic OS and decreases the expressionof intercellular adhesion molecule-1 (ICAM-1) a marker ofendothelial cell injury in the glomeruli of the KKAy miceSimilar effects were achieved in endothelial nitric oxide syn-thase (eNOS) knockout mice Moreover NO-NIF suppressesurinary angiotensinogen (AGT) excretion and intrarenalAGT protein expression in proximal tubular cells in theKKAy mice On the other hand hyperglycemia-inducedmitochondrial superoxide production was not attenuated byNO-NIF in cultured endothelial cells
Fujii and Berliner found EPR evidence for free radicaladducts of nifedipine in vivo [202] The nature of these rad-icals was surmised by comparing the reaction of illuminatednitrosonifedipine with polyunsaturated fatty acids Surpris-ingly identical radical spectra were detected from excisedliver doped with nonilluminated nifedipine suggesting thatthis drug can be enzymatically converted in vivo to its nitrosoanalogue without the requirement for illumination This isone of the first reports of in vivo EPR evidence for a class ofunsaturated fatty acid radical conjugates resulting from thenormal metabolism of a common drug
Dıaz-Araya et al [173] studied some 4-nitrophenyl-DHPson Fe3+ initiated LP in rat brain slices LP as measuredby MDA formation was inhibited by all the tested nitro-aryl derivatives of 14-DHP over a wide range of concen-trations On the basis of both time course and IC
50experi-
ments the tentative order of AOA on rat brain slices wasnicardipine gt nisoldipine gt (RSSR)-furnidipine gt (RRSS)-furnidipine gt nitrendipine gt nimodipine gt nifedipine14-DHP derivatives that lack a nitro group in the mole-cule (isradipine and amlodipine) also inhibited LP in ratbrain slices but at higher concentrations than that of nitro-substituted derivatives All tested compounds reduced andoxidized nitrosoaryl derivatives (26-dimethyl-4-(2-nitro-sophenyl)-35-pyridinedicarboxylic acid dimethyl ester (pho-tooxidation product of nifedipine ndash NTP) ao) and weremore potent inhibitors of LP than their parent molecules(Valenzuela et al [104])
The electrooxidation process of 4-nitrosoaromatic DHPsis a strongly pH-dependent (two-electron two-proton mech-anism) ECEC type of mechanism that is the sequenceeminusH+eminusH+ at pH gt 85 ECCE mechanism (eminusH+H+eminus)at pH lt 85 dominates Reduction reaction of nitroso groupis as follows R-NO + 2eminus + 2H+ rarr RNHOH (Bollo et al[203])
352 Lacidipine It is a generic DHP type antihypertensiveCA 35-diethyl 4-2-[(1E)-3-(tert-butoxy)-3-oxoprop-1-en-1-yl]phenyl-26-dimethyl-14-dihydropyridine-35-dicarboxy-late
Ursini [204] described redox behaviour of lacidipine andshowed its tissue protective features Cristofori et al studiedantiatherosclerotic activity in addition to lacidipinersquos CAand AO properties [205] Lacidipine reduced the extent ofatherosclerotic area in hypercholesterolemic apoE-deficientmice (these mice show widespread vascular lesions whichclosely resemble the inflammatory fibrous plaques seen inhumans in atherosclerosis) The reduction may be associatedwith the capacity of the drug to maintain endothelial NOlevels at concentrations useful to protect against vasculardamage This work suggested that DHPs modulate vascularrelaxation via increased release of NO
Herbette et al [178] remarked optimal hydrophobicity oflacidipine due to cinnamic acid substituent so membraneinteractions and facilitation of the treatment of atherosclero-sis could proceed (see also Section 331 (2)-(a))
353 Amlodipine Amlodipine (Norvasc) (RS)-3-ethyl5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-14-dihydropyridine-35-dicarboxylate (AML) hasan antioxidant effect on vessels in vitro and is a 3rd genera-tion of charged dihydropyridine CCB that is widely used forthe treatment of hypertensive patients
Amlodipine was shown to have the highest affinity(amlodipine gt verapamil ≫ diltiazem) for the membranebilayer (119870
119901= 104) It produced the significant changes in
membrane thermodynamic properties including a reductionin the thermal phase transition temperature (minus11) enthalpy(minus14) and cooperative unit size (minus59) relative to thecontrol phosphatidylcholine liposomes (Mason et al [49])
Amlodipine AOA is related to its reductant nature orhydrogen donor properties respectively Its ability for donat-ing protons and electrons to the lipid peroxide moleculesblocks the LP process
Amlodipine and even its enantiomers (Zhang et al [206])act as ROS andNOS effectors in several model systems of OSAntioxidant properties of amlodipine were recently reviewedby Vitolina et al [32] Both in vitro and in vivo studiesof amlodipine AO properties revealed inhibition of lipidsoxidative damage primarily those associated with cellularmembranes and lipoprotein particles (LDL) (Mason et al[50])
Under controlled experimental conditions in vitro amlo-dipine showed AOA and ARA by inhibition of lipid peroxideformation and trapping ROS Its scavenging activity forhydroxyl and peroxyl radicals at concentrations as low as100 nmolL (which is remarkably less compared to the classi-cal antioxidants GSH uric acid and Trolox) was shown to beindependent of the calcium channel modulation (Franzoni etal [207])
AML showed efficiency as scavenger of peroxyl radicals(TOSC assay 5945 plusmn 544 unitsmg) significantly stronger(gt50 119875 lt 0001) than GSH (2733plusmn 636 unitsmg) and 70weaker (119875 lt 00001) than uric acid (18144 plusmn 696 unitsmg)and Trolox (17522 plusmn 734 unitsmg)
20 Oxidative Medicine and Cellular Longevity
Of interest the scavenging capacity of AML towardshydroxyl radicals (1455 plusmn 154 unitsmg) was 320 higher(119875 lt 000001) than that of GSH (358 plusmn 112 unitsmg) 20higher than that of uric acid (1198plusmn121 unitsmg) and 100higher than that of Trolox (759 plusmn 143 unitsmg)
Amlodipine was shown to increase enzyme activity ofparaoxonase (PON) and glutathione peroxidase (GSH-Px)However it also decreases glutathione reductase (GSSG-R)activity and diminishes the concentration of the endogenousantioxidant 120572-tocopherol (vitamin E) Moreover AML in aconcentration of 2 ngmL decreased the content of malonicdialdehyde and activity of superoxide dismutase in the blood(Gatsura [208])
Verapamil and amlodipine produced a potent anti-ischemic effect and reduced area of myocardial infarction inrats The observed changes were accompanied by inhibitionof LP In contrast to verapamil in vitro application of AML ina dose of 50 ngmL decreased hemoglobin affinity for oxygenWhen present in a concentration of 2 ngmLAMDdecreasedthe content of MDA and activity of SOD in the blood
On the other hand amlodipine shows no activity relatedto inhibition of macrophage superoxide release and cellmigration which occurs as a consequence of decreasedTNF120572induced O
2
∙ releaseAmlodipine-induced reduction of OS in the brain is
associated with sympathoinhibitory effects in stroke-pronespontaneously hypertensive rats (SHRSP) (Hirooka et al[209]) Antihypertensive treatment with amlodipine reducedOS in all examined areas of the brain and decreased bloodpressure without a reflex increase in sympathetic nerveactivity Nicardipine another CA DHP surprisingly wassignificantly less active than amlodipine
354 Lercanidipine Tomlinson and Benzie reported AOeffect of lercanidipine [210] which is well known as anti-hypertensive drug Zanidip 2[(33-diphenylpropyl)(methyl)-amino]-11-dimethylethyl methyl 26-dimethyl-4-(3-nitro-phenyl)-14-dihydropyridine-35-dicarboxylate Compara-tive data about this drug AOA were presented in parts of thispaper about other individual CA DHPs and in the part aboutthe ex vivo DHPs effects on LDL
355 Nimodipine Nimodipine (ND) commercially knownas Nimotop is 3-(2-methoxyethyl) 5-propan-2-yl 26-dim-ethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxy-late It is centrally active CA
Treatment with glutathione blocked andwith nimodipineattenuated neuronal cell death caused by prolonged exposureof cell culture to 4-HNE (Faraqui [211])
Nascimento et al [212] found AO effect of nimodipine inyoung rats after pilocarpine- (PIL-) induced (in 400mgkg)seizures The PIL administration increased the striatal cata-lase (CAT) activity The administration of ND 30mgkg30min before PIL preserved normal value of CAT activityOn the other hand no difference was detected in the animalstreated with lower dose 10mgkg These results confirmthe neuroprotectiveantiepileptic effect of ND in young ratssuggesting that this drug acts positively on lipid peroxidation
(in both doses) Nimodipine cannot induce these effects viablockade of Ca2+ channel
Ismailoglu et al [213] studied the therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjury These beneficial effects in rats after cerebral corticalinjury seemed to be related to AOA of nimodipine
356 Benidipine Licensed in Japan and South Asia as CA(CCB) benidipine possesses AO properties Chemically it is5-methyl 3-[(3R)-1-(phenylmethyl)piperidin-3-yl] 26-dim-ethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxy-late (or its hydrochloride (4R)-rel-35-pyridinedicarboxylicacid 14-dihydro-26-dimethyl-4-(3-nitrophenyl)- 3-methyl5-[(3R)-1-(phenylmethyl)-3-piperidinyl] ester hydrochloride(1 1))
Benidipine influences processes connected with OS inseveral ways It prevents lysophosphatidylcholine- (lysoPC)-induced injury and ROS production in human aorticendothelial cells (HAECs) (Matsubara and Hasegawa [214])Matsubara et al [215] explained this effect based on stimula-tion of nitric oxide release
LysoPC is a component of oxidized low-density lipopro-teins (oxLDLs) which plays an important role in the patho-genesis of atherosclerosis Pretreatmentwith benidipine (03ndash3 120583molL) for 24 h protected against lysoPC-induced cyto-toxicity in the HAECs through inhibition of both lysoPC-stimulated ROS production and caspase-37-like activationwith a similar potency Since caspase-37 is involved inexecuting the apoptotic process the reduction of the activityof this enzyme by benidipine may explain the antiapoptoticeffect of the drug However benidipine did not suppresslysoPC-induced phosphorylation of mitogen-activated pro-tein kinases and Ca2+ influx in HAECs These results suggestthat the antioxidant properties of benidipine may be respon-sible for its ability to inhibit ROS production a possiblereason for reduced activation of caspase-37 In conclusionbenidipine suppresses lysoPC-induced endothelial dysfunc-tion through inhibition of ROS production which is due atleast in part to its antioxidant effect and not through theinhibition of L-type voltage-dependent calcium channels
Matsubara and Hasegawa [216] examined the effectsof benidipine on cytokine-induced expression of adhesionmolecules and chemokines (chemoattractants) which areimportant for the adhesion of monocytes to endotheliumPretreatment of HAECs with benidipine (03ndash10 120583molL)for 24 h significantly suppressed cytokine-induced vascularcell adhesion molecule-1 (VCAM-1) and intracellular celladhesion molecule-1 (ICAM-1) mRNA and protein expres-sion resulting in reduced adhesion of THP-1 monocytesBenidipine also suppressed induction of monocyte chemoat-tractant protein-1 (MCP-1) and interleukin-8 Benidipinealso inhibited redox-sensitive transcriptional nuclear factor-120581B (NF-120581B) pathway as determined by Western blotting ofinhibitory 120581B (I120581B) phosphorylation and luciferase reporterassay Results of analysis using optical isomers of benidip-ine and antioxidants suggest that these inhibitory effectswere dependent on pharmacological effects other than Ca2+antagonism Benidipine may thus have anti-inflammatoryproperties and benefits for the treatment of atherosclerosis
Oxidative Medicine and Cellular Longevity 21
Benidipine was also shown to inhibit ROS production inpolymorphonuclear leukocytes and oxidative stress in salt-loaded stroke-prone spontaneously hypertensive rats (Mat-subara et al [217])
It should be mentioned that other DHPs also haveendothelial AO actions [218]
357 Azelnidipine (AZL) Azelnidipine 3-[1-[di(phen-yl)methyl]azetidin-3-yl] 5-propan-2-yl 2-amino-6-methyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate(AZL) CAS number 123524-52-7 is commercially available4-nitroaryl-DHP type calcium antagonist with long-actingantihypertensive action (long-acting CA (CCB)) and a lowreported incidence of tachycardia It additionally possessesbeneficial effects in OS and diabetic conditions
Azelnidipine prevents cardiac dysfunction in strepto-zotocin-diabetic rats by reducing intracellular calcium accu-mulation (altering intracellular Ca2+ handling proteins) OSand apoptosis (Kain et al [219]) AZL can reduce the superox-ide production It exerts its protective effects by targeting theNADPH oxidase and mitochondrial redox enzymes AZL-treated diabetic rats express enhanced level of bcl-2 in thelysates of heart muscle indicating that AZL plays protectiverole in cardiac apoptosis
It has been previously observed that azelnidipine inhibitstumor necrosis factor-alpha-induced endothelial cell (EC)oxidative stress through its AO properties (Nakamura etal [220]) Azelnidipine but not nitrendipine completelyinhibits the Ang II-induced ROS generation in ECs (Matsuiet al [221])
Furthermore azelnidipine but not nitrendipine wasfound to partially restore decreased pigment epithelium-derived factor (PEDF) mRNA levels in Ang II-exposed ECsThis study suggests that AZL influence depends on its antiox-idative properties Authors concluded that upregulation ofPEDF by azelnidipine may become a therapeutic targetfor the treatment of diabetic retinopathy associated withhypertension
Antihypertensive agents with AO effects are potentiallyuseful for diabetic patients with hypertension While DHPtypeCAare among themost frequently used antihypertensivedrugs azelnidipine has been reported to have a unique AOeffect in vitro and in vivo in experimental animals (Ohmuraet al [222]) In hypertensive diabetic patients azelnidipinetreatment for 12 weeks induced a more significant decreasein erythrocyte LOOH level than amlodipine although thevalues related to blood pressure during each treatmentremained comparable These data confirm the usefulness ofLOOH level in erythrocyte membrane as a marker of OS invivo and indicate that azelnidipine has a unique antioxidativeproperty in humans
Daikuhara et al [223] reported the results of the OLCAstudy based on combination of (1) olmesartan and a calciumchannel blocker (azelnidipine) or (2) candesartan and a CCBamlodipine in two groups of diabetic hypertensive patientsPatients treated with the first combination presented highlypersistent early morning antihypertensive effect and strongerdecrease in heart rate fasting blood glucose andHbA1c levels
and microalbuminuria when compared to patients treatedwith the combination (2) Because diabetes is associated withsevere chronic OS the observed results might be at least in apart due to the AOA of azelnidipine
In favor of this are findings of Abe et al [224] who foundadditive antioxidative effects of azelnidipine on angiotensinreceptor blocker olmesartan treatment for type 2 diabeticpatients with albuminuria
Similarly the AOA of thiazolidinediones (insulin sensi-tizer) and their effect on cardiovascular function in type 2diabetic model rats and also those of some DHPs (nifedipineamlodipine or AZL commonly used antianginal and anti-hypertensive agents) in cultured human endothelial cells LPwere examined (Mizushige [225]) The AOA was evaluatedby measuring 8-iso-prostaglandine F
2120572concentration and
azelnidipine exhibited potent AOAInsulin (INS) resistance combined with hyperinsuline-
mia is involved in the generation of OS A relation-ship exists between increased production of ROS and thediverse pathogenic mechanisms involved in diabetic vascularcomplications including nephropathy Manabe et al [226]revealed that high doses of INS augmented mesangial cellproliferation through generation of intracellular ROS andactivation of redox signaling pathways Cell proliferation wasincreased in a dose-dependent manner by high doses of INS(01ndash10 120583M) but was inhibited by 01120583M AZL Namely theINS-increased phosphorylation of mitogen activated proteinkinaseextracellular signal-regulated kinase 12 (MAPKERK12) was inhibited by 01 120583MAZL The same AZL concen-tration blocked intracellular ROS production more effec-tively than 01 120583M nifedipine The NADPH oxidase inhibitorapocynin (001ndash01120583M) prevented INS-induced mesangialcell proliferation So azelnidipine inhibits insulin-inducedmesangial cell proliferation by inhibiting the productionof ROS Therefore azelnidipine may have the potential toprotect against the onset of diabetic nephropathy and slowits progression
Azelnidipine inhibited H2O2-induced cell death in
neonatal rat cardiomyocytes (Koyama et al [227]) Azelnidip-ine and nifedipine did not affect theH
2O2-induced activation
of extracellular signal-regulated protein kinases (ERK) andp38 MAPK (mitogen-activated protein kinase) In contrastazelnidipine but not nifedipine inhibited H
2O2-induced c-
Jun NH2-terminal kinases (JNK) activation Authors con-
cluded that azelnidipine has inhibited theH2O2-induced JNK
activation and cardiac cell death Therefore azelnidipine mayhave cardioprotective effects against OS
A specific atheroprotection activity of azelnidipine relatesto inhibition of TNF-120572-induced activator protein-1 activa-tion and interleukin-8 expression in human umbilical veinendothelial cells (HUVEC) through suppression of NADPHoxidase-mediated reactive oxygen species generation (Naka-mura et al [220]) TNF-120572 could play a central role in patho-genesis of insulin resistance and accelerated atherosclerosis inthe metabolic syndrome The concentration of AZL found tobe effective in these in vitro experiments is within therapeuticrange As EC do not possess voltage-operated L-type calciumchannels it is suggested that the beneficial effects of azelni-dipine are not likely due to CA property but to its unique AO
22 Oxidative Medicine and Cellular Longevity
ability Furthermore it has been recently found that serumlevels of monocyte chemoattractant protein-1 a biomarkerfor subclinical atherosclerosis were significantly decreased bythe AZL treatment in patients with essential hypertension Inthis paper [220] authors hypothesize that due to its uniqueTNF-120572 signalmodulatory activity and antioxidative propertyazelnidipine may be a promising DHP for targeting diabetesand cardiovascular diseases in hypertensive patients withmetabolic syndrome
Shinomiya et al [228] evaluated its AOA in culturedhuman arterial EC under OS Azelnidipine has shown apotent antioxidative effect that could be of significant clinicalbenefit when combined with its long-lasting antihypertensiveaction and low incidence of tachycardia
Azelnidipine inhibited TGF-1205731 and angiotensin II- (AngII-) activated 1205721(I) collagen mRNA expression in hepaticstellate cells (HSCs) (Ohyama et al [229]) FurthermoreTGF-1205731- and Ang II-induced OS and TGF-1205731-induced p38and JNK phosphorylation were reduced inHSCs treated withAZL Azelnidipine significantly decreased inflammatory cellinfiltration profibrotic genes expression HSC activation LPoxidative DNA damage and fibrosis in liver of CCl
4- or
TAA-treated mice Finally AZL prevented decrease of theexpression of some AO enzymes and accelerated regressionof liver fibrosis in CCl
4-treated mice Hence the antifibrotic
mechanism of AZL against CCl4-induced liver fibrosis in
mice may have been due to an increased level of AO defenseAs azelnidipine is widely used in clinical practice withoutserious adverse effects it may provide an effective newstrategy for antifibrotic therapy
358 Manidipine Manidipine (2-[4-(diphenylmethyl)pip-erazin-1-yl]ethyl methyl 26-dimethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate) is a DHP CCB withreported nephroprotective properties Calo et al [230] stud-ied effect of manidipine on gene expression and proteinlevel of OS related proteins p22(phox) (human neutrophilcytochrome b light chain (CYBA)) and heme oxygenase-1HO-1 Relevance for antihypertensive effects was revealedThe study assessed the effect of manidipine on normalsubjectsrsquo monocyte gene and protein expression of OS relatedproteins such as p22phox a NADPH oxidase system subunitcritical in generating O
2
∙minus and HO-1 induced by and pro-tective against OS Manidipine was compared with the ACEinhibitor captopril and the CCB nifedipine in the presenceand in the absence of sodiumarsenite (NaAsO
2) as an inducer
of OS Monocyte p22phox (CYBA) mRNA production wasreduced by both manidipine and captopril while no changeswere induced by nifedipine Manidipine increased monocyteHO-1 mRNA production while nifedipine and captoprilshowed no effect The effects of manidipine on p22phoxand HO-1 gene expression in the presence of OS were alsoconfirmed at the protein level Thus manidipine seems tosuppress p22phox and to increase the HO-1 mRNA produc-tion and protein level The manidipine-induced increase ofHO-1 gene and protein expression seems to be a peculiareffect of this drug since it is not observed with captopriland nifedipine This effect together with the reduction of
p22phoxmRNAproduction could play a role in its protectivemechanism against OS
359 Mebudipine The protective effect of mebudipine (14-dihydro-26-dimethyl-4-(3-nitrophenyl)-35-pyridinedicar-boxylic acid 3-methyl-5-tert-butyl ester BAY-n-6391) wasrevealed on OS and LP (MDA decrease SOD GPX andcatalase increase) in myocardial ischemic-reperfusion injuryin male rats (Ghyasi et al [231])
There are articles about other commercial and experi-mental DHPs on OS but we have reviewed only the mostcommonly studied compounds Effects of other commercialCA DHPs on OS are also mentioned in several parts of thisreview
36 14-DHPs Ca Agonists andTheir AOA and ARA For themost popular calcium agonist DHP Bay K 8644 no reactionwith peroxyl radicals was registered (Toniolo et al [114])However interactionwith other compounds possessing AOAand ARA (quercetin) was found
Opposite to that AON-acetylcysteine (NAC) diminishedincrease in Ca2+ transient amplitude and cell shorteninginduced by ISO and forskolin whereas NAC had no effecton the (S)-(minus)-methyl-14-dihydro-26-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylatemdash(minus)-BayK 8644-induced increases (Andersson et al [232])
Increased vasoconstriction responses to Bay K 8644 (3 times10minus7ndash3times 10minus5M)were significantly decreased by pyridoindoleantioxidant stobadine treatment in diabetes (Ceylan-Isik etal [233])
The functional interaction between two L-type Ca2+channel activators quercetin and Bay K 8644 has beeninvestigated in vascular smooth muscle cells Biological ARAcompound quercetin at nutritionally meaningful concen-trations limited the responsiveness of vascular L-type Ca2+channels to the pharmacological stimulation operated by BayK 8644 These data contribute to a better understanding ofquercetin effects on experimental in vivo cardioprotection(Saponara et al [234]) Thus these findings indicated thatalthough Bay K 8644 does not exert potent and direct AOAyet acting as calcium agonist it may affect efficiency of AOsubstances and vice versa
Interaction of grapefruit juice (containing quercetin andits analogues) with DHPs CA diminished effectiveness of CAaction of DHPs (Sica [235])
37 Interpretations of the Mechanism(s) of RadicalScavenging and AOA by DHPs
371 Molecular Mechanism(s) of Radical Scavenging andAOA of DHPs in the Model Systems 35-Dicarbonyl-14-di-hydropyridine derivatives possess powerful bis-120573-carbony-lvinyl-amino conjugation and for that reason cannot be con-sidered as ordinary amino antioxidants The electron andorH donation from DHPs ensures their reductant role andresults in AOA and ARA Oxidation reaction from DHPsresults in production of corresponding heteroaromatic pyri-dine derivatives
Oxidative Medicine and Cellular Longevity 23
Detailed studies were made about substituent in DHPring positions 14- namely 4-unsubstituted- 4-substituted4-alkyl- 4-aryl- 4-alkylaryl- ao 26- 35- (diacetyl ordialkoxycarbonyl chain ao) electronic and steric effects onAOA and ARA of DHPs [44 45 51] see Sections 331and 35 The bell-shaped dependence of DHPs AOA onthe 35-dialkoxycarbonyl- chain length was observed [4445 107 109 112] with the maximum activity at C
2H5ndash
C4H9 Decrease of AOA and incorporation into liposomes for
DHPs with alkyl chains longer than R gt C4H9further were
clarified as probable tendency to self-aggregation of thesecompounds ([51] and citation number 245 therein) Electronacceptorelectron donor properties are relevant for expres-sion of AOA or ARA of 35-disubstituted DHPs 35-Diacyl-substituted and 35-dicarbanilido- and 35-dipyridylamido-substituted DHPs are more active as AOs as their 35-dicyano-substituted analogues which have electron acceptorproperties [186]
Dubur et al [89] observed overwhelming steric influenceof substituents in position 4 of the DHP ring Gaviraghiet al [163 164] proposed that AO activity of DHPs ispartly dependent on capacity of the 14-DHP ring to donateelectrons to the propagating radical (ROO∙ or RO∙) and toreduce it to a less reactive form The abstraction (donation)of electron andor H in the oxidation and LP reactionstakes place from all 35-dicarbonyl-14-DHP systems andresults in the formation of corresponding pyridine derivatives(Augustyniak et al [51]) The physicochemical mechanism ofARA and AOA of 14-DHP has been extensively studied anddiscussed (Mulder et al [236]) but precise mechanisms oftheir activity need further clarification
The reactivity of C-4 substituted 14-DHPs possessingeither secondary or tertiary nitrogen atom in the DHP ringtoward alkyl alkylperoxyl radicals and ABTS radical cationwas determined in aqueous media at pH 74 [103] Thesecompounds reacted faster toward alkylperoxyl radicals andABTS radical cation than alkyl ones N-Ethyl-substitutedDHPs showed the lowest reactivity
The 4-methyl substituted DHP was the most reac-tive compound in previously mentioned reactions (Lopez-Alarcon et al [103]) However it was less active (068versus 10) than Trolox-C DHPs having electron-donatingsubstituents (4-Me-DHP and p-MeO-Phe-DHP) showed thehighest kinetic rate constants toward ABTS radical cation p-nitro-Phe-DHP a compound with an electron-withdrawingsubstituent showed a lower kinetic rate constant and N-alkyl-DHP compounds show kinetic rate constants lowerthan the -NH-DHP
Hydrogen at the 1-position of the DHP ring was revealedaccording to the deuteriumkinetic isotope effect studies to beinvolved in the proposedARAmechanismThis fact ismostlynoticeable in the case of alkyl radicals N-Ethyl-substitutedDHPs show the lowest reactivity when compared to Troloxor nisoldipine In all cases the respective pyridine derivativewas detected as the main product of the reaction (Lopez-Alarcon et al [103]) Authors indicate that the kinetic rateconstants toward alkyl alkylperoxyl andABTS radical cationdepend on the nature of the substituents in the C-4 positionof DHP and the presence of the secondary amine group in the
dihydropyridine ring that is the presence of the hydrogen in1-position
Yanez et al [197] have studied the reactivity of 11derivatives of 14-DHPs (including commercial CA) withalkylperoxyl radicals and ABTS radical cation The tested14-DHPs were 83-fold more reactive towards alkylperoxylradicals than to the ABTS cation radical All commercial14-DHP type CCBs were weaker than Trolox-C The par-ticipation of the hydrogen atom in the 1-position appearsto be very relevant for exhibited reactivity Hantzsch ester(diludine)was again found to be themost active compound inthe reaction with alkylperoxyl radicals 23-fold more activethan Trolox The photodegradation product of nifedipine(nitrosophenyl derivative of pyridine) also showed a highactivity Kinetic rate constants for the reaction between 14-DHP compounds and alkylperoxyl radicals exhibited a fairlygood linear correlation with the oxidation peak potentialof DHP derivatives However the activity of tested 14-DHPs towards ABTS radical cation showed an independencebetween kinetic rate constants and oxidation peak potentials
Kirule et al [195] andTirzit et al [196] studiedmechanismof AOA of 4-nitrophenyl-14-DHPs nifedipine and its ana-logues involving formation of 4-(21015840-nitrosophenyl)-pyridinederivative (as active principle) as a result of intramolecularredox reaction using chemical electrochemical and bio-chemical approaches (see Sections 331 and 351)
Nunez-Vergara et al [237] reported the electrochemicaloxidation of C4-hydroxyphenyl-substituted 14-DHP deriva-tives The oxidation proceeds via formation of the unstabledihydropyridyl radical as confirmed by controlled-potentialelectrolysis (CPE) and ESR experiments This type of 14-DHPs has significant activity towards the radicals even whencompared with commercial 14-DHP drugs with well-knownantioxidant ability
It was observed that nicardipine preferentially targets RO∙radicals and is inactive against ROO∙ Lacidipine on theother hand is equally active towards both types of radicals(Gaviraghi et al [164]) The cytoprotective effect againstexposure to H
2O2was more significant for lacidipine (ID
50=
14 nM its log119875 = 54 membrane partition = 136000 assumesposition located 7 A near to the membrane center otherless lipophilic DHPs located 12ndash16 A far from the center)as compared to amlodipine nifedipine and nicardipine insmooth muscle cell culture (Gaviraghi et al [164]) Oxidativeeffect of H
2O2shifts the Ca channel toward an open state
Thus the redox property of CCBs DHPs may augment theirCCB properties
Oxidation of pharmacologically active Hantzsch 14-dihydropyridines was found by electrogenerated superoxideusing a voltammetric approach in DMSO solutions (Ortiz etal [238] and Ortiz et al [239]) Raghuvanshi and Singh [240]have also reported oxidative aromatization of these DHPsinduced by superoxide
Chemiluminescence (CL) was used in the studies ana-lyzing the antioxidant activity of 12 various 4-flavonil-14-dihydropyridine derivatives (Kruk et al [241]) on a chemicalsystem involving a superoxide radical anion These deriva-tives showed structural similarity to flavonoids with respectto the presence of rings A B and C The results obtained in
24 Oxidative Medicine and Cellular Longevity
this study indicate that the tested derivatives may catalyzeconversion of superoxide radicals through mimicking theactivity of superoxide dismutase by delivering H+ for reac-tion
O2
minus∙+O2
minus∙+ 2H+ 997888rarr H
2O2+1O2
(3)
The enhanced emission of the light in the presence oftested compounds was significant and related to stimulatedproduction ofH
2O2and 1O
2fromO
2
∙The latter specieswereremoved from the reactionmixture by the following sequenceof reactions
H+
O2
minus∙997888rarr HO
2
∙
HO2
∙+O2
∙minus997888rarr HO
2
minus+1O2
2HO2
∙997888rarr H
2O2+1O2
2 (1O2) 997888rarr (O
2)2+ h]lowast
(4)
or to take part in spontaneous dismutation of H2O2
2H2O2997888rarr 2H
2O + 1O
2(5)
The authors have offered an original concept of action for 4-flavonil-14-dihydropyridine derivatives unrelated to that ofO2
∙ radical-trapping chain-breaking antioxidants Insteadthey showed that these compounds act similar to superoxidedismutases converting O
2
∙ to H2O2 Hydrogen peroxide
is less toxic for cells than O2
∙ because it is predominantlyremoved by peroxidases and catalases Finally AO effect ofthese DHPs differed from those mediated by flavonoids witha catechol structure of ring B which are well-known 1O
2
quenchersMulder and collaborators came to similar conclusions
especially related to molecular mechanisms of antioxidativeactivity of DHPs [236]TheAOproperties of Hantzsch 14-di-hydropyridine esters and two dibenzo-14-dihydropyridines910-dihydroacridine (DHAC) and N-methyl-910-dihydro-acridine (N-Me-DHAC) have been explored by determin-ing the autoxidation of styrene or cumene at 30∘C Theseexperiments showed that Hantzsch esters are virtually inac-tive as chain-breaking antioxidants (CB-AOs) contrary tothe findings observed by Lopez-Alarcon et al [103] whoused CB-AOA in aqueous media at pH 74 Their reactivitytoward peroxyl radicals was shown to be some 5 orders ofmagnitude lower than that of the excellent CB-AO 22578-pentamethyl-6-hydroxy-chroman (PMHC)
DHAC was found to be sim10 times less reactive thanPMHC kinetic measurements using DHAC N-deuterio-DHAC and N-Me-DHAC pointing out the abstraction ofN-H hydrogen in DHAC by peroxyl radicals despite the factthat the calculated C-H bond dissociation enthalpy (BDE) inDHAC is about 11 kcalmol lower than the N-H BDE Therates of hydrogen atom abstraction by the 22-diphenyl-1-picrylhydrazyl radical (DPPH∙) have also been determined
for the same series of compounds The trends in the peroxyl∙and DPPH∙ rate constants were found to be similar [236]
Tirzit et al [242] have observed quenching of singletoxygen by DHPs This observation paved the ground forfurther research related to reactions of DHPs with hydroxylradicals (Tirzit et al [243]) singlet oxygen (Kazush etal [94]) and mechanisms of action A series of 14-DHPderivatives in NAD-H-Cu2+-H
2O2system inhibited forming
of the hydroxyl radical (HO∙) while 14-DHP derivativeswith electron donor substituents in the molecule were shownto be capable themselves of generating HO∙ in the presenceof Cu2+ and H
2O2 Rubene et al [186] also described
interaction of 14-DHP derivatives with Fentonrsquos reagentwhich produces hydroxyl radical (HO∙) Rate constants ofthe DHPs reaction (1st order) with HO∙ radical were highin the range 109 L times mol times secminus1 close to that of NADHcysteine and thiourea 35-Diacetyl- derivatives reacted fastercompared to 35-dialkoxycarbonyl- ones The reaction ratedecrease was observed in the case of substitution at position4 as compared to 4-unsubstituted DHPs Some DHPs havingelectron donor -COOminus groups in the 35- or 26- positionsof DHP ring reacted immediately (having rate constantshigher as 109 L times mol times secminus1) Rate constants with HO
2
∙
and O2
∙minus radicals were of lower degree Thus DHPs actingas oxygen radical scavengers could effectively inhibit ROSrelated reactions of LP initiation stage
Nifedipine and nitrendipine reactivity toward singletoxygen was also studied [244] Nifedipine was shown tobe a good scavenger of excited oxygen mainly via physicaldeactivation with values of the total rate constant rangingfrom 208 times 105Mminus1 sminus1 (in dioxane) to 930 times 105Mminus1 sminus1(in propylene carbonate)The less reactive pathway generateda photooxidation product For that reason a mechanisminvolving a perepoxide-like encounter complex in the firststep of the reaction path was proposed (see [244] Figures8 and 9 therein) The dependence was observed on solventmicroscopic parameters of the total rate constant for the reac-tion between singlet oxygen and 14-DHPs These findingsshow that nifedipine possesses stronger protective activity inbiological systems than nitrendipine
Density-functional-theory (DFT) calculations made byWang et al [245] confirmed the former experimental obser-vations that Hantzsch ester diludine is potent antioxi-dant with high H atom-donating ability and relatively lowprooxidant activity Possible reaction pathways for radicalsderived from 14-dihydropyridine and the resonance modesfor radical species were given [245]
Moreover two ethoxycarbonyl (EtOCO) substituentsat C(2) and C(6) should further enhance Hantzsch esterdiludine H-atom-donating ability due to resonance effectsHowever DHPs should be used in nonpolar rather than inpolar solvents since in the latter not H-atom but electrontransfer is preferred in the radical scavenging process [245]
Mulder et al [246] proposed that quantum-thermochem-ical calculations must be used with caution to indicate ldquoapromising lead antioxidantrdquo as they criticized the density-functional-theory (DFT) calculations made by Wang et al[245]
Oxidative Medicine and Cellular Longevity 25
372 Possible Mechanisms of DHPs ARA and AOA in the Bio-logical Systems Interaction with Other OSModifiers Some ofthese mechanisms were already described (Sections 331 (2)-(b) 331 (2)-(c) 331 (3)-(b) 35)
Enzymatic sources of ROSwith confirmed functional rolein hypertension are NADPH oxidase NO synthase (NOS)xanthine oxidase and cyclooxygenase Godfraind [3] hasreviewed AO effects and protective action of calcium channelblockers (CCBs) Yao et al [247] observed antioxidant effects(as inhibition of LP) for cardio- and neuroprotective CCBs(3ndash300 120583molL) including 7 DHPs in homogenates of ratbrain IC
50values (120583M) were as follows nifedipine (515) gt
barnidipine (586) gt benidipine (712) gt nicardipine (1293)gt amlodipine (1355) gt nilvadipine (1673) gt nitrendipine(2521) gt diltiazem (gt300) = verapamil (gt300) There arealso research articles describing the AO properties of CCBsthrough direct scavenging effect or through preservationof the endogenous SOD activity These findings indicatethat CCBs may also act by reducing the production ofvasoconstrictors angiotensin and endothelin
When present in concentrations that can be achievedin plasma CCBs may inhibit LP formation [3] This AOactivity seems to be typical for high lipophilic CCBs becausetheir chemical structure facilitates proton-donating andresonance-stabilization mechanisms that quench the freeradical reaction Their insertion in the membrane nearpolyunsaturated fatty acids at relatively high concentrationspotentiates proton donation (or atomary H) to lipid peroxidemolecules thereby blocking the peroxidation process Theremaining unpaired free electron associated with the CCBmolecule can be stabilized in well-defined resonance struc-tures associated with the DHP ring (Mason et al [48])
The radical reaction (according to Godfraind [3]) thatdescribes the AO effects of a DHP CCBs is LOOlowast + DHPrarr LOOH + DHPlowast (where LOOlowast is lipid peroxide radical)which in general is reaction (7) of the LP reaction cascadeconsisting of sim10 reactions (Scheme 2) [89]
As the rate constants of in vitro interaction of 4-substituted DHPs with peroxyl radicals are three ordersof magnitude lower than that of the vitamin E derivativethese DHPs must be considered as weak AO (Ursini [204])However due to partition coefficient of DHPs in membranesand in case of specific binding high local concentration ofDHPs may be obtained
DHPs without CCB properties for instance Bay w 9798although structurally related to nifedipine inhibit TNF-120572-induced vascular cell adhesion molecule-1 expression inendothelial cells by suppressing reactive oxygen speciesgeneration [248]
Mitrega et al [249] have discovered that antiarrhythmicand hemodynamic effects of oxidized heteroaromatic DHPsoxy nifedipine oxy nimodipine oxy nitrendipine and oxynisoldipine suggest that CCB DHPs and their metabolitescould act at least in two ways targeting OS related eventsas reductants (see Section 351 (1)) andor bypassing OSrelatedmetabolic routes Authors postulated that contrary tocurrent belief NIF metabolites are pharmacologically activeATP sensitive potassium channels were mentioned as a tar-get
38 DHPs Anti- or Prooxidants Several substances (ascorbicacid being the most commonly studied) can serve either asantioxidants or as prooxidants depending on given condi-tions (Herbert [250]) Therefore Halliwell [251] has reporteddilemma related to polyphenols as possible antioxidantsand prooxidants causing experimental artifacts (about 25)by oxidation of antioxidant compounds in the cell culturemedia Nevertheless it is generally accepted opinion thatpolyphenols act as antioxidants in vivo Studies on DHPs alsoface such a dilemmaThe exact roles (anti- or prooxidative) ofany specific DHP depend on its structure appliedachievedconcentration and specificity of the targetexperimentaltesting system
This situation resembles the case of antioxidative effectsof tocopherol which depends on the fate of the secondaryradical as proposed by Winterbourn [252] The question wasldquoVitamin E - Pro- or Antioxidantrdquo
997888rarr chain termination of lipid peroxidation
(6)
Prooxidant
Toc∙ + Lipid-H 997888rarr Lipid∙ (in LDL particles) (7)
This example shows that generally speaking any AO mustfulfil several criteria to be considered as an effective com-pound physiologically
(i) It must be able to functionally interact with endoge-nous scavengers even at low concentrations
(ii) It must affect endogenous pathways of OS(iii) It should not have undesirable adverse effect(iv) It should manifest the antioxidant efficacy dependent
on the oxidant(v) It must discriminate among different strategies
needed for 1-electron and 2-electron processes(vi) Radical scavengers can be prooxidant unless linked to
a radical sink (Winterbourn [252])
According to these statements DHPs could be effective asAO under physiological conditions in vivo (Godfraind [3]and others [30 31 38]) and in vitro in various experimentalsystems (cell and tissue) (see Sections 33 34 35)
Hence calcium antagonists appeared to disrupt thefine balance between the production and scavenging ofROS Nifedipine verapamil and diltiazem were shown toinduce significant oxidative stress in the epididymal sperm(increased MDA and decreased catalase and superoxidedismutase activity) This may be the reason for the inductionof male infertility [253]
The dualism of 14-DHP effects has been recorded asinhibition or promotion of LP as quenching or initiating
26 Oxidative Medicine and Cellular Longevity
oxygen and nitrogen free radical chain reactions radiopro-tecting or radiosensitizing antagonizing or synergizing Ca2+in electromechanical coupling as well as in the membranestabilization or labilization
39 Could DHPs Be Involved in Antioxidative Stress Beforebeing applied in vivo the optimal dose and optimal timeintervals forDHPs applicationmust be knownNamely whileROS have been traditionally considered as toxic byproductsof aerobic metabolism we know nowadays that ROS may actas essential signaling molecules needed for the control ofmany different physiological processes Whether the role ofROS will be damaging protective or signaling depends onthe delicate equilibrium between time- and location-specificROS production and scavenging Accordingly the imbalanceof the increased AO potential so-called antioxidative stresscould be dangerous similar to chronic OS in particular incase of extended exposure Inappropriate interventions inthe oxidative homeostasis by excessive antioxidants especiallyin case of chronic exposure to antioxidants might havevery negative effects as was published in the ATBC studyshowing an increased cancer incidence in smokers treatedby excessive beta-carotene [254] Therefore overconsump-tion of any natural or synthetic AO including DHPs asdietary supplements or drugs must be avoided in order tosuppress oxidative damage and must not disrupt the well-integrated antioxidant defense network (Poljsak [255] andPoljsak and Milisav [256]) This is especially important whenadministrating lipid-soluble antioxidants that can be storedin biomembranes thus not only attenuating or preventing LPbut also affecting physiological effects of the natural antiox-idants in particular tocopherol The interrelationship withthe status of endogenous antioxidantsprooxidants should befollowed
DHPs primarily suppress the initiation stages of LPprocessThey do not entirely stop the LP propagation Actingsynergistically with tocopherol diludine may prevent patho-logical excess of ROS production within the lipid moiety ofthe cellular membranes and LDL However due to its lowsolubility and fast metabolism its concentration in the cellsis low For that reason it cannot cause antioxidative stresseven if used for an extended period of time Thus diludine(diethone) could be only a mild antioxidant it has potentialfor restoring the pool of natural antioxidants (as synergist of120572-tocopherol and polyphenols) in the cells
Moreover DHPs CA used for cardioprotection andvasodilatation as commercial drugs in low concentrationsare fast metabolized via CYP3A4 and for that reason theirapplication does not induce cellular AO stress [53 160]However Godfraind and Salomone [257] have postulated noevidence that allows recommending dietary supplementationwith antioxidants for the primary or secondary prevention ofcardiovascular disease
So far there are no reports on antioxidative stress causedby some DHPs diludine and its analogues Diludine andits analogues therefore could act as adaptogens supportinghormetic effects of mild oxidative stress These compoundsmay act as potential multisided modulators of Yin-Yang
cycles of redox and cell functions (the electroplasmic cycle)(Wagner et al [258])
4 Conclusions
14-Dihydropyridines (14-DHPs) have broad spectrum ofOS modulating activities DHPs have reducing and lipidperoxidation inhibitor properties act as reductants in simplechemical systems and stabilize various biological systems(LDL mitochondria microsomes cells and tissues) againstOS Examples and peculiarities and mechanisms of antiox-idant activity (AOA) and antiradical activity (ARA) as wellas stress-protective effect of DHPs including commercialcalcium antagonists (CA) were highlighted These activitiesdepend on various structural parameters related to DHPs(presence and character of substituents) lipophilicity anddepth of the incorporation in the biologicalmembranesTheyalso depend on the experimental model system for exploringthe lipid peroxidation or oxidative stress Stress-protectiveeffect of some metabolites of CA (nifedipine) is reviewedAlthough some DHPs including CA have prooxidant prop-erties (on epididymal sperm cells) they can generally beconsidered as potent antioxidants Therefore comparisonof the AOA and ARA of different DHPs (mutually andwith other AOs) was described in detail According to thedata presented the DHPs might be considered as bellwetheramong synthetic compounds targeting OS and as a kind ofpharmacological measure for respective field of organic andmedicinal chemistry
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
Authors from Latvian IOS acknowledge ESF 201300021DP1112013APIAVIAA011 and National Research Pro-gramme PUBLIC HEALTHBiomedicine of the Republicof Latvia for financial support administration of the Insti-tute for technical support and Rufus Smits PhD for con-sultations in English The support of Cooperation in Euro-pean System of Science and Technology (COST) Domain ofChemistry Molecular Sciences and Technologies (CMST)was of highest importance for preparation of this paper
[2] D J Triggle ldquo14-Dihydropyridines as calcium channel ligandsand privileged structuresrdquoCellular andMolecular Neurobiologyvol 23 no 3 pp 293ndash303 2003
[3] T Godfraind ldquoAntioxidant effects and the therapeutic modeof action of calcium channel blockers in hypertension andatherosclerosisrdquo Philosophical Transactions of the Royal SocietyB Biological Sciences vol 360 no 1464 pp 2259ndash2272 2005
[4] E Cadenas ldquoMitochondrial free radical production and cellsignalingrdquoMolecular Aspects of Medicine vol 25 no 1-2 pp 17ndash26 2004
[5] E Cadenas ldquoFree radicals oxidative stress and diseasesrdquo inLecture PSC 616 p 38 Missouri University of Science andTechnology Rolla Mo USA httpwwwcarnicominstituteorgarticlesenrique cadenaspdf
[6] K Rahman ldquoStudies on free radicals antioxidants and co-fac-torsrdquo Clinical Interventions in Aging vol 2 no 2 pp 219ndash2362007
[7] V Bocci and G Valacchi ldquoFree radicals and antioxidants howto reestablish redox homeostasis in chronic diseasesrdquo CurrentMedicinal Chemistry vol 20 no 27 pp 3397ndash3415 2013
[8] M Valko C J Rhodes J Moncol M Izakovic and M MazurldquoFree radicals metals and antioxidants in oxidative stress-induced cancerrdquo Chemico-Biological Interactions vol 160 no 1pp 1ndash40 2006
[9] G Bartosz ldquoReactive oxygen species destroyers or messen-gersrdquo Biochemical Pharmacology vol 77 no 8 pp 1303ndash13152009
[10] R Visconti and D Grieco ldquoNew insights on oxidative stress incancerrdquo Current Opinion in Drug Discovery and Developmentvol 12 no 2 pp 240ndash245 2009
[11] R N Kujundzic N Zarkovic and K G Troselj ldquoPyridinenucleotides in regulation of cell death and survival by redoxand non-redox reactionsrdquo Critical Reviews in Eukaryotic GeneExpression vol 24 no 4 pp 287ndash309 2014
[12] B Halliwell and J M C Gutteridge ldquoThe definition and mea-surement of antioxidants in biological systemsrdquo Free RadicalBiology and Medicine vol 18 no 1 pp 125ndash126 1995
[13] V D Kancheva and O T Kasaikina ldquoBio-antioxidantsmdashachemical base of their antioxidant activity and beneficial effect
on human healthrdquo Current Medicinal Chemistry vol 20 no 37pp 4784ndash4805 2013
[14] H V Panglossi Ed Frontiers in Antioxidants Research NovaScience Publishers New York NY USA 2006
[15] E B Burlakova E M Molochkina and G A NikiforovldquoHybrid antioxidantsrdquo Oxidation Communications vol 31 no4 pp 739ndash757 2008 httpmembraneustceducnpaperpdfHybrid20Antioxidantspdf
[16] A Bast and G R M M Haenen ldquoTen misconceptions aboutantioxidantsrdquo Trends in Pharmacological Sciences vol 34 no 8pp 430ndash436 2013
[17] E B Burlakova A V 0lesenko E M Molochkina N PPalmina and N G Khrapova Bioantioxidants for RadiationDamage and Malignant Growth Nauka Moscow Russia 1975(Russian)
[18] J Fang T Seki and H Maeda ldquoTherapeutic strategies by mod-ulating oxygen stress in cancer and inflammationrdquo AdvancedDrug Delivery Reviews vol 61 no 4 pp 290ndash302 2009
[19] M Valko D Leibfritz J Moncol M T D Cronin M Mazurand J Telser ldquoFree radicals and antioxidants in normal physi-ological functions and human diseaserdquo International Journal ofBiochemistry and Cell Biology vol 39 no 1 pp 44ndash84 2007
[20] M Jimenez-Del-Rio and C Velez-Pardo ldquoThe bad the goodand the ugly about oxidative stressrdquo Oxidative Medicine andCellular Longevity vol 2012 Article ID 163913 13 pages 2012
[21] C D Kamat S Gadal M Mhatre K S Williamson Q N Pyeand K Hensley ldquoAntioxidants in central nervous system dis-eases preclinical promise and translational challengesrdquo Journalof Alzheimerrsquos Disease vol 15 no 3 pp 473ndash493 2008
[22] A Pompella H Sies R Wacker et al ldquoThe use of totalantioxidant capacity as surrogate marker for food quality andits effect on health is to be discouragedrdquo Nutrition vol 30 no7-8 pp 791ndash793 2014
[23] Z Ye and H Song ldquoAntioxidant vitamins intake and the risk ofcoronary heart disease meta-analysis of cohort studiesrdquo Euro-pean Journal of Cardiovascular Prevention and Rehabilitationvol 15 no 1 pp 26ndash34 2008
[24] P Knekt J Ritz M A Pereira et al ldquoAntioxidant vitamins andcoronary heart disease risk a pooled analysis of 9 cohortsrdquoTheAmerican Journal of Clinical Nutrition vol 80 no 6 pp 1508ndash1520 2004
[25] A C Carr and M C M Vissers ldquoSynthetic or food-derivedvitamin Cmdashare they equally bioavailablerdquo Nutrients vol 5 no11 pp 4284ndash4304 2013
[26] R Tabrizchi ldquoEdaravoneMitsubishi-TokyordquoCurrentOpinion inInvestigational Drugs vol 1 no 3 pp 347ndash354 2000
[27] K Kikuchi S Tancharoen N Takeshige et al ldquoThe efficacy ofedaravone (radicut) a free radical scavenger for cardiovasculardiseaserdquo International Journal of Molecular Sciences vol 14 no7 pp 13909ndash13930 2013
[28] D Mauzerall and F H Westheimer ldquo1-Benzyldihydronicoti-namidemdasha model for reduced DPNrdquo Journal of the AmericanChemical Society vol 77 no 8 pp 2261ndash2264 1955 ChemicalAbstracts vol 50 Article ID 2588i 1956
[29] F Bossert and W Vater ldquo14-Dihydropyridinesmdasha basis fordeveloping new drugsrdquo Medicinal Research Reviews vol 9 no3 pp 291ndash324 1989
[30] G Swarnalatha G Prasanthi N Sirisha and CMadhusudhanaChetty ldquo14-Dihydropyridines a multtifunctional moleculemdash areviewrdquo International Journal of ChemTech Research vol 3 no1 pp 75ndash89 2011
28 Oxidative Medicine and Cellular Longevity
[31] M Cataldi and F Bruno ldquo14-Dihydropyridines the multiplepersonalities of a blockbuster drug familyrdquo Translational Medi-cine UniSa vol 4 no 2 pp 12ndash26 2012 httpwwwncbinlmnihgovpmcarticlesPMC3728803
[32] R Vitolina A Krauze G Duburs and A Velena ldquoAspects ofthe amlodipine pleiotropy in biochemistry pharmacology andclinicsrdquo International Journal of Pharmaceutical Sciences andResearch vol 3 no 5 pp 1215ndash1232 2012
[33] D Grover S N Mokale and M T Shete ldquoDihydropyridinea novel pharmacophorerdquo International Journal of Pharmaceu-tical Erudition vol 1 no 2 pp 16ndash29 2011 httppharmaeru-ditionorgContentPaper20111-RV-320Final2016-29pdf
[34] A M Vijesh A M Isloor S K Peethambar K N ShivanandaT Arulmoli and N A Isloor ldquoHantzsch reaction synthesis andcharacterization of somenew 14-dihydropyridine derivatives aspotent antimicrobial and antioxidant agentsrdquo European Journalof Medicinal Chemistry vol 46 no 11 pp 5591ndash5597 2011
[35] P Mehta and P Verma ldquoAntimicrobial activity of some deriva-tives of 14-dihydropyridinesrdquo Journal of Chemistry vol 2013Article ID 865128 4 pages 2013
[36] P Olejnıkova L Svorc D Olsovska et al ldquoAntimicrobialactivity of novel C2-substituted 14-dihydropyridine analoguesrdquoScientia Pharmaceutica vol 82 no 2 pp 221ndash232 2014
[37] S Sepehri H Perez Sanchez and A Fassihi ldquoHantzsch-typedihydropyridines and biginelli-type tetra-hydropyrimidinesa review of their chemotherapeutic activitiesrdquo Journal of Phar-macy amp Pharmaceutical Sciences vol 18 no 1 pp 1ndash52 2015httpsejournalslibraryualbertacaindexphpJPPSarticleview2383617863
[38] S A Khedkar and P B Auti ldquo14-Dihydropyridines a classof pharmacologically important moleculesrdquo Mini-Reviews inMedicinal Chemistry vol 14 no 3 pp 282ndash290 2014
[39] G D Tirzit and G Ya Duburs ldquo14-dihydropyridines as inhi-bitors of free-radical reactionsrdquo Chemistry of Heterocyclic Com-pounds vol 8 no 1 pp 126ndash127 1972 Translated from KhimiyaGeterotsiklicheskikh Soedinenii no1 pp 133ndash134 1972 (Rus-sian)
[40] I Bogeski R Kappl C Kummerow R Gulaboski M Hothand B A Niemeyer ldquoRedox regulation of calcium ion channelschemical and physiological aspectsrdquoCell Calcium vol 50 no 5pp 407ndash423 2011
[41] S A Giller G Y Dubur Y R Uldrikis et al ldquoDiludine [Themethod to obtain 35-dicarbonylderivatives of 26-dimethyl-14-dihydropyridines]rdquo Authors certificate of USSR no 3004651971 [Byull Izobret no13 p 95 1971] and following patentsPatent of England no 1294650 1973 Patent of France no2055458 1971 Patent of Japan no 702883 1973 Patent ofHolland no 149787 1976 Patent of Italy no 969022 1974 Patentof FRG no 2036403 1978 US Patent no 3883673 1975 USPatent no 3948924 1976
[42] S A Giller G Y Dubur Y R Uldrikis et al ldquoImprovementsin or relating to the stabilization of carotenerdquo GB Patent no1294650 1972
[43] S A Giller G Y Dubur Y R Uldrikis et al ldquoStabilization ofcarotenerdquo US Patent no 3883673 1975 Chemical Abstracts vol83 Article ID 95193 1975
[44] Yu A Zilber G Ya Dubur K K Kumsar and A Kh VelenaldquoThe effect of antioxidants on the peroxidation of bimole-cular phospholipid membranesrdquo Latvijas PSR ZA Vestis Izves-tia Akademii Nauk Latviyskoy SSR vol 6 pp 80ndash82 1971(Russian) translated from the original Russian Doc Accesion
No AD0771751 distributed by NTIS US Department of Com-merce httpwwwdticmildtictrfulltextu2771751pdf
[45] G Ya Dubur Yu A Zilbers A Kh Velena A O Kumerovaand G D Tirzitis ldquoMultistage study of regulation of peroxida-tion processes in biological membranes by antioxidants of 14-dihydropyridine grouprdquo Izvestiya Akademii Nauk LatviyskoySSR vol 336 no 7 pp 65ndash68 1975 (Russian)
[46] R P Mason and M W Trumbore ldquoDifferential membraneinteractions of calcium channel blockers Implications forantioxidant activityrdquo Biochemical Pharmacology vol 51 no 5pp 653ndash660 1996
[47] R P Mason M F Walter M W Trumbore E G Olmstead Jrand P E Mason ldquoMembrane antioxidant effects of the chargeddihydropyridine calcium antagonist amlodipinerdquo Journal ofMolecular and Cellular Cardiology vol 31 no 1 pp 275ndash2811999
[48] R PMason I T MakMW Trumbore and P EMason ldquoAnti-oxidant properties of calcium antagonists related to membranebiophysical interactionsrdquo American Journal of Cardiology vol84 no 4 pp 16ndash22 1999
[49] R PMasonMW Trumbore and P EMason ldquoMembrane bio-physical interaction of amlodipine and antioxidant propertiesrdquoDrugs vol 59 no 2 pp 9ndash16 2000 (French)
[50] R P Mason P Marche and T H Hintze ldquoNovel vascularbiology of third-generation L-type calcium channel antagonistsAncillary actions of amlodipinerdquo Arteriosclerosis Thrombosisand Vascular Biology vol 23 no 12 pp 2155ndash2163 2003
[51] A Augustyniak G Bartosz A Cipak et al ldquoNatural andsynthetic antioxidants an updated overviewrdquo Free RadicalResearch vol 44 no 10 pp 1216ndash1262 2010
[52] T Grune N Zarkovic and K Kostelidou ldquoLipid peroxidationresearch in Europe and the COST B35 action lsquoLipid Peroxida-tion Associated Disordersrsquordquo Free Radical Research vol 44 no10 pp 1095ndash1097 2010
[53] E Carosati P Ioan M Micucci et al ldquo14-Dihydropyridinescaffold in medicinal chemistry the story so far and perspec-tives (part 2) action in other targets and antitargetsrdquo CurrentMedicinal Chemistry vol 19 no 25 pp 4306ndash4323 2012
[54] U Eisner and J Kuthan ldquoThe chemistry of dihydropyridinesrdquoChemical Reviews vol 72 no 1 pp 1ndash42 1972 httpwwwsci-encemadnessorgtalkfilesphppid=138742ampaid=6475
[55] J Kuthan and A Kurfurst ldquoDevelopment in dihydropyri-dine chemistryrdquo Industrial amp Engineering Chemistry ProductResearch and Development vol 21 no 2 pp 191ndash261 1982
[56] A Sausins and G Duburs ldquoSynthesis of 14-dihydropyridinesby cyclocondensation reactionsrdquo Heterocycles vol 27 no 1 pp269ndash289 1988
[57] A E Sausins and G Y Duburs ldquoSynthesis of 14-dihydro-pyridines in cyclocondensation reactions (review)rdquo Chemistryof Heterocyclic Compounds vol 28 no 4 pp 363ndash391 1992Translated from Khimiya Geterotsiklicheskikh Soedinenii no 4pp 435ndash467 1992 (Russian)
[58] S Kazda ldquoTwenty years of dihydropyridinesrdquo in Dihydropy-ridines Progress in Pharmacology and Therapy W-D Busse BGarthoff and F Seuter Eds pp 1ndash12 Springer Verlag BerlinGermany 1993
[59] J-P Wan and Y Liu ldquoRecent advances in new multicomponentsynthesis of structurally diversified 14-dihydropyridinesrdquo RSCAdvances vol 2 no 26 pp 9763ndash9777 2012
[61] Reaxys Database[62] J Tuttle ldquoStructure mechanism and reactivity of hantzsch
estersrdquo in MacMillan Lab Group Meeting (082504) p 332004 httpwwwprincetoneduchemistrymacmillangroup-meetingsJBT20Hantzschpdf
[63] A Saini S Kumar and J S Sandhu ldquoHantzsch reaction recentadvances in Hantzsch 14-dihydropyridinesrdquo Journal of Sci-entific amp Industrial Research vol 67 pp 95ndash111 2008
[64] L LW Cheung S A Styler and A P Dicks ldquoRapid and conve-nient synthesis of the 14-dihydropyridine privileged structurerdquoJournal of Chemical Education vol 87 no 6 pp 628ndash630 2010
[65] A Kumar R A Maurya S Sharma M Kumar and G BhatialdquoSynthesis and biological evaluation of N-aryl-14-dihydro-pyridines as novel antidyslipidemic and antioxidant agentsrdquoEuropean Journal of Medicinal Chemistry vol 45 no 2 pp 501ndash509 2010
[66] R S Kumar A Idhayadhulla A J Abdul Nasser and J SelvinldquoSynthesis and anticoagulant activity of a new series of 14-dihydropyridine derivativesrdquo European Journal of MedicinalChemistry vol 46 no 2 pp 804ndash810 2011
[67] H A Stefani C B Oliveira R B Almeida et al ldquoDihydro-pyrimidin-(2H)-ones obtained by ultrasound irradiation anew class of potential antioxidant agentsrdquo European Journal ofMedicinal Chemistry vol 41 no 4 pp 513ndash518 2006
[68] H Sun C Shang L Jin and J Zhang ldquoSynthesis and antiox-idant activity of a series of novel 3-chalcone-substituted 14-dihydropyridine derivativesrdquoHeterocyclic Communications vol18 no 5-6 pp 239ndash243 2012
[69] D B Tikhonov and B S Zhorov ldquoStructural model for dihy-dropyridine binding to L-type calcium channelsrdquo The Journalof Biological Chemistry vol 284 no 28 pp 19006ndash19017 2009
[70] G Y Dubur and Y R Uldrikis ldquoThe oxidation of 14-dihydro-pyridinesrdquo Chemistry of Heterocyclic Compounds vol 6 no 1pp 80ndash84 1970 Translated from Khimiya GeterotsiklicheskikhSoedinenii no 1 pp 83ndash88 1970 (Russian)
[71] G Ya Duburs A O Kumerova and Ya R Uldrikis ldquoEnzymicoxidation of hydrogenated pyridines with peroxidase-hydrogenperoxide systemrdquoLatvijas PSRZAVestis vol 73 no 7 pp 73ndash771970 (Russian) Chemical Abstracts vol 73 Article ID 94913g1970
[72] K Xie Y-C Liu Y Cui J-GWang Y Fu andT CWMak ldquoN-methyl-(R)-3-(tert-butyl)-sulfinyl-14-dihydropyridine a novelNADHmodel compoundrdquoMolecules vol 12 no 3 pp 415ndash4222007
[73] S Tamagaki T Mimura and W Tagaki ldquoMetal-ion-facilitatedoxidations of dihydropyridines with molecular oxygen andhydrogen peroxiderdquo Journal of the Chemical Society PerkinTransactions 2 no 10 pp 1645ndash1650 1990
[74] D Tirzite G Tirzitis andD Antipova ldquoReductive ability of 14-dihydropyridine derivatives in relation to ions of trivalent ironrdquoChemistry of Heterocyclic Compounds vol 35 no 5 pp 592ndash594 1999
[76] J Ogle J Stradins and L Baumane ldquoFormation and decay offree cation-radicals in the course of electro-oxidation of 12- and14-dihydropyridines (Hantzsch esters)rdquo Electrochimica Actavol 39 no 1 pp 73ndash79 1994
[77] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for the
synthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts C Wittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Berlin Germany 2010
[78] WDu and Zh Yu ldquoBiomimetic in situ regeneration of cofactorsNAD(P)+ and NAD(P)H models hantzsch esters and dihy-drophenanthridinerdquo Synlett vol 23 no 9 pp 1300ndash1304 2012
[79] H K Chenault and G M Whitesides ldquoRegeneration ofnicotinamide cofactors for use in organic synthesisrdquo AppliedBiochemistry and Biotechnology vol 14 no 2 pp 147ndash197 1987
[80] Y R Uldrikis A A Zidermane E A Biseniex I E Preisa GY Dubur and G D Tirzit ldquoEsters of 26-dimethyl-14-dihydro-pyridine-35-dicarboxylic acid and method of obtainingthereofrdquo WO 8000345 A1 1978 httpworldwideespacenetcompublicationDetailsbiblioDB=EPODOCampII=1ampND=3ampadjacent=trueamplocale=en EPampFT=Dampdate=19800306ampCC=WOampNR=8000345A1ampKC=A1
[81] Y Sambongi H Nitta K Ichihashi M Futai and I Ueda ldquoAnovel water-soluble Hantzsch 14-dihydropyridine compoundthat functions in biological processes through NADH regener-ationrdquo Journal of Organic Chemistry vol 67 no 10 pp 3499ndash3501 2002
[82] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for thesynthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts ChWittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Verlag Berlin Germany 2010
[83] T Okamura T Kikuchi A Nagamine et al ldquoAn approach formeasuring in vivo cerebral redox states using the oxidative con-version of dihydropyridine to pyridinium ion and themetabolictrapping principlerdquo Free Radical Biology and Medicine vol 38no 9 pp 1197ndash1205 2005
[84] K A Schellenberg and F H Westheimer ldquoA free-radicaloxidation of a dihydropyridine1ardquo The Journal of OrganicChemistry vol 30 no 6 pp 1859ndash1862 1965
[85] K A Schellenberg ldquoReaction of hydroxyl radical with thymi-dine Scavenging by a dihydropyridinerdquo Federation Proceedingsvol 38 no 3 I p 1433 1979
[86] E S Huyser J A K Harmony and F L McMillian ldquoPeroxideoxidations of dihydropyridine derivativesrdquo Journal of the Amer-ican Chemical Society vol 94 no 9 pp 3176ndash3180 1972
[87] A Sakamoto S T Ohnishi and R Ogawa ldquoInhibition of lipidperoxidation by some dihydropyridine derivativesrdquo Journal ofAnesthesia vol 7 no 2 pp 193ndash197 1993
[88] R Hardeland ldquoReview Neuroprotection by radical avoidancesearch for suitable agentsrdquo Molecules vol 14 no 12 pp 5054ndash5102 2009
[89] G Ya Dubur A Kh Velena V M Gukasov and Yu AVladimirov ldquoRegulation of peroxidation of mitochondrialmembrane lipids initiated by Fe2+ ions by antoxidants of the14-dihydropyridine series in experiments in vitrordquo Biomed-itsinskaya Khimiya vol 22 no 5 pp 665ndash673 1976 (Russian)Chemical Abstracts vol 88 Article ID 2640 1977
[90] G RMMHaenenM J T J Arts A Bast andMD ColemanldquoStructure and activity in assessing antioxidant activity in vitroand in vivo a critical appraisal illustrated with the flavonoidsrdquoEnvironmental Toxicology and Pharmacology vol 21 no 2 pp191ndash198 2006
[91] G Tirzitis and G Bartosz ldquoDetermination of antiradical andantioxidant activity basic principles and new insightsrdquo ActaBiochimica Polonica vol 57 no 2 pp 139ndash142 2010
30 Oxidative Medicine and Cellular Longevity
[92] G R Buettner and R P Mason ldquoSpin-trapping methods fordetecting superoxide and hydroxyl free radicals in vitro and invivordquo inCritical Reviews of Oxidative Stress and Aging Advancesin Basic Science Diagnostics and Intervention R G Cutler andH Rodriguez Eds vol 1 chapter 2 pp 27ndash38World ScientificLondon UK 2003
[93] M M Tarpey and I Fridovich ldquoMethods of detection ofvascular reactive species Nitric oxide superoxide hydrogenperoxide and peroxynitriterdquo Circulation Research vol 89 no3 pp 224ndash236 2001
[94] E Y Kazush E I Sagun G D Tirzit and G Y DaburldquoQuenching of singlet oxygen by electron donating derivativesof 14-dihydropyridinerdquo Chemistry of Heterocyclic Compoundsvol 30 no 5 pp 562ndash563 1994
[95] G Tirzitis E Kazush and G Duburs ldquoReaction of 14-dihydropyridine derivatives with peroxynitrite anionrdquo Chem-istry of Heterocyclic Compounds vol 34 no 3 pp 321ndash3231998 (Russian) Translated from Khimiya GeterotsiklicheskikhSoedinenii no 3 pp 355ndash357 1998
[96] L J Nunez-Vergara C Lopez-Alarcon P A Navarrete-EncinaA M Atria C Camargo and J A Squella ldquoElectrochemicaland EPR characterization of 14-dihydropyridines Reactivitytowards alkyl radicalsrdquo Free Radical Research vol 37 no 1 pp109ndash120 2003
[97] D Tirzite A Krauze A Zubareva G Tirzitis and G DubursldquoSynthesis and antiradical activity of 5-acetyl-2-alkylthio-4-aryl-6-methyl-14-dihydropyridine-3-carboxylic acid nitrilesrdquoChemistry of Heterocyclic Compounds vol 38 no 7 pp 795ndash800 2002
[98] H Ohkawa N Ohishi and K Yagi ldquoAssay for lipid peroxidesin animal tissues by thiobarbituric acid reactionrdquo AnalyticalBiochemistry vol 95 no 2 pp 351ndash358 1979
[99] N Zarkovic ldquo4-Hydroxynonenal as a bioactive marker ofpathophysiological processesrdquo Molecular Aspects of Medicinevol 24 no 4-5 pp 281ndash291 2003
[100] M Parola G Bellomo G Robino G Barrera and M UDianzani ldquo4-Hydroxynonenal as a biological signal molecularbasis and pathophysiological implicationsrdquo Antioxidants andRedox Signaling vol 1 no 3 pp 255ndash284 1999
[101] T Lovakovic M Poljak-Blazi G Duburs et al ldquoGrowthmodulation of human cells in vitro by mild oxidative stressand 14-dihydropyridine derivative antioxidantsrdquo CollegiumAntropologicum vol 35 no 1 pp 137ndash141 2011
[102] R van den Berg G R M M Haenen H van den Bergand A Bast ldquoApplicability of an improved Trolox equivalentantioxidant capacity (TEAC) assay for evaluation of antioxidantcapacity measurements of mixturesrdquo Food Chemistry vol 66no 4 pp 511ndash517 1999
[103] C Lopez-Alarcon P Navarrete C Camargo J A Squella andL J Nunez-Vergara ldquoReactivity of 14-dihydropyridines towardalkyl alkylperoxyl radicals and ABTS radical cationrdquo ChemicalResearch in Toxicology vol 16 no 2 pp 208ndash215 2003
[104] V Valenzuela P Santander C Camargo J A Squella C Lopez-Alarcon and L J Nunez-Vergara ldquo14-Dihydropyridines reac-tivity of nitrosoaryl and nitroaryl derivatives with alkylperoxylradicals andABTS radical cationrdquo Free Radical Research vol 38no 7 pp 715ndash727 2004
[105] L G Tsetlin N A Chebotareva B I Kurganov A K VelenaG Y Dubur and V Z Lankin ldquoStudy of 14-dihydropyridinesas lipoxygenase inhibitors with the use of hydrated reversedmicellesrdquo Pharmaceutical Chemistry Journal vol 22 no 6 pp425ndash428 1988 (Russian)
[106] J Panek Z Reblova L Kocirkova et al ldquoAntioxidant activityof dihydropyridine derivativesrdquo Czech Journal of Food Sciencesvol 18 pp 144ndash145 2000
[107] G Tirzitis I Kirule and G Duburs ldquoAntioxidationsaktivitatder 35-dicarbonylderivate des 26-demethyl-14-dihydropyri-dinsrdquo Fett Wissenschaft TechnologieFat Science Technology vol90 no 10 pp 411ndash413 1988
[108] M Plotniece G Tirzitis Y Uldrikis et al ldquoSynthesis of 14-dihydropyridine derivatives having an oxy- alkoxy- or dimeth-ylaminophenyl substituent in the 4 position their antioxidantactivity and their binding to phospholipid membranesrdquo Chem-istry of Heterocyclic Compounds vol 32 no 10 pp 1166ndash11721996 Translated from Khimiya Geterotsiklicheskikh Soedineniino 10(352) pp 1358ndash1365 1996 (Russian)
[109] D Y Rubene V S Sharov V I Olenev G D Tirzit G Y Duburand Y A Vladimirov ldquoUse of chemiluminescent method forthe evaluation of antioxidant activity of some derivatives of 14-dihydropyridinerdquo Russian Journal of Physical Chemistry A vol55 no 2 pp 511ndash512 1981 (Russian)
[110] M C R Symons and JM C Gutteridge Free Radicals and IronChemistry Biology and Medicine Oxford Science PublicationsOxford University Press Oxford UK 1998
[111] M Repetto J Semprine and A Boveris ldquoLipid peroxidationchemical mechanism biological implications and analyticaldeterminationrdquo in Lipid Peroxidation A Catala Ed Section ILipid Peroxidation Chemical Mechanisms Antioxidants Bio-logical Implications of Biochemistry Genetics and MolecularBiology chapter 1 pp 3ndash30 InTech Rijeka Croatia 2012
[112] A Velena J Zilbers and G Duburs ldquoDerivatives of 14-dihydropyridines asmodulators of ascorbate-induced lipid per-oxidation and high-amplitude swelling ofmitochondria causedby ascorbate sodium linoleate and sodiumpyrophosphaterdquoCellBiochemistry and Function vol 17 no 4 pp 237ndash252 1999
[113] M V Bilenko L N Shelenkova G Y Dubur and A K VelenaldquoUse of antioxidants to prevent renal damage during acuteischemia and reperfusionrdquo Bulletin of Experimental Biology andMedicine vol 96 no 3 pp 1195ndash1198 1983 Translated fromByulletenrsquo Eksperimentalrsquonoi Biologii i Meditsiny vol 96 no 9pp 8ndash11 1983 (Russian)
[114] R Toniolo F Tubaro F Ursini and G Bontempelli ldquoAn elec-troanalytical investigation on the redox properties of calciumantagonist dihydropyridinesrdquo Electroanalysis vol 15 no 10 pp855ndash861 2003
[115] L Kourimska J Pokorny and G Tirzitis ldquoThe antioxidant aci-tivity of 26-dimethyl-35-diethoxycarbonyl-14-dihydropyri-dine in edible oilsrdquo Nahrung vol 37 no 1 pp 91ndash93 1993
[116] C Lopez-Alarcon H Speisky J A Squella C Olea-Azar CCamargo and L J Nunez-Vergara ldquoReactivity of 14-dihydro-pyridines toward SIN-1-derived peroxynitriterdquo PharmaceuticalResearch vol 21 no 10 pp 1750ndash1757 2004
[117] R A Olek W Ziolkowski J J Kaczor L Greci J Popinigisand J Antosiewicz ldquoAntioxidant activity of NADH and its ana-loguemdashan in vitro studyrdquo Journal of Biochemistry andMolecularBiology vol 37 no 4 pp 416ndash421 2004
[118] E Niki N Noguchi and N Gotoh ldquoInhibition of oxidativemodification of low density lipoprotein by antioxidantsrdquo Jour-nal of Nutritional Science andVitaminology vol 39 supplementpp S1ndashS8 1993
[119] N Rojstaczer and D J Triggle ldquoStructure-function relation-ships of calcium antagonists effect on oxidative modificationof low density lipoproteinrdquo Biochemical Pharmacology vol 51no 2 pp 141ndash150 1996
Oxidative Medicine and Cellular Longevity 31
[120] A Sevanian L Shen and FUrsini ldquoInhibition of LDLoxidationand oxidized LDL-induced cytotoxicity by dihydropyridinecalcium antagonistsrdquo Pharmaceutical Research vol 17 no 8 pp999ndash1006 2000
[121] A Negre-Salvayre and R Salvayre ldquoProtection by Ca2+ channelblockers (nifedipine diltiazem and verapamil) against the tox-icity of oxidized low density lipoprotein to cultured lymphoidcellsrdquo British Journal of Pharmacology vol 107 no 3 pp 738ndash744 1992
[122] A Negre-Salvayre G FitoussiM Troly and R Salvayre ldquoCom-parative cytoprotective effect of dihydropyridine calcium chan-nel blockers against the toxicity of oxidized low density lipopro-tein for cultured lymphoid cellsrdquo Biochemical Pharmacologyvol 44 no 12 pp 2379ndash2386 1992
[123] L Cominacini A F Pasini U Garbin et al ldquoAntioxidant activ-ity of different dihydropyridinesrdquo Biochemical and BiophysicalResearch Communications vol 302 no 4 pp 679ndash684 2003
[124] L Cominacini U Garbin A Fratta Pasini et al ldquoOxidized low-density lipoprotein increases the production of intracellularreactive oxygen species in endothelial cells inhibitory effect oflacidipinerdquo Journal of Hypertension vol 16 no 12 part 2 pp1913ndash1919 1998
[125] H M Lander ldquoAn essential role for free radicals and derivedspecies in signal transductionrdquo The FASEB Journal vol 11 no2 pp 118ndash124 1997
[126] M L L Martinez E Rizzi M M Castro et al ldquoLercanidipinedecreases vascular matrix metalloproteinase-2 activity andprotects against vascular dysfunction in diabetic ratsrdquo EuropeanJournal of Pharmacology vol 599 no 1ndash3 pp 110ndash116 2008
[127] P Lesnik C Dachet L Petit et al ldquoImpact of a combinationof a calcium antagonist and a 120573-blocker on cell- and copper-mediated oxidation of LDL and on the accumulation and effluxof cholesterol in human macrophages and murine J774 cellsrdquoArteriosclerosis Thrombosis and Vascular Biology vol 17 no 5pp 979ndash988 1997
[128] G Sobal E J Menzel and H Sinzinger ldquoCalcium antagonistsas inhibitors of in vitro low density lipoprotein oxidation andglycationrdquoBiochemical Pharmacology vol 61 no 3 pp 373ndash3792001
[129] E Lupo R Locher B Weisser and W Vetter ldquoIn vitro antiox-idant activity of calcium antagonists against LDL oxidationcompared with 120572-tocopherolrdquo Biochemical and BiophysicalResearch Communications vol 203 no 3 pp 1803ndash1808 1994
[130] J Zou Y Li H-Q Fan and J-G Wang ldquoEffects of dihydropy-ridine calcium channel blockers on oxidized low-density lipo-protein induced proliferation and oxidative stress of vascularsmooth muscle cellsrdquo BMC Research Notes vol 5 article 1682012
[131] C Napoli S Salomone T Godfraind et al ldquo14-Dihydro-pyridine calcium channel blockers inhibit plasma and LDL oxi-dation and formation of oxidation-specific epitopes in the arte-rial wall and prolong survival in stroke-prone spontaneouslyhypertensive ratsrdquo Stroke vol 30 no 9 pp 1907ndash1915 1999
[132] G Zernig I Graziadei T Moshammer C Zech N Reider andH Glossmann ldquoMitochondrial Ca2+ antagonist binding sitesare associated with an inner mitochondrial membrane anionchannelrdquo Molecular Pharmacology vol 38 no 3 pp 362ndash3691990
[133] F E Hunter Jr A Scott P E Hochstein et al ldquoStudies of themechanism of ascorbate-induced swelling and lysis of isolatedliver mitochondriardquo The Journal of Biological Chemistry vol239 pp 604ndash613 1964
[134] D R Janero B Burghardt and R Lopez ldquoProtection of cardiacmembrane phospholipid against oxidative injury by calciumantagonistsrdquoBiochemical Pharmacology vol 37 no 21 pp 4197ndash4203 1988
[135] A Karadag B Ozcelik and S S Saner ldquoReview of methods todetermine antioxidant capacitiesrdquo FoodAnalyticalMethods vol2 no 1 pp 41ndash60 2009
[136] Y I Gubskiı N V Litvinova and E V Shnurko-TabakovaldquoAntioxidant and antiradical activity of various classes of antiox-idantsrdquo Ukrainskiı Biokhimicheskiı Zhurnal vol 66 no 4 pp114ndash116 1994 (Russian)
[137] M Takei M Hiramatsu and A Mori ldquoInhibitory effects ofcalcium antagonists onmitochondrial swelling induced by lipidperoxidation or arachidonic acid in the rat brain in vitrordquoNeurochemical Research vol 19 no 9 pp 1199ndash1206 1994
[138] M Takei M Hiramatsu R Edamatsu and A Mori ldquoFreeradical scavenging by calcium antagonistsrdquo Neurosciences vol20 no 2 pp 75ndash82 1994
[139] Ya P Stradin G Ya Dubur Yu A Beilis Ya R Uldrikis andA F Korotkova ldquoVoltammetry of 14-dihydropyridine deriva-tives I Potentials of electrochemical oxidation of 35-diacyl-and 35-di(alkoxycarbonyl)-14-dihydropyridines in acetoni-trilerdquo Chemistry of Heterocyclic Compounds no 1 pp 84ndash871972 (Russian)
[140] E V Ivanov T V Ponomarjova G N Merkusev et al ldquoEinneuer Haut-Radioprotektor Diethon (experimentelle Unter-suchung)rdquo Radiobiologia Radiotherapia vol 31 no 1 pp 69ndash78 1990
[141] E V Ivanov T V Ponomareva G N Merkushev et al ldquoRadia-tion modulating properties of derivates of 14-dihydropyridineand 12345678910-decahydroacridine-18 dionerdquo Radiat-sionnaia Biologiia Radioecologiia vol 44 no 5 pp 550ndash5592004 (Russian)
[142] R O Vitolinia D A Berzinia A K Velena I A Vutsina A AKimenis and G Y Duburs ldquoThe protective effects of the cal-cium antagonist foridon in acute myocardial ischaemiardquo Kardi-ologiya vol 27 no 3 pp 90ndash93 1987 (Russian)
[143] A H Velena G Ya Duburs R O Vitolina et al ldquoEffect ofryodipine on electromechanical parameters of heart and vesselscAMP phosphodiesterase activity and swelling-contractioncycle of mitochondriardquo Arzneimittelforschung vol 35 no 6 pp907ndash914 1985
[144] L I Utno Z E Lipsberga A A Silova M I Girgensone EA Bisenieks and G I Ia ldquoCardioprotective properties of a 14-dihydropyridine derivative glutapyrone in deep hypothermiardquoBiulletenrsquo Eksperimentalrsquonoı Biologii i Meditsiny vol 108 no 11pp 558ndash561 1989 (Russian)
[145] M A S FernandesM S Santos J A F Vicente et al ldquoEffects of14-dihydropyridine derivatives (cerebrocrast gammapyroneglutapyrone and diethone) onmitochondrial bioenergetics andoxidative stress a comparative studyrdquoMitochondrion vol 3 no1 pp 47ndash59 2003
[146] M A S Fernandes M S Santos A J M Moreno et al ldquoEffectsof 5-acetyl(carbamoyl)-6-methylsulfanyl-14-dihydropyridine-5-carbonitriles on rat liver mitochondrial functionrdquo Toxicologyin Vitro vol 23 no 7 pp 1333ndash1341 2009
[147] L Klimaviciusa A Kalda A Kaasik et al ldquoNeuroprotectiveactivity of 14-dihydropyridine derivatives structure determi-nantsrdquo Proceedings of the Latvian Academy of Sciences BNatural Exact and Applied Sciences vol 61 no 1-2 pp 33ndash372007
32 Oxidative Medicine and Cellular Longevity
[148] L Klimaviciusa M A S Fernandes N Lencberga et alldquoTargeting the mitochondria by novel adamantane-containing14-dihydropyridine compoundsrdquo in Bioenergetics K B ClarkEd pp 257ndash272 InTech 2012
[149] V Klusa L Klimaviciusa G Duburs J Poikans and AZharkovsky ldquoAnti-neurotoxic effects of tauropyrone a taurineanaloguerdquo Advances in Experimental Medicine and Biology vol583 pp 499ndash508 2006
[150] N Sampson P Berger and Ch Zenzmaier ldquoRedox signalingas a therapeutic target to inhibit myofibroblast activation indegenerative fibrotic diseaserdquo BioMed Research Internationalvol 2014 Article ID 131737 14 pages 2014
[151] T L Leto and M Geiszt ldquoRole of Nox family NADPH oxidasesin host defenserdquoAntioxidantsampRedox Signaling vol 8 no 9-10pp 1549ndash1561 2006
[152] K K Griendling D Sorescu and M Ushio-Fukai ldquoNAD(P)Hoxidase role in cardiovascular biology and diseaserdquo CirculationResearch vol 86 no 5 pp 494ndash501 2000
[153] H Chen Y S Song and P H Chan ldquoInhibition of NADPHoxi-dase is neuroprotective after ischemia-reperfusionrdquo Journal ofCerebral Blood Flow and Metabolism vol 29 no 7 pp 1262ndash1272 2009
[154] P Hochstein and L Ernster ldquoADP-activated lipid peroxidationcoupled to the TPNH oxidase system of microsomesrdquo Biochem-ical and Biophysical Research Communications vol 12 no 5 pp388ndash394 1963
[155] I I Gubskiı AGGoriushkoNV Litvinova et al ldquoAntioxidantproperties and membranotropic effect of certain derivatives of14-dihydropyridinerdquo Ukrainskiı Biokhimicheskiı Zhurnal vol71 no 4 pp 35ndash39 1999 (Russian)
[156] F Engineer and R Sridhar ldquoInhibition of rat heart andliver microsomal lipid peroxidation by nifedipinerdquo BiochemicalPharmacology vol 38 no 8 pp 1279ndash1285 1989
[157] T Goncalves A P Carvalho and C R Oliveira ldquoAntioxidanteffect of calcium antagonists on microsomai membranes iso-lated from different brain areasrdquo European Journal of Pharma-cology vol 204 no 3 pp 315ndash322 1991
[158] M E Letelier P Izquierdo L Godoy A M Lepe and MFaundez ldquoLiver microsomal biotransformation of nitro-aryldrugs mechanism for potential oxidative stress inductionrdquoJournal of Applied Toxicology vol 24 no 6 pp 519ndash525 2004
[159] M E Letelier P Entrala C Lopez-Alarcon et al ldquoNitroaryl-14-dihydropyridines as antioxidants against rat liver microsomesoxidation induced by ironascorbate Nitrofurantoin and naph-thalenerdquo Toxicology in Vitro vol 21 no 8 pp 1610ndash1618 2007
[160] F P Guengerich W R Brian M Iwasaki M-A Sari CBaarnhielm and P Berntsson ldquoOxidation of dihydropyridinecalcium channel blockers and analogues by human liver cyto-chrome P-450 IIIA4rdquo Journal of Medicinal Chemistry vol 34no 6 pp 1838ndash1844 1991
[161] S H Park S-W RhaW-Y Shin et al ldquoAS-160 Calcium channelblockers of dihydropyridine class reduce the antiplatelet effectof Clopidogrel what is clinical impactrdquo The American Journalof Cardiology vol 107 no 8 supplement p 47A 2011
[162] C Asma and D M Reda ldquoEvaluation of dihydropyridinecalcium antagonist effects on the stress bioindicator orga-nism Saccharomyces cerevisiaerdquo Annals of Biological Researchvol 4 no 10 pp 40ndash46 2013 httpscholarsresearchlibrarycomABR-vol4-iss10ABR-2013-4-10-40-46pdf
[163] G Gaviraghi A M Pastorino E Ratti and D G TristldquoCalcium channel blockers with antioxidant activityrdquo in Free
Radicals Lipoprotein Oxidation andAtherosclerosis G BellomoG Finardi E Maggi and E Rice-Evans Eds pp 431ndash456Richelieu Press London UK 1995
[164] G Gaviraghi AM Pastorino E Ratti and D G Trist ldquoAntiox-idant dihydropyridines a new and comprehensive therapy forfree radical-induced cardiovascular diseasesrdquo in Free Radicalsin Biology and Environment F Minisci Ed vol 27 of NATOASI Series pp 193ndash221 Springer Dordrecht The Netherlands1997
[165] P D Henry ldquoAntiperoxidative actions of calcium antagonistsand atherogenesisrdquo Journal of Cardiovascular Pharmacologyvol 18 supplement 1 pp S6ndashS10 1991
[166] F Kouoh B Gressier T Dine et al ldquoAntioxidant effects andanti-elastase activity of the calcium antagonist nicardipine onactivated human and rabbit neutrophilsmdasha potential antiath-erosclerotic property of calcium antagonistsrdquo CardiovascularDrugs andTherapy vol 16 no 6 pp 515ndash520 2002
[167] S Parthasarathy D Litvinov K Selvarajan and M GarelnabildquoLipid peroxidation and decompositionmdashconflicting roles inplaque vulnerability and stabilityrdquo Biochimica et BiophysicaActa vol 1781 no 5 pp 221ndash231 2008
[168] D-Q Liu Z-Q Pang D-H Zhao and B-H Sheng ldquoEffects offuryl-dihydropyridines I on lipid peroxides of ischemic myo-cardium and ATPases activity of erythrocyte membranes inratsrdquo Acta Pharmacologica Sinica vol 12 no 3 pp 253ndash2561991
[169] V Lukic-Panin T Kamiya H Zhang et al ldquoPrevention of neu-ronal damage by calcium channel blockers with antioxidativeeffects after transient focal ischemia in ratsrdquo Brain Research vol1176 no 1 pp 143ndash150 2007
[170] Y Allanore D Borderie H Lemarechal O G Ekindjian andA Kahan ldquoAcute and sustained effects of dihydropyridine-typecalcium channel antagonists on oxidative stress in systemicsclerosisrdquo American Journal of Medicine vol 116 no 9 pp 595ndash600 2004
[171] I Casetta V Govoni and E Granieri ldquoOxidative stress antioxi-dants and neurodegenerative diseasesrdquo Current PharmaceuticalDesign vol 11 no 16 pp 2033ndash2052 2005
[172] M J T J Arts Assessing antioxidant activity [PhD the-sis] Maastricht University Maastricht The Netherlands 2007httparnounimaasnlshowcgifid=8676
[173] G Dıaz-Araya L Godoy L Naranjo A Squella M E Letelierand L J Nunez-Vergara ldquoAntioxidant effects of 14-dihydro-pyridine and nitroso aryl derivatives on the Fe+3ascorbate-stimulated lipid peroxidation in rat brain slicesrdquo General Phar-macology The Vascular System vol 31 no 3 pp 385ndash391 1998
[174] Y Fukuhara K Tsuchiya Y Horinouchi et al ldquoProtectiveeffect of photodegradation product of nifedipine against tumornecrosis factor 120572-induced oxidative stress in human glomerularendothelial cellsrdquo Journal of Medical Investigation vol 58 no1-2 pp 118ndash126 2011
[175] W Stengel M Jainz and K Andreas ldquoDifferent potencies ofdihydropyridine derivatives in blocking T-type but not L-typeCa2+ channels in neuroblastoma-glioma hybrid cellsrdquo EuropeanJournal of Pharmacology vol 342 no 2-3 pp 339ndash345 1998
[176] O M Panasenko D J Tirzite G D Tirzitis and G J DubursldquoEffect of some 14-dihydropyridine derivatives on structuralorganization of erythrocyte membranesrdquo Biologicheskie Mem-brany (Biochemistry (Moscow) Series A Membrane and CellBiology) vol 1 pp 919ndash925 1984 (Russian)
[177] L G Herbette Y M H Vant Erve and D G Rhodes ldquoInter-action of 14 dihydropyridine calcium channel antagonists with
Oxidative Medicine and Cellular Longevity 33
biological membranes lipid bilayer partitioning could occurbefore drug binding to receptorsrdquo Journal of Molecular andCellular Cardiology vol 21 no 2 pp 187ndash201 1989
[178] L G Herbette P E Mason G Gaviraghi T N Tulenko andR P Mason ldquoThe molecular basis for lacidipinersquos unique phar-macokinetics optimal hydrophobicity results in membraneinteractions that may facilitate the treatment of atherosclerosisrdquoJournal of Cardiovascular Pharmacology vol 23 supplement 5pp S16ndashS25 1994
[179] G V Belevitch G Y Dubur G E Dobretsov N K Kurek andM M Spirin ldquoCalcium antagonists riodipine nifedipine andverapamil binding to model and biological membranes fluore-scence analysisrdquo Biologicheskie Membrany (Biochemistry(Moscow) Series A Membrane and Cell Biology) vol 5 pp768ndash776 1988 (Russian)
[180] R P Mason G E Gonye D W Chester and L G HerbetteldquoPartitioning and location of Bay K 8644 14-dihydropyridinecalcium channel agonist in model and biological membranesrdquoBiophysical Journal vol 55 no 4 pp 769ndash778 1989
[181] M Cindric A Cipak J Serly et al ldquoReversal of multidrugresistance inmurine lymphoma cells by amphiphilic dihydropy-ridine antioxidant derivativerdquo Anticancer Research vol 30 no10 pp 4063ndash4070 2010
[182] F Shekari H Sadeghpour K Javidnia et al ldquoCytotoxic andmultidrug resistance reversal activities of novel 14-dihydro-pyridines against human cancer cellsrdquo European Journal ofPharmacology vol 746 no 1 pp 233ndash244 2015
[183] X-F Zhou Q Shao R A Coburn and M E Morris ldquoQuanti-tative structure-activity relationship and quantitative structure-pharmacokinetics relationship of 14-dihydropyridines andpyridines as multidrug resistance modulatorsrdquo PharmaceuticalResearch vol 22 no 12 pp 1989ndash1996 2005
[184] R Berkels T Breitenbach H Bartels et al ldquoDifferent antioxida-tive potencies of dihydropyridine calcium channel modulatorsin various modelsrdquo Vascular Pharmacology vol 42 no 4 pp145ndash152 2005
[185] S Borovic G Tirzitis D Tirzite et al ldquoBioactive 14-dihydro-isonicotinic acid derivatives prevent oxidative damage of livercellsrdquo European Journal of Pharmacology vol 537 no 1ndash3 pp12ndash19 2006
[186] D Ya Rubene G D Tirzitis and G Ya Duburs ldquoInteractionof some 14-dihydropyridine derivatives with Fentonrsquos reagentrdquoLatvijas PSRZinatnuAkademijas Vestis Kimijas Serija Proceed-ings of the Latvian SSR Academy of Sciences Chemistry Seriespp 212ndash216 1982 (Russian)
[187] K Ondrias V Misık D Gergel and A Stasko ldquoLipid per-oxidation of phosphatidylcholine liposomes depressed by thecalcium channel blockers nifedipine and verapamil and bythe antiarrhythmic-antihypoxic drug stobadinerdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1003 no 3pp 238ndash245 1989
[188] I T Mak and W B Weglicki ldquoComparative antioxidant acti-vities of propranolol nifedipine verapamil and diltiazemagainst sarcolemmal membrane lipid peroxidationrdquoCirculationResearch vol 66 no 5 pp 1449ndash1452 1990
[189] I T Mak P Boehme and W B Weglicki ldquoProtective effects ofcalcium channel blockers against free radical-impaired endo-thelial cell proliferationrdquo Biochemical Pharmacology vol 50 no9 pp 1531ndash1534 1995
[190] S Ray S Mondal and N Dana ldquoEvaluation of protective roleof nifedipine on lipid peroxidation using reduced glutathione as
model markerrdquo Oxidants and Antioxidants in Medical Sciencevol 1 no 2 pp 97ndash100 2012
[191] M Yamato T Shiba T Ide Y Honda K-I Yamada andH Tsutsui ldquoNifedipine treatment reduces brain damage aftertransient focal ischemia possibly through its antioxidativeeffectsrdquoHypertension Research vol 34 no 7 pp 840ndash845 2011
[192] V Chander and K Chopra ldquoNifedipine attenuates changes innitric oxide levels renal oxidative stress and nephrotoxicityinduced by cyclosporinerdquo Renal Failure vol 27 no 4 pp 441ndash450 2005
[193] K M Gaafa M M Badawy and A A Hamza ldquoThe protectiveeffects of ascorbic acid cimetidine and nifedipine on diethyl-dithiocarbamate-induced hepatic toxicity in albino ratsrdquo Drugand Chemical Toxicology vol 34 no 4 pp 405ndash419 2011
[194] H Sugawara K Tobise and S Onodera ldquoAbsence of antiox-idant effects of nifedipine and diltiazem on myocardial mem-brane lipid peroxidation in contrast with those of nisoldipineand propranololrdquo Biochemical Pharmacology vol 47 no 5 pp887ndash892 1994
[195] I E Kirule D Y Rubene E A Bisenieks G D Tirzit and GY Dubur ldquo4-Nitrophenyl-14-dihydropyridinesmdasha new groupof inhibitors of peroxide oxidationrdquo Chemistry of HeterocyclicCompounds vol 18 no 3 p 316 1982
[196] G D Tirzit I E Kirule L K Baumane R A Gavar Y PStradynrsquo andG YDubur ldquoMechanism of the antioxidant actionof 26-dimethyl-35-dimethoxy-carbonyl-4-(2-nitrophenyl)14-dihydropyridinerdquoChemistry ofHeterocyclic Compounds vol 20no 8 pp 915ndash918 1984
[197] C Yanez C Lopez-Alarcon C Camargo V Valenzuela J ASquella and L J Nunez-Vergara ldquoStructural effects on thereactivity 14-dihydropyridines with alkylperoxyl radicals andABTS radical cationrdquo Bioorganic and Medicinal Chemistry vol12 no 9 pp 2459ndash2468 2004
[198] VMisik A J Stasko D Gergel and K Ondrias ldquoSpin-trappingand antioxidant properties of illuminated and nonilluminatednifedipine and nimodipine in heart homogenate and modelsystemrdquo Molecular Pharmacology vol 40 no 3 pp 435ndash4391991
[199] K Ondrias V Misık A Stasko D Gergelrsquo and M HromadovaldquoComparison of antioxidant properties of nifedipine and illu-minated nifedipine with nitroso spin traps in low densitylipoproteins and phosphatidylcholine liposomesrdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1211 no 1pp 114ndash119 1994
[200] A Stasko V Brezova S Biskupic K Ondrias and V MisıkldquoReactive radical intermediates formed from illuminated nife-dipinerdquoFree Radical Biology andMedicine vol 17 no 6 pp 545ndash556 1994
[201] K Ishizawa Y Izawa-Ishizawa N Yamano et al ldquoNitrosoni-fedipine ameliorates the progression of type 2 diabetic nephro-pathy by exerting antioxidative effectsrdquo PLoS ONE vol 9 no 1Article ID e86335 2014
[202] H Fujii and L J Berliner ldquoIn vivo EPR evidence for free radicaladducts of nifedipinerdquoMagnetic Resonance in Medicine vol 42no 4 pp 691ndash694 1999
[203] S Bollo S Finger J C Sturm L J Nunez-Vergara and JA Squella ldquoCyclic voltammetry and scanning electrochemicalmicroscopy studies of the heterogeneous electron transferreaction of some nitrosoaromatic compoundsrdquo ElectrochimicaActa vol 52 no 15 pp 4892ndash4898 2007
34 Oxidative Medicine and Cellular Longevity
[204] F Ursini ldquoTissue protection by lacidipine insight from redoxbehaviorrdquo Journal of Cardiovascular Pharmacology vol 30supplement 2 pp S28ndashS30 1997
[205] P G Cristofori F A Crivellente I Faustinelli et al ldquoInvolve-ment of the nitric oxide system in the anti-atheroscleroticpotential of lacidipine in the apoE-deficient mouse a mor-phological functional and electrochemical studyrdquo ToxicologicPathology vol 32 no 4 pp 493ndash499 2004
[206] X-P Zhang E L Kit S Mital S Chahwala and T HHintze ldquoParadoxical release of nitric oxide by an L-type calciumchannel antagonist the R+ enantiomer of amlodipinerdquo Journalof Cardiovascular Pharmacology vol 39 no 2 pp 208ndash2142002
[207] F Franzoni G Santoro F Regoli et al ldquoAn in vitro study of theperoxyl and hydroxyl radical scavenging capacity of the calciumantagonist amlodipinerdquo Biomedicine and Pharmacotherapy vol58 no 8 pp 423ndash426 2004
[208] S V Gatsura ldquoOxygen-dependent mechanisms underlying theantiischemic effect of verapamil and amlodipinerdquo Bulletin ofExperimental Biology and Medicine vol 137 no 1 pp 40ndash422004
[209] Y Hirooka Y Kimura M Nozoe Y Sagara K Ito and KSunagawa ldquoAmlodipine-induced reduction of oxidative stressin the brain is associated with sympatho-inhibitory effects instroke-prone spontaneously hypertensive ratsrdquo HypertensionResearch vol 29 no 1 pp 49ndash56 2006
[210] B Tomlinson and I F F Benzie ldquoAntioxidant effect of lercani-dipine (note)rdquo Hypertension vol 42 no 4 pp e10ndashe11 2003
[211] A A Faraqui ldquoNeurochemical aspects of 4-hydroxynonenalrdquoin Lipid Mediators and Their Metabolism in the Brain A AFaraqui Ed chapter 6 pp 159ndash191 Springer New York NYUSA 2011
[212] V S NascimentoM S DrsquoAlva A AOliveira et al ldquoAntioxidanteffect of nimodipine in young rats after pilocarpine-inducedseizuresrdquo Pharmacology Biochemistry and Behavior vol 82 no1 pp 11ndash16 2005
[213] O Ismailoglu P Atilla S Palaoglu et al ldquoThe therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjuryrdquo Turkish Neurosurgery vol 22 no 6 pp 740ndash746 2012
[214] M Matsubara and K Hasegawa ldquoBenidipine a dihydropy-ridine-calcium channel blocker prevents lysophosphatidyl-choline-induced injury and reactive oxygen species productionin human aortic endothelial cellsrdquo Atherosclerosis vol 178 no1 pp 57ndash66 2005
[215] M Matsubara K Yao and K Hasegawa ldquoBenidipine adihydropyridine-calcium channel blocker inhibits lysophos-phatidylcholine-induced endothelial injury via stimulation ofnitric oxide releaserdquo Pharmacological Research vol 53 no 1 pp35ndash43 2006
[216] MMatsubara and K Hasegawa ldquoEffects of benidipine a dihyd-ropyridine-Ca2+ channel blocker on expression of cytokine-induced adhesion molecules and chemoattractants in humanaortic endothelial cellsrdquo European Journal of Pharmacology vol498 no 1ndash3 pp 303ndash314 2004
[217] M Matsubara O Akizuki J-I Ikeda K Saeki K Yao and KSasaki ldquoBenidipine an anti-hypertensive drug inhibits reactiveoxygen species production in polymorphonuclear leukocytesand oxidative stress in salt-loaded stroke-prone spontaneouslyhypertensive ratsrdquo European Journal of Pharmacology vol 580no 1-2 pp 201ndash213 2008
[218] A C Rosenkranz H Lob T Breitenbach R Berkels and RRoesen ldquoEndothelial antioxidant actions of dihydropyridines
and angiotensin converting enzyme inhibitorsrdquo European Jour-nal of Pharmacology vol 529 no 1ndash3 pp 55ndash62 2006
[219] V Kain S Kumar and S L Sitasawad ldquoAzelnidipine preventscardiac dysfunction in streptozotocin-diabetic rats by reducingintracellular calcium accumulation oxidative stress and apop-tosisrdquo Cardiovascular Diabetology vol 10 article 97 2011
[220] K Nakamura S Yamagishi and H Inoue ldquoUnique atheropro-tective property of azelnidipine a dihydropyridine-based cal-cium antagonistrdquoMedical Hypotheses vol 65 no 1 pp 155ndash1572005
[221] TMatsui S Yamagishi K Nakamura S Kikuchi andH InoueldquoAzelnidipine a dihydropyridine-based calcium antagonistinhibits angiotensin II-induced oxidative stress generation anddownregulation of pigment epithelium-derived factor mRNAlevels in microvascular endothelial cellsrdquo Drugs under Experi-mental and Clinical Research vol 31 no 5-6 pp 215ndash219 2005
[222] C Ohmura H Watada T Shimizu et al ldquoCalcium channelblocker azelnidipine reduces lipid hydroperoxides in patientswith type 2 diabetes independent of blood pressurerdquo EndocrineJournal vol 54 no 5 pp 805ndash811 2007
[223] H Daikuhara F Kikuchi and T Ishida ldquoThe combination ofOLmesartan and a CAlcium channel blocker (azelnidipine) orcandesartan and a calcium channel blocker (amlodipine) intype 2 diabetic hypertensive patients theOLCA studyrdquoDiabetesand Vascular Disease Research vol 9 no 4 pp 280ndash286 2012
[224] MAbe NMaruyama KOkada SMatsumoto KMatsumotoand M Soma ldquoAdditive antioxidative effects of azelnidipine onangiotensin receptor blocker olmesartan treatment for type 2diabetic patients with albuminuriardquoHypertension Research vol34 no 8 pp 935ndash941 2011
[225] K Mizushige ldquoAntioxidative activities of thiazolidinedionesand dihydropyridine-type calcium antagonistsrdquo IRYOmdashJapa-nese Journal of National Medical Services vol 59 no 11 pp 581ndash592 2005
[226] S Manabe T Okura T Fukuoka and J Higaki ldquoAntioxidativeeffects of azelnidipine on mesangial cell proliferation inducedby highly concentrated insulinrdquo European Journal of Pharma-cology vol 567 no 3 pp 252ndash257 2007
[227] Y Koyama Y Takeishi H Takahashi et al ldquoAzelnidipine inhi-bits H
2O2-induced cell death in neonatal rat cardiomyocytesrdquo
CardiovascularDrugs andTherapy vol 21 no 1 pp 69ndash72 2007[228] K Shinomiya K Mizushige M Fukunaga et al ldquoAntioxidant
effect of a new calcium antagonist azelnipidine in culturedhuman arterial endothelial cellsrdquo Journal of International Med-ical Research vol 32 no 2 pp 170ndash175 2004
[229] T Ohyama K Sato K Kishimoto et al ldquoAzelnidipine is acalcium blocker that attenuates liver fibrosis and may increaseantioxidant defencerdquo British Journal of Pharmacology vol 165no 4 pp 1173ndash1187 2012
[230] L A Calo F Zaghetto E Pagnin P A Davis A Sempliciniand A C Pessina ldquoEffect of manidipine on gene expressionand protein level of oxidative stress-related proteins p22phoxand HO-1 Relevance for antihypertensive and anti-remodelingeffectsrdquo Journal of Cardiovascular Pharmacology vol 43 no 4pp 531ndash538 2004
[231] R Ghyasi G Sepehri M Mohammadi R Badalzadeh and AGhyasi ldquoEffect of mebudipine on oxidative stress and lipid per-oxidation in myocardial ischemic-reperfusion injury in maleratrdquo Journal of Research in Medical Sciences vol 17 no 12 pp1150ndash1155 2012
Oxidative Medicine and Cellular Longevity 35
[232] DCAndersson J Fauconnier T Yamada et al ldquoMitochondrialproduction of reactive oxygen species contributes to the 120573-adrenergic stimulation of mouse cardiomycytesrdquoThe Journal ofPhysiology vol 589 no 7 pp 1791ndash1801 2011
[233] A F Ceylan-Isik N Ari M Stefek et al ldquoEffects of a long-term treatment with an antioxidant pyridoindole on vascularresponsiveness in diabetes-induced aging ratsrdquo Current AgingScience vol 4 no 2 pp 150ndash157 2011
[234] S Saponara G Sgaragli and F Fusi ldquoQuercetin antagonismof Bay K 8644 effects on rat tail artery L-type Ca2+ channelsrdquoEuropean Journal of Pharmacology vol 598 no 1ndash3 pp 75ndash802008
[235] D A Sica ldquoInteraction of grapefruit juice and calcium channelblockersrdquo American Journal of Hypertension vol 19 no 7 pp768ndash773 2006
[236] P Mulder G Litwinienko S Lin P D MacLean L R CBarclay and K U Ingold ldquoThe L-type calcium channel block-ers Hantzsch 14-dihydropyridines are not peroxyl radical-trapping chain-breaking antioxidantsrdquo Chemical Research inToxicology vol 19 no 1 pp 79ndash85 2006
[237] L J Nunez-Vergara R Salazar C Camargo et al ldquoOxidation ofC4-hydroxyphenyl 14-dihydropyridines in dimethylsulfoxideand its reactivity towards alkylperoxyl radicals in aqueousmediumrdquo Bioorganic and Medicinal Chemistry vol 15 no 12pp 4318ndash4326 2007
[238] M E Ortiz L J Nunez-Vergara and J A Squella ldquoRelativereactivity of dihydropyridine derivatives to electrogeneratedsuperoxide ion in DMSO solutions a voltammetric approachrdquoPharmaceutical Research vol 20 no 2 pp 292ndash296 2003
[239] M E Ortiz L J Nunez-Vergara C Camargo and J A SquellaldquoOxidation of Hantzsch 14-dihydropyridines of pharmacolog-ical significance by electrogenerated superoxiderdquo Pharmaceuti-cal Research vol 21 no 3 pp 428ndash435 2004
[240] R S Raghuvanshi and K N Singh ldquoSuperoxide induced oxida-tive aromatization of Hantzsch 14-dihydropyridinesrdquo IndianJournal of Chemistry Section B Organic and Medicinal Chem-istry vol 47 no 11 pp 1735ndash1738 2008
[241] I Kruk A Kladna K Lichszteld et al ldquoAntioxidant activityof 4-flavonil-14-dihydropyridine derivativesrdquo Biopolymers vol62 no 3 pp 163ndash167 2001
[242] G D Tirzit I M Byteva K I Salokhiddinov G P Gurinovichand G Y Dubur ldquo14-Dihydropyridine derivatives as deactiva-tors of singlet oxygenrdquo Chemistry of Heterocyclic Compoundsvol 17 no 7 pp 682ndash684 1981
[243] G D Tirzit E Y Kazush and G Y Dubur ldquoInfluence of14-dihydropyridine derivatives on the generation of hydroxylradicalsrdquo Chemistry of Heterocyclic Compounds vol 28 no 4pp 435ndash437 1992
[244] N A Pizarro-Urzua and L J Nunez-Vergara ldquoNifedipine andnitrendipine reactivity toward singlet oxygenrdquo Journal of Photo-chemistry and Photobiology A Chemistry vol 175 no 2-3 pp129ndash137 2005
[245] L-F Wang H-Y Zhang L Konga Z-W Chena and J-G ShildquoDFT calculations indicate that 14-dihydropyridine is a promis-ing lead antioxidantrdquo Helvetica Chimica Acta vol 87 no 6 pp1515ndash1521 2004
[246] P Mulder H-G Korth and K U Ingold ldquoWhy quantum-thermochemical calculations must be used with caution toindicate lsquoa promising lead antioxidantrsquordquoHelvetica Chimica Actavol 88 no 2 pp 370ndash374 2005
[247] K Yao Y Ina K Nagashima K Ohmori and T Ohno ldquoAntiox-idant effects of calcium antagonists in rat brain homogenatesrdquo
Biological and Pharmaceutical Bulletin vol 23 no 6 pp 766ndash769 2000
[248] T Matsui S-I Yamagishi K Nakamura and H Inoue ldquoBayw 9798 a dihydropyridine structurally related to nifedipinewith no calcium channel-blocking properties inhibits tumournecrosis factor-120572-induced vascular cell adhesion molecule-1expression in endothelial cells by suppressing reactive oxygenspecies generationrdquo Journal of International Medical Researchvol 35 no 6 pp 886ndash891 2007
[249] K AMitrega B VargheseM Porc and T F Krzeminski ldquoAnti-arrhythmic and hemodynamic effects of oxy nifedipine oxynimodipine oxy nitrendipine and oxy nisoldipinerdquo Pharmaco-logical Research vol 66 no 4 pp 300ndash308 2012
[250] V Herbert ldquoSymposium prooxidant effects of antioxidantvitamins Introductionrdquo The Journal of Nutrition vol 126 no4 supplement pp 1197Sndash1200S 1996 httpjnnutritionorgcontent1264 Suppl1197Sfullpdf
[251] B Halliwell ldquoAre polyphenols antioxidants or pro-oxidantsWhat do we learn from cell culture and in vivo studiesrdquoArchives of Biochemistry and Biophysics vol 476 no 2 pp 107ndash112 2008
[252] C Winterbourn Pro-Oxidants or Antioxidants ChristchurchSchool of Medicine Depatment of Pathology Free RadicalSchool SFRBMUniversity of Otago San Francisco Calif USA2009 httpwwwsfrbmorgfrsWinterbournpdf
[253] A Morakinyo B Iranloye and O Adegoke ldquoCalcium antag-onists modulate oxidative stress and acrosomal reaction in ratspermatozoardquo Archives of Medical Science vol 7 no 4 pp 613ndash618 2011
[254] The Alpha-Tocopherol Beta Carotene Cancer Prevention StudyGroup ldquoThe effect of vitamin E and beta carotene on theincidence of lung cancer and other cancers in male smokersrdquoTheNew England Journal of Medicine vol 330 no 15 pp 1029ndash1035 1994
[255] B Poljsak ldquoStrategies for reducing or preventing the generationof oxidative stressrdquo Oxidative Medicine and Cellular Longevityvol 2011 Article ID 194586 15 pages 2011
[256] B Poljsak and I Milisav ldquoThe neglected significance of lsquoanti-oxidative stressrsquordquoOxidativeMedicine and Cellular Longevity vol2012 Article ID 480895 12 pages 2012
[257] T Godfraind and S Salomone ldquoAmbiguities in dietary antiox-idant supplementation compared to calcium channel blockerstherapyrdquo Frontiers in Pharmacology vol 6 article 10 2015
[258] H Wagner H Norr and H Winterhoff ldquoDrugs with adap-togenic effects for strengthening the powers of resistancerdquoZeitschrift fur Phytotherapie vol 13 no 2 pp 42ndash54 1992
Oxidative Medicine and Cellular Longevity 3
increase mortality (2) when present at high doses antioxi-dants become prooxidant (3) theoretically antioxidants can-not behave as such (4) once used antioxidants are inactive(5) antioxidant drugs do not work
The first three ldquoprosrdquo clearly cross the line of realistic wayof thinking and cannot be considered seriously The ldquoprordquo4 was very informatively discussed by Pompella et al [22]who comprehensively presented current problems with themethods (ORAC oxygen radical absorbance capacity ferric-reducing ability of plasma and TEAC Trolox equivalentantioxidant capacity) routinely used formeasurement of totalantioxidant capacity (TAC) in plasma (Pompella et al 2014[22]) These include lack of needed specificity especially rel-evant for ORAC related measurements Instead precise mea-surement of specific compounds is recommended Regardingthe ldquoprordquo 5 the situation does not seem entirely clearas some published metastudies related to protective role ofvitamin C in coronary heart disease showed some contra-dictions (better protection with dietary vitamin C versussynthetic vitamin C) (Ye and Song [23] Knekt et al [24])In any event this kind of research is anything but simple asobserved health effects of fruit and vegetable ingestion arecertainly related not only to the content of vitamin C butalso to other macro- and micronutrients and phytochemi-cals proven to confer additional health benefits (Carr andVissers [25]) Similar to ldquoprosrdquo stated ldquocontrasrdquo seem to bea common misconcept related to the design of the study (thisis especially relevant for epidemiological studies) relevanceof a specific pathological condition and measurement of itsoutcomes and finally complexity of a living organism Forall these reasons there is the realistic need for well-designedepidemiological clinical and molecular studies that wouldoffer firm evidence and undoubtful conclusions on the role ofantioxidants on human health (see also Sections 38 and 39)
There are still unanswered questions related to oxidativestress and its mediators in pathogenesis of OS-associateddiseases However it is clear that overproduction of ROShas harmful cellular effects For that reason small syntheticantioxidants molecular scavengers have been developed tobe used in various pathological conditions The first oneimplemented in the clinic for acute brain infarction was3-methyl-1-phenyl-2-pyrazolin-5-one (MCI-186 EdaravoneRadicut norphenazone) approved until now only in Japan(Tabrizchi 2000 [26]) So far its free radical scavengingproperties were revealed by various biological effects (antiox-idant attenuation of cytokine production antiapoptoticantinecrotic and some other effects) as recently reviewed(Kikuchi et al [27])
3 14-Dihydropyridines A SeparateGroup of Bioantioxidants
14-Dihydropyridines could be used as model compounds forstudying molecular mechanisms of action modulated by cel-lular enzymes NADH and NAD(P)H due to their structuralanalogy to 14-dihydronicotinamide [28] This structure rep-resents the active part of these reduced coenzymes which areimportant modulators of various enzymatic redox reactionsand are involved in electron transfer
Chemically 14-dihydropyridines are synthetic hydro-genated N-heteroaromatic compounds They may have var-ious substituents at positions 26- 35- and 14- (Figures1ndash3) Their derivatives can be obtained synthetically in theHantzsch type cyclic condensation reactions
Bossert and Vater [29] postulated DHPs as a basis fordevelopment of new cardiovascular drugs Today there aremany marketed drugs which contain 14-DHP ring as basicscaffold [30ndash32] (Figures 1 and 2)
Grover et al [33] classified dihydropyridine nucleus (skel-eton) as a novel pharmacophore and offered some examplesrelated to DHPs pleiotropy So far AOAs have been revealedfor several groups of DHP compounds andDHP-based drugs[34ndash36] contributing to their well-known pleiotropic ways ofaction (antiaging neuroprotective anticancer antibacterial[37] and many more) These features are promising fordevelopment of novel drugs in the future [32 38]
It is well known that hydrogen donors such as aminesthiols (aminothiols) or phenols (plant phenols and polyphe-nols aswell as synthetic hindered phenols) act as antioxidantsprimarily through inhibition of oxidation reactions of variouschemical targetssubstrates Similarly depending on theirparticular chemical structure 14-dihydropyridines have sig-nificant hydrogen donor ability (see further in Section 32)This feature allows them to act as direct inhibitors of freeradical reactions It further classifies them as specific group ofdihydropyridine type of antioxidantsHowever under certainconditions primarily dependent on individual structure andapplied dose DHPs can act as prooxidants (see further inSection 38)
On the other hand some DHPs may exert synergisticeffects when applied together with other types of AOs [39]They can also be involved in the redox regulation of Ca2+ion channels [40] Namely oxidative stress characterized bysignificant increase of ROS closely relates to cellular imbal-ance of Ca2+ ions Such a CA activity of DHPs can also resultin the indirect OS modulation as an additional positive sideeffect Accordingly DHPs acting as CA and as antioxidantsmay modify various OS-associated pathological processes byinfluencing cellular redox signaling potential Additionallymultiple biological effects of DHPs attenuating OS could beimportant at drug-drug interactions by combination therapyusing DHPs and other CA andor antioxidants
It should be mentioned that the studies on the possibleAOA of 14-DHPs have begun due to the assumption thatthese substances could be useful for the design for novelantioxidants intended to be used primarily in the food tech-nology notably as animal chow stabilizers [41ndash43]TheAOAsof 14-dihydropyridine derivatives 26-dimethyl-35-dieth-oxycarbonyl-14-dihydropyridine (Hantzsch ester (HEH)diludine) and its close analogues 4-unsubstituted 14-DHPswere discovered by Latvian scientists that intended to usethem for the termination of the lipid peroxidation (LPO) invarious chemical lipid substratesmixtures target (solutionsemulsions and liposomes) [44 45] Afterwards antioxi-dant properties of several calcium antagonists DHPs werediscovered [31 46ndash53] Interestingly research on the AOAof DHPs on LPO continues nowadays including several
Figure 1 Structures of the most known 14-dihydropyridine derivatives and some non-DHP Ca2+ antagonists
interdisciplinary projects funded by EU in particular theCOST B35 action [51 52]
31 Synthesis of 14-Dihydropyridines Routes and ApproachesClassical 3-component Hantzsch synthesis of DHP com-pounds [54ndash57] is usually performed in solutions (includingionic liquids) by heating Discoveries related to this process
and published between 1986 and 1990 are summarized in thereview of Sausins and Duburs [57] In 1993 Kazda [58] hasreviewed ldquotwenty years of dihydropyridinesrdquo including theirsynthesis chemistry progress in pharmacology and therapyand some other applications Since then there were manyimportant discoveries in this field and there is a time fora review on ldquoanother twenty years of DHPsrdquo It has to be
Oxidative Medicine and Cellular Longevity 5
NH
Lercanidipine
NH
Cl
Felodipine
Cl
NH
Lacidipine
NH
Nicardipine
NH
Isradipine
NO
N
NH
COO
Azelnidipine
N
NH
Bay O 5572
NH
COO
Benidipine
N
NH
Manidipine
N N
NH
NC
Nivaldipine
NH
COOC(CH3)3
COOCH(CH3)2
Mebudipine
N
S
O
Diltiazem
N
S
O
O
H
O
Semotiadil
NH
COO
Barnidipine
N
H3C
H3C H3C
H3C
H3C
H3C
H3C
H3CO
H3C
H3C
H3C
H3CCH3
CH3 CH3CH3
CH3
CH3
OCH3
OCOCH3
CH3
CH3
CH3
CH3CH3
NH2
CH3
NO2NO2
H3COOC
H3COOC H3COOC
H3COOC
H3COOC
H3COOC
H3COOC
H3COOC H3COOC
H3COOCCOOC(CH3)2CH2N(CH3)CH2CH2CHPh2
COOCH(CH3)2
N(CH3)COOCH2 CH2CH2 Ph
COOC2H5 COOC2H5C2H5OOC
COOC(CH3)3
NO2NO2
NO2NO2
NO2
NO2
NO2
CH2Ph
CH2Ph
CH 2Ph
CH 2Ph
COO(CH2)7CH3(H3C)2HCOOC
COOCH2CH2
O(CH2)3N(CH3)CH2CH2O
N(CH3CH )2 2CH2
Figure 2 Structures of the most known 14-dihydropyridine derivatives and some non-DHP Ca2+ antagonists
mentioned that nearby this classical multicomponent synthe-sis also a process to obtain structurally diversified 14-dihyd-ropyridines at sophisticated conditions was recently reviewedby Wan and Liu [59]
Many discoveries relevant for novel routes in DHPdesigning and synthesis were published and deposited in
various databases (see httpwwworganic-chemistryorgnamedreactionshantzsch-dihydropyridine-synthesisshtm[60]) For example httpwwwscifindercom [1] databaselists approximately 1000 citations on the simple DHP com-pound diludine Reaxys database [61] contains data relatedto variations in starting materials intermediates as building
6 Oxidative Medicine and Cellular Longevity
NH
SCH3
CN
Cl
O
NH
SCH3 SCH3 SCH3
CN
O
NH
CN
O
NH
CN
OCl OCHF2 OCHF2
OSI-3701OSI-9642OSI-3761OSI-1146
H3C
H3C H3C
H3C H3C H2N
H3C H3C
Figure 3 Molecular structures of OSI-1146 OSI-3701 OSI-3761 and OSI-9642 (according to [146])
blocks media and reactions routes Water and ionic liquidsas reaction media microwave and infrared irradiation newcatalysts solid phase synthesis and biotechnology based andgreen chemistry approaches were also proposed as attractiveoptions for syntheses of DHPs [62ndash66]
Furthermore several new dihydropyrimidin-(2H)-ones(DHPMs) close analogues of DHPs were prepared in theBiginelli reaction under ultrasound irradiation and in thepresence of NH
4Cl Some of these compounds when tested
in vitro at concentrations higher than 100 120583M [67] showedAOAs manifested as inhibition of LPO induced by complexFe + EDTA and reduction of ROS levels
Recently Sun et al [68] reported about the synthesis andantioxidant activity of a series of novel 3-chalcone-substituted14-dihydropyridine derivatives based on dimethyl or diethyl26-dimethyl-4-phenyl-14-DHP-35-dicarboxylate
32 14-Dihydropyridines as Hydrogen Donors Steric elec-trostatic and hydrophobic descriptors in DHP moleculecould serve as its potential pharmacophores [2] In caseof Hantzsch ester this implies partly hydrogenated N-heteroaromatic DHP nucleus itself or its fragments that isNH group or C-4 H- atom as hydrogen donors necessaryfor the AO activity andor carboxylic ester side groups (itsC=O group and O atom as hydrogen bond acceptors) inpositions 3- and 5- and alkyl side groups in positions 2-and 6- (as hydrophobic features) (Grover et al [33] andTikhonov and Zhorov [69]) The presence of labile hydrogenatoms (mainly in positions 14-) in DHPs molecule assignssignificant hydrogen donating ability to these compounds
DHPs (26-dimethyl-14-dihydropyridine-35-dicarboxy-lic acid esters) can be oxidized in chemical (Dubur andUldrikis [70]) electrochemical enzymatic (Duburs et al[71]) and biological (including metabolism and biotransfor-mation) systems As already stated dihydropyridines (espe-cially unsubstituted in position 4) may transfer the hydro-gen similar to the reduced diphosphopyridine nucleotidesNADH and NADPH (Scheme 1) (Mauzerall and Westheimer[28]) while HEH hydrogen transfer studies and search fornovel NADHmodel compounds are continuously developing(Xie et al [72])
Tamagaki et al [73] observedmetal-ion-facilitated oxida-tions ofDHPswithmolecular oxygen andhydrogenperoxideOn the other side Tirzite et al [74] studied some 14-DHP derivatives as reductants in relation to trivalent iron
Hantzsch esters have been extensively utilized as stoichio-metric biomimetic reducing agents Recent summarized lit-erature about DHPs as reducing agents including referenceson diludine may be found on specialized websites httpwwworganic-chemistryorgchemicalsreductions [75]
DHPs form free radicals in chemical electrochemicaland biological oxidation processes The kinetic parametersand pathways of decay of the cationic radicals formed asprimary products in the course of electrooxidation of theesters of 12- and 14-dihydropyridine have been extensivelystudied [76]
The regenerative system of nicotinamide cofactors mayinvolve oxidizing or reducing reagents regulating enzymesand photochemical reactions Thus in situ regenerationof the consumed cofactors was observed in the biosys-tems engineering which create superior biocatalysts by thereduction of NAD(P)+ which can lead to the 14-DHPproduct (which is the only active form) and to the 16-DHP compound [77] The NADPH models of HEHs can beregenerated in situ as biomimetic hydrogen sources bymeansof transition metalBroslashnsted acid catalyzed relay asymmetrichydrogenation [78] General regeneration strategies werereviewed by Chenault and Whitesides [79] Based on thesestrategies particularly related to methods of preparation andpractical use of esters of 26-dimethyl-14-dihydropyridine-35-dicarboxylic acid as antioxidants that might be probablyapplicable for radioprotection and adjuvant treatment againstmetastases several patents were prepared [80]
Sambongi et al [81] have found that the novel water-soluble Hantzsch 14-dihydropyridine compound (the potas-sium salt of 26-dimethyl-14-dihydropyridine-35-dicar-boxylic acid monomethyl ester) functions in biological pro-cesses through regeneration of NADH Various parametersrelated to nicotinamide coenzymes regeneration especiallyin a light of chiral compounds have been published recently[82] while Okamura et al [83] reported the use of theoxidative conversion of dihydropyridine to pyridinium ionand the metabolic trapping principle as an approach formeasuring in vivo cerebral redox states
33 Antioxidant Activity (AOA) and Antiradical Activity(ARA) of 14-Dihydropyridines Antioxidative activity of 14-DHPs was first evaluated and studied in the Latvian IOS(Tirzit and Duburs [39] Zilber et al [44] and Dubur et al[45])
Oxidative Medicine and Cellular Longevity 7
N
O O
N
O O
R R
N
O Ominuseminus minuseminusminuseminus
minusH+
minusH+minusHminus
minusH∙
R998400(H)R998400H R998400(H)
oplus
R=H
Scheme 1 Reactions of 14-dihydropyridines leading to the formation of pyridine derivatives
In the field of ARA pioneering work was made by Schel-lenberg and Westheimer [84] in 1965 In 1979 Schellenberg[85] revealed the free radical oxidation of a dihydropyridinefollowing Huyser et al [86] who reported hydroxyl radicalquenching by DHPs especially Hantzsch ester studying freeradical oxidation of DHPs in vitro in the Fenton system
AOA and ARA of various 14-DHPs were further studiedby several different methods in both in vitro and ex vivoinvivo systems [3 31 44ndash53] CA nisoldipine nimodipinenitrendipine nifedipine and nicardipine have AOA thatcorrelates with their lipophilicity (modified Buege and Austrsquosmethod of TBA determination applied in model of rat braincortex ischemiareperfusion) [87]
N-Aryl-DHPs designed as sirtuin activators were furtherreported as suitable agents for neuroprotection due to theirradical avoidance properties (Hardeland [88])
14-DHPs inhibit free radicals and consequentially thecascade of events related to lipid peroxidation They mayinfluence several stages (initiation andor propagation) of thelipid peroxidation cascade which consist of sim10 reactions[89] (detailed discussion in Section 331 (2)-(b) Scheme 2)
However considering the great number of AO com-pounds (including DHPs) and the diversity in their actionmechanisms [90] in vivo studies are not always convincingand conclusive Therefore concise in vitro models are neces-sary to screen each compound with antioxidative propertiesAntioxidants are designed to react readily with oxidizingspecies and are often extensively oxidized already duringincubations at atmospheric oxygen tension (oxidation ofsome water-soluble DHPs in water (buffer) solutions is veryfast especially in the presence of light) Even during arelatively short incubation period the concentration can dropdrastically and the real potency of the compound could beunderestimated [90]
331 Common AOA and ARA Features of Some DHPs
(1) In Vitro (in Solutions Emulsions and Liposomes) Basicmolecular principles related to antioxidative and antiradi-cal activity of various antioxidants including DHPs werepublished recently [91] These data show that DHPs reactwith various types of free radical species stable free radicals(DPPH ao) and alkyl radicals and with oxygen and nitrogenfree radicals Some derivatives of DHPs may quench a singletoxygen and may react with peroxynitrite anion [92ndash95]
Reactivity of DHPs toward alkyl radicals was studiedelectrochemically [96]
The activity against DPPH radical was found for the5-acetyl-2-alkylthio-4-aryl-6-methyl-14-dihydropyridine-3-carboxylic acid nitriles [97] structural analogues of the5-acetyl(carbamoyl)-6-methylsulfanyl-14-DHP-carbonitrile(studied as mitochondriotropic compounds see further inthe text Section 331 (2)-(b))The highest antiradical activityoccurred for a compound which contains two hydroxylgroups in the 4-phenyl substituent
DHPs were proved to decrease oxygen uptake (2-3-fold) in the heme (methemoglobin hematin hemin andcytochrome C) catalysis by oxidation of emulsions of estersof unsaturated fatty acids and liposomes of phospholipidphosphatidylcholine (Zilber et al [44] and Dubur et al [45])
Reactivity of nitrosoaryl and nitroaryl derivatives of 14-DHPs toward alkyl alkylperoxyl radicals and ABTS radicalcation was found in various LP modeling systems suitablefor determination of DHPs AOA and ARE features [98ndash104] Diludine and foridone and its analogues were shown toinhibit lipid peroxidation through inhibitory effect on lipoxy-genase in emulsions and in reversed micelles (Tsetlin et al[105] and Panek et al [106]) In addition to inhibition of ther-mally initiated oxidation of methyloleate in the solution [107](where AOA of 4-unsubstituted 35-dicarbonylderivativesof 26-dimethyl-14-DHPs is not linearly dependent onthe inhibitor concentration) DHPs derivatives containinghydroxy alkoxy or dimethylaminophenyl substituents inposition 4 were shown to prevent loss of 120573-carotene in thedisperse system of 120573-carotene and methyllinoleate (Plotnieceet al [108])
The AOA of DHPs has been detected using differentmethods in various systems where lipid free radical gen-eration (nonenzymatic Fe2+-dependent andor enzymaticNADPH-dependent) took the place [109ndash112] This activitywas further confirmed in vivo through prevention of damagecaused by renal ischemia and reperfusion as shown fordiludine [113]
Some redox properties of calcium antagonist dihydropy-ridines were revealed through electroanalytical studies [114]Competitive kinetic procedure was used for exploring theAO capacity of five (four 14-DHPs lacidipine felodipinenifedipine and amlodipine and one 12-DHP compoundGR44966) CA and one calcium ion agonist (Bay K 8644) Allbut one (amlodipine) antagonist displayed an unambiguousAO capacity (crocin test) The calcium agonist DHP revealedno reaction with peroxyl radicals Lacidipine was the mosteffective A calcium agonist Bay K 8644 is quite resistant tooxidation and does not bind H+ This could be important
8 Oxidative Medicine and Cellular Longevity
fact in the interaction with the target proteins (it should bementioned that there are no studies on LP with other Ca2+agonists)
The decreased oxidation potential correlates with AOcapacity and increased basic characterThese findings suggestthe relevance of the electron density on the DHP ring
For all the DHP compounds investigated the overalloxidation process proceeds through two consecutive one-electron releases a primary one-electron step accompaniedby a fast proton release and the formation of a neutral radical(PyH∙) undergoing a second much easier one-electron step[114]
The final product is the protonated form of the parentpyridine derivative This pattern is relevant for the antioxida-tive activity since the radical intermediate is far less prone tobe reduced than oxidized
In the case of CA DHPs the release of protons compli-cates the overall oxidation process by introducing a ldquopara-siticrdquo side reaction where a coupling between protons and thestarting species takes place
This DHP self-protonation subtracts part of the originalspecies from the electrode process because the parent cationicspecies are no longer electroactive
Conversely the calcium agonist DHP which is less proneto be oxidized turned out to be so weak base to be evenunable to undergo the self-protonation reaction
Thus the combined effect of oxidation potentials andproton binding capacity of DHPs is a key element for theredox transition relevant for their AO activity Yet opposingeffects (antagonistic versus agonistic) on protein targets ascalcium ion channels connected with protein thiol oxidationto disulfide should be also considered [114]
Kourimska et al [115] found AO effect of diludine (HEH)in edible oil Reactivity of 14-DHPs toward SIN-1-derivedperoxynitrite was shown by Lopez-Alarcon et al [116] Oleket al [117] discovered antioxidative activity of NADH and itsanalogue in vitro
Further see as referred in several subparts below Sections34 35 and 37
(2) Ex Vivo (on Lipid Peroxidation in LDL MitochondriaMicrosomes and Cells) Main chemical structures of DHPsexamined in numerous studies and reviewed in this paper arepresented in Figures 1 and 2
(a) Various DHPs Calcium Antagonists as Inhibitors of LDLPeroxidation Free radicals induce peroxidation of LDLThis process proceeds by a chain mechanism which revealsphosphatidylcholine hydroperoxides and cholesteryl esterhydroperoxides as themajor primary products [118] Calciumantagonist DHPs could act as antioxidants on LDL at leastin three ways (1) as inhibitors of isolated LDL peroxi-dation caused by various inducers (Cu2+ ions UV lightand xanthinexanthine oxidase system) (2) if preincubatedwith cells preventing against intracellular LDL oxidation (3)preventing against the harmful effect of oxidized LDL on cellsand decreasing cytotoxicity [119ndash131]
Combined application of ascorbic acid and CA DHPs(amlodipine and felodipine) has an additive (cytoprotective
and LDL antioxidant activity) effect [120] It includes acombination of peroxide-degrading and peroxyl radical scav-enging reactions thus demonstrating the importance of LPduring LDL oxidation and cytotoxicity induced by oxidizedLDL Cytoprotection is associated with inhibition of oxidant-induced increases in intracellular free calcium
Similar to the othermodel systems the recorded values ofthe tested DHPs related to AO activity on LDL LP and relatedevents [119ndash131] depend on the prooxidant model system andmethods used for activity measuring (see Tables 1ndash5)
Commercial Ca2+ antagonists (including 14-DHP deri-vatives) as well as some other 14-DHPs with less CA activitywere shown to decrease the rate of oxidation (detected asTBARS) of low-density lipoprotein (LDL) induced by Cu2+ions (CuSO
4) in two different cell lines U937 human mono-
cyte-like and J774A1 murine monocyte-macrophage cellline (Rojstaczer and Triggle [119]) The strongest effect wasrecorded for vitamin E followed by felodipine 2-Cl analogueof nifedipine nifedipine amlodipine nitrendipine vera-pamil and diltiazem
Rojstaczer and Triggle [119] found that CA from differentchemical groups had a concentration-dependent effect asantioxidants against LDL oxidation (see Table 1) Howeverthe order of potency (activity rank order ARO) of the drug(s)again depends on the oxidation system and the antioxidantassay Both CA and antioxidative effects relate to the 2- (or o-orto-) substituent of the 4-phenyl ring in the same potencyorder 119900 gt 119898 ≫ 119901 [119] On the other hand the require-ment for the 14-DHP ring is essential for both AOA andCa2+channel antagonism A charged substituent at the position C-2 of the 14-DHP ring influences the AO activity (analogousto [46ndash53]) However some other factors should not beneglected for example although amlodipine has a positivelycharged amine at this position this modificationmakes it lesslipophilic and indirectly less potent antioxidant
Similar results were obtained when testing antioxidanteffect of CA on LDL peroxidation in bovine aortic endothelialcells (BAECs) (Cominacini et al [123] see Tables 2 and 3) aswell as in HUVECs (Lupo et al [129]) (see Table 4)
Cominacini et al [123] observed antioxidant effect ofCCBs and 120572-tocopherol in BAECs The order of potency(see Tables 2 and 3) [123] was however different than inU937 human monocyte-like and J774A1 murine monocyte-macrophage cells (see Rojstaczer and Triggle [119] Table 1)The tested DHPs were lacidipine amlodipine lercanidipinenimodipine and nifedipine (in two different intracellularconcentrations 2 and 4 fmol) ROS production was signif-icantly lowered only by lacidipine (which is the compoundwith the highest lipophilicity) and lercanidipine the effectof lacidipine was much more evident than lercanidipineSurprisingly amlodipine nimodipine and nifedipine had noeffect on ROS formation suggesting that the positive effectson the earliest events of atherosclerosis are a peculiarity oflacidipine molecule through its antioxidant activity
The strong AO action of lacidipine may be related tothe lipophilic cinnamic acid side chain which favors a drugpartitioning in the membrane due to favorable physicochem-ical (hydrophobic) interactions of drug hydrophobic residues
Oxidative Medicine and Cellular Longevity 9
Table 1 Relative structure-function relationships of calcium antagonists (DHPs verapamil and diltiazem) and vitamin E Effect on oxidativemodification of isolated ex vivo human low-density lipoprotein using two various oxidation systems (copper (II) ions induced and monocyteinduced) Compiled according to data presented by Rojstaczer and Triggle [119]
Compound
Systems of LDL oxidation
Copper (II) ions induced system (comparison of three methods) Monocyte induced celloxidation system
Methods
Reduction of TBARS level of LDL(relative efficacy)
Degradation of oxidized[125I] LDL by J774
macrophages
Relative electrophoreticmobility of LDL on
agarose gel
TBARS content of LDL(in )
Relative efficacy (activity rank order (ARO) ARO = I for the most effective) effective inhibitor concentration [IC] in120583M
with polyunsaturated groups of membrane phospholipidsHowever DHPs can also reduce the oxLDL-induced ROSconcentration by affecting some intracellular ROS producerssuch as NADPH oxidases xanthine oxidase and cyclooxyge-nase enzymes The activity of these enzymes contributes tointracellular ROS elevation [125]
Preincubation of HUVECs with lacidipine inhibited anincrease of intracellular ROS caused by oxidized LDL [124]
Lupo et al [129] have studied the dose-dependent (1 510 and 50 120583M) AOA of various CA (verapamil diltiazemand DHPs nifedipine amlodipine isradipine or lacidipine)
Table 3Modulation of ROS formation in BAECs by CA (DHPs andverapamil) and vitamin E Compiled according to data presented byCominacini et al [123]
Compound
Method of flow cytometry (reduced2101584071015840-dichlorofluorescein diacetate(DCFH-DA) oxidation by ROS)
Activity rank order(ARO = I for the highest activity ARO = III for
the mindest activity)(Effective [IC] 1 5 10 50 120583M)
Lacidipine + + + (ARO = I)Lercanidipine + + (ARO = II)Amlodipine No effectNifedipine No effectNimodipine No effectVerapamil + (ARO = III)120572-Tocopherol + + + (ARO = I)
against normolipidemic human blood LDL oxidation com-pared with 120572-tocopherol by measuring the content of TBARSand the diene formation (see Table 4)
10 Oxidative Medicine and Cellular Longevity
Table 4 Normolipidemic human blood LDL (025mgmL) in vitro oxidation in the presence of 5 120583M CuSO4and CA of 3 types (DHPs
verapamil and diltiazem) and vitamin E Compiled according to Lupo et al [129]
Compound
MethodsTBARS method (fluorimetry at 515 nm533 nm 4 hours
preincubation of LDL with compounds and copper (II)ions 320 TBARS increase in control during 4 h
period)
Inhibition of conjugated diene formation (at 234 nm)expressed as prolongation of induction period (in
of control) 119905contr = 368min
Effective [IC] (in 120583M)1 120583M 10120583M 50 120583M
Activity rank order (ARO= I for the highest activity
ARO = VII for themindest activity)
Effective [IC] (in 120583M)1 120583M 5 120583M 10120583M 50 120583M
Activity rank order (ARO= I for the highest activity
ARO = VII for themindest activity)
Nifedipine 10120583M50 120583M ARO = III
5 120583M10120583M 15050 120583M 213
ARO = III
Amlodipine 50 120583M ARO = IV5 120583M
10120583M 12250120583M 138
ARO = IVndashVI
Isradipine 50 120583M ARO = VI 10120583M 15050 120583M 183 ARO = IVndashVI
Lacidipine1 120583M10120583M50 120583M
ARO = II5 120583M
10120583M 19250 120583M 283
ARO = II
Verapamil 50 120583M ARO = V 10120583M 15050 120583M 178 ARO = IVndashVI
Diltiazem No effect No effect (ARO = VII) No effect No effect (ARO = VII)
Vitamin E1 120583M
10120583M (IC50)
50 120583M (20 of control)ARO = I
5 120583M10 120583M 23050 120583M 370
ARO = I
Table 5 Antiproliferative effect (oxLDL-induced HUVSMCs proliferation) of CA DHPs and simultaneous oxLDL-induced ROS productionscavenging Comparison with N-acetyl-L-cysteine NAC (intracellular ROS scavenger) Compiled according to data presented by Zou et al2012 [130]
DHP compound
MethodsAntiproliferative effect against proproliferative effectinduced by oxLDL (50 120583gmL) (UV detection of
formazan production from tetrazolium salt)
oxLDL-induced ROS production (fluorescent DCF(2101584071015840-dichlorofluorescein) production)
Effective [IC] in120583M and I in
Amlodipine 3 120583M I = 18 3 120583M 10 120583M No effectI = 20
S(minus)-Amlodipine No effect No effect
Lacidipine 10 120583M30 120583M
I = 21I = 27 10120583M Isim23 of control
N-Acetyl-L-cysteineNAC
mdash 5000 120583M(5mM) I = 28
As presented (Table 4 according to [129]) for diltiazem(poor lipid solubility) noAOwas detected whereas the otherCA and 120572-tocopherol have demonstrated AOA at least atconcentrations of 10 and 50120583M 120572-tocopherol gt lacidipinegt nifedipine gt isradipine verapamil and amlodipine Addi-tionally120572-tocopherol and lacidipinewere able to significantlyattenuate in vitro LDL oxidation at 1 and 5120583M Theseresults have confirmed the highest activity for the stronglylipophilic DHP type CA compound lacidipine This might be
a possible antiatherogenic mechanism of CA since oxidativemodification enhances the atherogenic potential of LDL
The lipid peroxidation of LDL promoted either by UVradiation or by copper ions was inhibited (antioxidant effect)by nisoldipine in a dose-dependentmanner (IC
50values were
evaluated at around 10 120583M) nimodipine was less potent (IC50
around 50ndash100 120583M) and nicardipine almost inactive In addi-tion to this indirect protective effect CA DHPs nisoldipineand nimodipine exerted direct protective effect on lymphoid
Oxidative Medicine and Cellular Longevity 11
cells against toxicity of previously oxidized LDL The IC50
values were 6 plusmn 2 and 80 plusmn 20 120583M respectively [122] Theinhibition of the cytotoxic effect of LDL oxidized in thepresence of DHP type Ca2+ channel blockers correlated wellwith protection from oxidation by these compounds Com-plete protection cannot be obtained because the DHPs arecytotoxic themselves The potential relevance to the preven-tion of atherogenesis is envisaged
DHP typeCCBnifedipinewas themost effective inhibitorof oxidation promoted either by UV radiation or by copperions in experiments with cultured lymphoid cells LDL (2mgapoBmL) CCBs from other two CCB classes diltiazem andverapamil were only poorly active or completely ineffective[121] The protective effect of nifedipine occurs at two levelsbesides its direct antioxidant effect by inhibition of LDLoxidation it also exhibits a direct cytoprotective effect againstcytotoxicity of oxidized LDL by yet unknown mechanismsThe protective effect of CCBs was not due to an inhibitionof LDL uptake This effect seems to be independent of theinhibition of LDL oxidation per se since LDL was oxidizedin the absence of the drug before the incubation withcells Moreover this direct protective effect was observedat lower concentrations (IC
50of 1 plusmn 02 120583M) compared to
the antioxidant effect (IC50
of TBARS inhibition is around10 plusmn 2 120583M at UV promoted and 4 plusmn 05 120583M by Cu2+ ionsinitiated) The AO effect of nifedipine is also correlated withthe protection of endogenous tocopherols (IC
50= 50 120583M)
It was suggested that the AO effect of CCBs protected cellsindirectly from the cytotoxic effect of oxidized LDL [121]
A recent study has reported that beneficial vascular effectsof lercanidipine in diabetic rats depend on its antioxidantactivity related to attenuating the increase in oxidativestress and in vascular matrix metalloproteinase-2 (MMP-2) (Martinez et al [126]) Lesnik et al [127] studied theimpact of a combination of this calcium antagonist and a120573-blocker atenolol on cell- and copper-mediated oxidationof LDL and on the accumulation and efflux of cholesterolin human macrophages and murine J774 cells They realizedthat lercanidipine reduced the oxidative modification of LDLrather than diminished cholesterol accumulation in humanfoam cells
Comparing the antioxidative action of CA (DHPs amlo-dipine lacidipine nifedipine and isradipine as well as diltia-zem and semotiadil) in the copper-catalyzed oxidation oflow-density lipoprotein (LDL) with that of glycated (g)gly-coxidated (go) LDL demonstrated that the strongest AOeffects during long-term LDL glycation are seen for isradip-ine lacidipine nifedipine and semotiadil [128] Inhibitoryeffects were in the range 10minus5ndash10minus3MAuthors suggested thatdue to the increased generation of ROS by glucose-modifiedLDL the chain-breaking capacity of CA may be overriddenThe AOA of CA depends on their lipophilicity and theirability to incorporate into the LDL particle that is to reachthe site of peroxidation CA like other AOs significantlyretards advanced glycation end products (AGE) formationwhereas initial glycation reactions such as Amadori productformation are only weakly inhibited The observation thatboth oxidative changes and at least long-termglycation effectsare indeed drastically reduced by CA is corroborated by
fluorescence analysis AGE-ELISA quantitation of lipid per-oxidation and TBARS measurement of long-term ggo LDL
The effects of lipophilic DHP calcium channel blockerson oxidized LDL-induced proliferation and oxidative stressof vascular smooth muscle cells were also studied [130] (seeTable 5)
Lacidipine and amlodipine reduced carotid intima-media thickness by decreasing proliferative effect of oxLDLwhereas (S-)-amlodipine had no antiproliferative effect ROS-MAPKs (mitogen-activated protein kinases) pathway mightbe involved in the mechanism
Both 14-DHP CCBs lacidipine and nifedipine reduceplasma and LDL oxidation and formation of oxidation-specific epitopes Their application may also relate to pro-longed survival of rats independently of blood pressuremod-ifications (in the SPSHR model 1mgkg per day lacidipineand 80mgkg per day nifedipine) These results suggestedthat the protective effect of these two 14-DHP drugs invivo as shown in cerebral ischemia and stroke may in partresult from inhibition of LDL oxidative process althoughthese two drugs possess different lipophilic properties [131]Both lacidipine (03 and 10mgkg) andnifedipine (80mgkg)prolonged lag time of the conjugated diene formation inLDL isolated from arterial wall and 119905max These drugssignificantly reduced electrophoreticmobility of oxLDL fromSPSHR subjected to XXO oxidation system 14-DHP CCBsalso protected apolipoprotein B which is important for thebinding with macrophage LDL receptor lysine residues Thedoses used (gt10minus6molL for SPSHR and normotensive WKYrats) however are 2 to 3 orders of magnitude higher thanthose inhibiting vascular smooth muscle contraction in vitroand in vivo They also exceed values that are commonlyused in clinical practice The daily dose of lacidipine forhypertensive patients is 007mgkg asymp4- to 14-fold lower thanthe 2 doses used in SPSHR The maximum daily dose ofnifedipine given to hypertensive patients is 20mgkg asymp40-fold lower thanwhatwere used [131]These discrepanciesmaybe related to differences in bioavailability of CA between ratsand humans [131]
Accordingly in routine clinical use 14-DHPCCBs donotreach the concentrations required for antioxidant activity invitro [131]
Another data concerning the effect of CA DHPs on OSrelated to LDL is presented under Section 35
(b) Effect of DHPs on Isolated Rat Liver and Heart Mitochon-dria As a major cellular source of oxygen radicals (Cadenas[4 5]) mitochondria are promising targets for pharmaco-logical and toxicological actions of various membrane-activecompounds including several 14-DHP derivatives Zernig etal [132] have discovered CA binding sites associated with aninner mitochondrial membrane anion channel
More than 40-year long research onmitochondrial effectsof the DHPs (on their bioenergetics chemiosmotic proper-ties and ion fluxes) clearly points them out as mitochondri-otropic compounds
The activity of the first 35 synthesized compounds(derivatives of 14-DHP their heteroaromatic analogues
12 Oxidative Medicine and Cellular Longevity
NAD-H+ and butylated hydroxytoluene (BHT BOT)) orig-inally was examined in rat liver mitochondrial LP system inthe presence of Fe2+ ions and using the ultraweak chemilu-minescence method (Dubur et al [89])
Several 14-DHP derivatives Hantzsch ester diludine andits analogues were found to be effective antioxidants in thisexperimental system changing the kinetics of LP lengtheningthe time of the appearance of the maximum of the slowburst of the chemiluminescence (latency latent period) anddiminishing the reaction rate (the tangent of the slope angleduring the time in which the amplitude of the slow burstcharacterizing LP rate increases) and its peak value Theirpresence has influenced the reaction constant 119870
6 in relation
to a very significant reduction of lipid hydroperoxides andorinactivation of free radicals as follows
ROO∙ + ROO∙ 997888rarr P + h]lowast termination (1)
(P = molecular products) or
ROO∙ + ROO∙ +H2O 997888rarr ROH + RO∙ + 1O
2
lowast (2)
In this study diludine was one of themost active compoundsDHPs had activity similar to the standard synthetic AO-BHT(ionol) However when plotted against applied concentrationand time window diludinersquos activity profile differed from thatof BHT
There were also similar studies (using different LP rateexperimental detection system and method Hunter et al[133]) based on exploring a group of 26 26-dimethyl-35-disubstituted- and 26-dimethyl-345-trisubstituted-14-dihydropyridines (14-H
2Py=14-DHPs) and five related pyri-
dines as inhibitors of rat liver Mit swelling (Δ119860520119905) and O
2
uptake by ascorbic acid- (AsA-) dependent lipid peroxidationand as modulators of Mit swelling induced by Na+-linoleateor Na+-pyrophosphate (Velena et al [112])
Some of tested 4-DHPs (4-unsubstituted 35-dialkoxy-carbonyl-26-dimethyl-14-DHPs and 35-diamido-26-dim-ethyl-14-DHPs both 4-unsubstituted or those possessinglipophilic 4-aryl- groups) have shown significant AO andmembrane stabilizing activity These studies further revealedthat 14-DHPs preferably act as AO during the stages ofinitiation and prolongation of LP chain reactions at lowconcentrations The studied 14-DHPs had IC
50(when 119881
0119881
or 1205911205910= 2) 01 120583M to 100 120583M and the minimal activity was
scored for oxidized (heteroaromatized) derivativesAt the concentration of 100120583M 35-di-n-butyloxycarbo-
nyl-26-dimethyl-14-DHP entirely stops mitochondrialswelling in the presence of 08mM Na+-pyrophosphateAt the same concentration the following compoundsalter the mitochondrial swelling rate in the presence ofnatural protonophore Na+-linoleate 35-di-p-hydroxyphen-oxycarbonyl- and 35-di-p-tolyloxycarbonyl-26-dimethyl-14-DHPs 35-diethoxycarbonyl-26-dimethyl-pyridine (oxi-dized form of Hantzsch ester) and more lipophilic 35-diamyloxycarbonyl-26-dimethyl-pyridine The alteration ofswelling may be scored as prolonged promoted acceleratedor inhibited The type of alteration depends on the structureand concentration of 14-DHPs the type of initiators of theswelling process and the medium composition
In accord with previously published Janerorsquos results (lackof AO for Ca2+ antagonists nifedipine and nicardipine evenat 500120583M concentration in LP tests performed on heartmembrane [134]) no antioxidative activity for 4-phenyl sub-stituted derivatives of 35-dialkoxycarbonyl 14-DHP (closeanalogues of Ca2+ antagonists) was found contrary to various4-nitrophenyl 14-DHP derivatives calcium antagonists forwhich the significant antioxidant activity was reported [3146ndash53]
Studies made on phosphatidylcholine liposomes (ourunpublished data) suggest approximately three and twotimes more antioxidative activity for 100 120583M 4-unsubstitutedDHP compound diludine when compared to 4-substitutedDHPs riodipinenifedipine and nicardipine respectively atmethemoglobin-induced LP (oxygraphy)
Inhibition of mitochondrial AsA-dependent LP and sta-bilization ofmitochondriawere shown to be characteristic fora large group of 14-DHP compounds [112] showing to pos-sess the AOA in simplest in vitro systems (Tirzit andDuburs [39] Zilber et al [44] and Dubur et al [45])based on reactions with the stable free radical 11-diphenyl-2-picrylhydrazyl (DPPH) LP of fatty acid ester (linethole andmethyloleate) emulsions and phospholipid (phosphatidyl-choline) liposomes Generally these properties did not coin-cide with Ca2+ antagonism Depending on DHP structure itseems that AOA properties are less specific than Ca2+ antago-nist properties Both properties may be interrelated but notinterdependent
These data show that the presence and the nature ofa substituent in position 4 as well as 35-substituentsare important factors for 14-DHP antioxidant effects invarious systems that is AsA-dependent nonenzymatic aswell as enzymatic NADPH-dependent lipid peroxidationSometimes the efficacy of inhibition of nonenzymatic LPby 14-DHPs is higher than the inhibition of the enzymaticLP However the action may be opposite stimulation of theLP Hantzsch ester (HEH diludine) and its close analoguesexhibited significant AOA and membrane stabilizing prop-erties in both AsA-dependent nonenzymatic peroxidationof mitochondria and NADPH-dependent enzymatic LP ofmicrosomes usually at similar 10 to 100120583M concentrations[112]
The order of AOpotency (IC50
values) in vitro depends ondrug structure as well as on the experimental conditions andspecificity of the biological system Eachmethod for determi-nation of AOA and ARA has advantages and disadvantages(Karadag et al [135])
Accordingly as reported by Gubskiı et al [136] IC50
forthe AsA-dependent LP was 025 120583M and 20 120583M for 14-DHPCa2+ antagonists nitrepine (nitrendipine) and nifedipinerespectively Takei et alrsquos [137 138] studies on mitochondrialswelling induced by LP or arachidonic acid in the rat braindetermined the IC
50values of 127 105 1568 and 384 120583Mfor
efonidipine nicardipine nifedipine and nimodipine respec-tively For LDL in the copper-induced oxidation system theorder of potencywas vitamin Egt felodipinegt 2-chlorophenylanalogue of nifedipine gt nifedipine gt amlodipine nitrendip-ine verapamil and diltiazem (Rojstaczer and Triggle [119])
Oxidative Medicine and Cellular Longevity 13
It was interesting to compare the AOAofDHPswith theirsusceptibility to oxidation that is electron and hydrogendonating properties
It has been estimated that electron donor substituentsin positions 2 and 6 of 14-DHP cycle usually promoteoxidation while electron acceptor substituents promotequench oxidation Stronger electron acceptors in positions 3and 5 also significantly quench oxidation These estimationsare based on studies including chemical enzymatic andelectrochemical oxidation of 14-DHPderivatives (Dubur andUldrikis [70] Duburs et al [71] and Stradin et al [139])
On the other hand diminished AOA of 14-DHP relatesto presence of substituents in position 4 (both electron donorand electron acceptor) (Velena et al [112])
35-Dicarbamoyl substituents possess minimal quench-ing feature and are followed by benzoyl- acetyl- andalkoxycarbonyl- groups Maximal decrease was obtainedwith condensed substituents (ie oxoindeno- or oxocyclo-hexeno- groups) and a CN-group 4-Unsubstituted 35-dicar-bamoyl derivatives can be easily oxidized and consequen-tially inactivated whereas 4-substituted 35-dicarbamoyl-14-DHPs possess an oxidation potential analogous to the 4-unsubstituted 35-COOR derivatives Therefore they haveadequate electron donor properties and are considerablystableThismay be the reason for significantmembrane stabi-lization upon exposure to 4-substituted derivatives Ofimportance their AOA was usually more pronounced incomparison to 4-unsubstituted derivatives
Among them 26-dimethyl-35-difurfuryloxycarbonyl-14-DHP showed the highest antioxidative activity In thegroup of 35-dialkoxycarbonyl derivatives the strongestactivity was attributed to compounds with medium lengthalkyl chains (i-butyl- t-butyl- and i-amyl- substituents) highlevel of lipophilicity minimal electron acceptor propertiesand moderate steric hindrance as contrasted to short or longalkyl chain ester derivatives (35-dimethoxycarbonyl- 35-diethoxycarbonyl derivatives and 35-didodecyloxycarbonylderivative) These data demonstrate the bell-shaped depen-dence of AOA on alkyl chain length [112] and are in accordwith results obtained in liposomes However these datadiffer from those obtained in emulsions where diludine wasthe most active compound Finally oxidized heteroaromaticderivatives showed only minimal activity
In both LP systems studied (AsA-dependent in mito-chondria and NADPH-dependent in microsomes) some of14-DHPs showed activity similar to classical antioxidantbutylated hydroxytoluene (ionol BHT) (Velena et al [112])However there was a significant difference related to con-centration and incubation time It allowed us to postu-late that 14-dihydropyridines (InH) acting as antioxidants-reductants and scavengers of reactive oxygen species and lipidfree radicals preferably influence initiation and propagation(prolongation) of lipid peroxidation chain reactions (1)ndash(5) according to Scheme 2 The phenomenon is particularlyprominent in the presence of Fe2+ and other ions of variablevalency
Chain break and termination reactions (6)ndash(10) of theLP reaction cascade [89] were influenced by 14-DHPs in alesser degree than were initiation and propagation steps This
may be important for their therapeutic effects even in theadvanced stages of LP
Scheme 2 (stages of initiation propagation and terminationof lipid peroxidation chain reactions (1ndash10)) Initiation andpropagation reactions are as follows
(8) RO∙ + In∙minus rarr Y (Y = molecular products)(9) ROO∙ + Fe2+ rarr Fe3+ + X (X = molecular products)(10) RO∙ + RO∙minus rarr Y (Y = molecular products)
In the reversible swelling of mitochondria accompanyingLP (initiated by mixture of 5mM GSSG1mM GSH) several14-DHPs showed low or no activity manifested only as adecrease of the swelling amplitude without a rate decreaseAn addition of GSH (4mM) or ATP to swollenmitochondriacaused their contraction in both control and tested systemIt may be suggested that 14-DHPs acting as antioxidantsin mitochondria preferably influence LP reactions initiatedby ions with variable valency or their complexes with hemetype compounds methemoglobin hemin hematin and soforth (Velena et al [112]) If the peroxidation process has amaximal velocity and 50 percent of initial O
2were consumed
14-DHPs cannot completely break the chain reactions andprevent subsequent membrane damage by addition of DHPsubstance at 10 120583M concentration at the moment of 50percent oxygen consumption the subsequent oxygen uptakeproceeded unchanged This observation is important for theapplication of DHPs as inhibitors of initiation and to a lesserdegree propagation stages of LP chain reactions
The influence of 14-DHPs on Mit swelling is not strictlyassociated with their own oxidation There is the possibilitythat the labilizing (or stabilizing) effect relates to surfaceactivity (connected with substituent lipophilicity) or may bethe consequence of complexation with some -OH (or -CH
3)
group sensitive receptors at the mitochondrial membraneNamely a bathochromic shift of the absorption band maxi-mum (about 10 nm) was observed in the visible region beforeswelling However after swelling in the presence of Na+linoleate the spectrum returns to its initial value [112]
Some 14-DHPs not only protect mitochondria againstswelling caused by AsA-dependent LP salts of fatty acids
14 Oxidative Medicine and Cellular Longevity
in vitro [112] but also have beneficial effects on repairingtheir integrity in vivo after exposure to irradiation hepato-toxins ischemia hypoxia or hypothermia Some of themwere shown to normalize the process of intracellular repara-tion and physiological regeneration of ultrastructures Theywere also shown to stimulate reparative processes If pre-treated with 14-DHPs irradiatedmitochondria will not swell(Ivanov et al [140 141])
Diludine ionol and some other AOs mitochondria pro-tectors act as anti-ischemic agents If applied prophylacticallyin vivo they may prevent ischemic and reperfusion lesionsin heart kidney and other organs (Bilenko et al [113]) Theeffect is dependent on applied dose timing and way ofapplicationWhen added onto the cryoconservationmediumfor mitochondria preservation 14-DHPs prevented decreaseof membrane potential normalized facilitated respirationand prevented loss of mitochondrial Na+ and Ca2+ ionsafter thawing ([112] see citation number 36 (Subbota et alKharkov 1984) therein) Diludine was stronger protectorwhen compared to ionol
CA drug foridone (riodipine) was shown to possesscardioprotective features primarily due to is protective effecton mitochondria exposed to OS [142 143]
Similarly the DHP water-soluble antiarrhythmic com-pound glutapyrone inhibits initiation of LP by free radicalsin erythrocytes and heart mitochondria Its cardioprotectiveeffect has been experimentally shown in heart mitochondrialmembranes especially during deep hypothermia (Utno et al[144])
Cerebrocrast was effective in several translation modelsmimicking pathological situations known to be associatedwith cellular OS The potential protective action of 14-DHP derivatives (4-substituted compounds cerebrocrastgammapyrone glutapyrone and 4-unsubstituted drug dieth-one) has been studied in rat liver in experimental modelsrelevant for oxidative stress and mitochondrial bioenergetics(Fernandes et al [145]) When succinate was used as therespiratory substrate higher concentrations (gt25 120583M) ofcerebrocrast depressed respiratory control ratio (RCR) ADPto oxygen ratio (ADPO) state 3 and uncoupled respirationrates transmembrane potential (deltapsi) and the phosphatecarrier rate At the same time state 4 respiration rate wasthree times increased At concentrations lower than 25120583Mcerebrocrast inhibited mitochondrial IMAC and partiallyprevented Ca2+-induced opening of the mitochondrial PTPGammapyrone glutapyrone and diethone did not inducethese phenomena When applied at concentrations up to100 120583M cerebrocrast gammapyrone and glutapyrone didnot affect ADPFe2+-induced LP of mitochondria in rat liver(as measured by oxygen consumption and TBARS forma-tion) On the other hand low diethone concentrations (upto 5 120583M) inhibited it in a dose-dependent manner Diethonealso prevented against deltapsi dissipation induced by LPinitiated by ADPFe2+ Based on these data it may bespeculated that cerebrocrast (inhibition of the IMAC) anddiethone (acting as an AO) may provide effective protectionof mitochondria during OS Cerebrocrast has shown sometherapeutic potential for treatment of several pathologicalconditions related to cellular OS [145]
5-Acetyl(carbamoyl)-6-methylsulfanyl-14-DHP-carbo-nitriles (Figure 3) with minor differences in their molecularstructure displaying antioxidant and antiradical activitiesin vitro show different biological activities Namely 4-p-chlorophenyl derivative OSI-1146 displays AO and anti-radical activities in cardiovascular OS models whereasOSI-3701 and OSI-3761 display hepatoprotective activityThus these compounds may be potentially useful for treat-ing several pathological processes including those associatedwith OS (Fernandes et al [146]) However besides mito-chondria the cellular targets for their pharmacologicalactions have not been fully investigated [146] All these com-pounds increase the susceptibility of Mit to MPT The mostpotent is OSI-3701 although it does not affect bioenergeticparameters
Although all these compounds protected mitochondriaagainst LP induced by the oxidant pair ADPFe2+ OSI-1146was shown to be the most potent Current data point outmitochondria as potential targets for protective and toxicactions of DHPs suggesting that the potential for their use astherapeutic agents should also take into consideration theirtoxic effects on mitochondria (Fernandes et al [146])
Several structurally different DHP derivatives (antioxi-dant diludine (diethone) as a 4-unsubstituted DHP 4-substi-tuted DHPs CA foridone (bicyclic compound) and the 4-phenyldiethone compound where phenyl group is joined tothe DHP in position 4) inhibited the 1-methyl-4-phenyl-pyridinium iodide (MPP+) induced ROS production incerebellar granule cells (CGC) with a distinct potency orderforidone (26-dimethyl-35-dimethoxycarbonyl-4-(o-difluo-romethoxyphenyl)-14-dihydropyridine) gt 26-dimethyl-35-diethoxycarbonyl-4-phenyl-14-dihydropyridine gt diludineThey also reversed the MPP+-induced decrease of the mito-chondrial membrane potential in the same order (Klimavi-ciusa et al [147]) Accordingly it was postulated that theclassical two-ring (bicyclic) structure of DHP derivativesrepresents an advantage in relation to neuroprotection andROS defense and is independent on compoundrsquos propertiesrelated to calcium ions
Novel adamantane-containing 14-DHP compounds (Kli-maviciusa et al [148]) were also found to improve mitochon-drial functions (MPP+ model) (Klimaviciusa et al [148])Klusa et al [149] have discovered antineurotoxic effects of14-DHP taurine derivative tauropyrone recorded as Mitfunction improvement
Many 14-DHPs including Ca2+ antagonists and AOmodify LP processes and influencemitochondrial function invarious organs (liver heart kidney and brain) in a differentway and degree Their beneficial action oxygen or lipidfree radical scavenging antioxidative effects binding withor intercalating into phospholipid bilayer regulation of iongating and regulation of mitochondrial permeability transi-tion pores (Tirzit and Duburs [39] Zilber et al [44] andDubur et al [45]) separately or in combination with eachother depends on two strong elements (1) their individ-ual structure including nature of substituents and theirpositions and (2) the nature of the biological system Forexample the direction of LP (inhibition of promotion) wasshown to depend on structure and concentration of applied
Oxidative Medicine and Cellular Longevity 15
14-DHPs as well as stages of chain reactions Accordinglymitochondrial swelling may be prolonged (retarded) accel-erated (promoted) or inhibited (Velena et al [112])
Therefore there is a ground for 14-dihydropyridineseither Ca2+ antagonists or antioxidants to be nominated asuseful tools in development of ldquomitochondrial drugsrdquo relatedto the control of OS
(c) DHPs as AOs in Endoplasmic Reticulum (Inhibition ofNADPH-Dependent LP System) Inhibition of NADPH Oxi-dase by DHPs Elevated level of NADPH oxidase 4- (NOX4-)derived hydrogen peroxide (H
2O2) joined with concomitant
decrease of nitric oxide (NO) mediated signaling and reac-tive oxygen species scavengers are considered to be centralfactor in molecular pathogenesis of fibrosis (Sampson etal [150]) Inhibition of microsomal NADPH-dependent LPwith particular focus on NADPH oxidases (NOX1ndash5 andDUOX1) may be very important for neuro- cardio- andhepatoprotection (Velena et al [112] Leto and Geiszt [151]Griendling et al [152] and Chen et al [153]) Endoplasmicreticulum may be an important target as this is where 14-DHPs could display their antioxidative properties (Velena etal [112] Leto and Geiszt [151] Griendling et al [152] andChen et al [153])
However the initiation of LP in the NADPH-dependentmicrosomal system does not appear to involve either super-oxide or hydrogen peroxide since neither SOD nor cata-lase can inhibit it On the other hand reduced iron playsan important role in both the initiation and propaga-tion of NADPH-dependent microsomal lipid peroxidation(Hochstein and Ernster [154] and Repetto et al [111])
Many DHPs possess inhibitory activity not only towardsAsA-dependent LP in mitochondria but also towardsNADPH-dependent LP as shown in isolated rat liver micro-somes (Velena et al [112]) This means that these compoundsinteract with the shared parts (nonenzymatic and enzymatic)of LP pathways
Microcalorimetry and fluorescent probes procedureswere used for studying the interaction of alpha-tocopheroland 14-DHPs with endoplasmic reticulum membranes andmodel systems human serum albumin and phospholipidbilayers [155] Modification of microviscosity of the endo-plasmatic reticular membranes depends on localization ofantioxidants within the protein structures or phospholipidphase Increase of membrane structuralization under theinfluence of 14-DHPs blocked their antioxidant action inspontaneous and induced lipid peroxidation
Inhibition of rat heart and liver microsomal lipid perox-idation by nifedipine was observed [156] while Goncalves etal [157] found antioxidant effect of calcium antagonists onmicrosomal membranes isolated from different brain areas
Nitroaryl-14-DHPs are both calcium channel antagonistsand antioxidant agents (Letelier et al [158 159]) commonlyused for treatment of cardiovascular diseases These drugsmust be metabolized through cytochrome P450 oxidativesystem (NADPH-cytochrome P450 reductase) mainly local-ized in the hepatic endoplasmic reticulum Several lipophilicdrugs generate OS while being metabolized by this cellularsystem Thus DHP antioxidant properties may prevent the
OS associated with hepatic biotransformation of drugs Var-ious commercial and new nitro-phenyl-DHPs were studiedagainst LP using rat liver microsomes under oxidative stress[159]
Incubation of rat liver microsomes with the 41015840-nitro-4-phenyl-14-DHP compounds (26-dimethyl-4-(41015840-nitro-phenyl)-14-dihydropyridin-35-diethyl-dicarboxylate andN-ethyl-26-dimethyl-4-(41015840-nitrophenyl)-14-dihydropyri-din-35-dimethyl-dicarboxylate) results in an inhibitionof LP the UDPGT (UDP-glucuronyltransferase) oxidativeactivation and the microsomal thiol oxidation induced byFe3+ascorbate a generator system of ROS This effect wasalso produced by nitrofurantoin and naphthalene in thepresence of NADPH
Interestingly IC50
ofDHPs obtained frommicrosomal LPassays decreased to the same extent as the microsomal thiolsoxidation provoked by Fe3+ascorbate [159] Neverthelessthe AO effects of a nitrophenyl-DHP compound in whichhydrogen at position one of the DHP ring was replaced bythe ethyl groupwere significantlyweaker Authors speculatedthat DHPs can resemble NADH transferring one hydrogenatom of 4-position (Hminus) to anion superoxide and another ofthe 1-position (H+) by way of a cationic radical intermediateto generate pyridine derivatives and water [159]
The AO effects of various tested DHP derivatives (m- andp-NO
2phenyl as well as methyl or ethyl and isopropyl-DHP
35-dicarboxylate derivatives) were not significantly differentThe authors assumed that the -NH- group of the dihydropy-ridine ring could contribute both to the development ofthe calcium channel antagonism and to the antioxidativeproperties of DHPs [159]
Prevention of the membrane LP seemingly depends onthe concentration of potential antioxidants such as vitaminE or even 14-DHP in lipids However only the differencesin synthetic DHPs lipophilicity cannot explain significantvariations of DHPs concentration in microsomal membraneand cannot clarify the strength of their antioxidative activityThis work [159] has further demonstrated that 14-DHPsmay prevent the OS induced by biotransformation of somedrugs for example antibiotic nitrofurantoin Simultaneousadministration of DHPs and nitrofurantoinmay be beneficialin reducing nitrofurantoin side effects
While most of Ca antagonist 14-DHPs are metabolizedby CYP3A4 (Guengerich et al [160]) not all of them are goodinhibitors of its activity Thus nicardipine but not nifedipineand nitrendipine inhibits CYP3A4 in vitro [53] Interactionof different DHPs with various types of cytochrome P450 wasdescribed by Carosati et al [53] It was also reported thatDHP class calcium channel blockers reduce the antiplateleteffect of clopidogrel (Park et al [161])This implies themutualinteractions of both drugs with CYP3A4
(3) In Vivo Evaluation of nifedipine effects on Saccharomycescerevisiaewas recently published (Asma andReda [162]) Sur-prisingly nifedipine exercised a toxic effect on Saccharomycescerevisiae shown through measuring cellular proliferationrespiratory activity and the level of some biomarkers (CATand MDA)
16 Oxidative Medicine and Cellular Longevity
However majority of data obtained on various animalcells and tissues by other authors show the protective role ofDHPs against both LP and oxidative stress [113 163 164]
The AOA attributed to many 14-DHPs Ca2+ antag-onists and other compounds reflecting on catalytic LDLperoxidation (see Section 331 (2) and Section 35) shouldencourage their testing for treating cardiovascular diseasesandor alterations of lipid metabolism
The possibility that 14-DHP-based calcium antagonistsexert an antiatherosclerotic action (via inhibition of LDLoxidation and other mechanisms) has been proved by manyexperimental data [165] and several clinical trials Besidesantihypertensive effect nicardipine was shown to possessantioxidative and antielastase activity [165 166] These prop-erties may be useful for prevention of inflammatory reactionwhich is relevant for hypertension pathogenesis
14-DHPs administration inhibits LDL oxidation medi-ated by oxygen radicals leading to decreased carotid inti-mal media thickness and reduced progression of coronaryatherosclerosis [130] It additionally preserves Apo B-100integrity against ROS Of importance antiatherogenic mech-anisms differ between animals and humans (primarily inthe stage of conversion of aldehydes to carboxylic acids)(Parthasarathy et al [167])
For example furyl-DHP compound (FDP-1 diethyl 26-dimethyl-4-(furyl)-14-dihydropyridine-35-dicarboxylate)was shown to act as an antioxidant (decreasing MDA GOTand FFA release of ischemic myocardium and inhibiting Ca-ATPase of erythrocyte membranes) preventing against heartmyocardium ischemia-reperfusion injury and arrhythmiawhen applied (in rats) at 10mgkg (Liu et al [168])
Similarly antioxidative effects of azelnidipine andamlodipine prevented neuronal damage by CCBs aftertransient focal ischemia in rats (Lukic-Panin et al [169])
Allanore et al [170] found that both nifedipine andnicardipine significantly decrease the mean level of plasmamarkers for oxidative stress in patients suffering from sys-temic sclerosis
Antioxidants may be considered as promising neuropro-tective compounds Still while experimental data demon-strate neuroprotective effect in vitro and in animal mod-els clinical evidence is still unsatisfactory and insufficient[171]
(a) Role of Metabolism of DHPs in Their AOA Metabolicpathways and ldquobioavailabilityrdquo of the probable AOA com-pound determine antioxidant activity in vivo Antioxidantmetabolites may vary in stability and activity leading to twoopposite scenarios lack or presence of activity substantiallycontributing to the overall AOA [172] Metabolic biotransfor-mation of DHPs includes oxidation (heteroaromatization)side chain ester group cleavage (deesterification) and 4-substituent abstraction ao [160] None of the DHPs metabo-lites was shown to be more toxic than original reduced formof the compound The commonly detected metabolites ofthe DHPs do not seem to possess the AO activity (withsome exceptions as in the case of metabolites of nifedipineand its analogues including nitrosonifedipine [173 174]) (seefurther in Section 35) Due to DHPs intrinsic instability
achieving andmaintaining an adequate concentrationmay beproblematic both in vitro and in vivo
(b) Role of Concentration and Lipophilicity (MembraneWateror LipidWater Partition Coefficients) of DHPs inTheir Actionas AOs and Antiradical Compounds Antioxidative effects ofany antioxidant depend on its concentration at the site ofaction This parameter is hardly measurable especially intwo-phase systems representing one of obstacles in com-parison to AOA upon applying various compounds [172]It is often incorrectly assumed that the concentrations inthe aqueous solution and at the site of action are the sameHowever even when the concentration in the aqueous phasemay be well controlled the concentration at the site ofaction in the lipid matrix of the membranes might fluctuatebetween different test compounds depending on a differencein lipophilicity [175] The prevention of the membrane LPalso seems to be dependent on the DHP concentration in thelipidmatrix (Mason andTrumbore [46]) and its amphiphilic-ity For example AOA of diludine is associated with itslipophilicity and consequential ability to be incorporatedinto liposomes (Panasenko et al [176]) It was also foundthat diludine easily incorporates into the outer monolayer oferythrocyte membranes [176]
Membranebuffer partition coefficients (lambda) weredirectly measured in the sarcolemma and sarcoplasmicreticulum membranes for three CA DHPs The obtainedvalues were in a broad range between 5000 and 150000(Herbette et al [177])These drugs interact primarily with themembrane bilayer component but may also bind to proteinsboth nonreceptors and receptors The intrinsic forward rateconstants for DHP binding to sarcolemmal calcium channelreceptors were apparently not strongly dependent on theirmembrane partition coefficients For example nimodipine(lambda = 6300) had a forward rate constant of 68 plusmn 06 times106Ms whereas the forward rate constant for Bay P 8857
(lambda = 149000) was 14plusmn08times107Ms Since these DHPsare highly liposoluble model calculations for this bindingreaction demonstrated that these rates on lipid solubilitywould probably not be reflected in the experimental forwardrate constants In addition the intrinsic forward rate constantfor nimodipine binding to sarcolemmal calcium channelreceptors was found not to be linearly dependent on theviscosity of the buffer medium over a fivefold range The rateof drug nonspecific binding to nonreceptor protein present inhighly purified sarcoplasmic reticulum membranes appearsto be extremely fast at least 103 times faster than specificdrug binding to the receptor in the sarcolemma Authorsconcluded that partitioning into the lipid bilayer matrix ofthe sarcolemma could be a general property of CA DHPsand may be a prerequisite for their binding to sarcolemmalmembrane receptors (Herbette et al [177])
The binding of DHP calcium channel agonists and antag-onists (including those with AO properties) to receptors incardiac sarcolemmal membranes is a complex reaction thatmay involve an interaction with the lipid bilayer matrix ofthe sarcolemma (Herbette et al [178]) Belevitch et al [179]studied the binding of DHP CCBs (riodipine and nifedip-ine) and verapamil to model and biological membranes by
Oxidative Medicine and Cellular Longevity 17
fluorescence analysis The consistent location of Ca agonistBay K 8644 was determined to be within the region ofthe first few methylene segments of the fatty acyl chains ofthe membranes (Mason et al [180]) This position is nearto that observed for the DHP calcium channel antagonistsnimodipine and Bay P 8857
Themajority of studies onOSwere performedwithDHPswith various lipophilicity but only a few studies reportedamphiphilicity ofDHPderivatives AmphiphilicDHPderiva-tive K-2-11 reduced the cellular generation of ROS It alsorevealed complete reversal of multidrug resistance (MDR) ofthe resistant cells K-2-11 was more efficient than well-knownMDR inhibitor verapamil Cytotoxic effects of anticancerdrug doxorubicin were enhanced by K-2-11 in bothMDR andparental nonresistant cell line (Cindric et al [181]) K-2-11suppresses increase of ROS and consequentially prevents NF-120581B activation leading to decreased expression of MDR1 andincreased expression of antiapoptotic genes This signalingswitch is necessary for restoring the chemosensitivity ofcancer cells This phenomenon is characteristic both for14-DHPs [182] (18 novel asymmetrical DHPs bearing 3-pyridyl methyl carboxylate and alkyl carboxylate moietiesat C3 and C5 positions resp as well as nitrophenyl orheteroaromatic rings at C4) and for their oxidized formspyridine compounds (Zhou et al [183])
34 Dependence of AOA of DHPs on the Experimental SystemAO effect of DHPs depends on their structure and theexperimental system used (in vitromodel system subcellularorganelle and cells ex vivo and in vivo) Ideally for theevaluation of the profile and value of DHPs AO propertieseach compound should be tested in as many systems aspossible (Dubur et al [45])
Lipidomics studies have been traditionally explored forstudying AOA of DHPs Proteomics methods are less rep-resented and are mostly focused on the properties of DHPsrelated to scavenging of protein free radicals So far there areno studies on the role of DHPs in scavenging nitrosoperoxy-carbonate the reactive species formed out of peroxynitrite inthe presence of carbon dioxide Although it was shown thatalbumin binds diludine no studies revealed the relevance ofthis effect for the AOA of diludine
There are findings showing that dihydropyridine calciumantagonists (DHPs CA) could indirectly play a beneficialprotective role during development of atherosclerosisNamely Berkels et al [184] have studied antioxidativeproperties of four substances the DHP prototype CAnifedipine the long-acting CA lacidipine the DHP calciumchannel agonist BayK8644 and the bulkyDHPderivate BayO 5572 in three different models (1) in an in vitro superoxideanion generating system (hypoxanthinexanthine oxidase)for testing the ldquopurerdquo antioxidative effect (2) in an artificialmembrane preparation (dimyristoylphosphatidylcholine) formimicking a more physiological environment and (3) underconditions of stimulated ROS release (hyperglycemia) fromnative endothelial cells derived from porcine coronary arter-ies
The study also revealed the potential correlation betweenlipophilic and AO properties of DHPs In the first model
Bay K 8644 was significantly more effective in scavengingsuperoxide anions than lacidipine Bay O 5572 or nifedipine(micro- to millimolar concentration range) Addition of anartificial membrane preparation resulted in an enhancedAO effect with lacidipine being the most effective DHP inquenching radicals (low micromolar concentration range)In the third model mimicking hyperglycemia (30mmolL)nifedipine was significantly more potent antioxidant (ther-apeutical nanomolar concentration range) than the otherDHPs Calculated lipophilicity of these four substances(lacidipine gt Bay O 5572 gt Bay K 8644 gt nifedipine) waspositively correlated with antioxidative potential only in thesecond experimental model It has been concluded that AOproperties of DHP substances need to be tested in variousmodels for demonstrating that nifedipine exhibits ROS-quenching properties in a therapeutic concentration range[184]
341 AOA of DHPs in Isolated Cells and Cell Cultures(Comparison with Other Simplest Systems) Although DHPspossess neuromodulatory andor antimutagenic propertiesthe mechanisms of action related to these phenomena arenot entirely elucidated Borovic et al [185] have studied 14-dihydroisonicotinic acid (14-DHINA) derivatives of 14-DHP water-soluble analogues of a well-known AO diludine(diethone) 26-dimethyl-35-diethoxycarbonyl-14-dihydro-isonicotinic acid sodium 2-(26-dimethyl-35-diethoxycar-bonyl-14-dihydropyridine-4-carboxamido)glutamate gluta-pyrone and sodium 2-(26-dimethyl-35-diethoxycarbonyl-14-dihydropyridine-4-carboxamido)ethane-sulphate tauro-pyrone as AO and bioprotectors (Figure 4)
14-DHINArsquos activities were studied in comparison toTrolox by NN-diphenyl-N1015840-picrylhydrazyl (DPPH∙) deoxy-ribose degradation ABTS∙ radical scavenging and AOA(antioxidative capacity method) assays copper-induced LPof cultured rat liver cells (MDA determination by HPLCand 4-hydroxynonenal-protein conjugates by dot-blot) 3H-thymidine incorporation and trypan blue assay for liver cellsgrowth and viability Ic decreased the amount of 4-HNE-protein adducts In all assays Ia was the most potent AOable to completely abolish copper induced LP of liver cellswhile Ic only slightly decreased it Thus AOA is importantactivity principle of Ia which was even superior to Trolox intreated cell cultures Ia (and its analogues) are easily oxidizedin the Fenton system (Rubene et al [186]) exerting ARA too
35 Peculiarities Related to Antioxidative and AntiradicalActivity of Some 14-DHPs Ca Antagonists Nine commer-cialized structurally and functionally different DHPs CAwill be discussed further Their common feature is ability toprevent OS This also counts for some of their metabolitesas already discussed The comparative effects of some DHPsCA on oxidative stress-induced modification of LDL werealready reviewed in Section 331 (2)-(a) AOA of CA DHPswas discussed in Sections 331 (2)-(b) and 331 (2)-(c)
351 Nifedipine and Its Close Analogues Nifedipine vera-pamil and antiarrhythmic-antihypoxic drug stobadin wereshown to depress lipid peroxidation of phosphatidylcholine
18 Oxidative Medicine and Cellular Longevity
NH
COOH
NH
COONa
Glutapyrone
NH
Gammapyrone
NH
C 2H5OOC COOC2H5
Tauropyrone
14-DHINA
H3C H3C
H3C
H3CCH3 CH3
CH3
CH3
COOC2H5COOC2H5
COOC2H5 C2H5OOCC2H5OOCC2H5OOC
CONHCH(CH2)2COONa CONH(CH2)3COONa
CONH(CH2)2SO3Na
Figure 4 Derivatives of 14-dihydroisonicotinic acid (14-DHINA)
liposomes (Ondrias et al [187]) However data obtained insome other experimental systems are conflicting
In an in vitromodel of sarcolemmal membrane lipid per-oxidation three calcium blockers (nifedipine verapamil anddiltiazem) exhibited concentration-dependent (10ndash400 120583M)inhibitory effects [188 189] Nifedipine the most effectivecalcium blocker was more than two-fold potent compared topropranolol achieving significant effect at 10 120583M Nifedipineprotective role on LP using reduced glutathione as modelmarker was recently described (Ray et al [190]) Antiper-oxidative properties of CA nifedipine and its analogueswere explored in different systemspathogenic processesatherogenesis (Henry [165]) brain focal ischemia (Yamatoet al [191]) nephroprotection related to cyclosporine intake(Chander and Chopra [192]) and hepatoprotection relatedto intake of diethyldithiocarbamate (Gaafa et al [193])Recent data suggest that nifedipine action as protector forendothelial cells proceeds independently from its CA proper-ties
The absence of antioxidant effects of nifedipine anddiltiazemonmyocardialmembrane lipid peroxidation oppo-site to nisoldipine and propranolol was also described[194] Nisoldipine and propranolol were shown to havea concentration-dependent antiperoxidant effect with IC
50
values of 282 and 501 120583M respectively Finally nisol-dipine appeared to possess dual antiperoxidant mecha-nisms involving both preventive and chain-breaking proper-ties
These findings were confirmed in some other studiesincluding reports on the lack of antioxidative activity ofnifedipine and nicardipine even at 500120583M concentrationin heart membrane lipid peroxidation tests [134] SimilarlyROS formation in bovine aorta smooth muscle cells was notaffected by addition of amlodipine nimodipine and nife-dipine [123]
(1) Metabolites of Nifedipine and Its Analogues as Antioxidantsand Regulators of OS Antioxidant activity of nifedipine35-dimethoxycarbonyl-26-dimethyl-4-(2-nitrophenyl)-14-dihydropyridine was originally studied in vitro by Kirule etal [195] and Tirzit et al [196] According to the kinetic dataof peroxide accumulation and the ESR spectra (inhibition ofthe autoxidation of methyl oleate in presence of nifedipine)AO action was exerted by the formation of nitroso analogueof the oxidized nifedipine nitroso nifedipine 26-dimethyl-4-(2-nitrosophenyl)-35-pyridine dicarboxylate (NO-NIF)This nitroso aromatic derivative can form nitroxyl radicalsexhibiting remarkable AOA in the presence of unsaturatedfatty acids and lipids [196]
The primary species of free radicals that have beenobtained and identified were ion radicals of the nitrophenyltype (Ogle et al [76]) Such a mechanism coincides withmechanisms proposed afterwards by Nunez-Vergara et al[96] Lopez-Alarcon et al [103] Valenzuela et al [104]Fukuhara et al [174] and Yanez et al [197]
There are also data showing that nitroso compounds mayinhibit LP by direct radical trapping and subsequent forma-tion of stable nitroxide radicals It was further found that thereactivity between the synthesized 14-DHP derivatives withalkylperoxyl radicals involves electron transfer reactionsThisis documented by the presence of pyridine as a final productof the reaction and complete oxidation of the nitroso groupin the case of the nitrosoaryl 14-dihydropyridine derivatives(Valenzuela et al [104]) Tested compounds reacted fastertoward alkylperoxyl radicals and ABTS radical cation thanalkyl ones (Lopez-Alarcon et al [103])
Nitrosonifedipine a photodegradation product of nifedi-pine significantly recovers cellular damage induced by tumornecrosis factor-alpha It also prevents toxic effects of cumeneperoxide which hampers integrity of cell membranes throughoxidative stress Its positive effects are equal to Trolox-C
Oxidative Medicine and Cellular Longevity 19
As a result nitrosonifedipine was already a long time agoclaimed as a candidate for a new class of antioxidative drugs(Kirule et al [195]) cellular protectors against oxidative stressin glomerular endothelial cells [174]
Moreover Misik et al [198] Ondrias et al [199] andStasko et al [200] studied AOA of nifedipine and its oxidizednitroso analogue NO-NIF prevents the progression of type2 diabetic nephropathy associated with endothelial dysfunc-tion through selective AO effects (Ishizawa et al [201]) NO-NIF administration reduces albuminuria and proteinuriaas well as glomerular expansion without affecting glucosemetabolism or systolic blood pressure NO-NIF also sup-presses renal and systemic OS and decreases the expressionof intercellular adhesion molecule-1 (ICAM-1) a marker ofendothelial cell injury in the glomeruli of the KKAy miceSimilar effects were achieved in endothelial nitric oxide syn-thase (eNOS) knockout mice Moreover NO-NIF suppressesurinary angiotensinogen (AGT) excretion and intrarenalAGT protein expression in proximal tubular cells in theKKAy mice On the other hand hyperglycemia-inducedmitochondrial superoxide production was not attenuated byNO-NIF in cultured endothelial cells
Fujii and Berliner found EPR evidence for free radicaladducts of nifedipine in vivo [202] The nature of these rad-icals was surmised by comparing the reaction of illuminatednitrosonifedipine with polyunsaturated fatty acids Surpris-ingly identical radical spectra were detected from excisedliver doped with nonilluminated nifedipine suggesting thatthis drug can be enzymatically converted in vivo to its nitrosoanalogue without the requirement for illumination This isone of the first reports of in vivo EPR evidence for a class ofunsaturated fatty acid radical conjugates resulting from thenormal metabolism of a common drug
Dıaz-Araya et al [173] studied some 4-nitrophenyl-DHPson Fe3+ initiated LP in rat brain slices LP as measuredby MDA formation was inhibited by all the tested nitro-aryl derivatives of 14-DHP over a wide range of concen-trations On the basis of both time course and IC
50experi-
ments the tentative order of AOA on rat brain slices wasnicardipine gt nisoldipine gt (RSSR)-furnidipine gt (RRSS)-furnidipine gt nitrendipine gt nimodipine gt nifedipine14-DHP derivatives that lack a nitro group in the mole-cule (isradipine and amlodipine) also inhibited LP in ratbrain slices but at higher concentrations than that of nitro-substituted derivatives All tested compounds reduced andoxidized nitrosoaryl derivatives (26-dimethyl-4-(2-nitro-sophenyl)-35-pyridinedicarboxylic acid dimethyl ester (pho-tooxidation product of nifedipine ndash NTP) ao) and weremore potent inhibitors of LP than their parent molecules(Valenzuela et al [104])
The electrooxidation process of 4-nitrosoaromatic DHPsis a strongly pH-dependent (two-electron two-proton mech-anism) ECEC type of mechanism that is the sequenceeminusH+eminusH+ at pH gt 85 ECCE mechanism (eminusH+H+eminus)at pH lt 85 dominates Reduction reaction of nitroso groupis as follows R-NO + 2eminus + 2H+ rarr RNHOH (Bollo et al[203])
352 Lacidipine It is a generic DHP type antihypertensiveCA 35-diethyl 4-2-[(1E)-3-(tert-butoxy)-3-oxoprop-1-en-1-yl]phenyl-26-dimethyl-14-dihydropyridine-35-dicarboxy-late
Ursini [204] described redox behaviour of lacidipine andshowed its tissue protective features Cristofori et al studiedantiatherosclerotic activity in addition to lacidipinersquos CAand AO properties [205] Lacidipine reduced the extent ofatherosclerotic area in hypercholesterolemic apoE-deficientmice (these mice show widespread vascular lesions whichclosely resemble the inflammatory fibrous plaques seen inhumans in atherosclerosis) The reduction may be associatedwith the capacity of the drug to maintain endothelial NOlevels at concentrations useful to protect against vasculardamage This work suggested that DHPs modulate vascularrelaxation via increased release of NO
Herbette et al [178] remarked optimal hydrophobicity oflacidipine due to cinnamic acid substituent so membraneinteractions and facilitation of the treatment of atherosclero-sis could proceed (see also Section 331 (2)-(a))
353 Amlodipine Amlodipine (Norvasc) (RS)-3-ethyl5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-14-dihydropyridine-35-dicarboxylate (AML) hasan antioxidant effect on vessels in vitro and is a 3rd genera-tion of charged dihydropyridine CCB that is widely used forthe treatment of hypertensive patients
Amlodipine was shown to have the highest affinity(amlodipine gt verapamil ≫ diltiazem) for the membranebilayer (119870
119901= 104) It produced the significant changes in
membrane thermodynamic properties including a reductionin the thermal phase transition temperature (minus11) enthalpy(minus14) and cooperative unit size (minus59) relative to thecontrol phosphatidylcholine liposomes (Mason et al [49])
Amlodipine AOA is related to its reductant nature orhydrogen donor properties respectively Its ability for donat-ing protons and electrons to the lipid peroxide moleculesblocks the LP process
Amlodipine and even its enantiomers (Zhang et al [206])act as ROS andNOS effectors in several model systems of OSAntioxidant properties of amlodipine were recently reviewedby Vitolina et al [32] Both in vitro and in vivo studiesof amlodipine AO properties revealed inhibition of lipidsoxidative damage primarily those associated with cellularmembranes and lipoprotein particles (LDL) (Mason et al[50])
Under controlled experimental conditions in vitro amlo-dipine showed AOA and ARA by inhibition of lipid peroxideformation and trapping ROS Its scavenging activity forhydroxyl and peroxyl radicals at concentrations as low as100 nmolL (which is remarkably less compared to the classi-cal antioxidants GSH uric acid and Trolox) was shown to beindependent of the calcium channel modulation (Franzoni etal [207])
AML showed efficiency as scavenger of peroxyl radicals(TOSC assay 5945 plusmn 544 unitsmg) significantly stronger(gt50 119875 lt 0001) than GSH (2733plusmn 636 unitsmg) and 70weaker (119875 lt 00001) than uric acid (18144 plusmn 696 unitsmg)and Trolox (17522 plusmn 734 unitsmg)
20 Oxidative Medicine and Cellular Longevity
Of interest the scavenging capacity of AML towardshydroxyl radicals (1455 plusmn 154 unitsmg) was 320 higher(119875 lt 000001) than that of GSH (358 plusmn 112 unitsmg) 20higher than that of uric acid (1198plusmn121 unitsmg) and 100higher than that of Trolox (759 plusmn 143 unitsmg)
Amlodipine was shown to increase enzyme activity ofparaoxonase (PON) and glutathione peroxidase (GSH-Px)However it also decreases glutathione reductase (GSSG-R)activity and diminishes the concentration of the endogenousantioxidant 120572-tocopherol (vitamin E) Moreover AML in aconcentration of 2 ngmL decreased the content of malonicdialdehyde and activity of superoxide dismutase in the blood(Gatsura [208])
Verapamil and amlodipine produced a potent anti-ischemic effect and reduced area of myocardial infarction inrats The observed changes were accompanied by inhibitionof LP In contrast to verapamil in vitro application of AML ina dose of 50 ngmL decreased hemoglobin affinity for oxygenWhen present in a concentration of 2 ngmLAMDdecreasedthe content of MDA and activity of SOD in the blood
On the other hand amlodipine shows no activity relatedto inhibition of macrophage superoxide release and cellmigration which occurs as a consequence of decreasedTNF120572induced O
2
∙ releaseAmlodipine-induced reduction of OS in the brain is
associated with sympathoinhibitory effects in stroke-pronespontaneously hypertensive rats (SHRSP) (Hirooka et al[209]) Antihypertensive treatment with amlodipine reducedOS in all examined areas of the brain and decreased bloodpressure without a reflex increase in sympathetic nerveactivity Nicardipine another CA DHP surprisingly wassignificantly less active than amlodipine
354 Lercanidipine Tomlinson and Benzie reported AOeffect of lercanidipine [210] which is well known as anti-hypertensive drug Zanidip 2[(33-diphenylpropyl)(methyl)-amino]-11-dimethylethyl methyl 26-dimethyl-4-(3-nitro-phenyl)-14-dihydropyridine-35-dicarboxylate Compara-tive data about this drug AOA were presented in parts of thispaper about other individual CA DHPs and in the part aboutthe ex vivo DHPs effects on LDL
355 Nimodipine Nimodipine (ND) commercially knownas Nimotop is 3-(2-methoxyethyl) 5-propan-2-yl 26-dim-ethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxy-late It is centrally active CA
Treatment with glutathione blocked andwith nimodipineattenuated neuronal cell death caused by prolonged exposureof cell culture to 4-HNE (Faraqui [211])
Nascimento et al [212] found AO effect of nimodipine inyoung rats after pilocarpine- (PIL-) induced (in 400mgkg)seizures The PIL administration increased the striatal cata-lase (CAT) activity The administration of ND 30mgkg30min before PIL preserved normal value of CAT activityOn the other hand no difference was detected in the animalstreated with lower dose 10mgkg These results confirmthe neuroprotectiveantiepileptic effect of ND in young ratssuggesting that this drug acts positively on lipid peroxidation
(in both doses) Nimodipine cannot induce these effects viablockade of Ca2+ channel
Ismailoglu et al [213] studied the therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjury These beneficial effects in rats after cerebral corticalinjury seemed to be related to AOA of nimodipine
356 Benidipine Licensed in Japan and South Asia as CA(CCB) benidipine possesses AO properties Chemically it is5-methyl 3-[(3R)-1-(phenylmethyl)piperidin-3-yl] 26-dim-ethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxy-late (or its hydrochloride (4R)-rel-35-pyridinedicarboxylicacid 14-dihydro-26-dimethyl-4-(3-nitrophenyl)- 3-methyl5-[(3R)-1-(phenylmethyl)-3-piperidinyl] ester hydrochloride(1 1))
Benidipine influences processes connected with OS inseveral ways It prevents lysophosphatidylcholine- (lysoPC)-induced injury and ROS production in human aorticendothelial cells (HAECs) (Matsubara and Hasegawa [214])Matsubara et al [215] explained this effect based on stimula-tion of nitric oxide release
LysoPC is a component of oxidized low-density lipopro-teins (oxLDLs) which plays an important role in the patho-genesis of atherosclerosis Pretreatmentwith benidipine (03ndash3 120583molL) for 24 h protected against lysoPC-induced cyto-toxicity in the HAECs through inhibition of both lysoPC-stimulated ROS production and caspase-37-like activationwith a similar potency Since caspase-37 is involved inexecuting the apoptotic process the reduction of the activityof this enzyme by benidipine may explain the antiapoptoticeffect of the drug However benidipine did not suppresslysoPC-induced phosphorylation of mitogen-activated pro-tein kinases and Ca2+ influx in HAECs These results suggestthat the antioxidant properties of benidipine may be respon-sible for its ability to inhibit ROS production a possiblereason for reduced activation of caspase-37 In conclusionbenidipine suppresses lysoPC-induced endothelial dysfunc-tion through inhibition of ROS production which is due atleast in part to its antioxidant effect and not through theinhibition of L-type voltage-dependent calcium channels
Matsubara and Hasegawa [216] examined the effectsof benidipine on cytokine-induced expression of adhesionmolecules and chemokines (chemoattractants) which areimportant for the adhesion of monocytes to endotheliumPretreatment of HAECs with benidipine (03ndash10 120583molL)for 24 h significantly suppressed cytokine-induced vascularcell adhesion molecule-1 (VCAM-1) and intracellular celladhesion molecule-1 (ICAM-1) mRNA and protein expres-sion resulting in reduced adhesion of THP-1 monocytesBenidipine also suppressed induction of monocyte chemoat-tractant protein-1 (MCP-1) and interleukin-8 Benidipinealso inhibited redox-sensitive transcriptional nuclear factor-120581B (NF-120581B) pathway as determined by Western blotting ofinhibitory 120581B (I120581B) phosphorylation and luciferase reporterassay Results of analysis using optical isomers of benidip-ine and antioxidants suggest that these inhibitory effectswere dependent on pharmacological effects other than Ca2+antagonism Benidipine may thus have anti-inflammatoryproperties and benefits for the treatment of atherosclerosis
Oxidative Medicine and Cellular Longevity 21
Benidipine was also shown to inhibit ROS production inpolymorphonuclear leukocytes and oxidative stress in salt-loaded stroke-prone spontaneously hypertensive rats (Mat-subara et al [217])
It should be mentioned that other DHPs also haveendothelial AO actions [218]
357 Azelnidipine (AZL) Azelnidipine 3-[1-[di(phen-yl)methyl]azetidin-3-yl] 5-propan-2-yl 2-amino-6-methyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate(AZL) CAS number 123524-52-7 is commercially available4-nitroaryl-DHP type calcium antagonist with long-actingantihypertensive action (long-acting CA (CCB)) and a lowreported incidence of tachycardia It additionally possessesbeneficial effects in OS and diabetic conditions
Azelnidipine prevents cardiac dysfunction in strepto-zotocin-diabetic rats by reducing intracellular calcium accu-mulation (altering intracellular Ca2+ handling proteins) OSand apoptosis (Kain et al [219]) AZL can reduce the superox-ide production It exerts its protective effects by targeting theNADPH oxidase and mitochondrial redox enzymes AZL-treated diabetic rats express enhanced level of bcl-2 in thelysates of heart muscle indicating that AZL plays protectiverole in cardiac apoptosis
It has been previously observed that azelnidipine inhibitstumor necrosis factor-alpha-induced endothelial cell (EC)oxidative stress through its AO properties (Nakamura etal [220]) Azelnidipine but not nitrendipine completelyinhibits the Ang II-induced ROS generation in ECs (Matsuiet al [221])
Furthermore azelnidipine but not nitrendipine wasfound to partially restore decreased pigment epithelium-derived factor (PEDF) mRNA levels in Ang II-exposed ECsThis study suggests that AZL influence depends on its antiox-idative properties Authors concluded that upregulation ofPEDF by azelnidipine may become a therapeutic targetfor the treatment of diabetic retinopathy associated withhypertension
Antihypertensive agents with AO effects are potentiallyuseful for diabetic patients with hypertension While DHPtypeCAare among themost frequently used antihypertensivedrugs azelnidipine has been reported to have a unique AOeffect in vitro and in vivo in experimental animals (Ohmuraet al [222]) In hypertensive diabetic patients azelnidipinetreatment for 12 weeks induced a more significant decreasein erythrocyte LOOH level than amlodipine although thevalues related to blood pressure during each treatmentremained comparable These data confirm the usefulness ofLOOH level in erythrocyte membrane as a marker of OS invivo and indicate that azelnidipine has a unique antioxidativeproperty in humans
Daikuhara et al [223] reported the results of the OLCAstudy based on combination of (1) olmesartan and a calciumchannel blocker (azelnidipine) or (2) candesartan and a CCBamlodipine in two groups of diabetic hypertensive patientsPatients treated with the first combination presented highlypersistent early morning antihypertensive effect and strongerdecrease in heart rate fasting blood glucose andHbA1c levels
and microalbuminuria when compared to patients treatedwith the combination (2) Because diabetes is associated withsevere chronic OS the observed results might be at least in apart due to the AOA of azelnidipine
In favor of this are findings of Abe et al [224] who foundadditive antioxidative effects of azelnidipine on angiotensinreceptor blocker olmesartan treatment for type 2 diabeticpatients with albuminuria
Similarly the AOA of thiazolidinediones (insulin sensi-tizer) and their effect on cardiovascular function in type 2diabetic model rats and also those of some DHPs (nifedipineamlodipine or AZL commonly used antianginal and anti-hypertensive agents) in cultured human endothelial cells LPwere examined (Mizushige [225]) The AOA was evaluatedby measuring 8-iso-prostaglandine F
2120572concentration and
azelnidipine exhibited potent AOAInsulin (INS) resistance combined with hyperinsuline-
mia is involved in the generation of OS A relation-ship exists between increased production of ROS and thediverse pathogenic mechanisms involved in diabetic vascularcomplications including nephropathy Manabe et al [226]revealed that high doses of INS augmented mesangial cellproliferation through generation of intracellular ROS andactivation of redox signaling pathways Cell proliferation wasincreased in a dose-dependent manner by high doses of INS(01ndash10 120583M) but was inhibited by 01120583M AZL Namely theINS-increased phosphorylation of mitogen activated proteinkinaseextracellular signal-regulated kinase 12 (MAPKERK12) was inhibited by 01 120583MAZL The same AZL concen-tration blocked intracellular ROS production more effec-tively than 01 120583M nifedipine The NADPH oxidase inhibitorapocynin (001ndash01120583M) prevented INS-induced mesangialcell proliferation So azelnidipine inhibits insulin-inducedmesangial cell proliferation by inhibiting the productionof ROS Therefore azelnidipine may have the potential toprotect against the onset of diabetic nephropathy and slowits progression
Azelnidipine inhibited H2O2-induced cell death in
neonatal rat cardiomyocytes (Koyama et al [227]) Azelnidip-ine and nifedipine did not affect theH
2O2-induced activation
of extracellular signal-regulated protein kinases (ERK) andp38 MAPK (mitogen-activated protein kinase) In contrastazelnidipine but not nifedipine inhibited H
2O2-induced c-
Jun NH2-terminal kinases (JNK) activation Authors con-
cluded that azelnidipine has inhibited theH2O2-induced JNK
activation and cardiac cell death Therefore azelnidipine mayhave cardioprotective effects against OS
A specific atheroprotection activity of azelnidipine relatesto inhibition of TNF-120572-induced activator protein-1 activa-tion and interleukin-8 expression in human umbilical veinendothelial cells (HUVEC) through suppression of NADPHoxidase-mediated reactive oxygen species generation (Naka-mura et al [220]) TNF-120572 could play a central role in patho-genesis of insulin resistance and accelerated atherosclerosis inthe metabolic syndrome The concentration of AZL found tobe effective in these in vitro experiments is within therapeuticrange As EC do not possess voltage-operated L-type calciumchannels it is suggested that the beneficial effects of azelni-dipine are not likely due to CA property but to its unique AO
22 Oxidative Medicine and Cellular Longevity
ability Furthermore it has been recently found that serumlevels of monocyte chemoattractant protein-1 a biomarkerfor subclinical atherosclerosis were significantly decreased bythe AZL treatment in patients with essential hypertension Inthis paper [220] authors hypothesize that due to its uniqueTNF-120572 signalmodulatory activity and antioxidative propertyazelnidipine may be a promising DHP for targeting diabetesand cardiovascular diseases in hypertensive patients withmetabolic syndrome
Shinomiya et al [228] evaluated its AOA in culturedhuman arterial EC under OS Azelnidipine has shown apotent antioxidative effect that could be of significant clinicalbenefit when combined with its long-lasting antihypertensiveaction and low incidence of tachycardia
Azelnidipine inhibited TGF-1205731 and angiotensin II- (AngII-) activated 1205721(I) collagen mRNA expression in hepaticstellate cells (HSCs) (Ohyama et al [229]) FurthermoreTGF-1205731- and Ang II-induced OS and TGF-1205731-induced p38and JNK phosphorylation were reduced inHSCs treated withAZL Azelnidipine significantly decreased inflammatory cellinfiltration profibrotic genes expression HSC activation LPoxidative DNA damage and fibrosis in liver of CCl
4- or
TAA-treated mice Finally AZL prevented decrease of theexpression of some AO enzymes and accelerated regressionof liver fibrosis in CCl
4-treated mice Hence the antifibrotic
mechanism of AZL against CCl4-induced liver fibrosis in
mice may have been due to an increased level of AO defenseAs azelnidipine is widely used in clinical practice withoutserious adverse effects it may provide an effective newstrategy for antifibrotic therapy
358 Manidipine Manidipine (2-[4-(diphenylmethyl)pip-erazin-1-yl]ethyl methyl 26-dimethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate) is a DHP CCB withreported nephroprotective properties Calo et al [230] stud-ied effect of manidipine on gene expression and proteinlevel of OS related proteins p22(phox) (human neutrophilcytochrome b light chain (CYBA)) and heme oxygenase-1HO-1 Relevance for antihypertensive effects was revealedThe study assessed the effect of manidipine on normalsubjectsrsquo monocyte gene and protein expression of OS relatedproteins such as p22phox a NADPH oxidase system subunitcritical in generating O
2
∙minus and HO-1 induced by and pro-tective against OS Manidipine was compared with the ACEinhibitor captopril and the CCB nifedipine in the presenceand in the absence of sodiumarsenite (NaAsO
2) as an inducer
of OS Monocyte p22phox (CYBA) mRNA production wasreduced by both manidipine and captopril while no changeswere induced by nifedipine Manidipine increased monocyteHO-1 mRNA production while nifedipine and captoprilshowed no effect The effects of manidipine on p22phoxand HO-1 gene expression in the presence of OS were alsoconfirmed at the protein level Thus manidipine seems tosuppress p22phox and to increase the HO-1 mRNA produc-tion and protein level The manidipine-induced increase ofHO-1 gene and protein expression seems to be a peculiareffect of this drug since it is not observed with captopriland nifedipine This effect together with the reduction of
p22phoxmRNAproduction could play a role in its protectivemechanism against OS
359 Mebudipine The protective effect of mebudipine (14-dihydro-26-dimethyl-4-(3-nitrophenyl)-35-pyridinedicar-boxylic acid 3-methyl-5-tert-butyl ester BAY-n-6391) wasrevealed on OS and LP (MDA decrease SOD GPX andcatalase increase) in myocardial ischemic-reperfusion injuryin male rats (Ghyasi et al [231])
There are articles about other commercial and experi-mental DHPs on OS but we have reviewed only the mostcommonly studied compounds Effects of other commercialCA DHPs on OS are also mentioned in several parts of thisreview
36 14-DHPs Ca Agonists andTheir AOA and ARA For themost popular calcium agonist DHP Bay K 8644 no reactionwith peroxyl radicals was registered (Toniolo et al [114])However interactionwith other compounds possessing AOAand ARA (quercetin) was found
Opposite to that AON-acetylcysteine (NAC) diminishedincrease in Ca2+ transient amplitude and cell shorteninginduced by ISO and forskolin whereas NAC had no effecton the (S)-(minus)-methyl-14-dihydro-26-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylatemdash(minus)-BayK 8644-induced increases (Andersson et al [232])
Increased vasoconstriction responses to Bay K 8644 (3 times10minus7ndash3times 10minus5M)were significantly decreased by pyridoindoleantioxidant stobadine treatment in diabetes (Ceylan-Isik etal [233])
The functional interaction between two L-type Ca2+channel activators quercetin and Bay K 8644 has beeninvestigated in vascular smooth muscle cells Biological ARAcompound quercetin at nutritionally meaningful concen-trations limited the responsiveness of vascular L-type Ca2+channels to the pharmacological stimulation operated by BayK 8644 These data contribute to a better understanding ofquercetin effects on experimental in vivo cardioprotection(Saponara et al [234]) Thus these findings indicated thatalthough Bay K 8644 does not exert potent and direct AOAyet acting as calcium agonist it may affect efficiency of AOsubstances and vice versa
Interaction of grapefruit juice (containing quercetin andits analogues) with DHPs CA diminished effectiveness of CAaction of DHPs (Sica [235])
37 Interpretations of the Mechanism(s) of RadicalScavenging and AOA by DHPs
371 Molecular Mechanism(s) of Radical Scavenging andAOA of DHPs in the Model Systems 35-Dicarbonyl-14-di-hydropyridine derivatives possess powerful bis-120573-carbony-lvinyl-amino conjugation and for that reason cannot be con-sidered as ordinary amino antioxidants The electron andorH donation from DHPs ensures their reductant role andresults in AOA and ARA Oxidation reaction from DHPsresults in production of corresponding heteroaromatic pyri-dine derivatives
Oxidative Medicine and Cellular Longevity 23
Detailed studies were made about substituent in DHPring positions 14- namely 4-unsubstituted- 4-substituted4-alkyl- 4-aryl- 4-alkylaryl- ao 26- 35- (diacetyl ordialkoxycarbonyl chain ao) electronic and steric effects onAOA and ARA of DHPs [44 45 51] see Sections 331and 35 The bell-shaped dependence of DHPs AOA onthe 35-dialkoxycarbonyl- chain length was observed [4445 107 109 112] with the maximum activity at C
2H5ndash
C4H9 Decrease of AOA and incorporation into liposomes for
DHPs with alkyl chains longer than R gt C4H9further were
clarified as probable tendency to self-aggregation of thesecompounds ([51] and citation number 245 therein) Electronacceptorelectron donor properties are relevant for expres-sion of AOA or ARA of 35-disubstituted DHPs 35-Diacyl-substituted and 35-dicarbanilido- and 35-dipyridylamido-substituted DHPs are more active as AOs as their 35-dicyano-substituted analogues which have electron acceptorproperties [186]
Dubur et al [89] observed overwhelming steric influenceof substituents in position 4 of the DHP ring Gaviraghiet al [163 164] proposed that AO activity of DHPs ispartly dependent on capacity of the 14-DHP ring to donateelectrons to the propagating radical (ROO∙ or RO∙) and toreduce it to a less reactive form The abstraction (donation)of electron andor H in the oxidation and LP reactionstakes place from all 35-dicarbonyl-14-DHP systems andresults in the formation of corresponding pyridine derivatives(Augustyniak et al [51]) The physicochemical mechanism ofARA and AOA of 14-DHP has been extensively studied anddiscussed (Mulder et al [236]) but precise mechanisms oftheir activity need further clarification
The reactivity of C-4 substituted 14-DHPs possessingeither secondary or tertiary nitrogen atom in the DHP ringtoward alkyl alkylperoxyl radicals and ABTS radical cationwas determined in aqueous media at pH 74 [103] Thesecompounds reacted faster toward alkylperoxyl radicals andABTS radical cation than alkyl ones N-Ethyl-substitutedDHPs showed the lowest reactivity
The 4-methyl substituted DHP was the most reac-tive compound in previously mentioned reactions (Lopez-Alarcon et al [103]) However it was less active (068versus 10) than Trolox-C DHPs having electron-donatingsubstituents (4-Me-DHP and p-MeO-Phe-DHP) showed thehighest kinetic rate constants toward ABTS radical cation p-nitro-Phe-DHP a compound with an electron-withdrawingsubstituent showed a lower kinetic rate constant and N-alkyl-DHP compounds show kinetic rate constants lowerthan the -NH-DHP
Hydrogen at the 1-position of the DHP ring was revealedaccording to the deuteriumkinetic isotope effect studies to beinvolved in the proposedARAmechanismThis fact ismostlynoticeable in the case of alkyl radicals N-Ethyl-substitutedDHPs show the lowest reactivity when compared to Troloxor nisoldipine In all cases the respective pyridine derivativewas detected as the main product of the reaction (Lopez-Alarcon et al [103]) Authors indicate that the kinetic rateconstants toward alkyl alkylperoxyl andABTS radical cationdepend on the nature of the substituents in the C-4 positionof DHP and the presence of the secondary amine group in the
dihydropyridine ring that is the presence of the hydrogen in1-position
Yanez et al [197] have studied the reactivity of 11derivatives of 14-DHPs (including commercial CA) withalkylperoxyl radicals and ABTS radical cation The tested14-DHPs were 83-fold more reactive towards alkylperoxylradicals than to the ABTS cation radical All commercial14-DHP type CCBs were weaker than Trolox-C The par-ticipation of the hydrogen atom in the 1-position appearsto be very relevant for exhibited reactivity Hantzsch ester(diludine)was again found to be themost active compound inthe reaction with alkylperoxyl radicals 23-fold more activethan Trolox The photodegradation product of nifedipine(nitrosophenyl derivative of pyridine) also showed a highactivity Kinetic rate constants for the reaction between 14-DHP compounds and alkylperoxyl radicals exhibited a fairlygood linear correlation with the oxidation peak potentialof DHP derivatives However the activity of tested 14-DHPs towards ABTS radical cation showed an independencebetween kinetic rate constants and oxidation peak potentials
Kirule et al [195] andTirzit et al [196] studiedmechanismof AOA of 4-nitrophenyl-14-DHPs nifedipine and its ana-logues involving formation of 4-(21015840-nitrosophenyl)-pyridinederivative (as active principle) as a result of intramolecularredox reaction using chemical electrochemical and bio-chemical approaches (see Sections 331 and 351)
Nunez-Vergara et al [237] reported the electrochemicaloxidation of C4-hydroxyphenyl-substituted 14-DHP deriva-tives The oxidation proceeds via formation of the unstabledihydropyridyl radical as confirmed by controlled-potentialelectrolysis (CPE) and ESR experiments This type of 14-DHPs has significant activity towards the radicals even whencompared with commercial 14-DHP drugs with well-knownantioxidant ability
It was observed that nicardipine preferentially targets RO∙radicals and is inactive against ROO∙ Lacidipine on theother hand is equally active towards both types of radicals(Gaviraghi et al [164]) The cytoprotective effect againstexposure to H
2O2was more significant for lacidipine (ID
50=
14 nM its log119875 = 54 membrane partition = 136000 assumesposition located 7 A near to the membrane center otherless lipophilic DHPs located 12ndash16 A far from the center)as compared to amlodipine nifedipine and nicardipine insmooth muscle cell culture (Gaviraghi et al [164]) Oxidativeeffect of H
2O2shifts the Ca channel toward an open state
Thus the redox property of CCBs DHPs may augment theirCCB properties
Oxidation of pharmacologically active Hantzsch 14-dihydropyridines was found by electrogenerated superoxideusing a voltammetric approach in DMSO solutions (Ortiz etal [238] and Ortiz et al [239]) Raghuvanshi and Singh [240]have also reported oxidative aromatization of these DHPsinduced by superoxide
Chemiluminescence (CL) was used in the studies ana-lyzing the antioxidant activity of 12 various 4-flavonil-14-dihydropyridine derivatives (Kruk et al [241]) on a chemicalsystem involving a superoxide radical anion These deriva-tives showed structural similarity to flavonoids with respectto the presence of rings A B and C The results obtained in
24 Oxidative Medicine and Cellular Longevity
this study indicate that the tested derivatives may catalyzeconversion of superoxide radicals through mimicking theactivity of superoxide dismutase by delivering H+ for reac-tion
O2
minus∙+O2
minus∙+ 2H+ 997888rarr H
2O2+1O2
(3)
The enhanced emission of the light in the presence oftested compounds was significant and related to stimulatedproduction ofH
2O2and 1O
2fromO
2
∙The latter specieswereremoved from the reactionmixture by the following sequenceof reactions
H+
O2
minus∙997888rarr HO
2
∙
HO2
∙+O2
∙minus997888rarr HO
2
minus+1O2
2HO2
∙997888rarr H
2O2+1O2
2 (1O2) 997888rarr (O
2)2+ h]lowast
(4)
or to take part in spontaneous dismutation of H2O2
2H2O2997888rarr 2H
2O + 1O
2(5)
The authors have offered an original concept of action for 4-flavonil-14-dihydropyridine derivatives unrelated to that ofO2
∙ radical-trapping chain-breaking antioxidants Insteadthey showed that these compounds act similar to superoxidedismutases converting O
2
∙ to H2O2 Hydrogen peroxide
is less toxic for cells than O2
∙ because it is predominantlyremoved by peroxidases and catalases Finally AO effect ofthese DHPs differed from those mediated by flavonoids witha catechol structure of ring B which are well-known 1O
2
quenchersMulder and collaborators came to similar conclusions
especially related to molecular mechanisms of antioxidativeactivity of DHPs [236]TheAOproperties of Hantzsch 14-di-hydropyridine esters and two dibenzo-14-dihydropyridines910-dihydroacridine (DHAC) and N-methyl-910-dihydro-acridine (N-Me-DHAC) have been explored by determin-ing the autoxidation of styrene or cumene at 30∘C Theseexperiments showed that Hantzsch esters are virtually inac-tive as chain-breaking antioxidants (CB-AOs) contrary tothe findings observed by Lopez-Alarcon et al [103] whoused CB-AOA in aqueous media at pH 74 Their reactivitytoward peroxyl radicals was shown to be some 5 orders ofmagnitude lower than that of the excellent CB-AO 22578-pentamethyl-6-hydroxy-chroman (PMHC)
DHAC was found to be sim10 times less reactive thanPMHC kinetic measurements using DHAC N-deuterio-DHAC and N-Me-DHAC pointing out the abstraction ofN-H hydrogen in DHAC by peroxyl radicals despite the factthat the calculated C-H bond dissociation enthalpy (BDE) inDHAC is about 11 kcalmol lower than the N-H BDE Therates of hydrogen atom abstraction by the 22-diphenyl-1-picrylhydrazyl radical (DPPH∙) have also been determined
for the same series of compounds The trends in the peroxyl∙and DPPH∙ rate constants were found to be similar [236]
Tirzit et al [242] have observed quenching of singletoxygen by DHPs This observation paved the ground forfurther research related to reactions of DHPs with hydroxylradicals (Tirzit et al [243]) singlet oxygen (Kazush etal [94]) and mechanisms of action A series of 14-DHPderivatives in NAD-H-Cu2+-H
2O2system inhibited forming
of the hydroxyl radical (HO∙) while 14-DHP derivativeswith electron donor substituents in the molecule were shownto be capable themselves of generating HO∙ in the presenceof Cu2+ and H
2O2 Rubene et al [186] also described
interaction of 14-DHP derivatives with Fentonrsquos reagentwhich produces hydroxyl radical (HO∙) Rate constants ofthe DHPs reaction (1st order) with HO∙ radical were highin the range 109 L times mol times secminus1 close to that of NADHcysteine and thiourea 35-Diacetyl- derivatives reacted fastercompared to 35-dialkoxycarbonyl- ones The reaction ratedecrease was observed in the case of substitution at position4 as compared to 4-unsubstituted DHPs Some DHPs havingelectron donor -COOminus groups in the 35- or 26- positionsof DHP ring reacted immediately (having rate constantshigher as 109 L times mol times secminus1) Rate constants with HO
2
∙
and O2
∙minus radicals were of lower degree Thus DHPs actingas oxygen radical scavengers could effectively inhibit ROSrelated reactions of LP initiation stage
Nifedipine and nitrendipine reactivity toward singletoxygen was also studied [244] Nifedipine was shown tobe a good scavenger of excited oxygen mainly via physicaldeactivation with values of the total rate constant rangingfrom 208 times 105Mminus1 sminus1 (in dioxane) to 930 times 105Mminus1 sminus1(in propylene carbonate)The less reactive pathway generateda photooxidation product For that reason a mechanisminvolving a perepoxide-like encounter complex in the firststep of the reaction path was proposed (see [244] Figures8 and 9 therein) The dependence was observed on solventmicroscopic parameters of the total rate constant for the reac-tion between singlet oxygen and 14-DHPs These findingsshow that nifedipine possesses stronger protective activity inbiological systems than nitrendipine
Density-functional-theory (DFT) calculations made byWang et al [245] confirmed the former experimental obser-vations that Hantzsch ester diludine is potent antioxi-dant with high H atom-donating ability and relatively lowprooxidant activity Possible reaction pathways for radicalsderived from 14-dihydropyridine and the resonance modesfor radical species were given [245]
Moreover two ethoxycarbonyl (EtOCO) substituentsat C(2) and C(6) should further enhance Hantzsch esterdiludine H-atom-donating ability due to resonance effectsHowever DHPs should be used in nonpolar rather than inpolar solvents since in the latter not H-atom but electrontransfer is preferred in the radical scavenging process [245]
Mulder et al [246] proposed that quantum-thermochem-ical calculations must be used with caution to indicate ldquoapromising lead antioxidantrdquo as they criticized the density-functional-theory (DFT) calculations made by Wang et al[245]
Oxidative Medicine and Cellular Longevity 25
372 Possible Mechanisms of DHPs ARA and AOA in the Bio-logical Systems Interaction with Other OSModifiers Some ofthese mechanisms were already described (Sections 331 (2)-(b) 331 (2)-(c) 331 (3)-(b) 35)
Enzymatic sources of ROSwith confirmed functional rolein hypertension are NADPH oxidase NO synthase (NOS)xanthine oxidase and cyclooxygenase Godfraind [3] hasreviewed AO effects and protective action of calcium channelblockers (CCBs) Yao et al [247] observed antioxidant effects(as inhibition of LP) for cardio- and neuroprotective CCBs(3ndash300 120583molL) including 7 DHPs in homogenates of ratbrain IC
50values (120583M) were as follows nifedipine (515) gt
barnidipine (586) gt benidipine (712) gt nicardipine (1293)gt amlodipine (1355) gt nilvadipine (1673) gt nitrendipine(2521) gt diltiazem (gt300) = verapamil (gt300) There arealso research articles describing the AO properties of CCBsthrough direct scavenging effect or through preservationof the endogenous SOD activity These findings indicatethat CCBs may also act by reducing the production ofvasoconstrictors angiotensin and endothelin
When present in concentrations that can be achievedin plasma CCBs may inhibit LP formation [3] This AOactivity seems to be typical for high lipophilic CCBs becausetheir chemical structure facilitates proton-donating andresonance-stabilization mechanisms that quench the freeradical reaction Their insertion in the membrane nearpolyunsaturated fatty acids at relatively high concentrationspotentiates proton donation (or atomary H) to lipid peroxidemolecules thereby blocking the peroxidation process Theremaining unpaired free electron associated with the CCBmolecule can be stabilized in well-defined resonance struc-tures associated with the DHP ring (Mason et al [48])
The radical reaction (according to Godfraind [3]) thatdescribes the AO effects of a DHP CCBs is LOOlowast + DHPrarr LOOH + DHPlowast (where LOOlowast is lipid peroxide radical)which in general is reaction (7) of the LP reaction cascadeconsisting of sim10 reactions (Scheme 2) [89]
As the rate constants of in vitro interaction of 4-substituted DHPs with peroxyl radicals are three ordersof magnitude lower than that of the vitamin E derivativethese DHPs must be considered as weak AO (Ursini [204])However due to partition coefficient of DHPs in membranesand in case of specific binding high local concentration ofDHPs may be obtained
DHPs without CCB properties for instance Bay w 9798although structurally related to nifedipine inhibit TNF-120572-induced vascular cell adhesion molecule-1 expression inendothelial cells by suppressing reactive oxygen speciesgeneration [248]
Mitrega et al [249] have discovered that antiarrhythmicand hemodynamic effects of oxidized heteroaromatic DHPsoxy nifedipine oxy nimodipine oxy nitrendipine and oxynisoldipine suggest that CCB DHPs and their metabolitescould act at least in two ways targeting OS related eventsas reductants (see Section 351 (1)) andor bypassing OSrelatedmetabolic routes Authors postulated that contrary tocurrent belief NIF metabolites are pharmacologically activeATP sensitive potassium channels were mentioned as a tar-get
38 DHPs Anti- or Prooxidants Several substances (ascorbicacid being the most commonly studied) can serve either asantioxidants or as prooxidants depending on given condi-tions (Herbert [250]) Therefore Halliwell [251] has reporteddilemma related to polyphenols as possible antioxidantsand prooxidants causing experimental artifacts (about 25)by oxidation of antioxidant compounds in the cell culturemedia Nevertheless it is generally accepted opinion thatpolyphenols act as antioxidants in vivo Studies on DHPs alsoface such a dilemmaThe exact roles (anti- or prooxidative) ofany specific DHP depend on its structure appliedachievedconcentration and specificity of the targetexperimentaltesting system
This situation resembles the case of antioxidative effectsof tocopherol which depends on the fate of the secondaryradical as proposed by Winterbourn [252] The question wasldquoVitamin E - Pro- or Antioxidantrdquo
997888rarr chain termination of lipid peroxidation
(6)
Prooxidant
Toc∙ + Lipid-H 997888rarr Lipid∙ (in LDL particles) (7)
This example shows that generally speaking any AO mustfulfil several criteria to be considered as an effective com-pound physiologically
(i) It must be able to functionally interact with endoge-nous scavengers even at low concentrations
(ii) It must affect endogenous pathways of OS(iii) It should not have undesirable adverse effect(iv) It should manifest the antioxidant efficacy dependent
on the oxidant(v) It must discriminate among different strategies
needed for 1-electron and 2-electron processes(vi) Radical scavengers can be prooxidant unless linked to
a radical sink (Winterbourn [252])
According to these statements DHPs could be effective asAO under physiological conditions in vivo (Godfraind [3]and others [30 31 38]) and in vitro in various experimentalsystems (cell and tissue) (see Sections 33 34 35)
Hence calcium antagonists appeared to disrupt thefine balance between the production and scavenging ofROS Nifedipine verapamil and diltiazem were shown toinduce significant oxidative stress in the epididymal sperm(increased MDA and decreased catalase and superoxidedismutase activity) This may be the reason for the inductionof male infertility [253]
The dualism of 14-DHP effects has been recorded asinhibition or promotion of LP as quenching or initiating
26 Oxidative Medicine and Cellular Longevity
oxygen and nitrogen free radical chain reactions radiopro-tecting or radiosensitizing antagonizing or synergizing Ca2+in electromechanical coupling as well as in the membranestabilization or labilization
39 Could DHPs Be Involved in Antioxidative Stress Beforebeing applied in vivo the optimal dose and optimal timeintervals forDHPs applicationmust be knownNamely whileROS have been traditionally considered as toxic byproductsof aerobic metabolism we know nowadays that ROS may actas essential signaling molecules needed for the control ofmany different physiological processes Whether the role ofROS will be damaging protective or signaling depends onthe delicate equilibrium between time- and location-specificROS production and scavenging Accordingly the imbalanceof the increased AO potential so-called antioxidative stresscould be dangerous similar to chronic OS in particular incase of extended exposure Inappropriate interventions inthe oxidative homeostasis by excessive antioxidants especiallyin case of chronic exposure to antioxidants might havevery negative effects as was published in the ATBC studyshowing an increased cancer incidence in smokers treatedby excessive beta-carotene [254] Therefore overconsump-tion of any natural or synthetic AO including DHPs asdietary supplements or drugs must be avoided in order tosuppress oxidative damage and must not disrupt the well-integrated antioxidant defense network (Poljsak [255] andPoljsak and Milisav [256]) This is especially important whenadministrating lipid-soluble antioxidants that can be storedin biomembranes thus not only attenuating or preventing LPbut also affecting physiological effects of the natural antiox-idants in particular tocopherol The interrelationship withthe status of endogenous antioxidantsprooxidants should befollowed
DHPs primarily suppress the initiation stages of LPprocessThey do not entirely stop the LP propagation Actingsynergistically with tocopherol diludine may prevent patho-logical excess of ROS production within the lipid moiety ofthe cellular membranes and LDL However due to its lowsolubility and fast metabolism its concentration in the cellsis low For that reason it cannot cause antioxidative stresseven if used for an extended period of time Thus diludine(diethone) could be only a mild antioxidant it has potentialfor restoring the pool of natural antioxidants (as synergist of120572-tocopherol and polyphenols) in the cells
Moreover DHPs CA used for cardioprotection andvasodilatation as commercial drugs in low concentrationsare fast metabolized via CYP3A4 and for that reason theirapplication does not induce cellular AO stress [53 160]However Godfraind and Salomone [257] have postulated noevidence that allows recommending dietary supplementationwith antioxidants for the primary or secondary prevention ofcardiovascular disease
So far there are no reports on antioxidative stress causedby some DHPs diludine and its analogues Diludine andits analogues therefore could act as adaptogens supportinghormetic effects of mild oxidative stress These compoundsmay act as potential multisided modulators of Yin-Yang
cycles of redox and cell functions (the electroplasmic cycle)(Wagner et al [258])
4 Conclusions
14-Dihydropyridines (14-DHPs) have broad spectrum ofOS modulating activities DHPs have reducing and lipidperoxidation inhibitor properties act as reductants in simplechemical systems and stabilize various biological systems(LDL mitochondria microsomes cells and tissues) againstOS Examples and peculiarities and mechanisms of antiox-idant activity (AOA) and antiradical activity (ARA) as wellas stress-protective effect of DHPs including commercialcalcium antagonists (CA) were highlighted These activitiesdepend on various structural parameters related to DHPs(presence and character of substituents) lipophilicity anddepth of the incorporation in the biologicalmembranesTheyalso depend on the experimental model system for exploringthe lipid peroxidation or oxidative stress Stress-protectiveeffect of some metabolites of CA (nifedipine) is reviewedAlthough some DHPs including CA have prooxidant prop-erties (on epididymal sperm cells) they can generally beconsidered as potent antioxidants Therefore comparisonof the AOA and ARA of different DHPs (mutually andwith other AOs) was described in detail According to thedata presented the DHPs might be considered as bellwetheramong synthetic compounds targeting OS and as a kind ofpharmacological measure for respective field of organic andmedicinal chemistry
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
Authors from Latvian IOS acknowledge ESF 201300021DP1112013APIAVIAA011 and National Research Pro-gramme PUBLIC HEALTHBiomedicine of the Republicof Latvia for financial support administration of the Insti-tute for technical support and Rufus Smits PhD for con-sultations in English The support of Cooperation in Euro-pean System of Science and Technology (COST) Domain ofChemistry Molecular Sciences and Technologies (CMST)was of highest importance for preparation of this paper
[2] D J Triggle ldquo14-Dihydropyridines as calcium channel ligandsand privileged structuresrdquoCellular andMolecular Neurobiologyvol 23 no 3 pp 293ndash303 2003
[3] T Godfraind ldquoAntioxidant effects and the therapeutic modeof action of calcium channel blockers in hypertension andatherosclerosisrdquo Philosophical Transactions of the Royal SocietyB Biological Sciences vol 360 no 1464 pp 2259ndash2272 2005
[4] E Cadenas ldquoMitochondrial free radical production and cellsignalingrdquoMolecular Aspects of Medicine vol 25 no 1-2 pp 17ndash26 2004
[5] E Cadenas ldquoFree radicals oxidative stress and diseasesrdquo inLecture PSC 616 p 38 Missouri University of Science andTechnology Rolla Mo USA httpwwwcarnicominstituteorgarticlesenrique cadenaspdf
[6] K Rahman ldquoStudies on free radicals antioxidants and co-fac-torsrdquo Clinical Interventions in Aging vol 2 no 2 pp 219ndash2362007
[7] V Bocci and G Valacchi ldquoFree radicals and antioxidants howto reestablish redox homeostasis in chronic diseasesrdquo CurrentMedicinal Chemistry vol 20 no 27 pp 3397ndash3415 2013
[8] M Valko C J Rhodes J Moncol M Izakovic and M MazurldquoFree radicals metals and antioxidants in oxidative stress-induced cancerrdquo Chemico-Biological Interactions vol 160 no 1pp 1ndash40 2006
[9] G Bartosz ldquoReactive oxygen species destroyers or messen-gersrdquo Biochemical Pharmacology vol 77 no 8 pp 1303ndash13152009
[10] R Visconti and D Grieco ldquoNew insights on oxidative stress incancerrdquo Current Opinion in Drug Discovery and Developmentvol 12 no 2 pp 240ndash245 2009
[11] R N Kujundzic N Zarkovic and K G Troselj ldquoPyridinenucleotides in regulation of cell death and survival by redoxand non-redox reactionsrdquo Critical Reviews in Eukaryotic GeneExpression vol 24 no 4 pp 287ndash309 2014
[12] B Halliwell and J M C Gutteridge ldquoThe definition and mea-surement of antioxidants in biological systemsrdquo Free RadicalBiology and Medicine vol 18 no 1 pp 125ndash126 1995
[13] V D Kancheva and O T Kasaikina ldquoBio-antioxidantsmdashachemical base of their antioxidant activity and beneficial effect
on human healthrdquo Current Medicinal Chemistry vol 20 no 37pp 4784ndash4805 2013
[14] H V Panglossi Ed Frontiers in Antioxidants Research NovaScience Publishers New York NY USA 2006
[15] E B Burlakova E M Molochkina and G A NikiforovldquoHybrid antioxidantsrdquo Oxidation Communications vol 31 no4 pp 739ndash757 2008 httpmembraneustceducnpaperpdfHybrid20Antioxidantspdf
[16] A Bast and G R M M Haenen ldquoTen misconceptions aboutantioxidantsrdquo Trends in Pharmacological Sciences vol 34 no 8pp 430ndash436 2013
[17] E B Burlakova A V 0lesenko E M Molochkina N PPalmina and N G Khrapova Bioantioxidants for RadiationDamage and Malignant Growth Nauka Moscow Russia 1975(Russian)
[18] J Fang T Seki and H Maeda ldquoTherapeutic strategies by mod-ulating oxygen stress in cancer and inflammationrdquo AdvancedDrug Delivery Reviews vol 61 no 4 pp 290ndash302 2009
[19] M Valko D Leibfritz J Moncol M T D Cronin M Mazurand J Telser ldquoFree radicals and antioxidants in normal physi-ological functions and human diseaserdquo International Journal ofBiochemistry and Cell Biology vol 39 no 1 pp 44ndash84 2007
[20] M Jimenez-Del-Rio and C Velez-Pardo ldquoThe bad the goodand the ugly about oxidative stressrdquo Oxidative Medicine andCellular Longevity vol 2012 Article ID 163913 13 pages 2012
[21] C D Kamat S Gadal M Mhatre K S Williamson Q N Pyeand K Hensley ldquoAntioxidants in central nervous system dis-eases preclinical promise and translational challengesrdquo Journalof Alzheimerrsquos Disease vol 15 no 3 pp 473ndash493 2008
[22] A Pompella H Sies R Wacker et al ldquoThe use of totalantioxidant capacity as surrogate marker for food quality andits effect on health is to be discouragedrdquo Nutrition vol 30 no7-8 pp 791ndash793 2014
[23] Z Ye and H Song ldquoAntioxidant vitamins intake and the risk ofcoronary heart disease meta-analysis of cohort studiesrdquo Euro-pean Journal of Cardiovascular Prevention and Rehabilitationvol 15 no 1 pp 26ndash34 2008
[24] P Knekt J Ritz M A Pereira et al ldquoAntioxidant vitamins andcoronary heart disease risk a pooled analysis of 9 cohortsrdquoTheAmerican Journal of Clinical Nutrition vol 80 no 6 pp 1508ndash1520 2004
[25] A C Carr and M C M Vissers ldquoSynthetic or food-derivedvitamin Cmdashare they equally bioavailablerdquo Nutrients vol 5 no11 pp 4284ndash4304 2013
[26] R Tabrizchi ldquoEdaravoneMitsubishi-TokyordquoCurrentOpinion inInvestigational Drugs vol 1 no 3 pp 347ndash354 2000
[27] K Kikuchi S Tancharoen N Takeshige et al ldquoThe efficacy ofedaravone (radicut) a free radical scavenger for cardiovasculardiseaserdquo International Journal of Molecular Sciences vol 14 no7 pp 13909ndash13930 2013
[28] D Mauzerall and F H Westheimer ldquo1-Benzyldihydronicoti-namidemdasha model for reduced DPNrdquo Journal of the AmericanChemical Society vol 77 no 8 pp 2261ndash2264 1955 ChemicalAbstracts vol 50 Article ID 2588i 1956
[29] F Bossert and W Vater ldquo14-Dihydropyridinesmdasha basis fordeveloping new drugsrdquo Medicinal Research Reviews vol 9 no3 pp 291ndash324 1989
[30] G Swarnalatha G Prasanthi N Sirisha and CMadhusudhanaChetty ldquo14-Dihydropyridines a multtifunctional moleculemdash areviewrdquo International Journal of ChemTech Research vol 3 no1 pp 75ndash89 2011
28 Oxidative Medicine and Cellular Longevity
[31] M Cataldi and F Bruno ldquo14-Dihydropyridines the multiplepersonalities of a blockbuster drug familyrdquo Translational Medi-cine UniSa vol 4 no 2 pp 12ndash26 2012 httpwwwncbinlmnihgovpmcarticlesPMC3728803
[32] R Vitolina A Krauze G Duburs and A Velena ldquoAspects ofthe amlodipine pleiotropy in biochemistry pharmacology andclinicsrdquo International Journal of Pharmaceutical Sciences andResearch vol 3 no 5 pp 1215ndash1232 2012
[33] D Grover S N Mokale and M T Shete ldquoDihydropyridinea novel pharmacophorerdquo International Journal of Pharmaceu-tical Erudition vol 1 no 2 pp 16ndash29 2011 httppharmaeru-ditionorgContentPaper20111-RV-320Final2016-29pdf
[34] A M Vijesh A M Isloor S K Peethambar K N ShivanandaT Arulmoli and N A Isloor ldquoHantzsch reaction synthesis andcharacterization of somenew 14-dihydropyridine derivatives aspotent antimicrobial and antioxidant agentsrdquo European Journalof Medicinal Chemistry vol 46 no 11 pp 5591ndash5597 2011
[35] P Mehta and P Verma ldquoAntimicrobial activity of some deriva-tives of 14-dihydropyridinesrdquo Journal of Chemistry vol 2013Article ID 865128 4 pages 2013
[36] P Olejnıkova L Svorc D Olsovska et al ldquoAntimicrobialactivity of novel C2-substituted 14-dihydropyridine analoguesrdquoScientia Pharmaceutica vol 82 no 2 pp 221ndash232 2014
[37] S Sepehri H Perez Sanchez and A Fassihi ldquoHantzsch-typedihydropyridines and biginelli-type tetra-hydropyrimidinesa review of their chemotherapeutic activitiesrdquo Journal of Phar-macy amp Pharmaceutical Sciences vol 18 no 1 pp 1ndash52 2015httpsejournalslibraryualbertacaindexphpJPPSarticleview2383617863
[38] S A Khedkar and P B Auti ldquo14-Dihydropyridines a classof pharmacologically important moleculesrdquo Mini-Reviews inMedicinal Chemistry vol 14 no 3 pp 282ndash290 2014
[39] G D Tirzit and G Ya Duburs ldquo14-dihydropyridines as inhi-bitors of free-radical reactionsrdquo Chemistry of Heterocyclic Com-pounds vol 8 no 1 pp 126ndash127 1972 Translated from KhimiyaGeterotsiklicheskikh Soedinenii no1 pp 133ndash134 1972 (Rus-sian)
[40] I Bogeski R Kappl C Kummerow R Gulaboski M Hothand B A Niemeyer ldquoRedox regulation of calcium ion channelschemical and physiological aspectsrdquoCell Calcium vol 50 no 5pp 407ndash423 2011
[41] S A Giller G Y Dubur Y R Uldrikis et al ldquoDiludine [Themethod to obtain 35-dicarbonylderivatives of 26-dimethyl-14-dihydropyridines]rdquo Authors certificate of USSR no 3004651971 [Byull Izobret no13 p 95 1971] and following patentsPatent of England no 1294650 1973 Patent of France no2055458 1971 Patent of Japan no 702883 1973 Patent ofHolland no 149787 1976 Patent of Italy no 969022 1974 Patentof FRG no 2036403 1978 US Patent no 3883673 1975 USPatent no 3948924 1976
[42] S A Giller G Y Dubur Y R Uldrikis et al ldquoImprovementsin or relating to the stabilization of carotenerdquo GB Patent no1294650 1972
[43] S A Giller G Y Dubur Y R Uldrikis et al ldquoStabilization ofcarotenerdquo US Patent no 3883673 1975 Chemical Abstracts vol83 Article ID 95193 1975
[44] Yu A Zilber G Ya Dubur K K Kumsar and A Kh VelenaldquoThe effect of antioxidants on the peroxidation of bimole-cular phospholipid membranesrdquo Latvijas PSR ZA Vestis Izves-tia Akademii Nauk Latviyskoy SSR vol 6 pp 80ndash82 1971(Russian) translated from the original Russian Doc Accesion
No AD0771751 distributed by NTIS US Department of Com-merce httpwwwdticmildtictrfulltextu2771751pdf
[45] G Ya Dubur Yu A Zilbers A Kh Velena A O Kumerovaand G D Tirzitis ldquoMultistage study of regulation of peroxida-tion processes in biological membranes by antioxidants of 14-dihydropyridine grouprdquo Izvestiya Akademii Nauk LatviyskoySSR vol 336 no 7 pp 65ndash68 1975 (Russian)
[46] R P Mason and M W Trumbore ldquoDifferential membraneinteractions of calcium channel blockers Implications forantioxidant activityrdquo Biochemical Pharmacology vol 51 no 5pp 653ndash660 1996
[47] R P Mason M F Walter M W Trumbore E G Olmstead Jrand P E Mason ldquoMembrane antioxidant effects of the chargeddihydropyridine calcium antagonist amlodipinerdquo Journal ofMolecular and Cellular Cardiology vol 31 no 1 pp 275ndash2811999
[48] R PMason I T MakMW Trumbore and P EMason ldquoAnti-oxidant properties of calcium antagonists related to membranebiophysical interactionsrdquo American Journal of Cardiology vol84 no 4 pp 16ndash22 1999
[49] R PMasonMW Trumbore and P EMason ldquoMembrane bio-physical interaction of amlodipine and antioxidant propertiesrdquoDrugs vol 59 no 2 pp 9ndash16 2000 (French)
[50] R P Mason P Marche and T H Hintze ldquoNovel vascularbiology of third-generation L-type calcium channel antagonistsAncillary actions of amlodipinerdquo Arteriosclerosis Thrombosisand Vascular Biology vol 23 no 12 pp 2155ndash2163 2003
[51] A Augustyniak G Bartosz A Cipak et al ldquoNatural andsynthetic antioxidants an updated overviewrdquo Free RadicalResearch vol 44 no 10 pp 1216ndash1262 2010
[52] T Grune N Zarkovic and K Kostelidou ldquoLipid peroxidationresearch in Europe and the COST B35 action lsquoLipid Peroxida-tion Associated Disordersrsquordquo Free Radical Research vol 44 no10 pp 1095ndash1097 2010
[53] E Carosati P Ioan M Micucci et al ldquo14-Dihydropyridinescaffold in medicinal chemistry the story so far and perspec-tives (part 2) action in other targets and antitargetsrdquo CurrentMedicinal Chemistry vol 19 no 25 pp 4306ndash4323 2012
[54] U Eisner and J Kuthan ldquoThe chemistry of dihydropyridinesrdquoChemical Reviews vol 72 no 1 pp 1ndash42 1972 httpwwwsci-encemadnessorgtalkfilesphppid=138742ampaid=6475
[55] J Kuthan and A Kurfurst ldquoDevelopment in dihydropyri-dine chemistryrdquo Industrial amp Engineering Chemistry ProductResearch and Development vol 21 no 2 pp 191ndash261 1982
[56] A Sausins and G Duburs ldquoSynthesis of 14-dihydropyridinesby cyclocondensation reactionsrdquo Heterocycles vol 27 no 1 pp269ndash289 1988
[57] A E Sausins and G Y Duburs ldquoSynthesis of 14-dihydro-pyridines in cyclocondensation reactions (review)rdquo Chemistryof Heterocyclic Compounds vol 28 no 4 pp 363ndash391 1992Translated from Khimiya Geterotsiklicheskikh Soedinenii no 4pp 435ndash467 1992 (Russian)
[58] S Kazda ldquoTwenty years of dihydropyridinesrdquo in Dihydropy-ridines Progress in Pharmacology and Therapy W-D Busse BGarthoff and F Seuter Eds pp 1ndash12 Springer Verlag BerlinGermany 1993
[59] J-P Wan and Y Liu ldquoRecent advances in new multicomponentsynthesis of structurally diversified 14-dihydropyridinesrdquo RSCAdvances vol 2 no 26 pp 9763ndash9777 2012
[61] Reaxys Database[62] J Tuttle ldquoStructure mechanism and reactivity of hantzsch
estersrdquo in MacMillan Lab Group Meeting (082504) p 332004 httpwwwprincetoneduchemistrymacmillangroup-meetingsJBT20Hantzschpdf
[63] A Saini S Kumar and J S Sandhu ldquoHantzsch reaction recentadvances in Hantzsch 14-dihydropyridinesrdquo Journal of Sci-entific amp Industrial Research vol 67 pp 95ndash111 2008
[64] L LW Cheung S A Styler and A P Dicks ldquoRapid and conve-nient synthesis of the 14-dihydropyridine privileged structurerdquoJournal of Chemical Education vol 87 no 6 pp 628ndash630 2010
[65] A Kumar R A Maurya S Sharma M Kumar and G BhatialdquoSynthesis and biological evaluation of N-aryl-14-dihydro-pyridines as novel antidyslipidemic and antioxidant agentsrdquoEuropean Journal of Medicinal Chemistry vol 45 no 2 pp 501ndash509 2010
[66] R S Kumar A Idhayadhulla A J Abdul Nasser and J SelvinldquoSynthesis and anticoagulant activity of a new series of 14-dihydropyridine derivativesrdquo European Journal of MedicinalChemistry vol 46 no 2 pp 804ndash810 2011
[67] H A Stefani C B Oliveira R B Almeida et al ldquoDihydro-pyrimidin-(2H)-ones obtained by ultrasound irradiation anew class of potential antioxidant agentsrdquo European Journal ofMedicinal Chemistry vol 41 no 4 pp 513ndash518 2006
[68] H Sun C Shang L Jin and J Zhang ldquoSynthesis and antiox-idant activity of a series of novel 3-chalcone-substituted 14-dihydropyridine derivativesrdquoHeterocyclic Communications vol18 no 5-6 pp 239ndash243 2012
[69] D B Tikhonov and B S Zhorov ldquoStructural model for dihy-dropyridine binding to L-type calcium channelsrdquo The Journalof Biological Chemistry vol 284 no 28 pp 19006ndash19017 2009
[70] G Y Dubur and Y R Uldrikis ldquoThe oxidation of 14-dihydro-pyridinesrdquo Chemistry of Heterocyclic Compounds vol 6 no 1pp 80ndash84 1970 Translated from Khimiya GeterotsiklicheskikhSoedinenii no 1 pp 83ndash88 1970 (Russian)
[71] G Ya Duburs A O Kumerova and Ya R Uldrikis ldquoEnzymicoxidation of hydrogenated pyridines with peroxidase-hydrogenperoxide systemrdquoLatvijas PSRZAVestis vol 73 no 7 pp 73ndash771970 (Russian) Chemical Abstracts vol 73 Article ID 94913g1970
[72] K Xie Y-C Liu Y Cui J-GWang Y Fu andT CWMak ldquoN-methyl-(R)-3-(tert-butyl)-sulfinyl-14-dihydropyridine a novelNADHmodel compoundrdquoMolecules vol 12 no 3 pp 415ndash4222007
[73] S Tamagaki T Mimura and W Tagaki ldquoMetal-ion-facilitatedoxidations of dihydropyridines with molecular oxygen andhydrogen peroxiderdquo Journal of the Chemical Society PerkinTransactions 2 no 10 pp 1645ndash1650 1990
[74] D Tirzite G Tirzitis andD Antipova ldquoReductive ability of 14-dihydropyridine derivatives in relation to ions of trivalent ironrdquoChemistry of Heterocyclic Compounds vol 35 no 5 pp 592ndash594 1999
[76] J Ogle J Stradins and L Baumane ldquoFormation and decay offree cation-radicals in the course of electro-oxidation of 12- and14-dihydropyridines (Hantzsch esters)rdquo Electrochimica Actavol 39 no 1 pp 73ndash79 1994
[77] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for the
synthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts C Wittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Berlin Germany 2010
[78] WDu and Zh Yu ldquoBiomimetic in situ regeneration of cofactorsNAD(P)+ and NAD(P)H models hantzsch esters and dihy-drophenanthridinerdquo Synlett vol 23 no 9 pp 1300ndash1304 2012
[79] H K Chenault and G M Whitesides ldquoRegeneration ofnicotinamide cofactors for use in organic synthesisrdquo AppliedBiochemistry and Biotechnology vol 14 no 2 pp 147ndash197 1987
[80] Y R Uldrikis A A Zidermane E A Biseniex I E Preisa GY Dubur and G D Tirzit ldquoEsters of 26-dimethyl-14-dihydro-pyridine-35-dicarboxylic acid and method of obtainingthereofrdquo WO 8000345 A1 1978 httpworldwideespacenetcompublicationDetailsbiblioDB=EPODOCampII=1ampND=3ampadjacent=trueamplocale=en EPampFT=Dampdate=19800306ampCC=WOampNR=8000345A1ampKC=A1
[81] Y Sambongi H Nitta K Ichihashi M Futai and I Ueda ldquoAnovel water-soluble Hantzsch 14-dihydropyridine compoundthat functions in biological processes through NADH regener-ationrdquo Journal of Organic Chemistry vol 67 no 10 pp 3499ndash3501 2002
[82] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for thesynthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts ChWittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Verlag Berlin Germany 2010
[83] T Okamura T Kikuchi A Nagamine et al ldquoAn approach formeasuring in vivo cerebral redox states using the oxidative con-version of dihydropyridine to pyridinium ion and themetabolictrapping principlerdquo Free Radical Biology and Medicine vol 38no 9 pp 1197ndash1205 2005
[84] K A Schellenberg and F H Westheimer ldquoA free-radicaloxidation of a dihydropyridine1ardquo The Journal of OrganicChemistry vol 30 no 6 pp 1859ndash1862 1965
[85] K A Schellenberg ldquoReaction of hydroxyl radical with thymi-dine Scavenging by a dihydropyridinerdquo Federation Proceedingsvol 38 no 3 I p 1433 1979
[86] E S Huyser J A K Harmony and F L McMillian ldquoPeroxideoxidations of dihydropyridine derivativesrdquo Journal of the Amer-ican Chemical Society vol 94 no 9 pp 3176ndash3180 1972
[87] A Sakamoto S T Ohnishi and R Ogawa ldquoInhibition of lipidperoxidation by some dihydropyridine derivativesrdquo Journal ofAnesthesia vol 7 no 2 pp 193ndash197 1993
[88] R Hardeland ldquoReview Neuroprotection by radical avoidancesearch for suitable agentsrdquo Molecules vol 14 no 12 pp 5054ndash5102 2009
[89] G Ya Dubur A Kh Velena V M Gukasov and Yu AVladimirov ldquoRegulation of peroxidation of mitochondrialmembrane lipids initiated by Fe2+ ions by antoxidants of the14-dihydropyridine series in experiments in vitrordquo Biomed-itsinskaya Khimiya vol 22 no 5 pp 665ndash673 1976 (Russian)Chemical Abstracts vol 88 Article ID 2640 1977
[90] G RMMHaenenM J T J Arts A Bast andMD ColemanldquoStructure and activity in assessing antioxidant activity in vitroand in vivo a critical appraisal illustrated with the flavonoidsrdquoEnvironmental Toxicology and Pharmacology vol 21 no 2 pp191ndash198 2006
[91] G Tirzitis and G Bartosz ldquoDetermination of antiradical andantioxidant activity basic principles and new insightsrdquo ActaBiochimica Polonica vol 57 no 2 pp 139ndash142 2010
30 Oxidative Medicine and Cellular Longevity
[92] G R Buettner and R P Mason ldquoSpin-trapping methods fordetecting superoxide and hydroxyl free radicals in vitro and invivordquo inCritical Reviews of Oxidative Stress and Aging Advancesin Basic Science Diagnostics and Intervention R G Cutler andH Rodriguez Eds vol 1 chapter 2 pp 27ndash38World ScientificLondon UK 2003
[93] M M Tarpey and I Fridovich ldquoMethods of detection ofvascular reactive species Nitric oxide superoxide hydrogenperoxide and peroxynitriterdquo Circulation Research vol 89 no3 pp 224ndash236 2001
[94] E Y Kazush E I Sagun G D Tirzit and G Y DaburldquoQuenching of singlet oxygen by electron donating derivativesof 14-dihydropyridinerdquo Chemistry of Heterocyclic Compoundsvol 30 no 5 pp 562ndash563 1994
[95] G Tirzitis E Kazush and G Duburs ldquoReaction of 14-dihydropyridine derivatives with peroxynitrite anionrdquo Chem-istry of Heterocyclic Compounds vol 34 no 3 pp 321ndash3231998 (Russian) Translated from Khimiya GeterotsiklicheskikhSoedinenii no 3 pp 355ndash357 1998
[96] L J Nunez-Vergara C Lopez-Alarcon P A Navarrete-EncinaA M Atria C Camargo and J A Squella ldquoElectrochemicaland EPR characterization of 14-dihydropyridines Reactivitytowards alkyl radicalsrdquo Free Radical Research vol 37 no 1 pp109ndash120 2003
[97] D Tirzite A Krauze A Zubareva G Tirzitis and G DubursldquoSynthesis and antiradical activity of 5-acetyl-2-alkylthio-4-aryl-6-methyl-14-dihydropyridine-3-carboxylic acid nitrilesrdquoChemistry of Heterocyclic Compounds vol 38 no 7 pp 795ndash800 2002
[98] H Ohkawa N Ohishi and K Yagi ldquoAssay for lipid peroxidesin animal tissues by thiobarbituric acid reactionrdquo AnalyticalBiochemistry vol 95 no 2 pp 351ndash358 1979
[99] N Zarkovic ldquo4-Hydroxynonenal as a bioactive marker ofpathophysiological processesrdquo Molecular Aspects of Medicinevol 24 no 4-5 pp 281ndash291 2003
[100] M Parola G Bellomo G Robino G Barrera and M UDianzani ldquo4-Hydroxynonenal as a biological signal molecularbasis and pathophysiological implicationsrdquo Antioxidants andRedox Signaling vol 1 no 3 pp 255ndash284 1999
[101] T Lovakovic M Poljak-Blazi G Duburs et al ldquoGrowthmodulation of human cells in vitro by mild oxidative stressand 14-dihydropyridine derivative antioxidantsrdquo CollegiumAntropologicum vol 35 no 1 pp 137ndash141 2011
[102] R van den Berg G R M M Haenen H van den Bergand A Bast ldquoApplicability of an improved Trolox equivalentantioxidant capacity (TEAC) assay for evaluation of antioxidantcapacity measurements of mixturesrdquo Food Chemistry vol 66no 4 pp 511ndash517 1999
[103] C Lopez-Alarcon P Navarrete C Camargo J A Squella andL J Nunez-Vergara ldquoReactivity of 14-dihydropyridines towardalkyl alkylperoxyl radicals and ABTS radical cationrdquo ChemicalResearch in Toxicology vol 16 no 2 pp 208ndash215 2003
[104] V Valenzuela P Santander C Camargo J A Squella C Lopez-Alarcon and L J Nunez-Vergara ldquo14-Dihydropyridines reac-tivity of nitrosoaryl and nitroaryl derivatives with alkylperoxylradicals andABTS radical cationrdquo Free Radical Research vol 38no 7 pp 715ndash727 2004
[105] L G Tsetlin N A Chebotareva B I Kurganov A K VelenaG Y Dubur and V Z Lankin ldquoStudy of 14-dihydropyridinesas lipoxygenase inhibitors with the use of hydrated reversedmicellesrdquo Pharmaceutical Chemistry Journal vol 22 no 6 pp425ndash428 1988 (Russian)
[106] J Panek Z Reblova L Kocirkova et al ldquoAntioxidant activityof dihydropyridine derivativesrdquo Czech Journal of Food Sciencesvol 18 pp 144ndash145 2000
[107] G Tirzitis I Kirule and G Duburs ldquoAntioxidationsaktivitatder 35-dicarbonylderivate des 26-demethyl-14-dihydropyri-dinsrdquo Fett Wissenschaft TechnologieFat Science Technology vol90 no 10 pp 411ndash413 1988
[108] M Plotniece G Tirzitis Y Uldrikis et al ldquoSynthesis of 14-dihydropyridine derivatives having an oxy- alkoxy- or dimeth-ylaminophenyl substituent in the 4 position their antioxidantactivity and their binding to phospholipid membranesrdquo Chem-istry of Heterocyclic Compounds vol 32 no 10 pp 1166ndash11721996 Translated from Khimiya Geterotsiklicheskikh Soedineniino 10(352) pp 1358ndash1365 1996 (Russian)
[109] D Y Rubene V S Sharov V I Olenev G D Tirzit G Y Duburand Y A Vladimirov ldquoUse of chemiluminescent method forthe evaluation of antioxidant activity of some derivatives of 14-dihydropyridinerdquo Russian Journal of Physical Chemistry A vol55 no 2 pp 511ndash512 1981 (Russian)
[110] M C R Symons and JM C Gutteridge Free Radicals and IronChemistry Biology and Medicine Oxford Science PublicationsOxford University Press Oxford UK 1998
[111] M Repetto J Semprine and A Boveris ldquoLipid peroxidationchemical mechanism biological implications and analyticaldeterminationrdquo in Lipid Peroxidation A Catala Ed Section ILipid Peroxidation Chemical Mechanisms Antioxidants Bio-logical Implications of Biochemistry Genetics and MolecularBiology chapter 1 pp 3ndash30 InTech Rijeka Croatia 2012
[112] A Velena J Zilbers and G Duburs ldquoDerivatives of 14-dihydropyridines asmodulators of ascorbate-induced lipid per-oxidation and high-amplitude swelling ofmitochondria causedby ascorbate sodium linoleate and sodiumpyrophosphaterdquoCellBiochemistry and Function vol 17 no 4 pp 237ndash252 1999
[113] M V Bilenko L N Shelenkova G Y Dubur and A K VelenaldquoUse of antioxidants to prevent renal damage during acuteischemia and reperfusionrdquo Bulletin of Experimental Biology andMedicine vol 96 no 3 pp 1195ndash1198 1983 Translated fromByulletenrsquo Eksperimentalrsquonoi Biologii i Meditsiny vol 96 no 9pp 8ndash11 1983 (Russian)
[114] R Toniolo F Tubaro F Ursini and G Bontempelli ldquoAn elec-troanalytical investigation on the redox properties of calciumantagonist dihydropyridinesrdquo Electroanalysis vol 15 no 10 pp855ndash861 2003
[115] L Kourimska J Pokorny and G Tirzitis ldquoThe antioxidant aci-tivity of 26-dimethyl-35-diethoxycarbonyl-14-dihydropyri-dine in edible oilsrdquo Nahrung vol 37 no 1 pp 91ndash93 1993
[116] C Lopez-Alarcon H Speisky J A Squella C Olea-Azar CCamargo and L J Nunez-Vergara ldquoReactivity of 14-dihydro-pyridines toward SIN-1-derived peroxynitriterdquo PharmaceuticalResearch vol 21 no 10 pp 1750ndash1757 2004
[117] R A Olek W Ziolkowski J J Kaczor L Greci J Popinigisand J Antosiewicz ldquoAntioxidant activity of NADH and its ana-loguemdashan in vitro studyrdquo Journal of Biochemistry andMolecularBiology vol 37 no 4 pp 416ndash421 2004
[118] E Niki N Noguchi and N Gotoh ldquoInhibition of oxidativemodification of low density lipoprotein by antioxidantsrdquo Jour-nal of Nutritional Science andVitaminology vol 39 supplementpp S1ndashS8 1993
[119] N Rojstaczer and D J Triggle ldquoStructure-function relation-ships of calcium antagonists effect on oxidative modificationof low density lipoproteinrdquo Biochemical Pharmacology vol 51no 2 pp 141ndash150 1996
Oxidative Medicine and Cellular Longevity 31
[120] A Sevanian L Shen and FUrsini ldquoInhibition of LDLoxidationand oxidized LDL-induced cytotoxicity by dihydropyridinecalcium antagonistsrdquo Pharmaceutical Research vol 17 no 8 pp999ndash1006 2000
[121] A Negre-Salvayre and R Salvayre ldquoProtection by Ca2+ channelblockers (nifedipine diltiazem and verapamil) against the tox-icity of oxidized low density lipoprotein to cultured lymphoidcellsrdquo British Journal of Pharmacology vol 107 no 3 pp 738ndash744 1992
[122] A Negre-Salvayre G FitoussiM Troly and R Salvayre ldquoCom-parative cytoprotective effect of dihydropyridine calcium chan-nel blockers against the toxicity of oxidized low density lipopro-tein for cultured lymphoid cellsrdquo Biochemical Pharmacologyvol 44 no 12 pp 2379ndash2386 1992
[123] L Cominacini A F Pasini U Garbin et al ldquoAntioxidant activ-ity of different dihydropyridinesrdquo Biochemical and BiophysicalResearch Communications vol 302 no 4 pp 679ndash684 2003
[124] L Cominacini U Garbin A Fratta Pasini et al ldquoOxidized low-density lipoprotein increases the production of intracellularreactive oxygen species in endothelial cells inhibitory effect oflacidipinerdquo Journal of Hypertension vol 16 no 12 part 2 pp1913ndash1919 1998
[125] H M Lander ldquoAn essential role for free radicals and derivedspecies in signal transductionrdquo The FASEB Journal vol 11 no2 pp 118ndash124 1997
[126] M L L Martinez E Rizzi M M Castro et al ldquoLercanidipinedecreases vascular matrix metalloproteinase-2 activity andprotects against vascular dysfunction in diabetic ratsrdquo EuropeanJournal of Pharmacology vol 599 no 1ndash3 pp 110ndash116 2008
[127] P Lesnik C Dachet L Petit et al ldquoImpact of a combinationof a calcium antagonist and a 120573-blocker on cell- and copper-mediated oxidation of LDL and on the accumulation and effluxof cholesterol in human macrophages and murine J774 cellsrdquoArteriosclerosis Thrombosis and Vascular Biology vol 17 no 5pp 979ndash988 1997
[128] G Sobal E J Menzel and H Sinzinger ldquoCalcium antagonistsas inhibitors of in vitro low density lipoprotein oxidation andglycationrdquoBiochemical Pharmacology vol 61 no 3 pp 373ndash3792001
[129] E Lupo R Locher B Weisser and W Vetter ldquoIn vitro antiox-idant activity of calcium antagonists against LDL oxidationcompared with 120572-tocopherolrdquo Biochemical and BiophysicalResearch Communications vol 203 no 3 pp 1803ndash1808 1994
[130] J Zou Y Li H-Q Fan and J-G Wang ldquoEffects of dihydropy-ridine calcium channel blockers on oxidized low-density lipo-protein induced proliferation and oxidative stress of vascularsmooth muscle cellsrdquo BMC Research Notes vol 5 article 1682012
[131] C Napoli S Salomone T Godfraind et al ldquo14-Dihydro-pyridine calcium channel blockers inhibit plasma and LDL oxi-dation and formation of oxidation-specific epitopes in the arte-rial wall and prolong survival in stroke-prone spontaneouslyhypertensive ratsrdquo Stroke vol 30 no 9 pp 1907ndash1915 1999
[132] G Zernig I Graziadei T Moshammer C Zech N Reider andH Glossmann ldquoMitochondrial Ca2+ antagonist binding sitesare associated with an inner mitochondrial membrane anionchannelrdquo Molecular Pharmacology vol 38 no 3 pp 362ndash3691990
[133] F E Hunter Jr A Scott P E Hochstein et al ldquoStudies of themechanism of ascorbate-induced swelling and lysis of isolatedliver mitochondriardquo The Journal of Biological Chemistry vol239 pp 604ndash613 1964
[134] D R Janero B Burghardt and R Lopez ldquoProtection of cardiacmembrane phospholipid against oxidative injury by calciumantagonistsrdquoBiochemical Pharmacology vol 37 no 21 pp 4197ndash4203 1988
[135] A Karadag B Ozcelik and S S Saner ldquoReview of methods todetermine antioxidant capacitiesrdquo FoodAnalyticalMethods vol2 no 1 pp 41ndash60 2009
[136] Y I Gubskiı N V Litvinova and E V Shnurko-TabakovaldquoAntioxidant and antiradical activity of various classes of antiox-idantsrdquo Ukrainskiı Biokhimicheskiı Zhurnal vol 66 no 4 pp114ndash116 1994 (Russian)
[137] M Takei M Hiramatsu and A Mori ldquoInhibitory effects ofcalcium antagonists onmitochondrial swelling induced by lipidperoxidation or arachidonic acid in the rat brain in vitrordquoNeurochemical Research vol 19 no 9 pp 1199ndash1206 1994
[138] M Takei M Hiramatsu R Edamatsu and A Mori ldquoFreeradical scavenging by calcium antagonistsrdquo Neurosciences vol20 no 2 pp 75ndash82 1994
[139] Ya P Stradin G Ya Dubur Yu A Beilis Ya R Uldrikis andA F Korotkova ldquoVoltammetry of 14-dihydropyridine deriva-tives I Potentials of electrochemical oxidation of 35-diacyl-and 35-di(alkoxycarbonyl)-14-dihydropyridines in acetoni-trilerdquo Chemistry of Heterocyclic Compounds no 1 pp 84ndash871972 (Russian)
[140] E V Ivanov T V Ponomarjova G N Merkusev et al ldquoEinneuer Haut-Radioprotektor Diethon (experimentelle Unter-suchung)rdquo Radiobiologia Radiotherapia vol 31 no 1 pp 69ndash78 1990
[141] E V Ivanov T V Ponomareva G N Merkushev et al ldquoRadia-tion modulating properties of derivates of 14-dihydropyridineand 12345678910-decahydroacridine-18 dionerdquo Radiat-sionnaia Biologiia Radioecologiia vol 44 no 5 pp 550ndash5592004 (Russian)
[142] R O Vitolinia D A Berzinia A K Velena I A Vutsina A AKimenis and G Y Duburs ldquoThe protective effects of the cal-cium antagonist foridon in acute myocardial ischaemiardquo Kardi-ologiya vol 27 no 3 pp 90ndash93 1987 (Russian)
[143] A H Velena G Ya Duburs R O Vitolina et al ldquoEffect ofryodipine on electromechanical parameters of heart and vesselscAMP phosphodiesterase activity and swelling-contractioncycle of mitochondriardquo Arzneimittelforschung vol 35 no 6 pp907ndash914 1985
[144] L I Utno Z E Lipsberga A A Silova M I Girgensone EA Bisenieks and G I Ia ldquoCardioprotective properties of a 14-dihydropyridine derivative glutapyrone in deep hypothermiardquoBiulletenrsquo Eksperimentalrsquonoı Biologii i Meditsiny vol 108 no 11pp 558ndash561 1989 (Russian)
[145] M A S FernandesM S Santos J A F Vicente et al ldquoEffects of14-dihydropyridine derivatives (cerebrocrast gammapyroneglutapyrone and diethone) onmitochondrial bioenergetics andoxidative stress a comparative studyrdquoMitochondrion vol 3 no1 pp 47ndash59 2003
[146] M A S Fernandes M S Santos A J M Moreno et al ldquoEffectsof 5-acetyl(carbamoyl)-6-methylsulfanyl-14-dihydropyridine-5-carbonitriles on rat liver mitochondrial functionrdquo Toxicologyin Vitro vol 23 no 7 pp 1333ndash1341 2009
[147] L Klimaviciusa A Kalda A Kaasik et al ldquoNeuroprotectiveactivity of 14-dihydropyridine derivatives structure determi-nantsrdquo Proceedings of the Latvian Academy of Sciences BNatural Exact and Applied Sciences vol 61 no 1-2 pp 33ndash372007
32 Oxidative Medicine and Cellular Longevity
[148] L Klimaviciusa M A S Fernandes N Lencberga et alldquoTargeting the mitochondria by novel adamantane-containing14-dihydropyridine compoundsrdquo in Bioenergetics K B ClarkEd pp 257ndash272 InTech 2012
[149] V Klusa L Klimaviciusa G Duburs J Poikans and AZharkovsky ldquoAnti-neurotoxic effects of tauropyrone a taurineanaloguerdquo Advances in Experimental Medicine and Biology vol583 pp 499ndash508 2006
[150] N Sampson P Berger and Ch Zenzmaier ldquoRedox signalingas a therapeutic target to inhibit myofibroblast activation indegenerative fibrotic diseaserdquo BioMed Research Internationalvol 2014 Article ID 131737 14 pages 2014
[151] T L Leto and M Geiszt ldquoRole of Nox family NADPH oxidasesin host defenserdquoAntioxidantsampRedox Signaling vol 8 no 9-10pp 1549ndash1561 2006
[152] K K Griendling D Sorescu and M Ushio-Fukai ldquoNAD(P)Hoxidase role in cardiovascular biology and diseaserdquo CirculationResearch vol 86 no 5 pp 494ndash501 2000
[153] H Chen Y S Song and P H Chan ldquoInhibition of NADPHoxi-dase is neuroprotective after ischemia-reperfusionrdquo Journal ofCerebral Blood Flow and Metabolism vol 29 no 7 pp 1262ndash1272 2009
[154] P Hochstein and L Ernster ldquoADP-activated lipid peroxidationcoupled to the TPNH oxidase system of microsomesrdquo Biochem-ical and Biophysical Research Communications vol 12 no 5 pp388ndash394 1963
[155] I I Gubskiı AGGoriushkoNV Litvinova et al ldquoAntioxidantproperties and membranotropic effect of certain derivatives of14-dihydropyridinerdquo Ukrainskiı Biokhimicheskiı Zhurnal vol71 no 4 pp 35ndash39 1999 (Russian)
[156] F Engineer and R Sridhar ldquoInhibition of rat heart andliver microsomal lipid peroxidation by nifedipinerdquo BiochemicalPharmacology vol 38 no 8 pp 1279ndash1285 1989
[157] T Goncalves A P Carvalho and C R Oliveira ldquoAntioxidanteffect of calcium antagonists on microsomai membranes iso-lated from different brain areasrdquo European Journal of Pharma-cology vol 204 no 3 pp 315ndash322 1991
[158] M E Letelier P Izquierdo L Godoy A M Lepe and MFaundez ldquoLiver microsomal biotransformation of nitro-aryldrugs mechanism for potential oxidative stress inductionrdquoJournal of Applied Toxicology vol 24 no 6 pp 519ndash525 2004
[159] M E Letelier P Entrala C Lopez-Alarcon et al ldquoNitroaryl-14-dihydropyridines as antioxidants against rat liver microsomesoxidation induced by ironascorbate Nitrofurantoin and naph-thalenerdquo Toxicology in Vitro vol 21 no 8 pp 1610ndash1618 2007
[160] F P Guengerich W R Brian M Iwasaki M-A Sari CBaarnhielm and P Berntsson ldquoOxidation of dihydropyridinecalcium channel blockers and analogues by human liver cyto-chrome P-450 IIIA4rdquo Journal of Medicinal Chemistry vol 34no 6 pp 1838ndash1844 1991
[161] S H Park S-W RhaW-Y Shin et al ldquoAS-160 Calcium channelblockers of dihydropyridine class reduce the antiplatelet effectof Clopidogrel what is clinical impactrdquo The American Journalof Cardiology vol 107 no 8 supplement p 47A 2011
[162] C Asma and D M Reda ldquoEvaluation of dihydropyridinecalcium antagonist effects on the stress bioindicator orga-nism Saccharomyces cerevisiaerdquo Annals of Biological Researchvol 4 no 10 pp 40ndash46 2013 httpscholarsresearchlibrarycomABR-vol4-iss10ABR-2013-4-10-40-46pdf
[163] G Gaviraghi A M Pastorino E Ratti and D G TristldquoCalcium channel blockers with antioxidant activityrdquo in Free
Radicals Lipoprotein Oxidation andAtherosclerosis G BellomoG Finardi E Maggi and E Rice-Evans Eds pp 431ndash456Richelieu Press London UK 1995
[164] G Gaviraghi AM Pastorino E Ratti and D G Trist ldquoAntiox-idant dihydropyridines a new and comprehensive therapy forfree radical-induced cardiovascular diseasesrdquo in Free Radicalsin Biology and Environment F Minisci Ed vol 27 of NATOASI Series pp 193ndash221 Springer Dordrecht The Netherlands1997
[165] P D Henry ldquoAntiperoxidative actions of calcium antagonistsand atherogenesisrdquo Journal of Cardiovascular Pharmacologyvol 18 supplement 1 pp S6ndashS10 1991
[166] F Kouoh B Gressier T Dine et al ldquoAntioxidant effects andanti-elastase activity of the calcium antagonist nicardipine onactivated human and rabbit neutrophilsmdasha potential antiath-erosclerotic property of calcium antagonistsrdquo CardiovascularDrugs andTherapy vol 16 no 6 pp 515ndash520 2002
[167] S Parthasarathy D Litvinov K Selvarajan and M GarelnabildquoLipid peroxidation and decompositionmdashconflicting roles inplaque vulnerability and stabilityrdquo Biochimica et BiophysicaActa vol 1781 no 5 pp 221ndash231 2008
[168] D-Q Liu Z-Q Pang D-H Zhao and B-H Sheng ldquoEffects offuryl-dihydropyridines I on lipid peroxides of ischemic myo-cardium and ATPases activity of erythrocyte membranes inratsrdquo Acta Pharmacologica Sinica vol 12 no 3 pp 253ndash2561991
[169] V Lukic-Panin T Kamiya H Zhang et al ldquoPrevention of neu-ronal damage by calcium channel blockers with antioxidativeeffects after transient focal ischemia in ratsrdquo Brain Research vol1176 no 1 pp 143ndash150 2007
[170] Y Allanore D Borderie H Lemarechal O G Ekindjian andA Kahan ldquoAcute and sustained effects of dihydropyridine-typecalcium channel antagonists on oxidative stress in systemicsclerosisrdquo American Journal of Medicine vol 116 no 9 pp 595ndash600 2004
[171] I Casetta V Govoni and E Granieri ldquoOxidative stress antioxi-dants and neurodegenerative diseasesrdquo Current PharmaceuticalDesign vol 11 no 16 pp 2033ndash2052 2005
[172] M J T J Arts Assessing antioxidant activity [PhD the-sis] Maastricht University Maastricht The Netherlands 2007httparnounimaasnlshowcgifid=8676
[173] G Dıaz-Araya L Godoy L Naranjo A Squella M E Letelierand L J Nunez-Vergara ldquoAntioxidant effects of 14-dihydro-pyridine and nitroso aryl derivatives on the Fe+3ascorbate-stimulated lipid peroxidation in rat brain slicesrdquo General Phar-macology The Vascular System vol 31 no 3 pp 385ndash391 1998
[174] Y Fukuhara K Tsuchiya Y Horinouchi et al ldquoProtectiveeffect of photodegradation product of nifedipine against tumornecrosis factor 120572-induced oxidative stress in human glomerularendothelial cellsrdquo Journal of Medical Investigation vol 58 no1-2 pp 118ndash126 2011
[175] W Stengel M Jainz and K Andreas ldquoDifferent potencies ofdihydropyridine derivatives in blocking T-type but not L-typeCa2+ channels in neuroblastoma-glioma hybrid cellsrdquo EuropeanJournal of Pharmacology vol 342 no 2-3 pp 339ndash345 1998
[176] O M Panasenko D J Tirzite G D Tirzitis and G J DubursldquoEffect of some 14-dihydropyridine derivatives on structuralorganization of erythrocyte membranesrdquo Biologicheskie Mem-brany (Biochemistry (Moscow) Series A Membrane and CellBiology) vol 1 pp 919ndash925 1984 (Russian)
[177] L G Herbette Y M H Vant Erve and D G Rhodes ldquoInter-action of 14 dihydropyridine calcium channel antagonists with
Oxidative Medicine and Cellular Longevity 33
biological membranes lipid bilayer partitioning could occurbefore drug binding to receptorsrdquo Journal of Molecular andCellular Cardiology vol 21 no 2 pp 187ndash201 1989
[178] L G Herbette P E Mason G Gaviraghi T N Tulenko andR P Mason ldquoThe molecular basis for lacidipinersquos unique phar-macokinetics optimal hydrophobicity results in membraneinteractions that may facilitate the treatment of atherosclerosisrdquoJournal of Cardiovascular Pharmacology vol 23 supplement 5pp S16ndashS25 1994
[179] G V Belevitch G Y Dubur G E Dobretsov N K Kurek andM M Spirin ldquoCalcium antagonists riodipine nifedipine andverapamil binding to model and biological membranes fluore-scence analysisrdquo Biologicheskie Membrany (Biochemistry(Moscow) Series A Membrane and Cell Biology) vol 5 pp768ndash776 1988 (Russian)
[180] R P Mason G E Gonye D W Chester and L G HerbetteldquoPartitioning and location of Bay K 8644 14-dihydropyridinecalcium channel agonist in model and biological membranesrdquoBiophysical Journal vol 55 no 4 pp 769ndash778 1989
[181] M Cindric A Cipak J Serly et al ldquoReversal of multidrugresistance inmurine lymphoma cells by amphiphilic dihydropy-ridine antioxidant derivativerdquo Anticancer Research vol 30 no10 pp 4063ndash4070 2010
[182] F Shekari H Sadeghpour K Javidnia et al ldquoCytotoxic andmultidrug resistance reversal activities of novel 14-dihydro-pyridines against human cancer cellsrdquo European Journal ofPharmacology vol 746 no 1 pp 233ndash244 2015
[183] X-F Zhou Q Shao R A Coburn and M E Morris ldquoQuanti-tative structure-activity relationship and quantitative structure-pharmacokinetics relationship of 14-dihydropyridines andpyridines as multidrug resistance modulatorsrdquo PharmaceuticalResearch vol 22 no 12 pp 1989ndash1996 2005
[184] R Berkels T Breitenbach H Bartels et al ldquoDifferent antioxida-tive potencies of dihydropyridine calcium channel modulatorsin various modelsrdquo Vascular Pharmacology vol 42 no 4 pp145ndash152 2005
[185] S Borovic G Tirzitis D Tirzite et al ldquoBioactive 14-dihydro-isonicotinic acid derivatives prevent oxidative damage of livercellsrdquo European Journal of Pharmacology vol 537 no 1ndash3 pp12ndash19 2006
[186] D Ya Rubene G D Tirzitis and G Ya Duburs ldquoInteractionof some 14-dihydropyridine derivatives with Fentonrsquos reagentrdquoLatvijas PSRZinatnuAkademijas Vestis Kimijas Serija Proceed-ings of the Latvian SSR Academy of Sciences Chemistry Seriespp 212ndash216 1982 (Russian)
[187] K Ondrias V Misık D Gergel and A Stasko ldquoLipid per-oxidation of phosphatidylcholine liposomes depressed by thecalcium channel blockers nifedipine and verapamil and bythe antiarrhythmic-antihypoxic drug stobadinerdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1003 no 3pp 238ndash245 1989
[188] I T Mak and W B Weglicki ldquoComparative antioxidant acti-vities of propranolol nifedipine verapamil and diltiazemagainst sarcolemmal membrane lipid peroxidationrdquoCirculationResearch vol 66 no 5 pp 1449ndash1452 1990
[189] I T Mak P Boehme and W B Weglicki ldquoProtective effects ofcalcium channel blockers against free radical-impaired endo-thelial cell proliferationrdquo Biochemical Pharmacology vol 50 no9 pp 1531ndash1534 1995
[190] S Ray S Mondal and N Dana ldquoEvaluation of protective roleof nifedipine on lipid peroxidation using reduced glutathione as
model markerrdquo Oxidants and Antioxidants in Medical Sciencevol 1 no 2 pp 97ndash100 2012
[191] M Yamato T Shiba T Ide Y Honda K-I Yamada andH Tsutsui ldquoNifedipine treatment reduces brain damage aftertransient focal ischemia possibly through its antioxidativeeffectsrdquoHypertension Research vol 34 no 7 pp 840ndash845 2011
[192] V Chander and K Chopra ldquoNifedipine attenuates changes innitric oxide levels renal oxidative stress and nephrotoxicityinduced by cyclosporinerdquo Renal Failure vol 27 no 4 pp 441ndash450 2005
[193] K M Gaafa M M Badawy and A A Hamza ldquoThe protectiveeffects of ascorbic acid cimetidine and nifedipine on diethyl-dithiocarbamate-induced hepatic toxicity in albino ratsrdquo Drugand Chemical Toxicology vol 34 no 4 pp 405ndash419 2011
[194] H Sugawara K Tobise and S Onodera ldquoAbsence of antiox-idant effects of nifedipine and diltiazem on myocardial mem-brane lipid peroxidation in contrast with those of nisoldipineand propranololrdquo Biochemical Pharmacology vol 47 no 5 pp887ndash892 1994
[195] I E Kirule D Y Rubene E A Bisenieks G D Tirzit and GY Dubur ldquo4-Nitrophenyl-14-dihydropyridinesmdasha new groupof inhibitors of peroxide oxidationrdquo Chemistry of HeterocyclicCompounds vol 18 no 3 p 316 1982
[196] G D Tirzit I E Kirule L K Baumane R A Gavar Y PStradynrsquo andG YDubur ldquoMechanism of the antioxidant actionof 26-dimethyl-35-dimethoxy-carbonyl-4-(2-nitrophenyl)14-dihydropyridinerdquoChemistry ofHeterocyclic Compounds vol 20no 8 pp 915ndash918 1984
[197] C Yanez C Lopez-Alarcon C Camargo V Valenzuela J ASquella and L J Nunez-Vergara ldquoStructural effects on thereactivity 14-dihydropyridines with alkylperoxyl radicals andABTS radical cationrdquo Bioorganic and Medicinal Chemistry vol12 no 9 pp 2459ndash2468 2004
[198] VMisik A J Stasko D Gergel and K Ondrias ldquoSpin-trappingand antioxidant properties of illuminated and nonilluminatednifedipine and nimodipine in heart homogenate and modelsystemrdquo Molecular Pharmacology vol 40 no 3 pp 435ndash4391991
[199] K Ondrias V Misık A Stasko D Gergelrsquo and M HromadovaldquoComparison of antioxidant properties of nifedipine and illu-minated nifedipine with nitroso spin traps in low densitylipoproteins and phosphatidylcholine liposomesrdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1211 no 1pp 114ndash119 1994
[200] A Stasko V Brezova S Biskupic K Ondrias and V MisıkldquoReactive radical intermediates formed from illuminated nife-dipinerdquoFree Radical Biology andMedicine vol 17 no 6 pp 545ndash556 1994
[201] K Ishizawa Y Izawa-Ishizawa N Yamano et al ldquoNitrosoni-fedipine ameliorates the progression of type 2 diabetic nephro-pathy by exerting antioxidative effectsrdquo PLoS ONE vol 9 no 1Article ID e86335 2014
[202] H Fujii and L J Berliner ldquoIn vivo EPR evidence for free radicaladducts of nifedipinerdquoMagnetic Resonance in Medicine vol 42no 4 pp 691ndash694 1999
[203] S Bollo S Finger J C Sturm L J Nunez-Vergara and JA Squella ldquoCyclic voltammetry and scanning electrochemicalmicroscopy studies of the heterogeneous electron transferreaction of some nitrosoaromatic compoundsrdquo ElectrochimicaActa vol 52 no 15 pp 4892ndash4898 2007
34 Oxidative Medicine and Cellular Longevity
[204] F Ursini ldquoTissue protection by lacidipine insight from redoxbehaviorrdquo Journal of Cardiovascular Pharmacology vol 30supplement 2 pp S28ndashS30 1997
[205] P G Cristofori F A Crivellente I Faustinelli et al ldquoInvolve-ment of the nitric oxide system in the anti-atheroscleroticpotential of lacidipine in the apoE-deficient mouse a mor-phological functional and electrochemical studyrdquo ToxicologicPathology vol 32 no 4 pp 493ndash499 2004
[206] X-P Zhang E L Kit S Mital S Chahwala and T HHintze ldquoParadoxical release of nitric oxide by an L-type calciumchannel antagonist the R+ enantiomer of amlodipinerdquo Journalof Cardiovascular Pharmacology vol 39 no 2 pp 208ndash2142002
[207] F Franzoni G Santoro F Regoli et al ldquoAn in vitro study of theperoxyl and hydroxyl radical scavenging capacity of the calciumantagonist amlodipinerdquo Biomedicine and Pharmacotherapy vol58 no 8 pp 423ndash426 2004
[208] S V Gatsura ldquoOxygen-dependent mechanisms underlying theantiischemic effect of verapamil and amlodipinerdquo Bulletin ofExperimental Biology and Medicine vol 137 no 1 pp 40ndash422004
[209] Y Hirooka Y Kimura M Nozoe Y Sagara K Ito and KSunagawa ldquoAmlodipine-induced reduction of oxidative stressin the brain is associated with sympatho-inhibitory effects instroke-prone spontaneously hypertensive ratsrdquo HypertensionResearch vol 29 no 1 pp 49ndash56 2006
[210] B Tomlinson and I F F Benzie ldquoAntioxidant effect of lercani-dipine (note)rdquo Hypertension vol 42 no 4 pp e10ndashe11 2003
[211] A A Faraqui ldquoNeurochemical aspects of 4-hydroxynonenalrdquoin Lipid Mediators and Their Metabolism in the Brain A AFaraqui Ed chapter 6 pp 159ndash191 Springer New York NYUSA 2011
[212] V S NascimentoM S DrsquoAlva A AOliveira et al ldquoAntioxidanteffect of nimodipine in young rats after pilocarpine-inducedseizuresrdquo Pharmacology Biochemistry and Behavior vol 82 no1 pp 11ndash16 2005
[213] O Ismailoglu P Atilla S Palaoglu et al ldquoThe therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjuryrdquo Turkish Neurosurgery vol 22 no 6 pp 740ndash746 2012
[214] M Matsubara and K Hasegawa ldquoBenidipine a dihydropy-ridine-calcium channel blocker prevents lysophosphatidyl-choline-induced injury and reactive oxygen species productionin human aortic endothelial cellsrdquo Atherosclerosis vol 178 no1 pp 57ndash66 2005
[215] M Matsubara K Yao and K Hasegawa ldquoBenidipine adihydropyridine-calcium channel blocker inhibits lysophos-phatidylcholine-induced endothelial injury via stimulation ofnitric oxide releaserdquo Pharmacological Research vol 53 no 1 pp35ndash43 2006
[216] MMatsubara and K Hasegawa ldquoEffects of benidipine a dihyd-ropyridine-Ca2+ channel blocker on expression of cytokine-induced adhesion molecules and chemoattractants in humanaortic endothelial cellsrdquo European Journal of Pharmacology vol498 no 1ndash3 pp 303ndash314 2004
[217] M Matsubara O Akizuki J-I Ikeda K Saeki K Yao and KSasaki ldquoBenidipine an anti-hypertensive drug inhibits reactiveoxygen species production in polymorphonuclear leukocytesand oxidative stress in salt-loaded stroke-prone spontaneouslyhypertensive ratsrdquo European Journal of Pharmacology vol 580no 1-2 pp 201ndash213 2008
[218] A C Rosenkranz H Lob T Breitenbach R Berkels and RRoesen ldquoEndothelial antioxidant actions of dihydropyridines
and angiotensin converting enzyme inhibitorsrdquo European Jour-nal of Pharmacology vol 529 no 1ndash3 pp 55ndash62 2006
[219] V Kain S Kumar and S L Sitasawad ldquoAzelnidipine preventscardiac dysfunction in streptozotocin-diabetic rats by reducingintracellular calcium accumulation oxidative stress and apop-tosisrdquo Cardiovascular Diabetology vol 10 article 97 2011
[220] K Nakamura S Yamagishi and H Inoue ldquoUnique atheropro-tective property of azelnidipine a dihydropyridine-based cal-cium antagonistrdquoMedical Hypotheses vol 65 no 1 pp 155ndash1572005
[221] TMatsui S Yamagishi K Nakamura S Kikuchi andH InoueldquoAzelnidipine a dihydropyridine-based calcium antagonistinhibits angiotensin II-induced oxidative stress generation anddownregulation of pigment epithelium-derived factor mRNAlevels in microvascular endothelial cellsrdquo Drugs under Experi-mental and Clinical Research vol 31 no 5-6 pp 215ndash219 2005
[222] C Ohmura H Watada T Shimizu et al ldquoCalcium channelblocker azelnidipine reduces lipid hydroperoxides in patientswith type 2 diabetes independent of blood pressurerdquo EndocrineJournal vol 54 no 5 pp 805ndash811 2007
[223] H Daikuhara F Kikuchi and T Ishida ldquoThe combination ofOLmesartan and a CAlcium channel blocker (azelnidipine) orcandesartan and a calcium channel blocker (amlodipine) intype 2 diabetic hypertensive patients theOLCA studyrdquoDiabetesand Vascular Disease Research vol 9 no 4 pp 280ndash286 2012
[224] MAbe NMaruyama KOkada SMatsumoto KMatsumotoand M Soma ldquoAdditive antioxidative effects of azelnidipine onangiotensin receptor blocker olmesartan treatment for type 2diabetic patients with albuminuriardquoHypertension Research vol34 no 8 pp 935ndash941 2011
[225] K Mizushige ldquoAntioxidative activities of thiazolidinedionesand dihydropyridine-type calcium antagonistsrdquo IRYOmdashJapa-nese Journal of National Medical Services vol 59 no 11 pp 581ndash592 2005
[226] S Manabe T Okura T Fukuoka and J Higaki ldquoAntioxidativeeffects of azelnidipine on mesangial cell proliferation inducedby highly concentrated insulinrdquo European Journal of Pharma-cology vol 567 no 3 pp 252ndash257 2007
[227] Y Koyama Y Takeishi H Takahashi et al ldquoAzelnidipine inhi-bits H
2O2-induced cell death in neonatal rat cardiomyocytesrdquo
CardiovascularDrugs andTherapy vol 21 no 1 pp 69ndash72 2007[228] K Shinomiya K Mizushige M Fukunaga et al ldquoAntioxidant
effect of a new calcium antagonist azelnipidine in culturedhuman arterial endothelial cellsrdquo Journal of International Med-ical Research vol 32 no 2 pp 170ndash175 2004
[229] T Ohyama K Sato K Kishimoto et al ldquoAzelnidipine is acalcium blocker that attenuates liver fibrosis and may increaseantioxidant defencerdquo British Journal of Pharmacology vol 165no 4 pp 1173ndash1187 2012
[230] L A Calo F Zaghetto E Pagnin P A Davis A Sempliciniand A C Pessina ldquoEffect of manidipine on gene expressionand protein level of oxidative stress-related proteins p22phoxand HO-1 Relevance for antihypertensive and anti-remodelingeffectsrdquo Journal of Cardiovascular Pharmacology vol 43 no 4pp 531ndash538 2004
[231] R Ghyasi G Sepehri M Mohammadi R Badalzadeh and AGhyasi ldquoEffect of mebudipine on oxidative stress and lipid per-oxidation in myocardial ischemic-reperfusion injury in maleratrdquo Journal of Research in Medical Sciences vol 17 no 12 pp1150ndash1155 2012
Oxidative Medicine and Cellular Longevity 35
[232] DCAndersson J Fauconnier T Yamada et al ldquoMitochondrialproduction of reactive oxygen species contributes to the 120573-adrenergic stimulation of mouse cardiomycytesrdquoThe Journal ofPhysiology vol 589 no 7 pp 1791ndash1801 2011
[233] A F Ceylan-Isik N Ari M Stefek et al ldquoEffects of a long-term treatment with an antioxidant pyridoindole on vascularresponsiveness in diabetes-induced aging ratsrdquo Current AgingScience vol 4 no 2 pp 150ndash157 2011
[234] S Saponara G Sgaragli and F Fusi ldquoQuercetin antagonismof Bay K 8644 effects on rat tail artery L-type Ca2+ channelsrdquoEuropean Journal of Pharmacology vol 598 no 1ndash3 pp 75ndash802008
[235] D A Sica ldquoInteraction of grapefruit juice and calcium channelblockersrdquo American Journal of Hypertension vol 19 no 7 pp768ndash773 2006
[236] P Mulder G Litwinienko S Lin P D MacLean L R CBarclay and K U Ingold ldquoThe L-type calcium channel block-ers Hantzsch 14-dihydropyridines are not peroxyl radical-trapping chain-breaking antioxidantsrdquo Chemical Research inToxicology vol 19 no 1 pp 79ndash85 2006
[237] L J Nunez-Vergara R Salazar C Camargo et al ldquoOxidation ofC4-hydroxyphenyl 14-dihydropyridines in dimethylsulfoxideand its reactivity towards alkylperoxyl radicals in aqueousmediumrdquo Bioorganic and Medicinal Chemistry vol 15 no 12pp 4318ndash4326 2007
[238] M E Ortiz L J Nunez-Vergara and J A Squella ldquoRelativereactivity of dihydropyridine derivatives to electrogeneratedsuperoxide ion in DMSO solutions a voltammetric approachrdquoPharmaceutical Research vol 20 no 2 pp 292ndash296 2003
[239] M E Ortiz L J Nunez-Vergara C Camargo and J A SquellaldquoOxidation of Hantzsch 14-dihydropyridines of pharmacolog-ical significance by electrogenerated superoxiderdquo Pharmaceuti-cal Research vol 21 no 3 pp 428ndash435 2004
[240] R S Raghuvanshi and K N Singh ldquoSuperoxide induced oxida-tive aromatization of Hantzsch 14-dihydropyridinesrdquo IndianJournal of Chemistry Section B Organic and Medicinal Chem-istry vol 47 no 11 pp 1735ndash1738 2008
[241] I Kruk A Kladna K Lichszteld et al ldquoAntioxidant activityof 4-flavonil-14-dihydropyridine derivativesrdquo Biopolymers vol62 no 3 pp 163ndash167 2001
[242] G D Tirzit I M Byteva K I Salokhiddinov G P Gurinovichand G Y Dubur ldquo14-Dihydropyridine derivatives as deactiva-tors of singlet oxygenrdquo Chemistry of Heterocyclic Compoundsvol 17 no 7 pp 682ndash684 1981
[243] G D Tirzit E Y Kazush and G Y Dubur ldquoInfluence of14-dihydropyridine derivatives on the generation of hydroxylradicalsrdquo Chemistry of Heterocyclic Compounds vol 28 no 4pp 435ndash437 1992
[244] N A Pizarro-Urzua and L J Nunez-Vergara ldquoNifedipine andnitrendipine reactivity toward singlet oxygenrdquo Journal of Photo-chemistry and Photobiology A Chemistry vol 175 no 2-3 pp129ndash137 2005
[245] L-F Wang H-Y Zhang L Konga Z-W Chena and J-G ShildquoDFT calculations indicate that 14-dihydropyridine is a promis-ing lead antioxidantrdquo Helvetica Chimica Acta vol 87 no 6 pp1515ndash1521 2004
[246] P Mulder H-G Korth and K U Ingold ldquoWhy quantum-thermochemical calculations must be used with caution toindicate lsquoa promising lead antioxidantrsquordquoHelvetica Chimica Actavol 88 no 2 pp 370ndash374 2005
[247] K Yao Y Ina K Nagashima K Ohmori and T Ohno ldquoAntiox-idant effects of calcium antagonists in rat brain homogenatesrdquo
Biological and Pharmaceutical Bulletin vol 23 no 6 pp 766ndash769 2000
[248] T Matsui S-I Yamagishi K Nakamura and H Inoue ldquoBayw 9798 a dihydropyridine structurally related to nifedipinewith no calcium channel-blocking properties inhibits tumournecrosis factor-120572-induced vascular cell adhesion molecule-1expression in endothelial cells by suppressing reactive oxygenspecies generationrdquo Journal of International Medical Researchvol 35 no 6 pp 886ndash891 2007
[249] K AMitrega B VargheseM Porc and T F Krzeminski ldquoAnti-arrhythmic and hemodynamic effects of oxy nifedipine oxynimodipine oxy nitrendipine and oxy nisoldipinerdquo Pharmaco-logical Research vol 66 no 4 pp 300ndash308 2012
[250] V Herbert ldquoSymposium prooxidant effects of antioxidantvitamins Introductionrdquo The Journal of Nutrition vol 126 no4 supplement pp 1197Sndash1200S 1996 httpjnnutritionorgcontent1264 Suppl1197Sfullpdf
[251] B Halliwell ldquoAre polyphenols antioxidants or pro-oxidantsWhat do we learn from cell culture and in vivo studiesrdquoArchives of Biochemistry and Biophysics vol 476 no 2 pp 107ndash112 2008
[252] C Winterbourn Pro-Oxidants or Antioxidants ChristchurchSchool of Medicine Depatment of Pathology Free RadicalSchool SFRBMUniversity of Otago San Francisco Calif USA2009 httpwwwsfrbmorgfrsWinterbournpdf
[253] A Morakinyo B Iranloye and O Adegoke ldquoCalcium antag-onists modulate oxidative stress and acrosomal reaction in ratspermatozoardquo Archives of Medical Science vol 7 no 4 pp 613ndash618 2011
[254] The Alpha-Tocopherol Beta Carotene Cancer Prevention StudyGroup ldquoThe effect of vitamin E and beta carotene on theincidence of lung cancer and other cancers in male smokersrdquoTheNew England Journal of Medicine vol 330 no 15 pp 1029ndash1035 1994
[255] B Poljsak ldquoStrategies for reducing or preventing the generationof oxidative stressrdquo Oxidative Medicine and Cellular Longevityvol 2011 Article ID 194586 15 pages 2011
[256] B Poljsak and I Milisav ldquoThe neglected significance of lsquoanti-oxidative stressrsquordquoOxidativeMedicine and Cellular Longevity vol2012 Article ID 480895 12 pages 2012
[257] T Godfraind and S Salomone ldquoAmbiguities in dietary antiox-idant supplementation compared to calcium channel blockerstherapyrdquo Frontiers in Pharmacology vol 6 article 10 2015
[258] H Wagner H Norr and H Winterhoff ldquoDrugs with adap-togenic effects for strengthening the powers of resistancerdquoZeitschrift fur Phytotherapie vol 13 no 2 pp 42ndash54 1992
Figure 1 Structures of the most known 14-dihydropyridine derivatives and some non-DHP Ca2+ antagonists
interdisciplinary projects funded by EU in particular theCOST B35 action [51 52]
31 Synthesis of 14-Dihydropyridines Routes and ApproachesClassical 3-component Hantzsch synthesis of DHP com-pounds [54ndash57] is usually performed in solutions (includingionic liquids) by heating Discoveries related to this process
and published between 1986 and 1990 are summarized in thereview of Sausins and Duburs [57] In 1993 Kazda [58] hasreviewed ldquotwenty years of dihydropyridinesrdquo including theirsynthesis chemistry progress in pharmacology and therapyand some other applications Since then there were manyimportant discoveries in this field and there is a time fora review on ldquoanother twenty years of DHPsrdquo It has to be
Oxidative Medicine and Cellular Longevity 5
NH
Lercanidipine
NH
Cl
Felodipine
Cl
NH
Lacidipine
NH
Nicardipine
NH
Isradipine
NO
N
NH
COO
Azelnidipine
N
NH
Bay O 5572
NH
COO
Benidipine
N
NH
Manidipine
N N
NH
NC
Nivaldipine
NH
COOC(CH3)3
COOCH(CH3)2
Mebudipine
N
S
O
Diltiazem
N
S
O
O
H
O
Semotiadil
NH
COO
Barnidipine
N
H3C
H3C H3C
H3C
H3C
H3C
H3C
H3CO
H3C
H3C
H3C
H3CCH3
CH3 CH3CH3
CH3
CH3
OCH3
OCOCH3
CH3
CH3
CH3
CH3CH3
NH2
CH3
NO2NO2
H3COOC
H3COOC H3COOC
H3COOC
H3COOC
H3COOC
H3COOC
H3COOC H3COOC
H3COOCCOOC(CH3)2CH2N(CH3)CH2CH2CHPh2
COOCH(CH3)2
N(CH3)COOCH2 CH2CH2 Ph
COOC2H5 COOC2H5C2H5OOC
COOC(CH3)3
NO2NO2
NO2NO2
NO2
NO2
NO2
CH2Ph
CH2Ph
CH 2Ph
CH 2Ph
COO(CH2)7CH3(H3C)2HCOOC
COOCH2CH2
O(CH2)3N(CH3)CH2CH2O
N(CH3CH )2 2CH2
Figure 2 Structures of the most known 14-dihydropyridine derivatives and some non-DHP Ca2+ antagonists
mentioned that nearby this classical multicomponent synthe-sis also a process to obtain structurally diversified 14-dihyd-ropyridines at sophisticated conditions was recently reviewedby Wan and Liu [59]
Many discoveries relevant for novel routes in DHPdesigning and synthesis were published and deposited in
various databases (see httpwwworganic-chemistryorgnamedreactionshantzsch-dihydropyridine-synthesisshtm[60]) For example httpwwwscifindercom [1] databaselists approximately 1000 citations on the simple DHP com-pound diludine Reaxys database [61] contains data relatedto variations in starting materials intermediates as building
6 Oxidative Medicine and Cellular Longevity
NH
SCH3
CN
Cl
O
NH
SCH3 SCH3 SCH3
CN
O
NH
CN
O
NH
CN
OCl OCHF2 OCHF2
OSI-3701OSI-9642OSI-3761OSI-1146
H3C
H3C H3C
H3C H3C H2N
H3C H3C
Figure 3 Molecular structures of OSI-1146 OSI-3701 OSI-3761 and OSI-9642 (according to [146])
blocks media and reactions routes Water and ionic liquidsas reaction media microwave and infrared irradiation newcatalysts solid phase synthesis and biotechnology based andgreen chemistry approaches were also proposed as attractiveoptions for syntheses of DHPs [62ndash66]
Furthermore several new dihydropyrimidin-(2H)-ones(DHPMs) close analogues of DHPs were prepared in theBiginelli reaction under ultrasound irradiation and in thepresence of NH
4Cl Some of these compounds when tested
in vitro at concentrations higher than 100 120583M [67] showedAOAs manifested as inhibition of LPO induced by complexFe + EDTA and reduction of ROS levels
Recently Sun et al [68] reported about the synthesis andantioxidant activity of a series of novel 3-chalcone-substituted14-dihydropyridine derivatives based on dimethyl or diethyl26-dimethyl-4-phenyl-14-DHP-35-dicarboxylate
32 14-Dihydropyridines as Hydrogen Donors Steric elec-trostatic and hydrophobic descriptors in DHP moleculecould serve as its potential pharmacophores [2] In caseof Hantzsch ester this implies partly hydrogenated N-heteroaromatic DHP nucleus itself or its fragments that isNH group or C-4 H- atom as hydrogen donors necessaryfor the AO activity andor carboxylic ester side groups (itsC=O group and O atom as hydrogen bond acceptors) inpositions 3- and 5- and alkyl side groups in positions 2-and 6- (as hydrophobic features) (Grover et al [33] andTikhonov and Zhorov [69]) The presence of labile hydrogenatoms (mainly in positions 14-) in DHPs molecule assignssignificant hydrogen donating ability to these compounds
DHPs (26-dimethyl-14-dihydropyridine-35-dicarboxy-lic acid esters) can be oxidized in chemical (Dubur andUldrikis [70]) electrochemical enzymatic (Duburs et al[71]) and biological (including metabolism and biotransfor-mation) systems As already stated dihydropyridines (espe-cially unsubstituted in position 4) may transfer the hydro-gen similar to the reduced diphosphopyridine nucleotidesNADH and NADPH (Scheme 1) (Mauzerall and Westheimer[28]) while HEH hydrogen transfer studies and search fornovel NADHmodel compounds are continuously developing(Xie et al [72])
Tamagaki et al [73] observedmetal-ion-facilitated oxida-tions ofDHPswithmolecular oxygen andhydrogenperoxideOn the other side Tirzite et al [74] studied some 14-DHP derivatives as reductants in relation to trivalent iron
Hantzsch esters have been extensively utilized as stoichio-metric biomimetic reducing agents Recent summarized lit-erature about DHPs as reducing agents including referenceson diludine may be found on specialized websites httpwwworganic-chemistryorgchemicalsreductions [75]
DHPs form free radicals in chemical electrochemicaland biological oxidation processes The kinetic parametersand pathways of decay of the cationic radicals formed asprimary products in the course of electrooxidation of theesters of 12- and 14-dihydropyridine have been extensivelystudied [76]
The regenerative system of nicotinamide cofactors mayinvolve oxidizing or reducing reagents regulating enzymesand photochemical reactions Thus in situ regenerationof the consumed cofactors was observed in the biosys-tems engineering which create superior biocatalysts by thereduction of NAD(P)+ which can lead to the 14-DHPproduct (which is the only active form) and to the 16-DHP compound [77] The NADPH models of HEHs can beregenerated in situ as biomimetic hydrogen sources bymeansof transition metalBroslashnsted acid catalyzed relay asymmetrichydrogenation [78] General regeneration strategies werereviewed by Chenault and Whitesides [79] Based on thesestrategies particularly related to methods of preparation andpractical use of esters of 26-dimethyl-14-dihydropyridine-35-dicarboxylic acid as antioxidants that might be probablyapplicable for radioprotection and adjuvant treatment againstmetastases several patents were prepared [80]
Sambongi et al [81] have found that the novel water-soluble Hantzsch 14-dihydropyridine compound (the potas-sium salt of 26-dimethyl-14-dihydropyridine-35-dicar-boxylic acid monomethyl ester) functions in biological pro-cesses through regeneration of NADH Various parametersrelated to nicotinamide coenzymes regeneration especiallyin a light of chiral compounds have been published recently[82] while Okamura et al [83] reported the use of theoxidative conversion of dihydropyridine to pyridinium ionand the metabolic trapping principle as an approach formeasuring in vivo cerebral redox states
33 Antioxidant Activity (AOA) and Antiradical Activity(ARA) of 14-Dihydropyridines Antioxidative activity of 14-DHPs was first evaluated and studied in the Latvian IOS(Tirzit and Duburs [39] Zilber et al [44] and Dubur et al[45])
Oxidative Medicine and Cellular Longevity 7
N
O O
N
O O
R R
N
O Ominuseminus minuseminusminuseminus
minusH+
minusH+minusHminus
minusH∙
R998400(H)R998400H R998400(H)
oplus
R=H
Scheme 1 Reactions of 14-dihydropyridines leading to the formation of pyridine derivatives
In the field of ARA pioneering work was made by Schel-lenberg and Westheimer [84] in 1965 In 1979 Schellenberg[85] revealed the free radical oxidation of a dihydropyridinefollowing Huyser et al [86] who reported hydroxyl radicalquenching by DHPs especially Hantzsch ester studying freeradical oxidation of DHPs in vitro in the Fenton system
AOA and ARA of various 14-DHPs were further studiedby several different methods in both in vitro and ex vivoinvivo systems [3 31 44ndash53] CA nisoldipine nimodipinenitrendipine nifedipine and nicardipine have AOA thatcorrelates with their lipophilicity (modified Buege and Austrsquosmethod of TBA determination applied in model of rat braincortex ischemiareperfusion) [87]
N-Aryl-DHPs designed as sirtuin activators were furtherreported as suitable agents for neuroprotection due to theirradical avoidance properties (Hardeland [88])
14-DHPs inhibit free radicals and consequentially thecascade of events related to lipid peroxidation They mayinfluence several stages (initiation andor propagation) of thelipid peroxidation cascade which consist of sim10 reactions[89] (detailed discussion in Section 331 (2)-(b) Scheme 2)
However considering the great number of AO com-pounds (including DHPs) and the diversity in their actionmechanisms [90] in vivo studies are not always convincingand conclusive Therefore concise in vitro models are neces-sary to screen each compound with antioxidative propertiesAntioxidants are designed to react readily with oxidizingspecies and are often extensively oxidized already duringincubations at atmospheric oxygen tension (oxidation ofsome water-soluble DHPs in water (buffer) solutions is veryfast especially in the presence of light) Even during arelatively short incubation period the concentration can dropdrastically and the real potency of the compound could beunderestimated [90]
331 Common AOA and ARA Features of Some DHPs
(1) In Vitro (in Solutions Emulsions and Liposomes) Basicmolecular principles related to antioxidative and antiradi-cal activity of various antioxidants including DHPs werepublished recently [91] These data show that DHPs reactwith various types of free radical species stable free radicals(DPPH ao) and alkyl radicals and with oxygen and nitrogenfree radicals Some derivatives of DHPs may quench a singletoxygen and may react with peroxynitrite anion [92ndash95]
Reactivity of DHPs toward alkyl radicals was studiedelectrochemically [96]
The activity against DPPH radical was found for the5-acetyl-2-alkylthio-4-aryl-6-methyl-14-dihydropyridine-3-carboxylic acid nitriles [97] structural analogues of the5-acetyl(carbamoyl)-6-methylsulfanyl-14-DHP-carbonitrile(studied as mitochondriotropic compounds see further inthe text Section 331 (2)-(b))The highest antiradical activityoccurred for a compound which contains two hydroxylgroups in the 4-phenyl substituent
DHPs were proved to decrease oxygen uptake (2-3-fold) in the heme (methemoglobin hematin hemin andcytochrome C) catalysis by oxidation of emulsions of estersof unsaturated fatty acids and liposomes of phospholipidphosphatidylcholine (Zilber et al [44] and Dubur et al [45])
Reactivity of nitrosoaryl and nitroaryl derivatives of 14-DHPs toward alkyl alkylperoxyl radicals and ABTS radicalcation was found in various LP modeling systems suitablefor determination of DHPs AOA and ARE features [98ndash104] Diludine and foridone and its analogues were shown toinhibit lipid peroxidation through inhibitory effect on lipoxy-genase in emulsions and in reversed micelles (Tsetlin et al[105] and Panek et al [106]) In addition to inhibition of ther-mally initiated oxidation of methyloleate in the solution [107](where AOA of 4-unsubstituted 35-dicarbonylderivativesof 26-dimethyl-14-DHPs is not linearly dependent onthe inhibitor concentration) DHPs derivatives containinghydroxy alkoxy or dimethylaminophenyl substituents inposition 4 were shown to prevent loss of 120573-carotene in thedisperse system of 120573-carotene and methyllinoleate (Plotnieceet al [108])
The AOA of DHPs has been detected using differentmethods in various systems where lipid free radical gen-eration (nonenzymatic Fe2+-dependent andor enzymaticNADPH-dependent) took the place [109ndash112] This activitywas further confirmed in vivo through prevention of damagecaused by renal ischemia and reperfusion as shown fordiludine [113]
Some redox properties of calcium antagonist dihydropy-ridines were revealed through electroanalytical studies [114]Competitive kinetic procedure was used for exploring theAO capacity of five (four 14-DHPs lacidipine felodipinenifedipine and amlodipine and one 12-DHP compoundGR44966) CA and one calcium ion agonist (Bay K 8644) Allbut one (amlodipine) antagonist displayed an unambiguousAO capacity (crocin test) The calcium agonist DHP revealedno reaction with peroxyl radicals Lacidipine was the mosteffective A calcium agonist Bay K 8644 is quite resistant tooxidation and does not bind H+ This could be important
8 Oxidative Medicine and Cellular Longevity
fact in the interaction with the target proteins (it should bementioned that there are no studies on LP with other Ca2+agonists)
The decreased oxidation potential correlates with AOcapacity and increased basic characterThese findings suggestthe relevance of the electron density on the DHP ring
For all the DHP compounds investigated the overalloxidation process proceeds through two consecutive one-electron releases a primary one-electron step accompaniedby a fast proton release and the formation of a neutral radical(PyH∙) undergoing a second much easier one-electron step[114]
The final product is the protonated form of the parentpyridine derivative This pattern is relevant for the antioxida-tive activity since the radical intermediate is far less prone tobe reduced than oxidized
In the case of CA DHPs the release of protons compli-cates the overall oxidation process by introducing a ldquopara-siticrdquo side reaction where a coupling between protons and thestarting species takes place
This DHP self-protonation subtracts part of the originalspecies from the electrode process because the parent cationicspecies are no longer electroactive
Conversely the calcium agonist DHP which is less proneto be oxidized turned out to be so weak base to be evenunable to undergo the self-protonation reaction
Thus the combined effect of oxidation potentials andproton binding capacity of DHPs is a key element for theredox transition relevant for their AO activity Yet opposingeffects (antagonistic versus agonistic) on protein targets ascalcium ion channels connected with protein thiol oxidationto disulfide should be also considered [114]
Kourimska et al [115] found AO effect of diludine (HEH)in edible oil Reactivity of 14-DHPs toward SIN-1-derivedperoxynitrite was shown by Lopez-Alarcon et al [116] Oleket al [117] discovered antioxidative activity of NADH and itsanalogue in vitro
Further see as referred in several subparts below Sections34 35 and 37
(2) Ex Vivo (on Lipid Peroxidation in LDL MitochondriaMicrosomes and Cells) Main chemical structures of DHPsexamined in numerous studies and reviewed in this paper arepresented in Figures 1 and 2
(a) Various DHPs Calcium Antagonists as Inhibitors of LDLPeroxidation Free radicals induce peroxidation of LDLThis process proceeds by a chain mechanism which revealsphosphatidylcholine hydroperoxides and cholesteryl esterhydroperoxides as themajor primary products [118] Calciumantagonist DHPs could act as antioxidants on LDL at leastin three ways (1) as inhibitors of isolated LDL peroxi-dation caused by various inducers (Cu2+ ions UV lightand xanthinexanthine oxidase system) (2) if preincubatedwith cells preventing against intracellular LDL oxidation (3)preventing against the harmful effect of oxidized LDL on cellsand decreasing cytotoxicity [119ndash131]
Combined application of ascorbic acid and CA DHPs(amlodipine and felodipine) has an additive (cytoprotective
and LDL antioxidant activity) effect [120] It includes acombination of peroxide-degrading and peroxyl radical scav-enging reactions thus demonstrating the importance of LPduring LDL oxidation and cytotoxicity induced by oxidizedLDL Cytoprotection is associated with inhibition of oxidant-induced increases in intracellular free calcium
Similar to the othermodel systems the recorded values ofthe tested DHPs related to AO activity on LDL LP and relatedevents [119ndash131] depend on the prooxidant model system andmethods used for activity measuring (see Tables 1ndash5)
Commercial Ca2+ antagonists (including 14-DHP deri-vatives) as well as some other 14-DHPs with less CA activitywere shown to decrease the rate of oxidation (detected asTBARS) of low-density lipoprotein (LDL) induced by Cu2+ions (CuSO
4) in two different cell lines U937 human mono-
cyte-like and J774A1 murine monocyte-macrophage cellline (Rojstaczer and Triggle [119]) The strongest effect wasrecorded for vitamin E followed by felodipine 2-Cl analogueof nifedipine nifedipine amlodipine nitrendipine vera-pamil and diltiazem
Rojstaczer and Triggle [119] found that CA from differentchemical groups had a concentration-dependent effect asantioxidants against LDL oxidation (see Table 1) Howeverthe order of potency (activity rank order ARO) of the drug(s)again depends on the oxidation system and the antioxidantassay Both CA and antioxidative effects relate to the 2- (or o-orto-) substituent of the 4-phenyl ring in the same potencyorder 119900 gt 119898 ≫ 119901 [119] On the other hand the require-ment for the 14-DHP ring is essential for both AOA andCa2+channel antagonism A charged substituent at the position C-2 of the 14-DHP ring influences the AO activity (analogousto [46ndash53]) However some other factors should not beneglected for example although amlodipine has a positivelycharged amine at this position this modificationmakes it lesslipophilic and indirectly less potent antioxidant
Similar results were obtained when testing antioxidanteffect of CA on LDL peroxidation in bovine aortic endothelialcells (BAECs) (Cominacini et al [123] see Tables 2 and 3) aswell as in HUVECs (Lupo et al [129]) (see Table 4)
Cominacini et al [123] observed antioxidant effect ofCCBs and 120572-tocopherol in BAECs The order of potency(see Tables 2 and 3) [123] was however different than inU937 human monocyte-like and J774A1 murine monocyte-macrophage cells (see Rojstaczer and Triggle [119] Table 1)The tested DHPs were lacidipine amlodipine lercanidipinenimodipine and nifedipine (in two different intracellularconcentrations 2 and 4 fmol) ROS production was signif-icantly lowered only by lacidipine (which is the compoundwith the highest lipophilicity) and lercanidipine the effectof lacidipine was much more evident than lercanidipineSurprisingly amlodipine nimodipine and nifedipine had noeffect on ROS formation suggesting that the positive effectson the earliest events of atherosclerosis are a peculiarity oflacidipine molecule through its antioxidant activity
The strong AO action of lacidipine may be related tothe lipophilic cinnamic acid side chain which favors a drugpartitioning in the membrane due to favorable physicochem-ical (hydrophobic) interactions of drug hydrophobic residues
Oxidative Medicine and Cellular Longevity 9
Table 1 Relative structure-function relationships of calcium antagonists (DHPs verapamil and diltiazem) and vitamin E Effect on oxidativemodification of isolated ex vivo human low-density lipoprotein using two various oxidation systems (copper (II) ions induced and monocyteinduced) Compiled according to data presented by Rojstaczer and Triggle [119]
Compound
Systems of LDL oxidation
Copper (II) ions induced system (comparison of three methods) Monocyte induced celloxidation system
Methods
Reduction of TBARS level of LDL(relative efficacy)
Degradation of oxidized[125I] LDL by J774
macrophages
Relative electrophoreticmobility of LDL on
agarose gel
TBARS content of LDL(in )
Relative efficacy (activity rank order (ARO) ARO = I for the most effective) effective inhibitor concentration [IC] in120583M
with polyunsaturated groups of membrane phospholipidsHowever DHPs can also reduce the oxLDL-induced ROSconcentration by affecting some intracellular ROS producerssuch as NADPH oxidases xanthine oxidase and cyclooxyge-nase enzymes The activity of these enzymes contributes tointracellular ROS elevation [125]
Preincubation of HUVECs with lacidipine inhibited anincrease of intracellular ROS caused by oxidized LDL [124]
Lupo et al [129] have studied the dose-dependent (1 510 and 50 120583M) AOA of various CA (verapamil diltiazemand DHPs nifedipine amlodipine isradipine or lacidipine)
Table 3Modulation of ROS formation in BAECs by CA (DHPs andverapamil) and vitamin E Compiled according to data presented byCominacini et al [123]
Compound
Method of flow cytometry (reduced2101584071015840-dichlorofluorescein diacetate(DCFH-DA) oxidation by ROS)
Activity rank order(ARO = I for the highest activity ARO = III for
the mindest activity)(Effective [IC] 1 5 10 50 120583M)
Lacidipine + + + (ARO = I)Lercanidipine + + (ARO = II)Amlodipine No effectNifedipine No effectNimodipine No effectVerapamil + (ARO = III)120572-Tocopherol + + + (ARO = I)
against normolipidemic human blood LDL oxidation com-pared with 120572-tocopherol by measuring the content of TBARSand the diene formation (see Table 4)
10 Oxidative Medicine and Cellular Longevity
Table 4 Normolipidemic human blood LDL (025mgmL) in vitro oxidation in the presence of 5 120583M CuSO4and CA of 3 types (DHPs
verapamil and diltiazem) and vitamin E Compiled according to Lupo et al [129]
Compound
MethodsTBARS method (fluorimetry at 515 nm533 nm 4 hours
preincubation of LDL with compounds and copper (II)ions 320 TBARS increase in control during 4 h
period)
Inhibition of conjugated diene formation (at 234 nm)expressed as prolongation of induction period (in
of control) 119905contr = 368min
Effective [IC] (in 120583M)1 120583M 10120583M 50 120583M
Activity rank order (ARO= I for the highest activity
ARO = VII for themindest activity)
Effective [IC] (in 120583M)1 120583M 5 120583M 10120583M 50 120583M
Activity rank order (ARO= I for the highest activity
ARO = VII for themindest activity)
Nifedipine 10120583M50 120583M ARO = III
5 120583M10120583M 15050 120583M 213
ARO = III
Amlodipine 50 120583M ARO = IV5 120583M
10120583M 12250120583M 138
ARO = IVndashVI
Isradipine 50 120583M ARO = VI 10120583M 15050 120583M 183 ARO = IVndashVI
Lacidipine1 120583M10120583M50 120583M
ARO = II5 120583M
10120583M 19250 120583M 283
ARO = II
Verapamil 50 120583M ARO = V 10120583M 15050 120583M 178 ARO = IVndashVI
Diltiazem No effect No effect (ARO = VII) No effect No effect (ARO = VII)
Vitamin E1 120583M
10120583M (IC50)
50 120583M (20 of control)ARO = I
5 120583M10 120583M 23050 120583M 370
ARO = I
Table 5 Antiproliferative effect (oxLDL-induced HUVSMCs proliferation) of CA DHPs and simultaneous oxLDL-induced ROS productionscavenging Comparison with N-acetyl-L-cysteine NAC (intracellular ROS scavenger) Compiled according to data presented by Zou et al2012 [130]
DHP compound
MethodsAntiproliferative effect against proproliferative effectinduced by oxLDL (50 120583gmL) (UV detection of
formazan production from tetrazolium salt)
oxLDL-induced ROS production (fluorescent DCF(2101584071015840-dichlorofluorescein) production)
Effective [IC] in120583M and I in
Amlodipine 3 120583M I = 18 3 120583M 10 120583M No effectI = 20
S(minus)-Amlodipine No effect No effect
Lacidipine 10 120583M30 120583M
I = 21I = 27 10120583M Isim23 of control
N-Acetyl-L-cysteineNAC
mdash 5000 120583M(5mM) I = 28
As presented (Table 4 according to [129]) for diltiazem(poor lipid solubility) noAOwas detected whereas the otherCA and 120572-tocopherol have demonstrated AOA at least atconcentrations of 10 and 50120583M 120572-tocopherol gt lacidipinegt nifedipine gt isradipine verapamil and amlodipine Addi-tionally120572-tocopherol and lacidipinewere able to significantlyattenuate in vitro LDL oxidation at 1 and 5120583M Theseresults have confirmed the highest activity for the stronglylipophilic DHP type CA compound lacidipine This might be
a possible antiatherogenic mechanism of CA since oxidativemodification enhances the atherogenic potential of LDL
The lipid peroxidation of LDL promoted either by UVradiation or by copper ions was inhibited (antioxidant effect)by nisoldipine in a dose-dependentmanner (IC
50values were
evaluated at around 10 120583M) nimodipine was less potent (IC50
around 50ndash100 120583M) and nicardipine almost inactive In addi-tion to this indirect protective effect CA DHPs nisoldipineand nimodipine exerted direct protective effect on lymphoid
Oxidative Medicine and Cellular Longevity 11
cells against toxicity of previously oxidized LDL The IC50
values were 6 plusmn 2 and 80 plusmn 20 120583M respectively [122] Theinhibition of the cytotoxic effect of LDL oxidized in thepresence of DHP type Ca2+ channel blockers correlated wellwith protection from oxidation by these compounds Com-plete protection cannot be obtained because the DHPs arecytotoxic themselves The potential relevance to the preven-tion of atherogenesis is envisaged
DHP typeCCBnifedipinewas themost effective inhibitorof oxidation promoted either by UV radiation or by copperions in experiments with cultured lymphoid cells LDL (2mgapoBmL) CCBs from other two CCB classes diltiazem andverapamil were only poorly active or completely ineffective[121] The protective effect of nifedipine occurs at two levelsbesides its direct antioxidant effect by inhibition of LDLoxidation it also exhibits a direct cytoprotective effect againstcytotoxicity of oxidized LDL by yet unknown mechanismsThe protective effect of CCBs was not due to an inhibitionof LDL uptake This effect seems to be independent of theinhibition of LDL oxidation per se since LDL was oxidizedin the absence of the drug before the incubation withcells Moreover this direct protective effect was observedat lower concentrations (IC
50of 1 plusmn 02 120583M) compared to
the antioxidant effect (IC50
of TBARS inhibition is around10 plusmn 2 120583M at UV promoted and 4 plusmn 05 120583M by Cu2+ ionsinitiated) The AO effect of nifedipine is also correlated withthe protection of endogenous tocopherols (IC
50= 50 120583M)
It was suggested that the AO effect of CCBs protected cellsindirectly from the cytotoxic effect of oxidized LDL [121]
A recent study has reported that beneficial vascular effectsof lercanidipine in diabetic rats depend on its antioxidantactivity related to attenuating the increase in oxidativestress and in vascular matrix metalloproteinase-2 (MMP-2) (Martinez et al [126]) Lesnik et al [127] studied theimpact of a combination of this calcium antagonist and a120573-blocker atenolol on cell- and copper-mediated oxidationof LDL and on the accumulation and efflux of cholesterolin human macrophages and murine J774 cells They realizedthat lercanidipine reduced the oxidative modification of LDLrather than diminished cholesterol accumulation in humanfoam cells
Comparing the antioxidative action of CA (DHPs amlo-dipine lacidipine nifedipine and isradipine as well as diltia-zem and semotiadil) in the copper-catalyzed oxidation oflow-density lipoprotein (LDL) with that of glycated (g)gly-coxidated (go) LDL demonstrated that the strongest AOeffects during long-term LDL glycation are seen for isradip-ine lacidipine nifedipine and semotiadil [128] Inhibitoryeffects were in the range 10minus5ndash10minus3MAuthors suggested thatdue to the increased generation of ROS by glucose-modifiedLDL the chain-breaking capacity of CA may be overriddenThe AOA of CA depends on their lipophilicity and theirability to incorporate into the LDL particle that is to reachthe site of peroxidation CA like other AOs significantlyretards advanced glycation end products (AGE) formationwhereas initial glycation reactions such as Amadori productformation are only weakly inhibited The observation thatboth oxidative changes and at least long-termglycation effectsare indeed drastically reduced by CA is corroborated by
fluorescence analysis AGE-ELISA quantitation of lipid per-oxidation and TBARS measurement of long-term ggo LDL
The effects of lipophilic DHP calcium channel blockerson oxidized LDL-induced proliferation and oxidative stressof vascular smooth muscle cells were also studied [130] (seeTable 5)
Lacidipine and amlodipine reduced carotid intima-media thickness by decreasing proliferative effect of oxLDLwhereas (S-)-amlodipine had no antiproliferative effect ROS-MAPKs (mitogen-activated protein kinases) pathway mightbe involved in the mechanism
Both 14-DHP CCBs lacidipine and nifedipine reduceplasma and LDL oxidation and formation of oxidation-specific epitopes Their application may also relate to pro-longed survival of rats independently of blood pressuremod-ifications (in the SPSHR model 1mgkg per day lacidipineand 80mgkg per day nifedipine) These results suggestedthat the protective effect of these two 14-DHP drugs invivo as shown in cerebral ischemia and stroke may in partresult from inhibition of LDL oxidative process althoughthese two drugs possess different lipophilic properties [131]Both lacidipine (03 and 10mgkg) andnifedipine (80mgkg)prolonged lag time of the conjugated diene formation inLDL isolated from arterial wall and 119905max These drugssignificantly reduced electrophoreticmobility of oxLDL fromSPSHR subjected to XXO oxidation system 14-DHP CCBsalso protected apolipoprotein B which is important for thebinding with macrophage LDL receptor lysine residues Thedoses used (gt10minus6molL for SPSHR and normotensive WKYrats) however are 2 to 3 orders of magnitude higher thanthose inhibiting vascular smooth muscle contraction in vitroand in vivo They also exceed values that are commonlyused in clinical practice The daily dose of lacidipine forhypertensive patients is 007mgkg asymp4- to 14-fold lower thanthe 2 doses used in SPSHR The maximum daily dose ofnifedipine given to hypertensive patients is 20mgkg asymp40-fold lower thanwhatwere used [131]These discrepanciesmaybe related to differences in bioavailability of CA between ratsand humans [131]
Accordingly in routine clinical use 14-DHPCCBs donotreach the concentrations required for antioxidant activity invitro [131]
Another data concerning the effect of CA DHPs on OSrelated to LDL is presented under Section 35
(b) Effect of DHPs on Isolated Rat Liver and Heart Mitochon-dria As a major cellular source of oxygen radicals (Cadenas[4 5]) mitochondria are promising targets for pharmaco-logical and toxicological actions of various membrane-activecompounds including several 14-DHP derivatives Zernig etal [132] have discovered CA binding sites associated with aninner mitochondrial membrane anion channel
More than 40-year long research onmitochondrial effectsof the DHPs (on their bioenergetics chemiosmotic proper-ties and ion fluxes) clearly points them out as mitochondri-otropic compounds
The activity of the first 35 synthesized compounds(derivatives of 14-DHP their heteroaromatic analogues
12 Oxidative Medicine and Cellular Longevity
NAD-H+ and butylated hydroxytoluene (BHT BOT)) orig-inally was examined in rat liver mitochondrial LP system inthe presence of Fe2+ ions and using the ultraweak chemilu-minescence method (Dubur et al [89])
Several 14-DHP derivatives Hantzsch ester diludine andits analogues were found to be effective antioxidants in thisexperimental system changing the kinetics of LP lengtheningthe time of the appearance of the maximum of the slowburst of the chemiluminescence (latency latent period) anddiminishing the reaction rate (the tangent of the slope angleduring the time in which the amplitude of the slow burstcharacterizing LP rate increases) and its peak value Theirpresence has influenced the reaction constant 119870
6 in relation
to a very significant reduction of lipid hydroperoxides andorinactivation of free radicals as follows
ROO∙ + ROO∙ 997888rarr P + h]lowast termination (1)
(P = molecular products) or
ROO∙ + ROO∙ +H2O 997888rarr ROH + RO∙ + 1O
2
lowast (2)
In this study diludine was one of themost active compoundsDHPs had activity similar to the standard synthetic AO-BHT(ionol) However when plotted against applied concentrationand time window diludinersquos activity profile differed from thatof BHT
There were also similar studies (using different LP rateexperimental detection system and method Hunter et al[133]) based on exploring a group of 26 26-dimethyl-35-disubstituted- and 26-dimethyl-345-trisubstituted-14-dihydropyridines (14-H
2Py=14-DHPs) and five related pyri-
dines as inhibitors of rat liver Mit swelling (Δ119860520119905) and O
2
uptake by ascorbic acid- (AsA-) dependent lipid peroxidationand as modulators of Mit swelling induced by Na+-linoleateor Na+-pyrophosphate (Velena et al [112])
Some of tested 4-DHPs (4-unsubstituted 35-dialkoxy-carbonyl-26-dimethyl-14-DHPs and 35-diamido-26-dim-ethyl-14-DHPs both 4-unsubstituted or those possessinglipophilic 4-aryl- groups) have shown significant AO andmembrane stabilizing activity These studies further revealedthat 14-DHPs preferably act as AO during the stages ofinitiation and prolongation of LP chain reactions at lowconcentrations The studied 14-DHPs had IC
50(when 119881
0119881
or 1205911205910= 2) 01 120583M to 100 120583M and the minimal activity was
scored for oxidized (heteroaromatized) derivativesAt the concentration of 100120583M 35-di-n-butyloxycarbo-
nyl-26-dimethyl-14-DHP entirely stops mitochondrialswelling in the presence of 08mM Na+-pyrophosphateAt the same concentration the following compoundsalter the mitochondrial swelling rate in the presence ofnatural protonophore Na+-linoleate 35-di-p-hydroxyphen-oxycarbonyl- and 35-di-p-tolyloxycarbonyl-26-dimethyl-14-DHPs 35-diethoxycarbonyl-26-dimethyl-pyridine (oxi-dized form of Hantzsch ester) and more lipophilic 35-diamyloxycarbonyl-26-dimethyl-pyridine The alteration ofswelling may be scored as prolonged promoted acceleratedor inhibited The type of alteration depends on the structureand concentration of 14-DHPs the type of initiators of theswelling process and the medium composition
In accord with previously published Janerorsquos results (lackof AO for Ca2+ antagonists nifedipine and nicardipine evenat 500120583M concentration in LP tests performed on heartmembrane [134]) no antioxidative activity for 4-phenyl sub-stituted derivatives of 35-dialkoxycarbonyl 14-DHP (closeanalogues of Ca2+ antagonists) was found contrary to various4-nitrophenyl 14-DHP derivatives calcium antagonists forwhich the significant antioxidant activity was reported [3146ndash53]
Studies made on phosphatidylcholine liposomes (ourunpublished data) suggest approximately three and twotimes more antioxidative activity for 100 120583M 4-unsubstitutedDHP compound diludine when compared to 4-substitutedDHPs riodipinenifedipine and nicardipine respectively atmethemoglobin-induced LP (oxygraphy)
Inhibition of mitochondrial AsA-dependent LP and sta-bilization ofmitochondriawere shown to be characteristic fora large group of 14-DHP compounds [112] showing to pos-sess the AOA in simplest in vitro systems (Tirzit andDuburs [39] Zilber et al [44] and Dubur et al [45])based on reactions with the stable free radical 11-diphenyl-2-picrylhydrazyl (DPPH) LP of fatty acid ester (linethole andmethyloleate) emulsions and phospholipid (phosphatidyl-choline) liposomes Generally these properties did not coin-cide with Ca2+ antagonism Depending on DHP structure itseems that AOA properties are less specific than Ca2+ antago-nist properties Both properties may be interrelated but notinterdependent
These data show that the presence and the nature ofa substituent in position 4 as well as 35-substituentsare important factors for 14-DHP antioxidant effects invarious systems that is AsA-dependent nonenzymatic aswell as enzymatic NADPH-dependent lipid peroxidationSometimes the efficacy of inhibition of nonenzymatic LPby 14-DHPs is higher than the inhibition of the enzymaticLP However the action may be opposite stimulation of theLP Hantzsch ester (HEH diludine) and its close analoguesexhibited significant AOA and membrane stabilizing prop-erties in both AsA-dependent nonenzymatic peroxidationof mitochondria and NADPH-dependent enzymatic LP ofmicrosomes usually at similar 10 to 100120583M concentrations[112]
The order of AOpotency (IC50
values) in vitro depends ondrug structure as well as on the experimental conditions andspecificity of the biological system Eachmethod for determi-nation of AOA and ARA has advantages and disadvantages(Karadag et al [135])
Accordingly as reported by Gubskiı et al [136] IC50
forthe AsA-dependent LP was 025 120583M and 20 120583M for 14-DHPCa2+ antagonists nitrepine (nitrendipine) and nifedipinerespectively Takei et alrsquos [137 138] studies on mitochondrialswelling induced by LP or arachidonic acid in the rat braindetermined the IC
50values of 127 105 1568 and 384 120583Mfor
efonidipine nicardipine nifedipine and nimodipine respec-tively For LDL in the copper-induced oxidation system theorder of potencywas vitamin Egt felodipinegt 2-chlorophenylanalogue of nifedipine gt nifedipine gt amlodipine nitrendip-ine verapamil and diltiazem (Rojstaczer and Triggle [119])
Oxidative Medicine and Cellular Longevity 13
It was interesting to compare the AOAofDHPswith theirsusceptibility to oxidation that is electron and hydrogendonating properties
It has been estimated that electron donor substituentsin positions 2 and 6 of 14-DHP cycle usually promoteoxidation while electron acceptor substituents promotequench oxidation Stronger electron acceptors in positions 3and 5 also significantly quench oxidation These estimationsare based on studies including chemical enzymatic andelectrochemical oxidation of 14-DHPderivatives (Dubur andUldrikis [70] Duburs et al [71] and Stradin et al [139])
On the other hand diminished AOA of 14-DHP relatesto presence of substituents in position 4 (both electron donorand electron acceptor) (Velena et al [112])
35-Dicarbamoyl substituents possess minimal quench-ing feature and are followed by benzoyl- acetyl- andalkoxycarbonyl- groups Maximal decrease was obtainedwith condensed substituents (ie oxoindeno- or oxocyclo-hexeno- groups) and a CN-group 4-Unsubstituted 35-dicar-bamoyl derivatives can be easily oxidized and consequen-tially inactivated whereas 4-substituted 35-dicarbamoyl-14-DHPs possess an oxidation potential analogous to the 4-unsubstituted 35-COOR derivatives Therefore they haveadequate electron donor properties and are considerablystableThismay be the reason for significantmembrane stabi-lization upon exposure to 4-substituted derivatives Ofimportance their AOA was usually more pronounced incomparison to 4-unsubstituted derivatives
Among them 26-dimethyl-35-difurfuryloxycarbonyl-14-DHP showed the highest antioxidative activity In thegroup of 35-dialkoxycarbonyl derivatives the strongestactivity was attributed to compounds with medium lengthalkyl chains (i-butyl- t-butyl- and i-amyl- substituents) highlevel of lipophilicity minimal electron acceptor propertiesand moderate steric hindrance as contrasted to short or longalkyl chain ester derivatives (35-dimethoxycarbonyl- 35-diethoxycarbonyl derivatives and 35-didodecyloxycarbonylderivative) These data demonstrate the bell-shaped depen-dence of AOA on alkyl chain length [112] and are in accordwith results obtained in liposomes However these datadiffer from those obtained in emulsions where diludine wasthe most active compound Finally oxidized heteroaromaticderivatives showed only minimal activity
In both LP systems studied (AsA-dependent in mito-chondria and NADPH-dependent in microsomes) some of14-DHPs showed activity similar to classical antioxidantbutylated hydroxytoluene (ionol BHT) (Velena et al [112])However there was a significant difference related to con-centration and incubation time It allowed us to postu-late that 14-dihydropyridines (InH) acting as antioxidants-reductants and scavengers of reactive oxygen species and lipidfree radicals preferably influence initiation and propagation(prolongation) of lipid peroxidation chain reactions (1)ndash(5) according to Scheme 2 The phenomenon is particularlyprominent in the presence of Fe2+ and other ions of variablevalency
Chain break and termination reactions (6)ndash(10) of theLP reaction cascade [89] were influenced by 14-DHPs in alesser degree than were initiation and propagation steps This
may be important for their therapeutic effects even in theadvanced stages of LP
Scheme 2 (stages of initiation propagation and terminationof lipid peroxidation chain reactions (1ndash10)) Initiation andpropagation reactions are as follows
(8) RO∙ + In∙minus rarr Y (Y = molecular products)(9) ROO∙ + Fe2+ rarr Fe3+ + X (X = molecular products)(10) RO∙ + RO∙minus rarr Y (Y = molecular products)
In the reversible swelling of mitochondria accompanyingLP (initiated by mixture of 5mM GSSG1mM GSH) several14-DHPs showed low or no activity manifested only as adecrease of the swelling amplitude without a rate decreaseAn addition of GSH (4mM) or ATP to swollenmitochondriacaused their contraction in both control and tested systemIt may be suggested that 14-DHPs acting as antioxidantsin mitochondria preferably influence LP reactions initiatedby ions with variable valency or their complexes with hemetype compounds methemoglobin hemin hematin and soforth (Velena et al [112]) If the peroxidation process has amaximal velocity and 50 percent of initial O
2were consumed
14-DHPs cannot completely break the chain reactions andprevent subsequent membrane damage by addition of DHPsubstance at 10 120583M concentration at the moment of 50percent oxygen consumption the subsequent oxygen uptakeproceeded unchanged This observation is important for theapplication of DHPs as inhibitors of initiation and to a lesserdegree propagation stages of LP chain reactions
The influence of 14-DHPs on Mit swelling is not strictlyassociated with their own oxidation There is the possibilitythat the labilizing (or stabilizing) effect relates to surfaceactivity (connected with substituent lipophilicity) or may bethe consequence of complexation with some -OH (or -CH
3)
group sensitive receptors at the mitochondrial membraneNamely a bathochromic shift of the absorption band maxi-mum (about 10 nm) was observed in the visible region beforeswelling However after swelling in the presence of Na+linoleate the spectrum returns to its initial value [112]
Some 14-DHPs not only protect mitochondria againstswelling caused by AsA-dependent LP salts of fatty acids
14 Oxidative Medicine and Cellular Longevity
in vitro [112] but also have beneficial effects on repairingtheir integrity in vivo after exposure to irradiation hepato-toxins ischemia hypoxia or hypothermia Some of themwere shown to normalize the process of intracellular repara-tion and physiological regeneration of ultrastructures Theywere also shown to stimulate reparative processes If pre-treated with 14-DHPs irradiatedmitochondria will not swell(Ivanov et al [140 141])
Diludine ionol and some other AOs mitochondria pro-tectors act as anti-ischemic agents If applied prophylacticallyin vivo they may prevent ischemic and reperfusion lesionsin heart kidney and other organs (Bilenko et al [113]) Theeffect is dependent on applied dose timing and way ofapplicationWhen added onto the cryoconservationmediumfor mitochondria preservation 14-DHPs prevented decreaseof membrane potential normalized facilitated respirationand prevented loss of mitochondrial Na+ and Ca2+ ionsafter thawing ([112] see citation number 36 (Subbota et alKharkov 1984) therein) Diludine was stronger protectorwhen compared to ionol
CA drug foridone (riodipine) was shown to possesscardioprotective features primarily due to is protective effecton mitochondria exposed to OS [142 143]
Similarly the DHP water-soluble antiarrhythmic com-pound glutapyrone inhibits initiation of LP by free radicalsin erythrocytes and heart mitochondria Its cardioprotectiveeffect has been experimentally shown in heart mitochondrialmembranes especially during deep hypothermia (Utno et al[144])
Cerebrocrast was effective in several translation modelsmimicking pathological situations known to be associatedwith cellular OS The potential protective action of 14-DHP derivatives (4-substituted compounds cerebrocrastgammapyrone glutapyrone and 4-unsubstituted drug dieth-one) has been studied in rat liver in experimental modelsrelevant for oxidative stress and mitochondrial bioenergetics(Fernandes et al [145]) When succinate was used as therespiratory substrate higher concentrations (gt25 120583M) ofcerebrocrast depressed respiratory control ratio (RCR) ADPto oxygen ratio (ADPO) state 3 and uncoupled respirationrates transmembrane potential (deltapsi) and the phosphatecarrier rate At the same time state 4 respiration rate wasthree times increased At concentrations lower than 25120583Mcerebrocrast inhibited mitochondrial IMAC and partiallyprevented Ca2+-induced opening of the mitochondrial PTPGammapyrone glutapyrone and diethone did not inducethese phenomena When applied at concentrations up to100 120583M cerebrocrast gammapyrone and glutapyrone didnot affect ADPFe2+-induced LP of mitochondria in rat liver(as measured by oxygen consumption and TBARS forma-tion) On the other hand low diethone concentrations (upto 5 120583M) inhibited it in a dose-dependent manner Diethonealso prevented against deltapsi dissipation induced by LPinitiated by ADPFe2+ Based on these data it may bespeculated that cerebrocrast (inhibition of the IMAC) anddiethone (acting as an AO) may provide effective protectionof mitochondria during OS Cerebrocrast has shown sometherapeutic potential for treatment of several pathologicalconditions related to cellular OS [145]
5-Acetyl(carbamoyl)-6-methylsulfanyl-14-DHP-carbo-nitriles (Figure 3) with minor differences in their molecularstructure displaying antioxidant and antiradical activitiesin vitro show different biological activities Namely 4-p-chlorophenyl derivative OSI-1146 displays AO and anti-radical activities in cardiovascular OS models whereasOSI-3701 and OSI-3761 display hepatoprotective activityThus these compounds may be potentially useful for treat-ing several pathological processes including those associatedwith OS (Fernandes et al [146]) However besides mito-chondria the cellular targets for their pharmacologicalactions have not been fully investigated [146] All these com-pounds increase the susceptibility of Mit to MPT The mostpotent is OSI-3701 although it does not affect bioenergeticparameters
Although all these compounds protected mitochondriaagainst LP induced by the oxidant pair ADPFe2+ OSI-1146was shown to be the most potent Current data point outmitochondria as potential targets for protective and toxicactions of DHPs suggesting that the potential for their use astherapeutic agents should also take into consideration theirtoxic effects on mitochondria (Fernandes et al [146])
Several structurally different DHP derivatives (antioxi-dant diludine (diethone) as a 4-unsubstituted DHP 4-substi-tuted DHPs CA foridone (bicyclic compound) and the 4-phenyldiethone compound where phenyl group is joined tothe DHP in position 4) inhibited the 1-methyl-4-phenyl-pyridinium iodide (MPP+) induced ROS production incerebellar granule cells (CGC) with a distinct potency orderforidone (26-dimethyl-35-dimethoxycarbonyl-4-(o-difluo-romethoxyphenyl)-14-dihydropyridine) gt 26-dimethyl-35-diethoxycarbonyl-4-phenyl-14-dihydropyridine gt diludineThey also reversed the MPP+-induced decrease of the mito-chondrial membrane potential in the same order (Klimavi-ciusa et al [147]) Accordingly it was postulated that theclassical two-ring (bicyclic) structure of DHP derivativesrepresents an advantage in relation to neuroprotection andROS defense and is independent on compoundrsquos propertiesrelated to calcium ions
Novel adamantane-containing 14-DHP compounds (Kli-maviciusa et al [148]) were also found to improve mitochon-drial functions (MPP+ model) (Klimaviciusa et al [148])Klusa et al [149] have discovered antineurotoxic effects of14-DHP taurine derivative tauropyrone recorded as Mitfunction improvement
Many 14-DHPs including Ca2+ antagonists and AOmodify LP processes and influencemitochondrial function invarious organs (liver heart kidney and brain) in a differentway and degree Their beneficial action oxygen or lipidfree radical scavenging antioxidative effects binding withor intercalating into phospholipid bilayer regulation of iongating and regulation of mitochondrial permeability transi-tion pores (Tirzit and Duburs [39] Zilber et al [44] andDubur et al [45]) separately or in combination with eachother depends on two strong elements (1) their individ-ual structure including nature of substituents and theirpositions and (2) the nature of the biological system Forexample the direction of LP (inhibition of promotion) wasshown to depend on structure and concentration of applied
Oxidative Medicine and Cellular Longevity 15
14-DHPs as well as stages of chain reactions Accordinglymitochondrial swelling may be prolonged (retarded) accel-erated (promoted) or inhibited (Velena et al [112])
Therefore there is a ground for 14-dihydropyridineseither Ca2+ antagonists or antioxidants to be nominated asuseful tools in development of ldquomitochondrial drugsrdquo relatedto the control of OS
(c) DHPs as AOs in Endoplasmic Reticulum (Inhibition ofNADPH-Dependent LP System) Inhibition of NADPH Oxi-dase by DHPs Elevated level of NADPH oxidase 4- (NOX4-)derived hydrogen peroxide (H
2O2) joined with concomitant
decrease of nitric oxide (NO) mediated signaling and reac-tive oxygen species scavengers are considered to be centralfactor in molecular pathogenesis of fibrosis (Sampson etal [150]) Inhibition of microsomal NADPH-dependent LPwith particular focus on NADPH oxidases (NOX1ndash5 andDUOX1) may be very important for neuro- cardio- andhepatoprotection (Velena et al [112] Leto and Geiszt [151]Griendling et al [152] and Chen et al [153]) Endoplasmicreticulum may be an important target as this is where 14-DHPs could display their antioxidative properties (Velena etal [112] Leto and Geiszt [151] Griendling et al [152] andChen et al [153])
However the initiation of LP in the NADPH-dependentmicrosomal system does not appear to involve either super-oxide or hydrogen peroxide since neither SOD nor cata-lase can inhibit it On the other hand reduced iron playsan important role in both the initiation and propaga-tion of NADPH-dependent microsomal lipid peroxidation(Hochstein and Ernster [154] and Repetto et al [111])
Many DHPs possess inhibitory activity not only towardsAsA-dependent LP in mitochondria but also towardsNADPH-dependent LP as shown in isolated rat liver micro-somes (Velena et al [112]) This means that these compoundsinteract with the shared parts (nonenzymatic and enzymatic)of LP pathways
Microcalorimetry and fluorescent probes procedureswere used for studying the interaction of alpha-tocopheroland 14-DHPs with endoplasmic reticulum membranes andmodel systems human serum albumin and phospholipidbilayers [155] Modification of microviscosity of the endo-plasmatic reticular membranes depends on localization ofantioxidants within the protein structures or phospholipidphase Increase of membrane structuralization under theinfluence of 14-DHPs blocked their antioxidant action inspontaneous and induced lipid peroxidation
Inhibition of rat heart and liver microsomal lipid perox-idation by nifedipine was observed [156] while Goncalves etal [157] found antioxidant effect of calcium antagonists onmicrosomal membranes isolated from different brain areas
Nitroaryl-14-DHPs are both calcium channel antagonistsand antioxidant agents (Letelier et al [158 159]) commonlyused for treatment of cardiovascular diseases These drugsmust be metabolized through cytochrome P450 oxidativesystem (NADPH-cytochrome P450 reductase) mainly local-ized in the hepatic endoplasmic reticulum Several lipophilicdrugs generate OS while being metabolized by this cellularsystem Thus DHP antioxidant properties may prevent the
OS associated with hepatic biotransformation of drugs Var-ious commercial and new nitro-phenyl-DHPs were studiedagainst LP using rat liver microsomes under oxidative stress[159]
Incubation of rat liver microsomes with the 41015840-nitro-4-phenyl-14-DHP compounds (26-dimethyl-4-(41015840-nitro-phenyl)-14-dihydropyridin-35-diethyl-dicarboxylate andN-ethyl-26-dimethyl-4-(41015840-nitrophenyl)-14-dihydropyri-din-35-dimethyl-dicarboxylate) results in an inhibitionof LP the UDPGT (UDP-glucuronyltransferase) oxidativeactivation and the microsomal thiol oxidation induced byFe3+ascorbate a generator system of ROS This effect wasalso produced by nitrofurantoin and naphthalene in thepresence of NADPH
Interestingly IC50
ofDHPs obtained frommicrosomal LPassays decreased to the same extent as the microsomal thiolsoxidation provoked by Fe3+ascorbate [159] Neverthelessthe AO effects of a nitrophenyl-DHP compound in whichhydrogen at position one of the DHP ring was replaced bythe ethyl groupwere significantlyweaker Authors speculatedthat DHPs can resemble NADH transferring one hydrogenatom of 4-position (Hminus) to anion superoxide and another ofthe 1-position (H+) by way of a cationic radical intermediateto generate pyridine derivatives and water [159]
The AO effects of various tested DHP derivatives (m- andp-NO
2phenyl as well as methyl or ethyl and isopropyl-DHP
35-dicarboxylate derivatives) were not significantly differentThe authors assumed that the -NH- group of the dihydropy-ridine ring could contribute both to the development ofthe calcium channel antagonism and to the antioxidativeproperties of DHPs [159]
Prevention of the membrane LP seemingly depends onthe concentration of potential antioxidants such as vitaminE or even 14-DHP in lipids However only the differencesin synthetic DHPs lipophilicity cannot explain significantvariations of DHPs concentration in microsomal membraneand cannot clarify the strength of their antioxidative activityThis work [159] has further demonstrated that 14-DHPsmay prevent the OS induced by biotransformation of somedrugs for example antibiotic nitrofurantoin Simultaneousadministration of DHPs and nitrofurantoinmay be beneficialin reducing nitrofurantoin side effects
While most of Ca antagonist 14-DHPs are metabolizedby CYP3A4 (Guengerich et al [160]) not all of them are goodinhibitors of its activity Thus nicardipine but not nifedipineand nitrendipine inhibits CYP3A4 in vitro [53] Interactionof different DHPs with various types of cytochrome P450 wasdescribed by Carosati et al [53] It was also reported thatDHP class calcium channel blockers reduce the antiplateleteffect of clopidogrel (Park et al [161])This implies themutualinteractions of both drugs with CYP3A4
(3) In Vivo Evaluation of nifedipine effects on Saccharomycescerevisiaewas recently published (Asma andReda [162]) Sur-prisingly nifedipine exercised a toxic effect on Saccharomycescerevisiae shown through measuring cellular proliferationrespiratory activity and the level of some biomarkers (CATand MDA)
16 Oxidative Medicine and Cellular Longevity
However majority of data obtained on various animalcells and tissues by other authors show the protective role ofDHPs against both LP and oxidative stress [113 163 164]
The AOA attributed to many 14-DHPs Ca2+ antag-onists and other compounds reflecting on catalytic LDLperoxidation (see Section 331 (2) and Section 35) shouldencourage their testing for treating cardiovascular diseasesandor alterations of lipid metabolism
The possibility that 14-DHP-based calcium antagonistsexert an antiatherosclerotic action (via inhibition of LDLoxidation and other mechanisms) has been proved by manyexperimental data [165] and several clinical trials Besidesantihypertensive effect nicardipine was shown to possessantioxidative and antielastase activity [165 166] These prop-erties may be useful for prevention of inflammatory reactionwhich is relevant for hypertension pathogenesis
14-DHPs administration inhibits LDL oxidation medi-ated by oxygen radicals leading to decreased carotid inti-mal media thickness and reduced progression of coronaryatherosclerosis [130] It additionally preserves Apo B-100integrity against ROS Of importance antiatherogenic mech-anisms differ between animals and humans (primarily inthe stage of conversion of aldehydes to carboxylic acids)(Parthasarathy et al [167])
For example furyl-DHP compound (FDP-1 diethyl 26-dimethyl-4-(furyl)-14-dihydropyridine-35-dicarboxylate)was shown to act as an antioxidant (decreasing MDA GOTand FFA release of ischemic myocardium and inhibiting Ca-ATPase of erythrocyte membranes) preventing against heartmyocardium ischemia-reperfusion injury and arrhythmiawhen applied (in rats) at 10mgkg (Liu et al [168])
Similarly antioxidative effects of azelnidipine andamlodipine prevented neuronal damage by CCBs aftertransient focal ischemia in rats (Lukic-Panin et al [169])
Allanore et al [170] found that both nifedipine andnicardipine significantly decrease the mean level of plasmamarkers for oxidative stress in patients suffering from sys-temic sclerosis
Antioxidants may be considered as promising neuropro-tective compounds Still while experimental data demon-strate neuroprotective effect in vitro and in animal mod-els clinical evidence is still unsatisfactory and insufficient[171]
(a) Role of Metabolism of DHPs in Their AOA Metabolicpathways and ldquobioavailabilityrdquo of the probable AOA com-pound determine antioxidant activity in vivo Antioxidantmetabolites may vary in stability and activity leading to twoopposite scenarios lack or presence of activity substantiallycontributing to the overall AOA [172] Metabolic biotransfor-mation of DHPs includes oxidation (heteroaromatization)side chain ester group cleavage (deesterification) and 4-substituent abstraction ao [160] None of the DHPs metabo-lites was shown to be more toxic than original reduced formof the compound The commonly detected metabolites ofthe DHPs do not seem to possess the AO activity (withsome exceptions as in the case of metabolites of nifedipineand its analogues including nitrosonifedipine [173 174]) (seefurther in Section 35) Due to DHPs intrinsic instability
achieving andmaintaining an adequate concentrationmay beproblematic both in vitro and in vivo
(b) Role of Concentration and Lipophilicity (MembraneWateror LipidWater Partition Coefficients) of DHPs inTheir Actionas AOs and Antiradical Compounds Antioxidative effects ofany antioxidant depend on its concentration at the site ofaction This parameter is hardly measurable especially intwo-phase systems representing one of obstacles in com-parison to AOA upon applying various compounds [172]It is often incorrectly assumed that the concentrations inthe aqueous solution and at the site of action are the sameHowever even when the concentration in the aqueous phasemay be well controlled the concentration at the site ofaction in the lipid matrix of the membranes might fluctuatebetween different test compounds depending on a differencein lipophilicity [175] The prevention of the membrane LPalso seems to be dependent on the DHP concentration in thelipidmatrix (Mason andTrumbore [46]) and its amphiphilic-ity For example AOA of diludine is associated with itslipophilicity and consequential ability to be incorporatedinto liposomes (Panasenko et al [176]) It was also foundthat diludine easily incorporates into the outer monolayer oferythrocyte membranes [176]
Membranebuffer partition coefficients (lambda) weredirectly measured in the sarcolemma and sarcoplasmicreticulum membranes for three CA DHPs The obtainedvalues were in a broad range between 5000 and 150000(Herbette et al [177])These drugs interact primarily with themembrane bilayer component but may also bind to proteinsboth nonreceptors and receptors The intrinsic forward rateconstants for DHP binding to sarcolemmal calcium channelreceptors were apparently not strongly dependent on theirmembrane partition coefficients For example nimodipine(lambda = 6300) had a forward rate constant of 68 plusmn 06 times106Ms whereas the forward rate constant for Bay P 8857
(lambda = 149000) was 14plusmn08times107Ms Since these DHPsare highly liposoluble model calculations for this bindingreaction demonstrated that these rates on lipid solubilitywould probably not be reflected in the experimental forwardrate constants In addition the intrinsic forward rate constantfor nimodipine binding to sarcolemmal calcium channelreceptors was found not to be linearly dependent on theviscosity of the buffer medium over a fivefold range The rateof drug nonspecific binding to nonreceptor protein present inhighly purified sarcoplasmic reticulum membranes appearsto be extremely fast at least 103 times faster than specificdrug binding to the receptor in the sarcolemma Authorsconcluded that partitioning into the lipid bilayer matrix ofthe sarcolemma could be a general property of CA DHPsand may be a prerequisite for their binding to sarcolemmalmembrane receptors (Herbette et al [177])
The binding of DHP calcium channel agonists and antag-onists (including those with AO properties) to receptors incardiac sarcolemmal membranes is a complex reaction thatmay involve an interaction with the lipid bilayer matrix ofthe sarcolemma (Herbette et al [178]) Belevitch et al [179]studied the binding of DHP CCBs (riodipine and nifedip-ine) and verapamil to model and biological membranes by
Oxidative Medicine and Cellular Longevity 17
fluorescence analysis The consistent location of Ca agonistBay K 8644 was determined to be within the region ofthe first few methylene segments of the fatty acyl chains ofthe membranes (Mason et al [180]) This position is nearto that observed for the DHP calcium channel antagonistsnimodipine and Bay P 8857
Themajority of studies onOSwere performedwithDHPswith various lipophilicity but only a few studies reportedamphiphilicity ofDHPderivatives AmphiphilicDHPderiva-tive K-2-11 reduced the cellular generation of ROS It alsorevealed complete reversal of multidrug resistance (MDR) ofthe resistant cells K-2-11 was more efficient than well-knownMDR inhibitor verapamil Cytotoxic effects of anticancerdrug doxorubicin were enhanced by K-2-11 in bothMDR andparental nonresistant cell line (Cindric et al [181]) K-2-11suppresses increase of ROS and consequentially prevents NF-120581B activation leading to decreased expression of MDR1 andincreased expression of antiapoptotic genes This signalingswitch is necessary for restoring the chemosensitivity ofcancer cells This phenomenon is characteristic both for14-DHPs [182] (18 novel asymmetrical DHPs bearing 3-pyridyl methyl carboxylate and alkyl carboxylate moietiesat C3 and C5 positions resp as well as nitrophenyl orheteroaromatic rings at C4) and for their oxidized formspyridine compounds (Zhou et al [183])
34 Dependence of AOA of DHPs on the Experimental SystemAO effect of DHPs depends on their structure and theexperimental system used (in vitromodel system subcellularorganelle and cells ex vivo and in vivo) Ideally for theevaluation of the profile and value of DHPs AO propertieseach compound should be tested in as many systems aspossible (Dubur et al [45])
Lipidomics studies have been traditionally explored forstudying AOA of DHPs Proteomics methods are less rep-resented and are mostly focused on the properties of DHPsrelated to scavenging of protein free radicals So far there areno studies on the role of DHPs in scavenging nitrosoperoxy-carbonate the reactive species formed out of peroxynitrite inthe presence of carbon dioxide Although it was shown thatalbumin binds diludine no studies revealed the relevance ofthis effect for the AOA of diludine
There are findings showing that dihydropyridine calciumantagonists (DHPs CA) could indirectly play a beneficialprotective role during development of atherosclerosisNamely Berkels et al [184] have studied antioxidativeproperties of four substances the DHP prototype CAnifedipine the long-acting CA lacidipine the DHP calciumchannel agonist BayK8644 and the bulkyDHPderivate BayO 5572 in three different models (1) in an in vitro superoxideanion generating system (hypoxanthinexanthine oxidase)for testing the ldquopurerdquo antioxidative effect (2) in an artificialmembrane preparation (dimyristoylphosphatidylcholine) formimicking a more physiological environment and (3) underconditions of stimulated ROS release (hyperglycemia) fromnative endothelial cells derived from porcine coronary arter-ies
The study also revealed the potential correlation betweenlipophilic and AO properties of DHPs In the first model
Bay K 8644 was significantly more effective in scavengingsuperoxide anions than lacidipine Bay O 5572 or nifedipine(micro- to millimolar concentration range) Addition of anartificial membrane preparation resulted in an enhancedAO effect with lacidipine being the most effective DHP inquenching radicals (low micromolar concentration range)In the third model mimicking hyperglycemia (30mmolL)nifedipine was significantly more potent antioxidant (ther-apeutical nanomolar concentration range) than the otherDHPs Calculated lipophilicity of these four substances(lacidipine gt Bay O 5572 gt Bay K 8644 gt nifedipine) waspositively correlated with antioxidative potential only in thesecond experimental model It has been concluded that AOproperties of DHP substances need to be tested in variousmodels for demonstrating that nifedipine exhibits ROS-quenching properties in a therapeutic concentration range[184]
341 AOA of DHPs in Isolated Cells and Cell Cultures(Comparison with Other Simplest Systems) Although DHPspossess neuromodulatory andor antimutagenic propertiesthe mechanisms of action related to these phenomena arenot entirely elucidated Borovic et al [185] have studied 14-dihydroisonicotinic acid (14-DHINA) derivatives of 14-DHP water-soluble analogues of a well-known AO diludine(diethone) 26-dimethyl-35-diethoxycarbonyl-14-dihydro-isonicotinic acid sodium 2-(26-dimethyl-35-diethoxycar-bonyl-14-dihydropyridine-4-carboxamido)glutamate gluta-pyrone and sodium 2-(26-dimethyl-35-diethoxycarbonyl-14-dihydropyridine-4-carboxamido)ethane-sulphate tauro-pyrone as AO and bioprotectors (Figure 4)
14-DHINArsquos activities were studied in comparison toTrolox by NN-diphenyl-N1015840-picrylhydrazyl (DPPH∙) deoxy-ribose degradation ABTS∙ radical scavenging and AOA(antioxidative capacity method) assays copper-induced LPof cultured rat liver cells (MDA determination by HPLCand 4-hydroxynonenal-protein conjugates by dot-blot) 3H-thymidine incorporation and trypan blue assay for liver cellsgrowth and viability Ic decreased the amount of 4-HNE-protein adducts In all assays Ia was the most potent AOable to completely abolish copper induced LP of liver cellswhile Ic only slightly decreased it Thus AOA is importantactivity principle of Ia which was even superior to Trolox intreated cell cultures Ia (and its analogues) are easily oxidizedin the Fenton system (Rubene et al [186]) exerting ARA too
35 Peculiarities Related to Antioxidative and AntiradicalActivity of Some 14-DHPs Ca Antagonists Nine commer-cialized structurally and functionally different DHPs CAwill be discussed further Their common feature is ability toprevent OS This also counts for some of their metabolitesas already discussed The comparative effects of some DHPsCA on oxidative stress-induced modification of LDL werealready reviewed in Section 331 (2)-(a) AOA of CA DHPswas discussed in Sections 331 (2)-(b) and 331 (2)-(c)
351 Nifedipine and Its Close Analogues Nifedipine vera-pamil and antiarrhythmic-antihypoxic drug stobadin wereshown to depress lipid peroxidation of phosphatidylcholine
18 Oxidative Medicine and Cellular Longevity
NH
COOH
NH
COONa
Glutapyrone
NH
Gammapyrone
NH
C 2H5OOC COOC2H5
Tauropyrone
14-DHINA
H3C H3C
H3C
H3CCH3 CH3
CH3
CH3
COOC2H5COOC2H5
COOC2H5 C2H5OOCC2H5OOCC2H5OOC
CONHCH(CH2)2COONa CONH(CH2)3COONa
CONH(CH2)2SO3Na
Figure 4 Derivatives of 14-dihydroisonicotinic acid (14-DHINA)
liposomes (Ondrias et al [187]) However data obtained insome other experimental systems are conflicting
In an in vitromodel of sarcolemmal membrane lipid per-oxidation three calcium blockers (nifedipine verapamil anddiltiazem) exhibited concentration-dependent (10ndash400 120583M)inhibitory effects [188 189] Nifedipine the most effectivecalcium blocker was more than two-fold potent compared topropranolol achieving significant effect at 10 120583M Nifedipineprotective role on LP using reduced glutathione as modelmarker was recently described (Ray et al [190]) Antiper-oxidative properties of CA nifedipine and its analogueswere explored in different systemspathogenic processesatherogenesis (Henry [165]) brain focal ischemia (Yamatoet al [191]) nephroprotection related to cyclosporine intake(Chander and Chopra [192]) and hepatoprotection relatedto intake of diethyldithiocarbamate (Gaafa et al [193])Recent data suggest that nifedipine action as protector forendothelial cells proceeds independently from its CA proper-ties
The absence of antioxidant effects of nifedipine anddiltiazemonmyocardialmembrane lipid peroxidation oppo-site to nisoldipine and propranolol was also described[194] Nisoldipine and propranolol were shown to havea concentration-dependent antiperoxidant effect with IC
50
values of 282 and 501 120583M respectively Finally nisol-dipine appeared to possess dual antiperoxidant mecha-nisms involving both preventive and chain-breaking proper-ties
These findings were confirmed in some other studiesincluding reports on the lack of antioxidative activity ofnifedipine and nicardipine even at 500120583M concentrationin heart membrane lipid peroxidation tests [134] SimilarlyROS formation in bovine aorta smooth muscle cells was notaffected by addition of amlodipine nimodipine and nife-dipine [123]
(1) Metabolites of Nifedipine and Its Analogues as Antioxidantsand Regulators of OS Antioxidant activity of nifedipine35-dimethoxycarbonyl-26-dimethyl-4-(2-nitrophenyl)-14-dihydropyridine was originally studied in vitro by Kirule etal [195] and Tirzit et al [196] According to the kinetic dataof peroxide accumulation and the ESR spectra (inhibition ofthe autoxidation of methyl oleate in presence of nifedipine)AO action was exerted by the formation of nitroso analogueof the oxidized nifedipine nitroso nifedipine 26-dimethyl-4-(2-nitrosophenyl)-35-pyridine dicarboxylate (NO-NIF)This nitroso aromatic derivative can form nitroxyl radicalsexhibiting remarkable AOA in the presence of unsaturatedfatty acids and lipids [196]
The primary species of free radicals that have beenobtained and identified were ion radicals of the nitrophenyltype (Ogle et al [76]) Such a mechanism coincides withmechanisms proposed afterwards by Nunez-Vergara et al[96] Lopez-Alarcon et al [103] Valenzuela et al [104]Fukuhara et al [174] and Yanez et al [197]
There are also data showing that nitroso compounds mayinhibit LP by direct radical trapping and subsequent forma-tion of stable nitroxide radicals It was further found that thereactivity between the synthesized 14-DHP derivatives withalkylperoxyl radicals involves electron transfer reactionsThisis documented by the presence of pyridine as a final productof the reaction and complete oxidation of the nitroso groupin the case of the nitrosoaryl 14-dihydropyridine derivatives(Valenzuela et al [104]) Tested compounds reacted fastertoward alkylperoxyl radicals and ABTS radical cation thanalkyl ones (Lopez-Alarcon et al [103])
Nitrosonifedipine a photodegradation product of nifedi-pine significantly recovers cellular damage induced by tumornecrosis factor-alpha It also prevents toxic effects of cumeneperoxide which hampers integrity of cell membranes throughoxidative stress Its positive effects are equal to Trolox-C
Oxidative Medicine and Cellular Longevity 19
As a result nitrosonifedipine was already a long time agoclaimed as a candidate for a new class of antioxidative drugs(Kirule et al [195]) cellular protectors against oxidative stressin glomerular endothelial cells [174]
Moreover Misik et al [198] Ondrias et al [199] andStasko et al [200] studied AOA of nifedipine and its oxidizednitroso analogue NO-NIF prevents the progression of type2 diabetic nephropathy associated with endothelial dysfunc-tion through selective AO effects (Ishizawa et al [201]) NO-NIF administration reduces albuminuria and proteinuriaas well as glomerular expansion without affecting glucosemetabolism or systolic blood pressure NO-NIF also sup-presses renal and systemic OS and decreases the expressionof intercellular adhesion molecule-1 (ICAM-1) a marker ofendothelial cell injury in the glomeruli of the KKAy miceSimilar effects were achieved in endothelial nitric oxide syn-thase (eNOS) knockout mice Moreover NO-NIF suppressesurinary angiotensinogen (AGT) excretion and intrarenalAGT protein expression in proximal tubular cells in theKKAy mice On the other hand hyperglycemia-inducedmitochondrial superoxide production was not attenuated byNO-NIF in cultured endothelial cells
Fujii and Berliner found EPR evidence for free radicaladducts of nifedipine in vivo [202] The nature of these rad-icals was surmised by comparing the reaction of illuminatednitrosonifedipine with polyunsaturated fatty acids Surpris-ingly identical radical spectra were detected from excisedliver doped with nonilluminated nifedipine suggesting thatthis drug can be enzymatically converted in vivo to its nitrosoanalogue without the requirement for illumination This isone of the first reports of in vivo EPR evidence for a class ofunsaturated fatty acid radical conjugates resulting from thenormal metabolism of a common drug
Dıaz-Araya et al [173] studied some 4-nitrophenyl-DHPson Fe3+ initiated LP in rat brain slices LP as measuredby MDA formation was inhibited by all the tested nitro-aryl derivatives of 14-DHP over a wide range of concen-trations On the basis of both time course and IC
50experi-
ments the tentative order of AOA on rat brain slices wasnicardipine gt nisoldipine gt (RSSR)-furnidipine gt (RRSS)-furnidipine gt nitrendipine gt nimodipine gt nifedipine14-DHP derivatives that lack a nitro group in the mole-cule (isradipine and amlodipine) also inhibited LP in ratbrain slices but at higher concentrations than that of nitro-substituted derivatives All tested compounds reduced andoxidized nitrosoaryl derivatives (26-dimethyl-4-(2-nitro-sophenyl)-35-pyridinedicarboxylic acid dimethyl ester (pho-tooxidation product of nifedipine ndash NTP) ao) and weremore potent inhibitors of LP than their parent molecules(Valenzuela et al [104])
The electrooxidation process of 4-nitrosoaromatic DHPsis a strongly pH-dependent (two-electron two-proton mech-anism) ECEC type of mechanism that is the sequenceeminusH+eminusH+ at pH gt 85 ECCE mechanism (eminusH+H+eminus)at pH lt 85 dominates Reduction reaction of nitroso groupis as follows R-NO + 2eminus + 2H+ rarr RNHOH (Bollo et al[203])
352 Lacidipine It is a generic DHP type antihypertensiveCA 35-diethyl 4-2-[(1E)-3-(tert-butoxy)-3-oxoprop-1-en-1-yl]phenyl-26-dimethyl-14-dihydropyridine-35-dicarboxy-late
Ursini [204] described redox behaviour of lacidipine andshowed its tissue protective features Cristofori et al studiedantiatherosclerotic activity in addition to lacidipinersquos CAand AO properties [205] Lacidipine reduced the extent ofatherosclerotic area in hypercholesterolemic apoE-deficientmice (these mice show widespread vascular lesions whichclosely resemble the inflammatory fibrous plaques seen inhumans in atherosclerosis) The reduction may be associatedwith the capacity of the drug to maintain endothelial NOlevels at concentrations useful to protect against vasculardamage This work suggested that DHPs modulate vascularrelaxation via increased release of NO
Herbette et al [178] remarked optimal hydrophobicity oflacidipine due to cinnamic acid substituent so membraneinteractions and facilitation of the treatment of atherosclero-sis could proceed (see also Section 331 (2)-(a))
353 Amlodipine Amlodipine (Norvasc) (RS)-3-ethyl5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-14-dihydropyridine-35-dicarboxylate (AML) hasan antioxidant effect on vessels in vitro and is a 3rd genera-tion of charged dihydropyridine CCB that is widely used forthe treatment of hypertensive patients
Amlodipine was shown to have the highest affinity(amlodipine gt verapamil ≫ diltiazem) for the membranebilayer (119870
119901= 104) It produced the significant changes in
membrane thermodynamic properties including a reductionin the thermal phase transition temperature (minus11) enthalpy(minus14) and cooperative unit size (minus59) relative to thecontrol phosphatidylcholine liposomes (Mason et al [49])
Amlodipine AOA is related to its reductant nature orhydrogen donor properties respectively Its ability for donat-ing protons and electrons to the lipid peroxide moleculesblocks the LP process
Amlodipine and even its enantiomers (Zhang et al [206])act as ROS andNOS effectors in several model systems of OSAntioxidant properties of amlodipine were recently reviewedby Vitolina et al [32] Both in vitro and in vivo studiesof amlodipine AO properties revealed inhibition of lipidsoxidative damage primarily those associated with cellularmembranes and lipoprotein particles (LDL) (Mason et al[50])
Under controlled experimental conditions in vitro amlo-dipine showed AOA and ARA by inhibition of lipid peroxideformation and trapping ROS Its scavenging activity forhydroxyl and peroxyl radicals at concentrations as low as100 nmolL (which is remarkably less compared to the classi-cal antioxidants GSH uric acid and Trolox) was shown to beindependent of the calcium channel modulation (Franzoni etal [207])
AML showed efficiency as scavenger of peroxyl radicals(TOSC assay 5945 plusmn 544 unitsmg) significantly stronger(gt50 119875 lt 0001) than GSH (2733plusmn 636 unitsmg) and 70weaker (119875 lt 00001) than uric acid (18144 plusmn 696 unitsmg)and Trolox (17522 plusmn 734 unitsmg)
20 Oxidative Medicine and Cellular Longevity
Of interest the scavenging capacity of AML towardshydroxyl radicals (1455 plusmn 154 unitsmg) was 320 higher(119875 lt 000001) than that of GSH (358 plusmn 112 unitsmg) 20higher than that of uric acid (1198plusmn121 unitsmg) and 100higher than that of Trolox (759 plusmn 143 unitsmg)
Amlodipine was shown to increase enzyme activity ofparaoxonase (PON) and glutathione peroxidase (GSH-Px)However it also decreases glutathione reductase (GSSG-R)activity and diminishes the concentration of the endogenousantioxidant 120572-tocopherol (vitamin E) Moreover AML in aconcentration of 2 ngmL decreased the content of malonicdialdehyde and activity of superoxide dismutase in the blood(Gatsura [208])
Verapamil and amlodipine produced a potent anti-ischemic effect and reduced area of myocardial infarction inrats The observed changes were accompanied by inhibitionof LP In contrast to verapamil in vitro application of AML ina dose of 50 ngmL decreased hemoglobin affinity for oxygenWhen present in a concentration of 2 ngmLAMDdecreasedthe content of MDA and activity of SOD in the blood
On the other hand amlodipine shows no activity relatedto inhibition of macrophage superoxide release and cellmigration which occurs as a consequence of decreasedTNF120572induced O
2
∙ releaseAmlodipine-induced reduction of OS in the brain is
associated with sympathoinhibitory effects in stroke-pronespontaneously hypertensive rats (SHRSP) (Hirooka et al[209]) Antihypertensive treatment with amlodipine reducedOS in all examined areas of the brain and decreased bloodpressure without a reflex increase in sympathetic nerveactivity Nicardipine another CA DHP surprisingly wassignificantly less active than amlodipine
354 Lercanidipine Tomlinson and Benzie reported AOeffect of lercanidipine [210] which is well known as anti-hypertensive drug Zanidip 2[(33-diphenylpropyl)(methyl)-amino]-11-dimethylethyl methyl 26-dimethyl-4-(3-nitro-phenyl)-14-dihydropyridine-35-dicarboxylate Compara-tive data about this drug AOA were presented in parts of thispaper about other individual CA DHPs and in the part aboutthe ex vivo DHPs effects on LDL
355 Nimodipine Nimodipine (ND) commercially knownas Nimotop is 3-(2-methoxyethyl) 5-propan-2-yl 26-dim-ethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxy-late It is centrally active CA
Treatment with glutathione blocked andwith nimodipineattenuated neuronal cell death caused by prolonged exposureof cell culture to 4-HNE (Faraqui [211])
Nascimento et al [212] found AO effect of nimodipine inyoung rats after pilocarpine- (PIL-) induced (in 400mgkg)seizures The PIL administration increased the striatal cata-lase (CAT) activity The administration of ND 30mgkg30min before PIL preserved normal value of CAT activityOn the other hand no difference was detected in the animalstreated with lower dose 10mgkg These results confirmthe neuroprotectiveantiepileptic effect of ND in young ratssuggesting that this drug acts positively on lipid peroxidation
(in both doses) Nimodipine cannot induce these effects viablockade of Ca2+ channel
Ismailoglu et al [213] studied the therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjury These beneficial effects in rats after cerebral corticalinjury seemed to be related to AOA of nimodipine
356 Benidipine Licensed in Japan and South Asia as CA(CCB) benidipine possesses AO properties Chemically it is5-methyl 3-[(3R)-1-(phenylmethyl)piperidin-3-yl] 26-dim-ethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxy-late (or its hydrochloride (4R)-rel-35-pyridinedicarboxylicacid 14-dihydro-26-dimethyl-4-(3-nitrophenyl)- 3-methyl5-[(3R)-1-(phenylmethyl)-3-piperidinyl] ester hydrochloride(1 1))
Benidipine influences processes connected with OS inseveral ways It prevents lysophosphatidylcholine- (lysoPC)-induced injury and ROS production in human aorticendothelial cells (HAECs) (Matsubara and Hasegawa [214])Matsubara et al [215] explained this effect based on stimula-tion of nitric oxide release
LysoPC is a component of oxidized low-density lipopro-teins (oxLDLs) which plays an important role in the patho-genesis of atherosclerosis Pretreatmentwith benidipine (03ndash3 120583molL) for 24 h protected against lysoPC-induced cyto-toxicity in the HAECs through inhibition of both lysoPC-stimulated ROS production and caspase-37-like activationwith a similar potency Since caspase-37 is involved inexecuting the apoptotic process the reduction of the activityof this enzyme by benidipine may explain the antiapoptoticeffect of the drug However benidipine did not suppresslysoPC-induced phosphorylation of mitogen-activated pro-tein kinases and Ca2+ influx in HAECs These results suggestthat the antioxidant properties of benidipine may be respon-sible for its ability to inhibit ROS production a possiblereason for reduced activation of caspase-37 In conclusionbenidipine suppresses lysoPC-induced endothelial dysfunc-tion through inhibition of ROS production which is due atleast in part to its antioxidant effect and not through theinhibition of L-type voltage-dependent calcium channels
Matsubara and Hasegawa [216] examined the effectsof benidipine on cytokine-induced expression of adhesionmolecules and chemokines (chemoattractants) which areimportant for the adhesion of monocytes to endotheliumPretreatment of HAECs with benidipine (03ndash10 120583molL)for 24 h significantly suppressed cytokine-induced vascularcell adhesion molecule-1 (VCAM-1) and intracellular celladhesion molecule-1 (ICAM-1) mRNA and protein expres-sion resulting in reduced adhesion of THP-1 monocytesBenidipine also suppressed induction of monocyte chemoat-tractant protein-1 (MCP-1) and interleukin-8 Benidipinealso inhibited redox-sensitive transcriptional nuclear factor-120581B (NF-120581B) pathway as determined by Western blotting ofinhibitory 120581B (I120581B) phosphorylation and luciferase reporterassay Results of analysis using optical isomers of benidip-ine and antioxidants suggest that these inhibitory effectswere dependent on pharmacological effects other than Ca2+antagonism Benidipine may thus have anti-inflammatoryproperties and benefits for the treatment of atherosclerosis
Oxidative Medicine and Cellular Longevity 21
Benidipine was also shown to inhibit ROS production inpolymorphonuclear leukocytes and oxidative stress in salt-loaded stroke-prone spontaneously hypertensive rats (Mat-subara et al [217])
It should be mentioned that other DHPs also haveendothelial AO actions [218]
357 Azelnidipine (AZL) Azelnidipine 3-[1-[di(phen-yl)methyl]azetidin-3-yl] 5-propan-2-yl 2-amino-6-methyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate(AZL) CAS number 123524-52-7 is commercially available4-nitroaryl-DHP type calcium antagonist with long-actingantihypertensive action (long-acting CA (CCB)) and a lowreported incidence of tachycardia It additionally possessesbeneficial effects in OS and diabetic conditions
Azelnidipine prevents cardiac dysfunction in strepto-zotocin-diabetic rats by reducing intracellular calcium accu-mulation (altering intracellular Ca2+ handling proteins) OSand apoptosis (Kain et al [219]) AZL can reduce the superox-ide production It exerts its protective effects by targeting theNADPH oxidase and mitochondrial redox enzymes AZL-treated diabetic rats express enhanced level of bcl-2 in thelysates of heart muscle indicating that AZL plays protectiverole in cardiac apoptosis
It has been previously observed that azelnidipine inhibitstumor necrosis factor-alpha-induced endothelial cell (EC)oxidative stress through its AO properties (Nakamura etal [220]) Azelnidipine but not nitrendipine completelyinhibits the Ang II-induced ROS generation in ECs (Matsuiet al [221])
Furthermore azelnidipine but not nitrendipine wasfound to partially restore decreased pigment epithelium-derived factor (PEDF) mRNA levels in Ang II-exposed ECsThis study suggests that AZL influence depends on its antiox-idative properties Authors concluded that upregulation ofPEDF by azelnidipine may become a therapeutic targetfor the treatment of diabetic retinopathy associated withhypertension
Antihypertensive agents with AO effects are potentiallyuseful for diabetic patients with hypertension While DHPtypeCAare among themost frequently used antihypertensivedrugs azelnidipine has been reported to have a unique AOeffect in vitro and in vivo in experimental animals (Ohmuraet al [222]) In hypertensive diabetic patients azelnidipinetreatment for 12 weeks induced a more significant decreasein erythrocyte LOOH level than amlodipine although thevalues related to blood pressure during each treatmentremained comparable These data confirm the usefulness ofLOOH level in erythrocyte membrane as a marker of OS invivo and indicate that azelnidipine has a unique antioxidativeproperty in humans
Daikuhara et al [223] reported the results of the OLCAstudy based on combination of (1) olmesartan and a calciumchannel blocker (azelnidipine) or (2) candesartan and a CCBamlodipine in two groups of diabetic hypertensive patientsPatients treated with the first combination presented highlypersistent early morning antihypertensive effect and strongerdecrease in heart rate fasting blood glucose andHbA1c levels
and microalbuminuria when compared to patients treatedwith the combination (2) Because diabetes is associated withsevere chronic OS the observed results might be at least in apart due to the AOA of azelnidipine
In favor of this are findings of Abe et al [224] who foundadditive antioxidative effects of azelnidipine on angiotensinreceptor blocker olmesartan treatment for type 2 diabeticpatients with albuminuria
Similarly the AOA of thiazolidinediones (insulin sensi-tizer) and their effect on cardiovascular function in type 2diabetic model rats and also those of some DHPs (nifedipineamlodipine or AZL commonly used antianginal and anti-hypertensive agents) in cultured human endothelial cells LPwere examined (Mizushige [225]) The AOA was evaluatedby measuring 8-iso-prostaglandine F
2120572concentration and
azelnidipine exhibited potent AOAInsulin (INS) resistance combined with hyperinsuline-
mia is involved in the generation of OS A relation-ship exists between increased production of ROS and thediverse pathogenic mechanisms involved in diabetic vascularcomplications including nephropathy Manabe et al [226]revealed that high doses of INS augmented mesangial cellproliferation through generation of intracellular ROS andactivation of redox signaling pathways Cell proliferation wasincreased in a dose-dependent manner by high doses of INS(01ndash10 120583M) but was inhibited by 01120583M AZL Namely theINS-increased phosphorylation of mitogen activated proteinkinaseextracellular signal-regulated kinase 12 (MAPKERK12) was inhibited by 01 120583MAZL The same AZL concen-tration blocked intracellular ROS production more effec-tively than 01 120583M nifedipine The NADPH oxidase inhibitorapocynin (001ndash01120583M) prevented INS-induced mesangialcell proliferation So azelnidipine inhibits insulin-inducedmesangial cell proliferation by inhibiting the productionof ROS Therefore azelnidipine may have the potential toprotect against the onset of diabetic nephropathy and slowits progression
Azelnidipine inhibited H2O2-induced cell death in
neonatal rat cardiomyocytes (Koyama et al [227]) Azelnidip-ine and nifedipine did not affect theH
2O2-induced activation
of extracellular signal-regulated protein kinases (ERK) andp38 MAPK (mitogen-activated protein kinase) In contrastazelnidipine but not nifedipine inhibited H
2O2-induced c-
Jun NH2-terminal kinases (JNK) activation Authors con-
cluded that azelnidipine has inhibited theH2O2-induced JNK
activation and cardiac cell death Therefore azelnidipine mayhave cardioprotective effects against OS
A specific atheroprotection activity of azelnidipine relatesto inhibition of TNF-120572-induced activator protein-1 activa-tion and interleukin-8 expression in human umbilical veinendothelial cells (HUVEC) through suppression of NADPHoxidase-mediated reactive oxygen species generation (Naka-mura et al [220]) TNF-120572 could play a central role in patho-genesis of insulin resistance and accelerated atherosclerosis inthe metabolic syndrome The concentration of AZL found tobe effective in these in vitro experiments is within therapeuticrange As EC do not possess voltage-operated L-type calciumchannels it is suggested that the beneficial effects of azelni-dipine are not likely due to CA property but to its unique AO
22 Oxidative Medicine and Cellular Longevity
ability Furthermore it has been recently found that serumlevels of monocyte chemoattractant protein-1 a biomarkerfor subclinical atherosclerosis were significantly decreased bythe AZL treatment in patients with essential hypertension Inthis paper [220] authors hypothesize that due to its uniqueTNF-120572 signalmodulatory activity and antioxidative propertyazelnidipine may be a promising DHP for targeting diabetesand cardiovascular diseases in hypertensive patients withmetabolic syndrome
Shinomiya et al [228] evaluated its AOA in culturedhuman arterial EC under OS Azelnidipine has shown apotent antioxidative effect that could be of significant clinicalbenefit when combined with its long-lasting antihypertensiveaction and low incidence of tachycardia
Azelnidipine inhibited TGF-1205731 and angiotensin II- (AngII-) activated 1205721(I) collagen mRNA expression in hepaticstellate cells (HSCs) (Ohyama et al [229]) FurthermoreTGF-1205731- and Ang II-induced OS and TGF-1205731-induced p38and JNK phosphorylation were reduced inHSCs treated withAZL Azelnidipine significantly decreased inflammatory cellinfiltration profibrotic genes expression HSC activation LPoxidative DNA damage and fibrosis in liver of CCl
4- or
TAA-treated mice Finally AZL prevented decrease of theexpression of some AO enzymes and accelerated regressionof liver fibrosis in CCl
4-treated mice Hence the antifibrotic
mechanism of AZL against CCl4-induced liver fibrosis in
mice may have been due to an increased level of AO defenseAs azelnidipine is widely used in clinical practice withoutserious adverse effects it may provide an effective newstrategy for antifibrotic therapy
358 Manidipine Manidipine (2-[4-(diphenylmethyl)pip-erazin-1-yl]ethyl methyl 26-dimethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate) is a DHP CCB withreported nephroprotective properties Calo et al [230] stud-ied effect of manidipine on gene expression and proteinlevel of OS related proteins p22(phox) (human neutrophilcytochrome b light chain (CYBA)) and heme oxygenase-1HO-1 Relevance for antihypertensive effects was revealedThe study assessed the effect of manidipine on normalsubjectsrsquo monocyte gene and protein expression of OS relatedproteins such as p22phox a NADPH oxidase system subunitcritical in generating O
2
∙minus and HO-1 induced by and pro-tective against OS Manidipine was compared with the ACEinhibitor captopril and the CCB nifedipine in the presenceand in the absence of sodiumarsenite (NaAsO
2) as an inducer
of OS Monocyte p22phox (CYBA) mRNA production wasreduced by both manidipine and captopril while no changeswere induced by nifedipine Manidipine increased monocyteHO-1 mRNA production while nifedipine and captoprilshowed no effect The effects of manidipine on p22phoxand HO-1 gene expression in the presence of OS were alsoconfirmed at the protein level Thus manidipine seems tosuppress p22phox and to increase the HO-1 mRNA produc-tion and protein level The manidipine-induced increase ofHO-1 gene and protein expression seems to be a peculiareffect of this drug since it is not observed with captopriland nifedipine This effect together with the reduction of
p22phoxmRNAproduction could play a role in its protectivemechanism against OS
359 Mebudipine The protective effect of mebudipine (14-dihydro-26-dimethyl-4-(3-nitrophenyl)-35-pyridinedicar-boxylic acid 3-methyl-5-tert-butyl ester BAY-n-6391) wasrevealed on OS and LP (MDA decrease SOD GPX andcatalase increase) in myocardial ischemic-reperfusion injuryin male rats (Ghyasi et al [231])
There are articles about other commercial and experi-mental DHPs on OS but we have reviewed only the mostcommonly studied compounds Effects of other commercialCA DHPs on OS are also mentioned in several parts of thisreview
36 14-DHPs Ca Agonists andTheir AOA and ARA For themost popular calcium agonist DHP Bay K 8644 no reactionwith peroxyl radicals was registered (Toniolo et al [114])However interactionwith other compounds possessing AOAand ARA (quercetin) was found
Opposite to that AON-acetylcysteine (NAC) diminishedincrease in Ca2+ transient amplitude and cell shorteninginduced by ISO and forskolin whereas NAC had no effecton the (S)-(minus)-methyl-14-dihydro-26-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylatemdash(minus)-BayK 8644-induced increases (Andersson et al [232])
Increased vasoconstriction responses to Bay K 8644 (3 times10minus7ndash3times 10minus5M)were significantly decreased by pyridoindoleantioxidant stobadine treatment in diabetes (Ceylan-Isik etal [233])
The functional interaction between two L-type Ca2+channel activators quercetin and Bay K 8644 has beeninvestigated in vascular smooth muscle cells Biological ARAcompound quercetin at nutritionally meaningful concen-trations limited the responsiveness of vascular L-type Ca2+channels to the pharmacological stimulation operated by BayK 8644 These data contribute to a better understanding ofquercetin effects on experimental in vivo cardioprotection(Saponara et al [234]) Thus these findings indicated thatalthough Bay K 8644 does not exert potent and direct AOAyet acting as calcium agonist it may affect efficiency of AOsubstances and vice versa
Interaction of grapefruit juice (containing quercetin andits analogues) with DHPs CA diminished effectiveness of CAaction of DHPs (Sica [235])
37 Interpretations of the Mechanism(s) of RadicalScavenging and AOA by DHPs
371 Molecular Mechanism(s) of Radical Scavenging andAOA of DHPs in the Model Systems 35-Dicarbonyl-14-di-hydropyridine derivatives possess powerful bis-120573-carbony-lvinyl-amino conjugation and for that reason cannot be con-sidered as ordinary amino antioxidants The electron andorH donation from DHPs ensures their reductant role andresults in AOA and ARA Oxidation reaction from DHPsresults in production of corresponding heteroaromatic pyri-dine derivatives
Oxidative Medicine and Cellular Longevity 23
Detailed studies were made about substituent in DHPring positions 14- namely 4-unsubstituted- 4-substituted4-alkyl- 4-aryl- 4-alkylaryl- ao 26- 35- (diacetyl ordialkoxycarbonyl chain ao) electronic and steric effects onAOA and ARA of DHPs [44 45 51] see Sections 331and 35 The bell-shaped dependence of DHPs AOA onthe 35-dialkoxycarbonyl- chain length was observed [4445 107 109 112] with the maximum activity at C
2H5ndash
C4H9 Decrease of AOA and incorporation into liposomes for
DHPs with alkyl chains longer than R gt C4H9further were
clarified as probable tendency to self-aggregation of thesecompounds ([51] and citation number 245 therein) Electronacceptorelectron donor properties are relevant for expres-sion of AOA or ARA of 35-disubstituted DHPs 35-Diacyl-substituted and 35-dicarbanilido- and 35-dipyridylamido-substituted DHPs are more active as AOs as their 35-dicyano-substituted analogues which have electron acceptorproperties [186]
Dubur et al [89] observed overwhelming steric influenceof substituents in position 4 of the DHP ring Gaviraghiet al [163 164] proposed that AO activity of DHPs ispartly dependent on capacity of the 14-DHP ring to donateelectrons to the propagating radical (ROO∙ or RO∙) and toreduce it to a less reactive form The abstraction (donation)of electron andor H in the oxidation and LP reactionstakes place from all 35-dicarbonyl-14-DHP systems andresults in the formation of corresponding pyridine derivatives(Augustyniak et al [51]) The physicochemical mechanism ofARA and AOA of 14-DHP has been extensively studied anddiscussed (Mulder et al [236]) but precise mechanisms oftheir activity need further clarification
The reactivity of C-4 substituted 14-DHPs possessingeither secondary or tertiary nitrogen atom in the DHP ringtoward alkyl alkylperoxyl radicals and ABTS radical cationwas determined in aqueous media at pH 74 [103] Thesecompounds reacted faster toward alkylperoxyl radicals andABTS radical cation than alkyl ones N-Ethyl-substitutedDHPs showed the lowest reactivity
The 4-methyl substituted DHP was the most reac-tive compound in previously mentioned reactions (Lopez-Alarcon et al [103]) However it was less active (068versus 10) than Trolox-C DHPs having electron-donatingsubstituents (4-Me-DHP and p-MeO-Phe-DHP) showed thehighest kinetic rate constants toward ABTS radical cation p-nitro-Phe-DHP a compound with an electron-withdrawingsubstituent showed a lower kinetic rate constant and N-alkyl-DHP compounds show kinetic rate constants lowerthan the -NH-DHP
Hydrogen at the 1-position of the DHP ring was revealedaccording to the deuteriumkinetic isotope effect studies to beinvolved in the proposedARAmechanismThis fact ismostlynoticeable in the case of alkyl radicals N-Ethyl-substitutedDHPs show the lowest reactivity when compared to Troloxor nisoldipine In all cases the respective pyridine derivativewas detected as the main product of the reaction (Lopez-Alarcon et al [103]) Authors indicate that the kinetic rateconstants toward alkyl alkylperoxyl andABTS radical cationdepend on the nature of the substituents in the C-4 positionof DHP and the presence of the secondary amine group in the
dihydropyridine ring that is the presence of the hydrogen in1-position
Yanez et al [197] have studied the reactivity of 11derivatives of 14-DHPs (including commercial CA) withalkylperoxyl radicals and ABTS radical cation The tested14-DHPs were 83-fold more reactive towards alkylperoxylradicals than to the ABTS cation radical All commercial14-DHP type CCBs were weaker than Trolox-C The par-ticipation of the hydrogen atom in the 1-position appearsto be very relevant for exhibited reactivity Hantzsch ester(diludine)was again found to be themost active compound inthe reaction with alkylperoxyl radicals 23-fold more activethan Trolox The photodegradation product of nifedipine(nitrosophenyl derivative of pyridine) also showed a highactivity Kinetic rate constants for the reaction between 14-DHP compounds and alkylperoxyl radicals exhibited a fairlygood linear correlation with the oxidation peak potentialof DHP derivatives However the activity of tested 14-DHPs towards ABTS radical cation showed an independencebetween kinetic rate constants and oxidation peak potentials
Kirule et al [195] andTirzit et al [196] studiedmechanismof AOA of 4-nitrophenyl-14-DHPs nifedipine and its ana-logues involving formation of 4-(21015840-nitrosophenyl)-pyridinederivative (as active principle) as a result of intramolecularredox reaction using chemical electrochemical and bio-chemical approaches (see Sections 331 and 351)
Nunez-Vergara et al [237] reported the electrochemicaloxidation of C4-hydroxyphenyl-substituted 14-DHP deriva-tives The oxidation proceeds via formation of the unstabledihydropyridyl radical as confirmed by controlled-potentialelectrolysis (CPE) and ESR experiments This type of 14-DHPs has significant activity towards the radicals even whencompared with commercial 14-DHP drugs with well-knownantioxidant ability
It was observed that nicardipine preferentially targets RO∙radicals and is inactive against ROO∙ Lacidipine on theother hand is equally active towards both types of radicals(Gaviraghi et al [164]) The cytoprotective effect againstexposure to H
2O2was more significant for lacidipine (ID
50=
14 nM its log119875 = 54 membrane partition = 136000 assumesposition located 7 A near to the membrane center otherless lipophilic DHPs located 12ndash16 A far from the center)as compared to amlodipine nifedipine and nicardipine insmooth muscle cell culture (Gaviraghi et al [164]) Oxidativeeffect of H
2O2shifts the Ca channel toward an open state
Thus the redox property of CCBs DHPs may augment theirCCB properties
Oxidation of pharmacologically active Hantzsch 14-dihydropyridines was found by electrogenerated superoxideusing a voltammetric approach in DMSO solutions (Ortiz etal [238] and Ortiz et al [239]) Raghuvanshi and Singh [240]have also reported oxidative aromatization of these DHPsinduced by superoxide
Chemiluminescence (CL) was used in the studies ana-lyzing the antioxidant activity of 12 various 4-flavonil-14-dihydropyridine derivatives (Kruk et al [241]) on a chemicalsystem involving a superoxide radical anion These deriva-tives showed structural similarity to flavonoids with respectto the presence of rings A B and C The results obtained in
24 Oxidative Medicine and Cellular Longevity
this study indicate that the tested derivatives may catalyzeconversion of superoxide radicals through mimicking theactivity of superoxide dismutase by delivering H+ for reac-tion
O2
minus∙+O2
minus∙+ 2H+ 997888rarr H
2O2+1O2
(3)
The enhanced emission of the light in the presence oftested compounds was significant and related to stimulatedproduction ofH
2O2and 1O
2fromO
2
∙The latter specieswereremoved from the reactionmixture by the following sequenceof reactions
H+
O2
minus∙997888rarr HO
2
∙
HO2
∙+O2
∙minus997888rarr HO
2
minus+1O2
2HO2
∙997888rarr H
2O2+1O2
2 (1O2) 997888rarr (O
2)2+ h]lowast
(4)
or to take part in spontaneous dismutation of H2O2
2H2O2997888rarr 2H
2O + 1O
2(5)
The authors have offered an original concept of action for 4-flavonil-14-dihydropyridine derivatives unrelated to that ofO2
∙ radical-trapping chain-breaking antioxidants Insteadthey showed that these compounds act similar to superoxidedismutases converting O
2
∙ to H2O2 Hydrogen peroxide
is less toxic for cells than O2
∙ because it is predominantlyremoved by peroxidases and catalases Finally AO effect ofthese DHPs differed from those mediated by flavonoids witha catechol structure of ring B which are well-known 1O
2
quenchersMulder and collaborators came to similar conclusions
especially related to molecular mechanisms of antioxidativeactivity of DHPs [236]TheAOproperties of Hantzsch 14-di-hydropyridine esters and two dibenzo-14-dihydropyridines910-dihydroacridine (DHAC) and N-methyl-910-dihydro-acridine (N-Me-DHAC) have been explored by determin-ing the autoxidation of styrene or cumene at 30∘C Theseexperiments showed that Hantzsch esters are virtually inac-tive as chain-breaking antioxidants (CB-AOs) contrary tothe findings observed by Lopez-Alarcon et al [103] whoused CB-AOA in aqueous media at pH 74 Their reactivitytoward peroxyl radicals was shown to be some 5 orders ofmagnitude lower than that of the excellent CB-AO 22578-pentamethyl-6-hydroxy-chroman (PMHC)
DHAC was found to be sim10 times less reactive thanPMHC kinetic measurements using DHAC N-deuterio-DHAC and N-Me-DHAC pointing out the abstraction ofN-H hydrogen in DHAC by peroxyl radicals despite the factthat the calculated C-H bond dissociation enthalpy (BDE) inDHAC is about 11 kcalmol lower than the N-H BDE Therates of hydrogen atom abstraction by the 22-diphenyl-1-picrylhydrazyl radical (DPPH∙) have also been determined
for the same series of compounds The trends in the peroxyl∙and DPPH∙ rate constants were found to be similar [236]
Tirzit et al [242] have observed quenching of singletoxygen by DHPs This observation paved the ground forfurther research related to reactions of DHPs with hydroxylradicals (Tirzit et al [243]) singlet oxygen (Kazush etal [94]) and mechanisms of action A series of 14-DHPderivatives in NAD-H-Cu2+-H
2O2system inhibited forming
of the hydroxyl radical (HO∙) while 14-DHP derivativeswith electron donor substituents in the molecule were shownto be capable themselves of generating HO∙ in the presenceof Cu2+ and H
2O2 Rubene et al [186] also described
interaction of 14-DHP derivatives with Fentonrsquos reagentwhich produces hydroxyl radical (HO∙) Rate constants ofthe DHPs reaction (1st order) with HO∙ radical were highin the range 109 L times mol times secminus1 close to that of NADHcysteine and thiourea 35-Diacetyl- derivatives reacted fastercompared to 35-dialkoxycarbonyl- ones The reaction ratedecrease was observed in the case of substitution at position4 as compared to 4-unsubstituted DHPs Some DHPs havingelectron donor -COOminus groups in the 35- or 26- positionsof DHP ring reacted immediately (having rate constantshigher as 109 L times mol times secminus1) Rate constants with HO
2
∙
and O2
∙minus radicals were of lower degree Thus DHPs actingas oxygen radical scavengers could effectively inhibit ROSrelated reactions of LP initiation stage
Nifedipine and nitrendipine reactivity toward singletoxygen was also studied [244] Nifedipine was shown tobe a good scavenger of excited oxygen mainly via physicaldeactivation with values of the total rate constant rangingfrom 208 times 105Mminus1 sminus1 (in dioxane) to 930 times 105Mminus1 sminus1(in propylene carbonate)The less reactive pathway generateda photooxidation product For that reason a mechanisminvolving a perepoxide-like encounter complex in the firststep of the reaction path was proposed (see [244] Figures8 and 9 therein) The dependence was observed on solventmicroscopic parameters of the total rate constant for the reac-tion between singlet oxygen and 14-DHPs These findingsshow that nifedipine possesses stronger protective activity inbiological systems than nitrendipine
Density-functional-theory (DFT) calculations made byWang et al [245] confirmed the former experimental obser-vations that Hantzsch ester diludine is potent antioxi-dant with high H atom-donating ability and relatively lowprooxidant activity Possible reaction pathways for radicalsderived from 14-dihydropyridine and the resonance modesfor radical species were given [245]
Moreover two ethoxycarbonyl (EtOCO) substituentsat C(2) and C(6) should further enhance Hantzsch esterdiludine H-atom-donating ability due to resonance effectsHowever DHPs should be used in nonpolar rather than inpolar solvents since in the latter not H-atom but electrontransfer is preferred in the radical scavenging process [245]
Mulder et al [246] proposed that quantum-thermochem-ical calculations must be used with caution to indicate ldquoapromising lead antioxidantrdquo as they criticized the density-functional-theory (DFT) calculations made by Wang et al[245]
Oxidative Medicine and Cellular Longevity 25
372 Possible Mechanisms of DHPs ARA and AOA in the Bio-logical Systems Interaction with Other OSModifiers Some ofthese mechanisms were already described (Sections 331 (2)-(b) 331 (2)-(c) 331 (3)-(b) 35)
Enzymatic sources of ROSwith confirmed functional rolein hypertension are NADPH oxidase NO synthase (NOS)xanthine oxidase and cyclooxygenase Godfraind [3] hasreviewed AO effects and protective action of calcium channelblockers (CCBs) Yao et al [247] observed antioxidant effects(as inhibition of LP) for cardio- and neuroprotective CCBs(3ndash300 120583molL) including 7 DHPs in homogenates of ratbrain IC
50values (120583M) were as follows nifedipine (515) gt
barnidipine (586) gt benidipine (712) gt nicardipine (1293)gt amlodipine (1355) gt nilvadipine (1673) gt nitrendipine(2521) gt diltiazem (gt300) = verapamil (gt300) There arealso research articles describing the AO properties of CCBsthrough direct scavenging effect or through preservationof the endogenous SOD activity These findings indicatethat CCBs may also act by reducing the production ofvasoconstrictors angiotensin and endothelin
When present in concentrations that can be achievedin plasma CCBs may inhibit LP formation [3] This AOactivity seems to be typical for high lipophilic CCBs becausetheir chemical structure facilitates proton-donating andresonance-stabilization mechanisms that quench the freeradical reaction Their insertion in the membrane nearpolyunsaturated fatty acids at relatively high concentrationspotentiates proton donation (or atomary H) to lipid peroxidemolecules thereby blocking the peroxidation process Theremaining unpaired free electron associated with the CCBmolecule can be stabilized in well-defined resonance struc-tures associated with the DHP ring (Mason et al [48])
The radical reaction (according to Godfraind [3]) thatdescribes the AO effects of a DHP CCBs is LOOlowast + DHPrarr LOOH + DHPlowast (where LOOlowast is lipid peroxide radical)which in general is reaction (7) of the LP reaction cascadeconsisting of sim10 reactions (Scheme 2) [89]
As the rate constants of in vitro interaction of 4-substituted DHPs with peroxyl radicals are three ordersof magnitude lower than that of the vitamin E derivativethese DHPs must be considered as weak AO (Ursini [204])However due to partition coefficient of DHPs in membranesand in case of specific binding high local concentration ofDHPs may be obtained
DHPs without CCB properties for instance Bay w 9798although structurally related to nifedipine inhibit TNF-120572-induced vascular cell adhesion molecule-1 expression inendothelial cells by suppressing reactive oxygen speciesgeneration [248]
Mitrega et al [249] have discovered that antiarrhythmicand hemodynamic effects of oxidized heteroaromatic DHPsoxy nifedipine oxy nimodipine oxy nitrendipine and oxynisoldipine suggest that CCB DHPs and their metabolitescould act at least in two ways targeting OS related eventsas reductants (see Section 351 (1)) andor bypassing OSrelatedmetabolic routes Authors postulated that contrary tocurrent belief NIF metabolites are pharmacologically activeATP sensitive potassium channels were mentioned as a tar-get
38 DHPs Anti- or Prooxidants Several substances (ascorbicacid being the most commonly studied) can serve either asantioxidants or as prooxidants depending on given condi-tions (Herbert [250]) Therefore Halliwell [251] has reporteddilemma related to polyphenols as possible antioxidantsand prooxidants causing experimental artifacts (about 25)by oxidation of antioxidant compounds in the cell culturemedia Nevertheless it is generally accepted opinion thatpolyphenols act as antioxidants in vivo Studies on DHPs alsoface such a dilemmaThe exact roles (anti- or prooxidative) ofany specific DHP depend on its structure appliedachievedconcentration and specificity of the targetexperimentaltesting system
This situation resembles the case of antioxidative effectsof tocopherol which depends on the fate of the secondaryradical as proposed by Winterbourn [252] The question wasldquoVitamin E - Pro- or Antioxidantrdquo
997888rarr chain termination of lipid peroxidation
(6)
Prooxidant
Toc∙ + Lipid-H 997888rarr Lipid∙ (in LDL particles) (7)
This example shows that generally speaking any AO mustfulfil several criteria to be considered as an effective com-pound physiologically
(i) It must be able to functionally interact with endoge-nous scavengers even at low concentrations
(ii) It must affect endogenous pathways of OS(iii) It should not have undesirable adverse effect(iv) It should manifest the antioxidant efficacy dependent
on the oxidant(v) It must discriminate among different strategies
needed for 1-electron and 2-electron processes(vi) Radical scavengers can be prooxidant unless linked to
a radical sink (Winterbourn [252])
According to these statements DHPs could be effective asAO under physiological conditions in vivo (Godfraind [3]and others [30 31 38]) and in vitro in various experimentalsystems (cell and tissue) (see Sections 33 34 35)
Hence calcium antagonists appeared to disrupt thefine balance between the production and scavenging ofROS Nifedipine verapamil and diltiazem were shown toinduce significant oxidative stress in the epididymal sperm(increased MDA and decreased catalase and superoxidedismutase activity) This may be the reason for the inductionof male infertility [253]
The dualism of 14-DHP effects has been recorded asinhibition or promotion of LP as quenching or initiating
26 Oxidative Medicine and Cellular Longevity
oxygen and nitrogen free radical chain reactions radiopro-tecting or radiosensitizing antagonizing or synergizing Ca2+in electromechanical coupling as well as in the membranestabilization or labilization
39 Could DHPs Be Involved in Antioxidative Stress Beforebeing applied in vivo the optimal dose and optimal timeintervals forDHPs applicationmust be knownNamely whileROS have been traditionally considered as toxic byproductsof aerobic metabolism we know nowadays that ROS may actas essential signaling molecules needed for the control ofmany different physiological processes Whether the role ofROS will be damaging protective or signaling depends onthe delicate equilibrium between time- and location-specificROS production and scavenging Accordingly the imbalanceof the increased AO potential so-called antioxidative stresscould be dangerous similar to chronic OS in particular incase of extended exposure Inappropriate interventions inthe oxidative homeostasis by excessive antioxidants especiallyin case of chronic exposure to antioxidants might havevery negative effects as was published in the ATBC studyshowing an increased cancer incidence in smokers treatedby excessive beta-carotene [254] Therefore overconsump-tion of any natural or synthetic AO including DHPs asdietary supplements or drugs must be avoided in order tosuppress oxidative damage and must not disrupt the well-integrated antioxidant defense network (Poljsak [255] andPoljsak and Milisav [256]) This is especially important whenadministrating lipid-soluble antioxidants that can be storedin biomembranes thus not only attenuating or preventing LPbut also affecting physiological effects of the natural antiox-idants in particular tocopherol The interrelationship withthe status of endogenous antioxidantsprooxidants should befollowed
DHPs primarily suppress the initiation stages of LPprocessThey do not entirely stop the LP propagation Actingsynergistically with tocopherol diludine may prevent patho-logical excess of ROS production within the lipid moiety ofthe cellular membranes and LDL However due to its lowsolubility and fast metabolism its concentration in the cellsis low For that reason it cannot cause antioxidative stresseven if used for an extended period of time Thus diludine(diethone) could be only a mild antioxidant it has potentialfor restoring the pool of natural antioxidants (as synergist of120572-tocopherol and polyphenols) in the cells
Moreover DHPs CA used for cardioprotection andvasodilatation as commercial drugs in low concentrationsare fast metabolized via CYP3A4 and for that reason theirapplication does not induce cellular AO stress [53 160]However Godfraind and Salomone [257] have postulated noevidence that allows recommending dietary supplementationwith antioxidants for the primary or secondary prevention ofcardiovascular disease
So far there are no reports on antioxidative stress causedby some DHPs diludine and its analogues Diludine andits analogues therefore could act as adaptogens supportinghormetic effects of mild oxidative stress These compoundsmay act as potential multisided modulators of Yin-Yang
cycles of redox and cell functions (the electroplasmic cycle)(Wagner et al [258])
4 Conclusions
14-Dihydropyridines (14-DHPs) have broad spectrum ofOS modulating activities DHPs have reducing and lipidperoxidation inhibitor properties act as reductants in simplechemical systems and stabilize various biological systems(LDL mitochondria microsomes cells and tissues) againstOS Examples and peculiarities and mechanisms of antiox-idant activity (AOA) and antiradical activity (ARA) as wellas stress-protective effect of DHPs including commercialcalcium antagonists (CA) were highlighted These activitiesdepend on various structural parameters related to DHPs(presence and character of substituents) lipophilicity anddepth of the incorporation in the biologicalmembranesTheyalso depend on the experimental model system for exploringthe lipid peroxidation or oxidative stress Stress-protectiveeffect of some metabolites of CA (nifedipine) is reviewedAlthough some DHPs including CA have prooxidant prop-erties (on epididymal sperm cells) they can generally beconsidered as potent antioxidants Therefore comparisonof the AOA and ARA of different DHPs (mutually andwith other AOs) was described in detail According to thedata presented the DHPs might be considered as bellwetheramong synthetic compounds targeting OS and as a kind ofpharmacological measure for respective field of organic andmedicinal chemistry
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
Authors from Latvian IOS acknowledge ESF 201300021DP1112013APIAVIAA011 and National Research Pro-gramme PUBLIC HEALTHBiomedicine of the Republicof Latvia for financial support administration of the Insti-tute for technical support and Rufus Smits PhD for con-sultations in English The support of Cooperation in Euro-pean System of Science and Technology (COST) Domain ofChemistry Molecular Sciences and Technologies (CMST)was of highest importance for preparation of this paper
[2] D J Triggle ldquo14-Dihydropyridines as calcium channel ligandsand privileged structuresrdquoCellular andMolecular Neurobiologyvol 23 no 3 pp 293ndash303 2003
[3] T Godfraind ldquoAntioxidant effects and the therapeutic modeof action of calcium channel blockers in hypertension andatherosclerosisrdquo Philosophical Transactions of the Royal SocietyB Biological Sciences vol 360 no 1464 pp 2259ndash2272 2005
[4] E Cadenas ldquoMitochondrial free radical production and cellsignalingrdquoMolecular Aspects of Medicine vol 25 no 1-2 pp 17ndash26 2004
[5] E Cadenas ldquoFree radicals oxidative stress and diseasesrdquo inLecture PSC 616 p 38 Missouri University of Science andTechnology Rolla Mo USA httpwwwcarnicominstituteorgarticlesenrique cadenaspdf
[6] K Rahman ldquoStudies on free radicals antioxidants and co-fac-torsrdquo Clinical Interventions in Aging vol 2 no 2 pp 219ndash2362007
[7] V Bocci and G Valacchi ldquoFree radicals and antioxidants howto reestablish redox homeostasis in chronic diseasesrdquo CurrentMedicinal Chemistry vol 20 no 27 pp 3397ndash3415 2013
[8] M Valko C J Rhodes J Moncol M Izakovic and M MazurldquoFree radicals metals and antioxidants in oxidative stress-induced cancerrdquo Chemico-Biological Interactions vol 160 no 1pp 1ndash40 2006
[9] G Bartosz ldquoReactive oxygen species destroyers or messen-gersrdquo Biochemical Pharmacology vol 77 no 8 pp 1303ndash13152009
[10] R Visconti and D Grieco ldquoNew insights on oxidative stress incancerrdquo Current Opinion in Drug Discovery and Developmentvol 12 no 2 pp 240ndash245 2009
[11] R N Kujundzic N Zarkovic and K G Troselj ldquoPyridinenucleotides in regulation of cell death and survival by redoxand non-redox reactionsrdquo Critical Reviews in Eukaryotic GeneExpression vol 24 no 4 pp 287ndash309 2014
[12] B Halliwell and J M C Gutteridge ldquoThe definition and mea-surement of antioxidants in biological systemsrdquo Free RadicalBiology and Medicine vol 18 no 1 pp 125ndash126 1995
[13] V D Kancheva and O T Kasaikina ldquoBio-antioxidantsmdashachemical base of their antioxidant activity and beneficial effect
on human healthrdquo Current Medicinal Chemistry vol 20 no 37pp 4784ndash4805 2013
[14] H V Panglossi Ed Frontiers in Antioxidants Research NovaScience Publishers New York NY USA 2006
[15] E B Burlakova E M Molochkina and G A NikiforovldquoHybrid antioxidantsrdquo Oxidation Communications vol 31 no4 pp 739ndash757 2008 httpmembraneustceducnpaperpdfHybrid20Antioxidantspdf
[16] A Bast and G R M M Haenen ldquoTen misconceptions aboutantioxidantsrdquo Trends in Pharmacological Sciences vol 34 no 8pp 430ndash436 2013
[17] E B Burlakova A V 0lesenko E M Molochkina N PPalmina and N G Khrapova Bioantioxidants for RadiationDamage and Malignant Growth Nauka Moscow Russia 1975(Russian)
[18] J Fang T Seki and H Maeda ldquoTherapeutic strategies by mod-ulating oxygen stress in cancer and inflammationrdquo AdvancedDrug Delivery Reviews vol 61 no 4 pp 290ndash302 2009
[19] M Valko D Leibfritz J Moncol M T D Cronin M Mazurand J Telser ldquoFree radicals and antioxidants in normal physi-ological functions and human diseaserdquo International Journal ofBiochemistry and Cell Biology vol 39 no 1 pp 44ndash84 2007
[20] M Jimenez-Del-Rio and C Velez-Pardo ldquoThe bad the goodand the ugly about oxidative stressrdquo Oxidative Medicine andCellular Longevity vol 2012 Article ID 163913 13 pages 2012
[21] C D Kamat S Gadal M Mhatre K S Williamson Q N Pyeand K Hensley ldquoAntioxidants in central nervous system dis-eases preclinical promise and translational challengesrdquo Journalof Alzheimerrsquos Disease vol 15 no 3 pp 473ndash493 2008
[22] A Pompella H Sies R Wacker et al ldquoThe use of totalantioxidant capacity as surrogate marker for food quality andits effect on health is to be discouragedrdquo Nutrition vol 30 no7-8 pp 791ndash793 2014
[23] Z Ye and H Song ldquoAntioxidant vitamins intake and the risk ofcoronary heart disease meta-analysis of cohort studiesrdquo Euro-pean Journal of Cardiovascular Prevention and Rehabilitationvol 15 no 1 pp 26ndash34 2008
[24] P Knekt J Ritz M A Pereira et al ldquoAntioxidant vitamins andcoronary heart disease risk a pooled analysis of 9 cohortsrdquoTheAmerican Journal of Clinical Nutrition vol 80 no 6 pp 1508ndash1520 2004
[25] A C Carr and M C M Vissers ldquoSynthetic or food-derivedvitamin Cmdashare they equally bioavailablerdquo Nutrients vol 5 no11 pp 4284ndash4304 2013
[26] R Tabrizchi ldquoEdaravoneMitsubishi-TokyordquoCurrentOpinion inInvestigational Drugs vol 1 no 3 pp 347ndash354 2000
[27] K Kikuchi S Tancharoen N Takeshige et al ldquoThe efficacy ofedaravone (radicut) a free radical scavenger for cardiovasculardiseaserdquo International Journal of Molecular Sciences vol 14 no7 pp 13909ndash13930 2013
[28] D Mauzerall and F H Westheimer ldquo1-Benzyldihydronicoti-namidemdasha model for reduced DPNrdquo Journal of the AmericanChemical Society vol 77 no 8 pp 2261ndash2264 1955 ChemicalAbstracts vol 50 Article ID 2588i 1956
[29] F Bossert and W Vater ldquo14-Dihydropyridinesmdasha basis fordeveloping new drugsrdquo Medicinal Research Reviews vol 9 no3 pp 291ndash324 1989
[30] G Swarnalatha G Prasanthi N Sirisha and CMadhusudhanaChetty ldquo14-Dihydropyridines a multtifunctional moleculemdash areviewrdquo International Journal of ChemTech Research vol 3 no1 pp 75ndash89 2011
28 Oxidative Medicine and Cellular Longevity
[31] M Cataldi and F Bruno ldquo14-Dihydropyridines the multiplepersonalities of a blockbuster drug familyrdquo Translational Medi-cine UniSa vol 4 no 2 pp 12ndash26 2012 httpwwwncbinlmnihgovpmcarticlesPMC3728803
[32] R Vitolina A Krauze G Duburs and A Velena ldquoAspects ofthe amlodipine pleiotropy in biochemistry pharmacology andclinicsrdquo International Journal of Pharmaceutical Sciences andResearch vol 3 no 5 pp 1215ndash1232 2012
[33] D Grover S N Mokale and M T Shete ldquoDihydropyridinea novel pharmacophorerdquo International Journal of Pharmaceu-tical Erudition vol 1 no 2 pp 16ndash29 2011 httppharmaeru-ditionorgContentPaper20111-RV-320Final2016-29pdf
[34] A M Vijesh A M Isloor S K Peethambar K N ShivanandaT Arulmoli and N A Isloor ldquoHantzsch reaction synthesis andcharacterization of somenew 14-dihydropyridine derivatives aspotent antimicrobial and antioxidant agentsrdquo European Journalof Medicinal Chemistry vol 46 no 11 pp 5591ndash5597 2011
[35] P Mehta and P Verma ldquoAntimicrobial activity of some deriva-tives of 14-dihydropyridinesrdquo Journal of Chemistry vol 2013Article ID 865128 4 pages 2013
[36] P Olejnıkova L Svorc D Olsovska et al ldquoAntimicrobialactivity of novel C2-substituted 14-dihydropyridine analoguesrdquoScientia Pharmaceutica vol 82 no 2 pp 221ndash232 2014
[37] S Sepehri H Perez Sanchez and A Fassihi ldquoHantzsch-typedihydropyridines and biginelli-type tetra-hydropyrimidinesa review of their chemotherapeutic activitiesrdquo Journal of Phar-macy amp Pharmaceutical Sciences vol 18 no 1 pp 1ndash52 2015httpsejournalslibraryualbertacaindexphpJPPSarticleview2383617863
[38] S A Khedkar and P B Auti ldquo14-Dihydropyridines a classof pharmacologically important moleculesrdquo Mini-Reviews inMedicinal Chemistry vol 14 no 3 pp 282ndash290 2014
[39] G D Tirzit and G Ya Duburs ldquo14-dihydropyridines as inhi-bitors of free-radical reactionsrdquo Chemistry of Heterocyclic Com-pounds vol 8 no 1 pp 126ndash127 1972 Translated from KhimiyaGeterotsiklicheskikh Soedinenii no1 pp 133ndash134 1972 (Rus-sian)
[40] I Bogeski R Kappl C Kummerow R Gulaboski M Hothand B A Niemeyer ldquoRedox regulation of calcium ion channelschemical and physiological aspectsrdquoCell Calcium vol 50 no 5pp 407ndash423 2011
[41] S A Giller G Y Dubur Y R Uldrikis et al ldquoDiludine [Themethod to obtain 35-dicarbonylderivatives of 26-dimethyl-14-dihydropyridines]rdquo Authors certificate of USSR no 3004651971 [Byull Izobret no13 p 95 1971] and following patentsPatent of England no 1294650 1973 Patent of France no2055458 1971 Patent of Japan no 702883 1973 Patent ofHolland no 149787 1976 Patent of Italy no 969022 1974 Patentof FRG no 2036403 1978 US Patent no 3883673 1975 USPatent no 3948924 1976
[42] S A Giller G Y Dubur Y R Uldrikis et al ldquoImprovementsin or relating to the stabilization of carotenerdquo GB Patent no1294650 1972
[43] S A Giller G Y Dubur Y R Uldrikis et al ldquoStabilization ofcarotenerdquo US Patent no 3883673 1975 Chemical Abstracts vol83 Article ID 95193 1975
[44] Yu A Zilber G Ya Dubur K K Kumsar and A Kh VelenaldquoThe effect of antioxidants on the peroxidation of bimole-cular phospholipid membranesrdquo Latvijas PSR ZA Vestis Izves-tia Akademii Nauk Latviyskoy SSR vol 6 pp 80ndash82 1971(Russian) translated from the original Russian Doc Accesion
No AD0771751 distributed by NTIS US Department of Com-merce httpwwwdticmildtictrfulltextu2771751pdf
[45] G Ya Dubur Yu A Zilbers A Kh Velena A O Kumerovaand G D Tirzitis ldquoMultistage study of regulation of peroxida-tion processes in biological membranes by antioxidants of 14-dihydropyridine grouprdquo Izvestiya Akademii Nauk LatviyskoySSR vol 336 no 7 pp 65ndash68 1975 (Russian)
[46] R P Mason and M W Trumbore ldquoDifferential membraneinteractions of calcium channel blockers Implications forantioxidant activityrdquo Biochemical Pharmacology vol 51 no 5pp 653ndash660 1996
[47] R P Mason M F Walter M W Trumbore E G Olmstead Jrand P E Mason ldquoMembrane antioxidant effects of the chargeddihydropyridine calcium antagonist amlodipinerdquo Journal ofMolecular and Cellular Cardiology vol 31 no 1 pp 275ndash2811999
[48] R PMason I T MakMW Trumbore and P EMason ldquoAnti-oxidant properties of calcium antagonists related to membranebiophysical interactionsrdquo American Journal of Cardiology vol84 no 4 pp 16ndash22 1999
[49] R PMasonMW Trumbore and P EMason ldquoMembrane bio-physical interaction of amlodipine and antioxidant propertiesrdquoDrugs vol 59 no 2 pp 9ndash16 2000 (French)
[50] R P Mason P Marche and T H Hintze ldquoNovel vascularbiology of third-generation L-type calcium channel antagonistsAncillary actions of amlodipinerdquo Arteriosclerosis Thrombosisand Vascular Biology vol 23 no 12 pp 2155ndash2163 2003
[51] A Augustyniak G Bartosz A Cipak et al ldquoNatural andsynthetic antioxidants an updated overviewrdquo Free RadicalResearch vol 44 no 10 pp 1216ndash1262 2010
[52] T Grune N Zarkovic and K Kostelidou ldquoLipid peroxidationresearch in Europe and the COST B35 action lsquoLipid Peroxida-tion Associated Disordersrsquordquo Free Radical Research vol 44 no10 pp 1095ndash1097 2010
[53] E Carosati P Ioan M Micucci et al ldquo14-Dihydropyridinescaffold in medicinal chemistry the story so far and perspec-tives (part 2) action in other targets and antitargetsrdquo CurrentMedicinal Chemistry vol 19 no 25 pp 4306ndash4323 2012
[54] U Eisner and J Kuthan ldquoThe chemistry of dihydropyridinesrdquoChemical Reviews vol 72 no 1 pp 1ndash42 1972 httpwwwsci-encemadnessorgtalkfilesphppid=138742ampaid=6475
[55] J Kuthan and A Kurfurst ldquoDevelopment in dihydropyri-dine chemistryrdquo Industrial amp Engineering Chemistry ProductResearch and Development vol 21 no 2 pp 191ndash261 1982
[56] A Sausins and G Duburs ldquoSynthesis of 14-dihydropyridinesby cyclocondensation reactionsrdquo Heterocycles vol 27 no 1 pp269ndash289 1988
[57] A E Sausins and G Y Duburs ldquoSynthesis of 14-dihydro-pyridines in cyclocondensation reactions (review)rdquo Chemistryof Heterocyclic Compounds vol 28 no 4 pp 363ndash391 1992Translated from Khimiya Geterotsiklicheskikh Soedinenii no 4pp 435ndash467 1992 (Russian)
[58] S Kazda ldquoTwenty years of dihydropyridinesrdquo in Dihydropy-ridines Progress in Pharmacology and Therapy W-D Busse BGarthoff and F Seuter Eds pp 1ndash12 Springer Verlag BerlinGermany 1993
[59] J-P Wan and Y Liu ldquoRecent advances in new multicomponentsynthesis of structurally diversified 14-dihydropyridinesrdquo RSCAdvances vol 2 no 26 pp 9763ndash9777 2012
[61] Reaxys Database[62] J Tuttle ldquoStructure mechanism and reactivity of hantzsch
estersrdquo in MacMillan Lab Group Meeting (082504) p 332004 httpwwwprincetoneduchemistrymacmillangroup-meetingsJBT20Hantzschpdf
[63] A Saini S Kumar and J S Sandhu ldquoHantzsch reaction recentadvances in Hantzsch 14-dihydropyridinesrdquo Journal of Sci-entific amp Industrial Research vol 67 pp 95ndash111 2008
[64] L LW Cheung S A Styler and A P Dicks ldquoRapid and conve-nient synthesis of the 14-dihydropyridine privileged structurerdquoJournal of Chemical Education vol 87 no 6 pp 628ndash630 2010
[65] A Kumar R A Maurya S Sharma M Kumar and G BhatialdquoSynthesis and biological evaluation of N-aryl-14-dihydro-pyridines as novel antidyslipidemic and antioxidant agentsrdquoEuropean Journal of Medicinal Chemistry vol 45 no 2 pp 501ndash509 2010
[66] R S Kumar A Idhayadhulla A J Abdul Nasser and J SelvinldquoSynthesis and anticoagulant activity of a new series of 14-dihydropyridine derivativesrdquo European Journal of MedicinalChemistry vol 46 no 2 pp 804ndash810 2011
[67] H A Stefani C B Oliveira R B Almeida et al ldquoDihydro-pyrimidin-(2H)-ones obtained by ultrasound irradiation anew class of potential antioxidant agentsrdquo European Journal ofMedicinal Chemistry vol 41 no 4 pp 513ndash518 2006
[68] H Sun C Shang L Jin and J Zhang ldquoSynthesis and antiox-idant activity of a series of novel 3-chalcone-substituted 14-dihydropyridine derivativesrdquoHeterocyclic Communications vol18 no 5-6 pp 239ndash243 2012
[69] D B Tikhonov and B S Zhorov ldquoStructural model for dihy-dropyridine binding to L-type calcium channelsrdquo The Journalof Biological Chemistry vol 284 no 28 pp 19006ndash19017 2009
[70] G Y Dubur and Y R Uldrikis ldquoThe oxidation of 14-dihydro-pyridinesrdquo Chemistry of Heterocyclic Compounds vol 6 no 1pp 80ndash84 1970 Translated from Khimiya GeterotsiklicheskikhSoedinenii no 1 pp 83ndash88 1970 (Russian)
[71] G Ya Duburs A O Kumerova and Ya R Uldrikis ldquoEnzymicoxidation of hydrogenated pyridines with peroxidase-hydrogenperoxide systemrdquoLatvijas PSRZAVestis vol 73 no 7 pp 73ndash771970 (Russian) Chemical Abstracts vol 73 Article ID 94913g1970
[72] K Xie Y-C Liu Y Cui J-GWang Y Fu andT CWMak ldquoN-methyl-(R)-3-(tert-butyl)-sulfinyl-14-dihydropyridine a novelNADHmodel compoundrdquoMolecules vol 12 no 3 pp 415ndash4222007
[73] S Tamagaki T Mimura and W Tagaki ldquoMetal-ion-facilitatedoxidations of dihydropyridines with molecular oxygen andhydrogen peroxiderdquo Journal of the Chemical Society PerkinTransactions 2 no 10 pp 1645ndash1650 1990
[74] D Tirzite G Tirzitis andD Antipova ldquoReductive ability of 14-dihydropyridine derivatives in relation to ions of trivalent ironrdquoChemistry of Heterocyclic Compounds vol 35 no 5 pp 592ndash594 1999
[76] J Ogle J Stradins and L Baumane ldquoFormation and decay offree cation-radicals in the course of electro-oxidation of 12- and14-dihydropyridines (Hantzsch esters)rdquo Electrochimica Actavol 39 no 1 pp 73ndash79 1994
[77] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for the
synthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts C Wittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Berlin Germany 2010
[78] WDu and Zh Yu ldquoBiomimetic in situ regeneration of cofactorsNAD(P)+ and NAD(P)H models hantzsch esters and dihy-drophenanthridinerdquo Synlett vol 23 no 9 pp 1300ndash1304 2012
[79] H K Chenault and G M Whitesides ldquoRegeneration ofnicotinamide cofactors for use in organic synthesisrdquo AppliedBiochemistry and Biotechnology vol 14 no 2 pp 147ndash197 1987
[80] Y R Uldrikis A A Zidermane E A Biseniex I E Preisa GY Dubur and G D Tirzit ldquoEsters of 26-dimethyl-14-dihydro-pyridine-35-dicarboxylic acid and method of obtainingthereofrdquo WO 8000345 A1 1978 httpworldwideespacenetcompublicationDetailsbiblioDB=EPODOCampII=1ampND=3ampadjacent=trueamplocale=en EPampFT=Dampdate=19800306ampCC=WOampNR=8000345A1ampKC=A1
[81] Y Sambongi H Nitta K Ichihashi M Futai and I Ueda ldquoAnovel water-soluble Hantzsch 14-dihydropyridine compoundthat functions in biological processes through NADH regener-ationrdquo Journal of Organic Chemistry vol 67 no 10 pp 3499ndash3501 2002
[82] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for thesynthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts ChWittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Verlag Berlin Germany 2010
[83] T Okamura T Kikuchi A Nagamine et al ldquoAn approach formeasuring in vivo cerebral redox states using the oxidative con-version of dihydropyridine to pyridinium ion and themetabolictrapping principlerdquo Free Radical Biology and Medicine vol 38no 9 pp 1197ndash1205 2005
[84] K A Schellenberg and F H Westheimer ldquoA free-radicaloxidation of a dihydropyridine1ardquo The Journal of OrganicChemistry vol 30 no 6 pp 1859ndash1862 1965
[85] K A Schellenberg ldquoReaction of hydroxyl radical with thymi-dine Scavenging by a dihydropyridinerdquo Federation Proceedingsvol 38 no 3 I p 1433 1979
[86] E S Huyser J A K Harmony and F L McMillian ldquoPeroxideoxidations of dihydropyridine derivativesrdquo Journal of the Amer-ican Chemical Society vol 94 no 9 pp 3176ndash3180 1972
[87] A Sakamoto S T Ohnishi and R Ogawa ldquoInhibition of lipidperoxidation by some dihydropyridine derivativesrdquo Journal ofAnesthesia vol 7 no 2 pp 193ndash197 1993
[88] R Hardeland ldquoReview Neuroprotection by radical avoidancesearch for suitable agentsrdquo Molecules vol 14 no 12 pp 5054ndash5102 2009
[89] G Ya Dubur A Kh Velena V M Gukasov and Yu AVladimirov ldquoRegulation of peroxidation of mitochondrialmembrane lipids initiated by Fe2+ ions by antoxidants of the14-dihydropyridine series in experiments in vitrordquo Biomed-itsinskaya Khimiya vol 22 no 5 pp 665ndash673 1976 (Russian)Chemical Abstracts vol 88 Article ID 2640 1977
[90] G RMMHaenenM J T J Arts A Bast andMD ColemanldquoStructure and activity in assessing antioxidant activity in vitroand in vivo a critical appraisal illustrated with the flavonoidsrdquoEnvironmental Toxicology and Pharmacology vol 21 no 2 pp191ndash198 2006
[91] G Tirzitis and G Bartosz ldquoDetermination of antiradical andantioxidant activity basic principles and new insightsrdquo ActaBiochimica Polonica vol 57 no 2 pp 139ndash142 2010
30 Oxidative Medicine and Cellular Longevity
[92] G R Buettner and R P Mason ldquoSpin-trapping methods fordetecting superoxide and hydroxyl free radicals in vitro and invivordquo inCritical Reviews of Oxidative Stress and Aging Advancesin Basic Science Diagnostics and Intervention R G Cutler andH Rodriguez Eds vol 1 chapter 2 pp 27ndash38World ScientificLondon UK 2003
[93] M M Tarpey and I Fridovich ldquoMethods of detection ofvascular reactive species Nitric oxide superoxide hydrogenperoxide and peroxynitriterdquo Circulation Research vol 89 no3 pp 224ndash236 2001
[94] E Y Kazush E I Sagun G D Tirzit and G Y DaburldquoQuenching of singlet oxygen by electron donating derivativesof 14-dihydropyridinerdquo Chemistry of Heterocyclic Compoundsvol 30 no 5 pp 562ndash563 1994
[95] G Tirzitis E Kazush and G Duburs ldquoReaction of 14-dihydropyridine derivatives with peroxynitrite anionrdquo Chem-istry of Heterocyclic Compounds vol 34 no 3 pp 321ndash3231998 (Russian) Translated from Khimiya GeterotsiklicheskikhSoedinenii no 3 pp 355ndash357 1998
[96] L J Nunez-Vergara C Lopez-Alarcon P A Navarrete-EncinaA M Atria C Camargo and J A Squella ldquoElectrochemicaland EPR characterization of 14-dihydropyridines Reactivitytowards alkyl radicalsrdquo Free Radical Research vol 37 no 1 pp109ndash120 2003
[97] D Tirzite A Krauze A Zubareva G Tirzitis and G DubursldquoSynthesis and antiradical activity of 5-acetyl-2-alkylthio-4-aryl-6-methyl-14-dihydropyridine-3-carboxylic acid nitrilesrdquoChemistry of Heterocyclic Compounds vol 38 no 7 pp 795ndash800 2002
[98] H Ohkawa N Ohishi and K Yagi ldquoAssay for lipid peroxidesin animal tissues by thiobarbituric acid reactionrdquo AnalyticalBiochemistry vol 95 no 2 pp 351ndash358 1979
[99] N Zarkovic ldquo4-Hydroxynonenal as a bioactive marker ofpathophysiological processesrdquo Molecular Aspects of Medicinevol 24 no 4-5 pp 281ndash291 2003
[100] M Parola G Bellomo G Robino G Barrera and M UDianzani ldquo4-Hydroxynonenal as a biological signal molecularbasis and pathophysiological implicationsrdquo Antioxidants andRedox Signaling vol 1 no 3 pp 255ndash284 1999
[101] T Lovakovic M Poljak-Blazi G Duburs et al ldquoGrowthmodulation of human cells in vitro by mild oxidative stressand 14-dihydropyridine derivative antioxidantsrdquo CollegiumAntropologicum vol 35 no 1 pp 137ndash141 2011
[102] R van den Berg G R M M Haenen H van den Bergand A Bast ldquoApplicability of an improved Trolox equivalentantioxidant capacity (TEAC) assay for evaluation of antioxidantcapacity measurements of mixturesrdquo Food Chemistry vol 66no 4 pp 511ndash517 1999
[103] C Lopez-Alarcon P Navarrete C Camargo J A Squella andL J Nunez-Vergara ldquoReactivity of 14-dihydropyridines towardalkyl alkylperoxyl radicals and ABTS radical cationrdquo ChemicalResearch in Toxicology vol 16 no 2 pp 208ndash215 2003
[104] V Valenzuela P Santander C Camargo J A Squella C Lopez-Alarcon and L J Nunez-Vergara ldquo14-Dihydropyridines reac-tivity of nitrosoaryl and nitroaryl derivatives with alkylperoxylradicals andABTS radical cationrdquo Free Radical Research vol 38no 7 pp 715ndash727 2004
[105] L G Tsetlin N A Chebotareva B I Kurganov A K VelenaG Y Dubur and V Z Lankin ldquoStudy of 14-dihydropyridinesas lipoxygenase inhibitors with the use of hydrated reversedmicellesrdquo Pharmaceutical Chemistry Journal vol 22 no 6 pp425ndash428 1988 (Russian)
[106] J Panek Z Reblova L Kocirkova et al ldquoAntioxidant activityof dihydropyridine derivativesrdquo Czech Journal of Food Sciencesvol 18 pp 144ndash145 2000
[107] G Tirzitis I Kirule and G Duburs ldquoAntioxidationsaktivitatder 35-dicarbonylderivate des 26-demethyl-14-dihydropyri-dinsrdquo Fett Wissenschaft TechnologieFat Science Technology vol90 no 10 pp 411ndash413 1988
[108] M Plotniece G Tirzitis Y Uldrikis et al ldquoSynthesis of 14-dihydropyridine derivatives having an oxy- alkoxy- or dimeth-ylaminophenyl substituent in the 4 position their antioxidantactivity and their binding to phospholipid membranesrdquo Chem-istry of Heterocyclic Compounds vol 32 no 10 pp 1166ndash11721996 Translated from Khimiya Geterotsiklicheskikh Soedineniino 10(352) pp 1358ndash1365 1996 (Russian)
[109] D Y Rubene V S Sharov V I Olenev G D Tirzit G Y Duburand Y A Vladimirov ldquoUse of chemiluminescent method forthe evaluation of antioxidant activity of some derivatives of 14-dihydropyridinerdquo Russian Journal of Physical Chemistry A vol55 no 2 pp 511ndash512 1981 (Russian)
[110] M C R Symons and JM C Gutteridge Free Radicals and IronChemistry Biology and Medicine Oxford Science PublicationsOxford University Press Oxford UK 1998
[111] M Repetto J Semprine and A Boveris ldquoLipid peroxidationchemical mechanism biological implications and analyticaldeterminationrdquo in Lipid Peroxidation A Catala Ed Section ILipid Peroxidation Chemical Mechanisms Antioxidants Bio-logical Implications of Biochemistry Genetics and MolecularBiology chapter 1 pp 3ndash30 InTech Rijeka Croatia 2012
[112] A Velena J Zilbers and G Duburs ldquoDerivatives of 14-dihydropyridines asmodulators of ascorbate-induced lipid per-oxidation and high-amplitude swelling ofmitochondria causedby ascorbate sodium linoleate and sodiumpyrophosphaterdquoCellBiochemistry and Function vol 17 no 4 pp 237ndash252 1999
[113] M V Bilenko L N Shelenkova G Y Dubur and A K VelenaldquoUse of antioxidants to prevent renal damage during acuteischemia and reperfusionrdquo Bulletin of Experimental Biology andMedicine vol 96 no 3 pp 1195ndash1198 1983 Translated fromByulletenrsquo Eksperimentalrsquonoi Biologii i Meditsiny vol 96 no 9pp 8ndash11 1983 (Russian)
[114] R Toniolo F Tubaro F Ursini and G Bontempelli ldquoAn elec-troanalytical investigation on the redox properties of calciumantagonist dihydropyridinesrdquo Electroanalysis vol 15 no 10 pp855ndash861 2003
[115] L Kourimska J Pokorny and G Tirzitis ldquoThe antioxidant aci-tivity of 26-dimethyl-35-diethoxycarbonyl-14-dihydropyri-dine in edible oilsrdquo Nahrung vol 37 no 1 pp 91ndash93 1993
[116] C Lopez-Alarcon H Speisky J A Squella C Olea-Azar CCamargo and L J Nunez-Vergara ldquoReactivity of 14-dihydro-pyridines toward SIN-1-derived peroxynitriterdquo PharmaceuticalResearch vol 21 no 10 pp 1750ndash1757 2004
[117] R A Olek W Ziolkowski J J Kaczor L Greci J Popinigisand J Antosiewicz ldquoAntioxidant activity of NADH and its ana-loguemdashan in vitro studyrdquo Journal of Biochemistry andMolecularBiology vol 37 no 4 pp 416ndash421 2004
[118] E Niki N Noguchi and N Gotoh ldquoInhibition of oxidativemodification of low density lipoprotein by antioxidantsrdquo Jour-nal of Nutritional Science andVitaminology vol 39 supplementpp S1ndashS8 1993
[119] N Rojstaczer and D J Triggle ldquoStructure-function relation-ships of calcium antagonists effect on oxidative modificationof low density lipoproteinrdquo Biochemical Pharmacology vol 51no 2 pp 141ndash150 1996
Oxidative Medicine and Cellular Longevity 31
[120] A Sevanian L Shen and FUrsini ldquoInhibition of LDLoxidationand oxidized LDL-induced cytotoxicity by dihydropyridinecalcium antagonistsrdquo Pharmaceutical Research vol 17 no 8 pp999ndash1006 2000
[121] A Negre-Salvayre and R Salvayre ldquoProtection by Ca2+ channelblockers (nifedipine diltiazem and verapamil) against the tox-icity of oxidized low density lipoprotein to cultured lymphoidcellsrdquo British Journal of Pharmacology vol 107 no 3 pp 738ndash744 1992
[122] A Negre-Salvayre G FitoussiM Troly and R Salvayre ldquoCom-parative cytoprotective effect of dihydropyridine calcium chan-nel blockers against the toxicity of oxidized low density lipopro-tein for cultured lymphoid cellsrdquo Biochemical Pharmacologyvol 44 no 12 pp 2379ndash2386 1992
[123] L Cominacini A F Pasini U Garbin et al ldquoAntioxidant activ-ity of different dihydropyridinesrdquo Biochemical and BiophysicalResearch Communications vol 302 no 4 pp 679ndash684 2003
[124] L Cominacini U Garbin A Fratta Pasini et al ldquoOxidized low-density lipoprotein increases the production of intracellularreactive oxygen species in endothelial cells inhibitory effect oflacidipinerdquo Journal of Hypertension vol 16 no 12 part 2 pp1913ndash1919 1998
[125] H M Lander ldquoAn essential role for free radicals and derivedspecies in signal transductionrdquo The FASEB Journal vol 11 no2 pp 118ndash124 1997
[126] M L L Martinez E Rizzi M M Castro et al ldquoLercanidipinedecreases vascular matrix metalloproteinase-2 activity andprotects against vascular dysfunction in diabetic ratsrdquo EuropeanJournal of Pharmacology vol 599 no 1ndash3 pp 110ndash116 2008
[127] P Lesnik C Dachet L Petit et al ldquoImpact of a combinationof a calcium antagonist and a 120573-blocker on cell- and copper-mediated oxidation of LDL and on the accumulation and effluxof cholesterol in human macrophages and murine J774 cellsrdquoArteriosclerosis Thrombosis and Vascular Biology vol 17 no 5pp 979ndash988 1997
[128] G Sobal E J Menzel and H Sinzinger ldquoCalcium antagonistsas inhibitors of in vitro low density lipoprotein oxidation andglycationrdquoBiochemical Pharmacology vol 61 no 3 pp 373ndash3792001
[129] E Lupo R Locher B Weisser and W Vetter ldquoIn vitro antiox-idant activity of calcium antagonists against LDL oxidationcompared with 120572-tocopherolrdquo Biochemical and BiophysicalResearch Communications vol 203 no 3 pp 1803ndash1808 1994
[130] J Zou Y Li H-Q Fan and J-G Wang ldquoEffects of dihydropy-ridine calcium channel blockers on oxidized low-density lipo-protein induced proliferation and oxidative stress of vascularsmooth muscle cellsrdquo BMC Research Notes vol 5 article 1682012
[131] C Napoli S Salomone T Godfraind et al ldquo14-Dihydro-pyridine calcium channel blockers inhibit plasma and LDL oxi-dation and formation of oxidation-specific epitopes in the arte-rial wall and prolong survival in stroke-prone spontaneouslyhypertensive ratsrdquo Stroke vol 30 no 9 pp 1907ndash1915 1999
[132] G Zernig I Graziadei T Moshammer C Zech N Reider andH Glossmann ldquoMitochondrial Ca2+ antagonist binding sitesare associated with an inner mitochondrial membrane anionchannelrdquo Molecular Pharmacology vol 38 no 3 pp 362ndash3691990
[133] F E Hunter Jr A Scott P E Hochstein et al ldquoStudies of themechanism of ascorbate-induced swelling and lysis of isolatedliver mitochondriardquo The Journal of Biological Chemistry vol239 pp 604ndash613 1964
[134] D R Janero B Burghardt and R Lopez ldquoProtection of cardiacmembrane phospholipid against oxidative injury by calciumantagonistsrdquoBiochemical Pharmacology vol 37 no 21 pp 4197ndash4203 1988
[135] A Karadag B Ozcelik and S S Saner ldquoReview of methods todetermine antioxidant capacitiesrdquo FoodAnalyticalMethods vol2 no 1 pp 41ndash60 2009
[136] Y I Gubskiı N V Litvinova and E V Shnurko-TabakovaldquoAntioxidant and antiradical activity of various classes of antiox-idantsrdquo Ukrainskiı Biokhimicheskiı Zhurnal vol 66 no 4 pp114ndash116 1994 (Russian)
[137] M Takei M Hiramatsu and A Mori ldquoInhibitory effects ofcalcium antagonists onmitochondrial swelling induced by lipidperoxidation or arachidonic acid in the rat brain in vitrordquoNeurochemical Research vol 19 no 9 pp 1199ndash1206 1994
[138] M Takei M Hiramatsu R Edamatsu and A Mori ldquoFreeradical scavenging by calcium antagonistsrdquo Neurosciences vol20 no 2 pp 75ndash82 1994
[139] Ya P Stradin G Ya Dubur Yu A Beilis Ya R Uldrikis andA F Korotkova ldquoVoltammetry of 14-dihydropyridine deriva-tives I Potentials of electrochemical oxidation of 35-diacyl-and 35-di(alkoxycarbonyl)-14-dihydropyridines in acetoni-trilerdquo Chemistry of Heterocyclic Compounds no 1 pp 84ndash871972 (Russian)
[140] E V Ivanov T V Ponomarjova G N Merkusev et al ldquoEinneuer Haut-Radioprotektor Diethon (experimentelle Unter-suchung)rdquo Radiobiologia Radiotherapia vol 31 no 1 pp 69ndash78 1990
[141] E V Ivanov T V Ponomareva G N Merkushev et al ldquoRadia-tion modulating properties of derivates of 14-dihydropyridineand 12345678910-decahydroacridine-18 dionerdquo Radiat-sionnaia Biologiia Radioecologiia vol 44 no 5 pp 550ndash5592004 (Russian)
[142] R O Vitolinia D A Berzinia A K Velena I A Vutsina A AKimenis and G Y Duburs ldquoThe protective effects of the cal-cium antagonist foridon in acute myocardial ischaemiardquo Kardi-ologiya vol 27 no 3 pp 90ndash93 1987 (Russian)
[143] A H Velena G Ya Duburs R O Vitolina et al ldquoEffect ofryodipine on electromechanical parameters of heart and vesselscAMP phosphodiesterase activity and swelling-contractioncycle of mitochondriardquo Arzneimittelforschung vol 35 no 6 pp907ndash914 1985
[144] L I Utno Z E Lipsberga A A Silova M I Girgensone EA Bisenieks and G I Ia ldquoCardioprotective properties of a 14-dihydropyridine derivative glutapyrone in deep hypothermiardquoBiulletenrsquo Eksperimentalrsquonoı Biologii i Meditsiny vol 108 no 11pp 558ndash561 1989 (Russian)
[145] M A S FernandesM S Santos J A F Vicente et al ldquoEffects of14-dihydropyridine derivatives (cerebrocrast gammapyroneglutapyrone and diethone) onmitochondrial bioenergetics andoxidative stress a comparative studyrdquoMitochondrion vol 3 no1 pp 47ndash59 2003
[146] M A S Fernandes M S Santos A J M Moreno et al ldquoEffectsof 5-acetyl(carbamoyl)-6-methylsulfanyl-14-dihydropyridine-5-carbonitriles on rat liver mitochondrial functionrdquo Toxicologyin Vitro vol 23 no 7 pp 1333ndash1341 2009
[147] L Klimaviciusa A Kalda A Kaasik et al ldquoNeuroprotectiveactivity of 14-dihydropyridine derivatives structure determi-nantsrdquo Proceedings of the Latvian Academy of Sciences BNatural Exact and Applied Sciences vol 61 no 1-2 pp 33ndash372007
32 Oxidative Medicine and Cellular Longevity
[148] L Klimaviciusa M A S Fernandes N Lencberga et alldquoTargeting the mitochondria by novel adamantane-containing14-dihydropyridine compoundsrdquo in Bioenergetics K B ClarkEd pp 257ndash272 InTech 2012
[149] V Klusa L Klimaviciusa G Duburs J Poikans and AZharkovsky ldquoAnti-neurotoxic effects of tauropyrone a taurineanaloguerdquo Advances in Experimental Medicine and Biology vol583 pp 499ndash508 2006
[150] N Sampson P Berger and Ch Zenzmaier ldquoRedox signalingas a therapeutic target to inhibit myofibroblast activation indegenerative fibrotic diseaserdquo BioMed Research Internationalvol 2014 Article ID 131737 14 pages 2014
[151] T L Leto and M Geiszt ldquoRole of Nox family NADPH oxidasesin host defenserdquoAntioxidantsampRedox Signaling vol 8 no 9-10pp 1549ndash1561 2006
[152] K K Griendling D Sorescu and M Ushio-Fukai ldquoNAD(P)Hoxidase role in cardiovascular biology and diseaserdquo CirculationResearch vol 86 no 5 pp 494ndash501 2000
[153] H Chen Y S Song and P H Chan ldquoInhibition of NADPHoxi-dase is neuroprotective after ischemia-reperfusionrdquo Journal ofCerebral Blood Flow and Metabolism vol 29 no 7 pp 1262ndash1272 2009
[154] P Hochstein and L Ernster ldquoADP-activated lipid peroxidationcoupled to the TPNH oxidase system of microsomesrdquo Biochem-ical and Biophysical Research Communications vol 12 no 5 pp388ndash394 1963
[155] I I Gubskiı AGGoriushkoNV Litvinova et al ldquoAntioxidantproperties and membranotropic effect of certain derivatives of14-dihydropyridinerdquo Ukrainskiı Biokhimicheskiı Zhurnal vol71 no 4 pp 35ndash39 1999 (Russian)
[156] F Engineer and R Sridhar ldquoInhibition of rat heart andliver microsomal lipid peroxidation by nifedipinerdquo BiochemicalPharmacology vol 38 no 8 pp 1279ndash1285 1989
[157] T Goncalves A P Carvalho and C R Oliveira ldquoAntioxidanteffect of calcium antagonists on microsomai membranes iso-lated from different brain areasrdquo European Journal of Pharma-cology vol 204 no 3 pp 315ndash322 1991
[158] M E Letelier P Izquierdo L Godoy A M Lepe and MFaundez ldquoLiver microsomal biotransformation of nitro-aryldrugs mechanism for potential oxidative stress inductionrdquoJournal of Applied Toxicology vol 24 no 6 pp 519ndash525 2004
[159] M E Letelier P Entrala C Lopez-Alarcon et al ldquoNitroaryl-14-dihydropyridines as antioxidants against rat liver microsomesoxidation induced by ironascorbate Nitrofurantoin and naph-thalenerdquo Toxicology in Vitro vol 21 no 8 pp 1610ndash1618 2007
[160] F P Guengerich W R Brian M Iwasaki M-A Sari CBaarnhielm and P Berntsson ldquoOxidation of dihydropyridinecalcium channel blockers and analogues by human liver cyto-chrome P-450 IIIA4rdquo Journal of Medicinal Chemistry vol 34no 6 pp 1838ndash1844 1991
[161] S H Park S-W RhaW-Y Shin et al ldquoAS-160 Calcium channelblockers of dihydropyridine class reduce the antiplatelet effectof Clopidogrel what is clinical impactrdquo The American Journalof Cardiology vol 107 no 8 supplement p 47A 2011
[162] C Asma and D M Reda ldquoEvaluation of dihydropyridinecalcium antagonist effects on the stress bioindicator orga-nism Saccharomyces cerevisiaerdquo Annals of Biological Researchvol 4 no 10 pp 40ndash46 2013 httpscholarsresearchlibrarycomABR-vol4-iss10ABR-2013-4-10-40-46pdf
[163] G Gaviraghi A M Pastorino E Ratti and D G TristldquoCalcium channel blockers with antioxidant activityrdquo in Free
Radicals Lipoprotein Oxidation andAtherosclerosis G BellomoG Finardi E Maggi and E Rice-Evans Eds pp 431ndash456Richelieu Press London UK 1995
[164] G Gaviraghi AM Pastorino E Ratti and D G Trist ldquoAntiox-idant dihydropyridines a new and comprehensive therapy forfree radical-induced cardiovascular diseasesrdquo in Free Radicalsin Biology and Environment F Minisci Ed vol 27 of NATOASI Series pp 193ndash221 Springer Dordrecht The Netherlands1997
[165] P D Henry ldquoAntiperoxidative actions of calcium antagonistsand atherogenesisrdquo Journal of Cardiovascular Pharmacologyvol 18 supplement 1 pp S6ndashS10 1991
[166] F Kouoh B Gressier T Dine et al ldquoAntioxidant effects andanti-elastase activity of the calcium antagonist nicardipine onactivated human and rabbit neutrophilsmdasha potential antiath-erosclerotic property of calcium antagonistsrdquo CardiovascularDrugs andTherapy vol 16 no 6 pp 515ndash520 2002
[167] S Parthasarathy D Litvinov K Selvarajan and M GarelnabildquoLipid peroxidation and decompositionmdashconflicting roles inplaque vulnerability and stabilityrdquo Biochimica et BiophysicaActa vol 1781 no 5 pp 221ndash231 2008
[168] D-Q Liu Z-Q Pang D-H Zhao and B-H Sheng ldquoEffects offuryl-dihydropyridines I on lipid peroxides of ischemic myo-cardium and ATPases activity of erythrocyte membranes inratsrdquo Acta Pharmacologica Sinica vol 12 no 3 pp 253ndash2561991
[169] V Lukic-Panin T Kamiya H Zhang et al ldquoPrevention of neu-ronal damage by calcium channel blockers with antioxidativeeffects after transient focal ischemia in ratsrdquo Brain Research vol1176 no 1 pp 143ndash150 2007
[170] Y Allanore D Borderie H Lemarechal O G Ekindjian andA Kahan ldquoAcute and sustained effects of dihydropyridine-typecalcium channel antagonists on oxidative stress in systemicsclerosisrdquo American Journal of Medicine vol 116 no 9 pp 595ndash600 2004
[171] I Casetta V Govoni and E Granieri ldquoOxidative stress antioxi-dants and neurodegenerative diseasesrdquo Current PharmaceuticalDesign vol 11 no 16 pp 2033ndash2052 2005
[172] M J T J Arts Assessing antioxidant activity [PhD the-sis] Maastricht University Maastricht The Netherlands 2007httparnounimaasnlshowcgifid=8676
[173] G Dıaz-Araya L Godoy L Naranjo A Squella M E Letelierand L J Nunez-Vergara ldquoAntioxidant effects of 14-dihydro-pyridine and nitroso aryl derivatives on the Fe+3ascorbate-stimulated lipid peroxidation in rat brain slicesrdquo General Phar-macology The Vascular System vol 31 no 3 pp 385ndash391 1998
[174] Y Fukuhara K Tsuchiya Y Horinouchi et al ldquoProtectiveeffect of photodegradation product of nifedipine against tumornecrosis factor 120572-induced oxidative stress in human glomerularendothelial cellsrdquo Journal of Medical Investigation vol 58 no1-2 pp 118ndash126 2011
[175] W Stengel M Jainz and K Andreas ldquoDifferent potencies ofdihydropyridine derivatives in blocking T-type but not L-typeCa2+ channels in neuroblastoma-glioma hybrid cellsrdquo EuropeanJournal of Pharmacology vol 342 no 2-3 pp 339ndash345 1998
[176] O M Panasenko D J Tirzite G D Tirzitis and G J DubursldquoEffect of some 14-dihydropyridine derivatives on structuralorganization of erythrocyte membranesrdquo Biologicheskie Mem-brany (Biochemistry (Moscow) Series A Membrane and CellBiology) vol 1 pp 919ndash925 1984 (Russian)
[177] L G Herbette Y M H Vant Erve and D G Rhodes ldquoInter-action of 14 dihydropyridine calcium channel antagonists with
Oxidative Medicine and Cellular Longevity 33
biological membranes lipid bilayer partitioning could occurbefore drug binding to receptorsrdquo Journal of Molecular andCellular Cardiology vol 21 no 2 pp 187ndash201 1989
[178] L G Herbette P E Mason G Gaviraghi T N Tulenko andR P Mason ldquoThe molecular basis for lacidipinersquos unique phar-macokinetics optimal hydrophobicity results in membraneinteractions that may facilitate the treatment of atherosclerosisrdquoJournal of Cardiovascular Pharmacology vol 23 supplement 5pp S16ndashS25 1994
[179] G V Belevitch G Y Dubur G E Dobretsov N K Kurek andM M Spirin ldquoCalcium antagonists riodipine nifedipine andverapamil binding to model and biological membranes fluore-scence analysisrdquo Biologicheskie Membrany (Biochemistry(Moscow) Series A Membrane and Cell Biology) vol 5 pp768ndash776 1988 (Russian)
[180] R P Mason G E Gonye D W Chester and L G HerbetteldquoPartitioning and location of Bay K 8644 14-dihydropyridinecalcium channel agonist in model and biological membranesrdquoBiophysical Journal vol 55 no 4 pp 769ndash778 1989
[181] M Cindric A Cipak J Serly et al ldquoReversal of multidrugresistance inmurine lymphoma cells by amphiphilic dihydropy-ridine antioxidant derivativerdquo Anticancer Research vol 30 no10 pp 4063ndash4070 2010
[182] F Shekari H Sadeghpour K Javidnia et al ldquoCytotoxic andmultidrug resistance reversal activities of novel 14-dihydro-pyridines against human cancer cellsrdquo European Journal ofPharmacology vol 746 no 1 pp 233ndash244 2015
[183] X-F Zhou Q Shao R A Coburn and M E Morris ldquoQuanti-tative structure-activity relationship and quantitative structure-pharmacokinetics relationship of 14-dihydropyridines andpyridines as multidrug resistance modulatorsrdquo PharmaceuticalResearch vol 22 no 12 pp 1989ndash1996 2005
[184] R Berkels T Breitenbach H Bartels et al ldquoDifferent antioxida-tive potencies of dihydropyridine calcium channel modulatorsin various modelsrdquo Vascular Pharmacology vol 42 no 4 pp145ndash152 2005
[185] S Borovic G Tirzitis D Tirzite et al ldquoBioactive 14-dihydro-isonicotinic acid derivatives prevent oxidative damage of livercellsrdquo European Journal of Pharmacology vol 537 no 1ndash3 pp12ndash19 2006
[186] D Ya Rubene G D Tirzitis and G Ya Duburs ldquoInteractionof some 14-dihydropyridine derivatives with Fentonrsquos reagentrdquoLatvijas PSRZinatnuAkademijas Vestis Kimijas Serija Proceed-ings of the Latvian SSR Academy of Sciences Chemistry Seriespp 212ndash216 1982 (Russian)
[187] K Ondrias V Misık D Gergel and A Stasko ldquoLipid per-oxidation of phosphatidylcholine liposomes depressed by thecalcium channel blockers nifedipine and verapamil and bythe antiarrhythmic-antihypoxic drug stobadinerdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1003 no 3pp 238ndash245 1989
[188] I T Mak and W B Weglicki ldquoComparative antioxidant acti-vities of propranolol nifedipine verapamil and diltiazemagainst sarcolemmal membrane lipid peroxidationrdquoCirculationResearch vol 66 no 5 pp 1449ndash1452 1990
[189] I T Mak P Boehme and W B Weglicki ldquoProtective effects ofcalcium channel blockers against free radical-impaired endo-thelial cell proliferationrdquo Biochemical Pharmacology vol 50 no9 pp 1531ndash1534 1995
[190] S Ray S Mondal and N Dana ldquoEvaluation of protective roleof nifedipine on lipid peroxidation using reduced glutathione as
model markerrdquo Oxidants and Antioxidants in Medical Sciencevol 1 no 2 pp 97ndash100 2012
[191] M Yamato T Shiba T Ide Y Honda K-I Yamada andH Tsutsui ldquoNifedipine treatment reduces brain damage aftertransient focal ischemia possibly through its antioxidativeeffectsrdquoHypertension Research vol 34 no 7 pp 840ndash845 2011
[192] V Chander and K Chopra ldquoNifedipine attenuates changes innitric oxide levels renal oxidative stress and nephrotoxicityinduced by cyclosporinerdquo Renal Failure vol 27 no 4 pp 441ndash450 2005
[193] K M Gaafa M M Badawy and A A Hamza ldquoThe protectiveeffects of ascorbic acid cimetidine and nifedipine on diethyl-dithiocarbamate-induced hepatic toxicity in albino ratsrdquo Drugand Chemical Toxicology vol 34 no 4 pp 405ndash419 2011
[194] H Sugawara K Tobise and S Onodera ldquoAbsence of antiox-idant effects of nifedipine and diltiazem on myocardial mem-brane lipid peroxidation in contrast with those of nisoldipineand propranololrdquo Biochemical Pharmacology vol 47 no 5 pp887ndash892 1994
[195] I E Kirule D Y Rubene E A Bisenieks G D Tirzit and GY Dubur ldquo4-Nitrophenyl-14-dihydropyridinesmdasha new groupof inhibitors of peroxide oxidationrdquo Chemistry of HeterocyclicCompounds vol 18 no 3 p 316 1982
[196] G D Tirzit I E Kirule L K Baumane R A Gavar Y PStradynrsquo andG YDubur ldquoMechanism of the antioxidant actionof 26-dimethyl-35-dimethoxy-carbonyl-4-(2-nitrophenyl)14-dihydropyridinerdquoChemistry ofHeterocyclic Compounds vol 20no 8 pp 915ndash918 1984
[197] C Yanez C Lopez-Alarcon C Camargo V Valenzuela J ASquella and L J Nunez-Vergara ldquoStructural effects on thereactivity 14-dihydropyridines with alkylperoxyl radicals andABTS radical cationrdquo Bioorganic and Medicinal Chemistry vol12 no 9 pp 2459ndash2468 2004
[198] VMisik A J Stasko D Gergel and K Ondrias ldquoSpin-trappingand antioxidant properties of illuminated and nonilluminatednifedipine and nimodipine in heart homogenate and modelsystemrdquo Molecular Pharmacology vol 40 no 3 pp 435ndash4391991
[199] K Ondrias V Misık A Stasko D Gergelrsquo and M HromadovaldquoComparison of antioxidant properties of nifedipine and illu-minated nifedipine with nitroso spin traps in low densitylipoproteins and phosphatidylcholine liposomesrdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1211 no 1pp 114ndash119 1994
[200] A Stasko V Brezova S Biskupic K Ondrias and V MisıkldquoReactive radical intermediates formed from illuminated nife-dipinerdquoFree Radical Biology andMedicine vol 17 no 6 pp 545ndash556 1994
[201] K Ishizawa Y Izawa-Ishizawa N Yamano et al ldquoNitrosoni-fedipine ameliorates the progression of type 2 diabetic nephro-pathy by exerting antioxidative effectsrdquo PLoS ONE vol 9 no 1Article ID e86335 2014
[202] H Fujii and L J Berliner ldquoIn vivo EPR evidence for free radicaladducts of nifedipinerdquoMagnetic Resonance in Medicine vol 42no 4 pp 691ndash694 1999
[203] S Bollo S Finger J C Sturm L J Nunez-Vergara and JA Squella ldquoCyclic voltammetry and scanning electrochemicalmicroscopy studies of the heterogeneous electron transferreaction of some nitrosoaromatic compoundsrdquo ElectrochimicaActa vol 52 no 15 pp 4892ndash4898 2007
34 Oxidative Medicine and Cellular Longevity
[204] F Ursini ldquoTissue protection by lacidipine insight from redoxbehaviorrdquo Journal of Cardiovascular Pharmacology vol 30supplement 2 pp S28ndashS30 1997
[205] P G Cristofori F A Crivellente I Faustinelli et al ldquoInvolve-ment of the nitric oxide system in the anti-atheroscleroticpotential of lacidipine in the apoE-deficient mouse a mor-phological functional and electrochemical studyrdquo ToxicologicPathology vol 32 no 4 pp 493ndash499 2004
[206] X-P Zhang E L Kit S Mital S Chahwala and T HHintze ldquoParadoxical release of nitric oxide by an L-type calciumchannel antagonist the R+ enantiomer of amlodipinerdquo Journalof Cardiovascular Pharmacology vol 39 no 2 pp 208ndash2142002
[207] F Franzoni G Santoro F Regoli et al ldquoAn in vitro study of theperoxyl and hydroxyl radical scavenging capacity of the calciumantagonist amlodipinerdquo Biomedicine and Pharmacotherapy vol58 no 8 pp 423ndash426 2004
[208] S V Gatsura ldquoOxygen-dependent mechanisms underlying theantiischemic effect of verapamil and amlodipinerdquo Bulletin ofExperimental Biology and Medicine vol 137 no 1 pp 40ndash422004
[209] Y Hirooka Y Kimura M Nozoe Y Sagara K Ito and KSunagawa ldquoAmlodipine-induced reduction of oxidative stressin the brain is associated with sympatho-inhibitory effects instroke-prone spontaneously hypertensive ratsrdquo HypertensionResearch vol 29 no 1 pp 49ndash56 2006
[210] B Tomlinson and I F F Benzie ldquoAntioxidant effect of lercani-dipine (note)rdquo Hypertension vol 42 no 4 pp e10ndashe11 2003
[211] A A Faraqui ldquoNeurochemical aspects of 4-hydroxynonenalrdquoin Lipid Mediators and Their Metabolism in the Brain A AFaraqui Ed chapter 6 pp 159ndash191 Springer New York NYUSA 2011
[212] V S NascimentoM S DrsquoAlva A AOliveira et al ldquoAntioxidanteffect of nimodipine in young rats after pilocarpine-inducedseizuresrdquo Pharmacology Biochemistry and Behavior vol 82 no1 pp 11ndash16 2005
[213] O Ismailoglu P Atilla S Palaoglu et al ldquoThe therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjuryrdquo Turkish Neurosurgery vol 22 no 6 pp 740ndash746 2012
[214] M Matsubara and K Hasegawa ldquoBenidipine a dihydropy-ridine-calcium channel blocker prevents lysophosphatidyl-choline-induced injury and reactive oxygen species productionin human aortic endothelial cellsrdquo Atherosclerosis vol 178 no1 pp 57ndash66 2005
[215] M Matsubara K Yao and K Hasegawa ldquoBenidipine adihydropyridine-calcium channel blocker inhibits lysophos-phatidylcholine-induced endothelial injury via stimulation ofnitric oxide releaserdquo Pharmacological Research vol 53 no 1 pp35ndash43 2006
[216] MMatsubara and K Hasegawa ldquoEffects of benidipine a dihyd-ropyridine-Ca2+ channel blocker on expression of cytokine-induced adhesion molecules and chemoattractants in humanaortic endothelial cellsrdquo European Journal of Pharmacology vol498 no 1ndash3 pp 303ndash314 2004
[217] M Matsubara O Akizuki J-I Ikeda K Saeki K Yao and KSasaki ldquoBenidipine an anti-hypertensive drug inhibits reactiveoxygen species production in polymorphonuclear leukocytesand oxidative stress in salt-loaded stroke-prone spontaneouslyhypertensive ratsrdquo European Journal of Pharmacology vol 580no 1-2 pp 201ndash213 2008
[218] A C Rosenkranz H Lob T Breitenbach R Berkels and RRoesen ldquoEndothelial antioxidant actions of dihydropyridines
and angiotensin converting enzyme inhibitorsrdquo European Jour-nal of Pharmacology vol 529 no 1ndash3 pp 55ndash62 2006
[219] V Kain S Kumar and S L Sitasawad ldquoAzelnidipine preventscardiac dysfunction in streptozotocin-diabetic rats by reducingintracellular calcium accumulation oxidative stress and apop-tosisrdquo Cardiovascular Diabetology vol 10 article 97 2011
[220] K Nakamura S Yamagishi and H Inoue ldquoUnique atheropro-tective property of azelnidipine a dihydropyridine-based cal-cium antagonistrdquoMedical Hypotheses vol 65 no 1 pp 155ndash1572005
[221] TMatsui S Yamagishi K Nakamura S Kikuchi andH InoueldquoAzelnidipine a dihydropyridine-based calcium antagonistinhibits angiotensin II-induced oxidative stress generation anddownregulation of pigment epithelium-derived factor mRNAlevels in microvascular endothelial cellsrdquo Drugs under Experi-mental and Clinical Research vol 31 no 5-6 pp 215ndash219 2005
[222] C Ohmura H Watada T Shimizu et al ldquoCalcium channelblocker azelnidipine reduces lipid hydroperoxides in patientswith type 2 diabetes independent of blood pressurerdquo EndocrineJournal vol 54 no 5 pp 805ndash811 2007
[223] H Daikuhara F Kikuchi and T Ishida ldquoThe combination ofOLmesartan and a CAlcium channel blocker (azelnidipine) orcandesartan and a calcium channel blocker (amlodipine) intype 2 diabetic hypertensive patients theOLCA studyrdquoDiabetesand Vascular Disease Research vol 9 no 4 pp 280ndash286 2012
[224] MAbe NMaruyama KOkada SMatsumoto KMatsumotoand M Soma ldquoAdditive antioxidative effects of azelnidipine onangiotensin receptor blocker olmesartan treatment for type 2diabetic patients with albuminuriardquoHypertension Research vol34 no 8 pp 935ndash941 2011
[225] K Mizushige ldquoAntioxidative activities of thiazolidinedionesand dihydropyridine-type calcium antagonistsrdquo IRYOmdashJapa-nese Journal of National Medical Services vol 59 no 11 pp 581ndash592 2005
[226] S Manabe T Okura T Fukuoka and J Higaki ldquoAntioxidativeeffects of azelnidipine on mesangial cell proliferation inducedby highly concentrated insulinrdquo European Journal of Pharma-cology vol 567 no 3 pp 252ndash257 2007
[227] Y Koyama Y Takeishi H Takahashi et al ldquoAzelnidipine inhi-bits H
2O2-induced cell death in neonatal rat cardiomyocytesrdquo
CardiovascularDrugs andTherapy vol 21 no 1 pp 69ndash72 2007[228] K Shinomiya K Mizushige M Fukunaga et al ldquoAntioxidant
effect of a new calcium antagonist azelnipidine in culturedhuman arterial endothelial cellsrdquo Journal of International Med-ical Research vol 32 no 2 pp 170ndash175 2004
[229] T Ohyama K Sato K Kishimoto et al ldquoAzelnidipine is acalcium blocker that attenuates liver fibrosis and may increaseantioxidant defencerdquo British Journal of Pharmacology vol 165no 4 pp 1173ndash1187 2012
[230] L A Calo F Zaghetto E Pagnin P A Davis A Sempliciniand A C Pessina ldquoEffect of manidipine on gene expressionand protein level of oxidative stress-related proteins p22phoxand HO-1 Relevance for antihypertensive and anti-remodelingeffectsrdquo Journal of Cardiovascular Pharmacology vol 43 no 4pp 531ndash538 2004
[231] R Ghyasi G Sepehri M Mohammadi R Badalzadeh and AGhyasi ldquoEffect of mebudipine on oxidative stress and lipid per-oxidation in myocardial ischemic-reperfusion injury in maleratrdquo Journal of Research in Medical Sciences vol 17 no 12 pp1150ndash1155 2012
Oxidative Medicine and Cellular Longevity 35
[232] DCAndersson J Fauconnier T Yamada et al ldquoMitochondrialproduction of reactive oxygen species contributes to the 120573-adrenergic stimulation of mouse cardiomycytesrdquoThe Journal ofPhysiology vol 589 no 7 pp 1791ndash1801 2011
[233] A F Ceylan-Isik N Ari M Stefek et al ldquoEffects of a long-term treatment with an antioxidant pyridoindole on vascularresponsiveness in diabetes-induced aging ratsrdquo Current AgingScience vol 4 no 2 pp 150ndash157 2011
[234] S Saponara G Sgaragli and F Fusi ldquoQuercetin antagonismof Bay K 8644 effects on rat tail artery L-type Ca2+ channelsrdquoEuropean Journal of Pharmacology vol 598 no 1ndash3 pp 75ndash802008
[235] D A Sica ldquoInteraction of grapefruit juice and calcium channelblockersrdquo American Journal of Hypertension vol 19 no 7 pp768ndash773 2006
[236] P Mulder G Litwinienko S Lin P D MacLean L R CBarclay and K U Ingold ldquoThe L-type calcium channel block-ers Hantzsch 14-dihydropyridines are not peroxyl radical-trapping chain-breaking antioxidantsrdquo Chemical Research inToxicology vol 19 no 1 pp 79ndash85 2006
[237] L J Nunez-Vergara R Salazar C Camargo et al ldquoOxidation ofC4-hydroxyphenyl 14-dihydropyridines in dimethylsulfoxideand its reactivity towards alkylperoxyl radicals in aqueousmediumrdquo Bioorganic and Medicinal Chemistry vol 15 no 12pp 4318ndash4326 2007
[238] M E Ortiz L J Nunez-Vergara and J A Squella ldquoRelativereactivity of dihydropyridine derivatives to electrogeneratedsuperoxide ion in DMSO solutions a voltammetric approachrdquoPharmaceutical Research vol 20 no 2 pp 292ndash296 2003
[239] M E Ortiz L J Nunez-Vergara C Camargo and J A SquellaldquoOxidation of Hantzsch 14-dihydropyridines of pharmacolog-ical significance by electrogenerated superoxiderdquo Pharmaceuti-cal Research vol 21 no 3 pp 428ndash435 2004
[240] R S Raghuvanshi and K N Singh ldquoSuperoxide induced oxida-tive aromatization of Hantzsch 14-dihydropyridinesrdquo IndianJournal of Chemistry Section B Organic and Medicinal Chem-istry vol 47 no 11 pp 1735ndash1738 2008
[241] I Kruk A Kladna K Lichszteld et al ldquoAntioxidant activityof 4-flavonil-14-dihydropyridine derivativesrdquo Biopolymers vol62 no 3 pp 163ndash167 2001
[242] G D Tirzit I M Byteva K I Salokhiddinov G P Gurinovichand G Y Dubur ldquo14-Dihydropyridine derivatives as deactiva-tors of singlet oxygenrdquo Chemistry of Heterocyclic Compoundsvol 17 no 7 pp 682ndash684 1981
[243] G D Tirzit E Y Kazush and G Y Dubur ldquoInfluence of14-dihydropyridine derivatives on the generation of hydroxylradicalsrdquo Chemistry of Heterocyclic Compounds vol 28 no 4pp 435ndash437 1992
[244] N A Pizarro-Urzua and L J Nunez-Vergara ldquoNifedipine andnitrendipine reactivity toward singlet oxygenrdquo Journal of Photo-chemistry and Photobiology A Chemistry vol 175 no 2-3 pp129ndash137 2005
[245] L-F Wang H-Y Zhang L Konga Z-W Chena and J-G ShildquoDFT calculations indicate that 14-dihydropyridine is a promis-ing lead antioxidantrdquo Helvetica Chimica Acta vol 87 no 6 pp1515ndash1521 2004
[246] P Mulder H-G Korth and K U Ingold ldquoWhy quantum-thermochemical calculations must be used with caution toindicate lsquoa promising lead antioxidantrsquordquoHelvetica Chimica Actavol 88 no 2 pp 370ndash374 2005
[247] K Yao Y Ina K Nagashima K Ohmori and T Ohno ldquoAntiox-idant effects of calcium antagonists in rat brain homogenatesrdquo
Biological and Pharmaceutical Bulletin vol 23 no 6 pp 766ndash769 2000
[248] T Matsui S-I Yamagishi K Nakamura and H Inoue ldquoBayw 9798 a dihydropyridine structurally related to nifedipinewith no calcium channel-blocking properties inhibits tumournecrosis factor-120572-induced vascular cell adhesion molecule-1expression in endothelial cells by suppressing reactive oxygenspecies generationrdquo Journal of International Medical Researchvol 35 no 6 pp 886ndash891 2007
[249] K AMitrega B VargheseM Porc and T F Krzeminski ldquoAnti-arrhythmic and hemodynamic effects of oxy nifedipine oxynimodipine oxy nitrendipine and oxy nisoldipinerdquo Pharmaco-logical Research vol 66 no 4 pp 300ndash308 2012
[250] V Herbert ldquoSymposium prooxidant effects of antioxidantvitamins Introductionrdquo The Journal of Nutrition vol 126 no4 supplement pp 1197Sndash1200S 1996 httpjnnutritionorgcontent1264 Suppl1197Sfullpdf
[251] B Halliwell ldquoAre polyphenols antioxidants or pro-oxidantsWhat do we learn from cell culture and in vivo studiesrdquoArchives of Biochemistry and Biophysics vol 476 no 2 pp 107ndash112 2008
[252] C Winterbourn Pro-Oxidants or Antioxidants ChristchurchSchool of Medicine Depatment of Pathology Free RadicalSchool SFRBMUniversity of Otago San Francisco Calif USA2009 httpwwwsfrbmorgfrsWinterbournpdf
[253] A Morakinyo B Iranloye and O Adegoke ldquoCalcium antag-onists modulate oxidative stress and acrosomal reaction in ratspermatozoardquo Archives of Medical Science vol 7 no 4 pp 613ndash618 2011
[254] The Alpha-Tocopherol Beta Carotene Cancer Prevention StudyGroup ldquoThe effect of vitamin E and beta carotene on theincidence of lung cancer and other cancers in male smokersrdquoTheNew England Journal of Medicine vol 330 no 15 pp 1029ndash1035 1994
[255] B Poljsak ldquoStrategies for reducing or preventing the generationof oxidative stressrdquo Oxidative Medicine and Cellular Longevityvol 2011 Article ID 194586 15 pages 2011
[256] B Poljsak and I Milisav ldquoThe neglected significance of lsquoanti-oxidative stressrsquordquoOxidativeMedicine and Cellular Longevity vol2012 Article ID 480895 12 pages 2012
[257] T Godfraind and S Salomone ldquoAmbiguities in dietary antiox-idant supplementation compared to calcium channel blockerstherapyrdquo Frontiers in Pharmacology vol 6 article 10 2015
[258] H Wagner H Norr and H Winterhoff ldquoDrugs with adap-togenic effects for strengthening the powers of resistancerdquoZeitschrift fur Phytotherapie vol 13 no 2 pp 42ndash54 1992
Oxidative Medicine and Cellular Longevity 5
NH
Lercanidipine
NH
Cl
Felodipine
Cl
NH
Lacidipine
NH
Nicardipine
NH
Isradipine
NO
N
NH
COO
Azelnidipine
N
NH
Bay O 5572
NH
COO
Benidipine
N
NH
Manidipine
N N
NH
NC
Nivaldipine
NH
COOC(CH3)3
COOCH(CH3)2
Mebudipine
N
S
O
Diltiazem
N
S
O
O
H
O
Semotiadil
NH
COO
Barnidipine
N
H3C
H3C H3C
H3C
H3C
H3C
H3C
H3CO
H3C
H3C
H3C
H3CCH3
CH3 CH3CH3
CH3
CH3
OCH3
OCOCH3
CH3
CH3
CH3
CH3CH3
NH2
CH3
NO2NO2
H3COOC
H3COOC H3COOC
H3COOC
H3COOC
H3COOC
H3COOC
H3COOC H3COOC
H3COOCCOOC(CH3)2CH2N(CH3)CH2CH2CHPh2
COOCH(CH3)2
N(CH3)COOCH2 CH2CH2 Ph
COOC2H5 COOC2H5C2H5OOC
COOC(CH3)3
NO2NO2
NO2NO2
NO2
NO2
NO2
CH2Ph
CH2Ph
CH 2Ph
CH 2Ph
COO(CH2)7CH3(H3C)2HCOOC
COOCH2CH2
O(CH2)3N(CH3)CH2CH2O
N(CH3CH )2 2CH2
Figure 2 Structures of the most known 14-dihydropyridine derivatives and some non-DHP Ca2+ antagonists
mentioned that nearby this classical multicomponent synthe-sis also a process to obtain structurally diversified 14-dihyd-ropyridines at sophisticated conditions was recently reviewedby Wan and Liu [59]
Many discoveries relevant for novel routes in DHPdesigning and synthesis were published and deposited in
various databases (see httpwwworganic-chemistryorgnamedreactionshantzsch-dihydropyridine-synthesisshtm[60]) For example httpwwwscifindercom [1] databaselists approximately 1000 citations on the simple DHP com-pound diludine Reaxys database [61] contains data relatedto variations in starting materials intermediates as building
6 Oxidative Medicine and Cellular Longevity
NH
SCH3
CN
Cl
O
NH
SCH3 SCH3 SCH3
CN
O
NH
CN
O
NH
CN
OCl OCHF2 OCHF2
OSI-3701OSI-9642OSI-3761OSI-1146
H3C
H3C H3C
H3C H3C H2N
H3C H3C
Figure 3 Molecular structures of OSI-1146 OSI-3701 OSI-3761 and OSI-9642 (according to [146])
blocks media and reactions routes Water and ionic liquidsas reaction media microwave and infrared irradiation newcatalysts solid phase synthesis and biotechnology based andgreen chemistry approaches were also proposed as attractiveoptions for syntheses of DHPs [62ndash66]
Furthermore several new dihydropyrimidin-(2H)-ones(DHPMs) close analogues of DHPs were prepared in theBiginelli reaction under ultrasound irradiation and in thepresence of NH
4Cl Some of these compounds when tested
in vitro at concentrations higher than 100 120583M [67] showedAOAs manifested as inhibition of LPO induced by complexFe + EDTA and reduction of ROS levels
Recently Sun et al [68] reported about the synthesis andantioxidant activity of a series of novel 3-chalcone-substituted14-dihydropyridine derivatives based on dimethyl or diethyl26-dimethyl-4-phenyl-14-DHP-35-dicarboxylate
32 14-Dihydropyridines as Hydrogen Donors Steric elec-trostatic and hydrophobic descriptors in DHP moleculecould serve as its potential pharmacophores [2] In caseof Hantzsch ester this implies partly hydrogenated N-heteroaromatic DHP nucleus itself or its fragments that isNH group or C-4 H- atom as hydrogen donors necessaryfor the AO activity andor carboxylic ester side groups (itsC=O group and O atom as hydrogen bond acceptors) inpositions 3- and 5- and alkyl side groups in positions 2-and 6- (as hydrophobic features) (Grover et al [33] andTikhonov and Zhorov [69]) The presence of labile hydrogenatoms (mainly in positions 14-) in DHPs molecule assignssignificant hydrogen donating ability to these compounds
DHPs (26-dimethyl-14-dihydropyridine-35-dicarboxy-lic acid esters) can be oxidized in chemical (Dubur andUldrikis [70]) electrochemical enzymatic (Duburs et al[71]) and biological (including metabolism and biotransfor-mation) systems As already stated dihydropyridines (espe-cially unsubstituted in position 4) may transfer the hydro-gen similar to the reduced diphosphopyridine nucleotidesNADH and NADPH (Scheme 1) (Mauzerall and Westheimer[28]) while HEH hydrogen transfer studies and search fornovel NADHmodel compounds are continuously developing(Xie et al [72])
Tamagaki et al [73] observedmetal-ion-facilitated oxida-tions ofDHPswithmolecular oxygen andhydrogenperoxideOn the other side Tirzite et al [74] studied some 14-DHP derivatives as reductants in relation to trivalent iron
Hantzsch esters have been extensively utilized as stoichio-metric biomimetic reducing agents Recent summarized lit-erature about DHPs as reducing agents including referenceson diludine may be found on specialized websites httpwwworganic-chemistryorgchemicalsreductions [75]
DHPs form free radicals in chemical electrochemicaland biological oxidation processes The kinetic parametersand pathways of decay of the cationic radicals formed asprimary products in the course of electrooxidation of theesters of 12- and 14-dihydropyridine have been extensivelystudied [76]
The regenerative system of nicotinamide cofactors mayinvolve oxidizing or reducing reagents regulating enzymesand photochemical reactions Thus in situ regenerationof the consumed cofactors was observed in the biosys-tems engineering which create superior biocatalysts by thereduction of NAD(P)+ which can lead to the 14-DHPproduct (which is the only active form) and to the 16-DHP compound [77] The NADPH models of HEHs can beregenerated in situ as biomimetic hydrogen sources bymeansof transition metalBroslashnsted acid catalyzed relay asymmetrichydrogenation [78] General regeneration strategies werereviewed by Chenault and Whitesides [79] Based on thesestrategies particularly related to methods of preparation andpractical use of esters of 26-dimethyl-14-dihydropyridine-35-dicarboxylic acid as antioxidants that might be probablyapplicable for radioprotection and adjuvant treatment againstmetastases several patents were prepared [80]
Sambongi et al [81] have found that the novel water-soluble Hantzsch 14-dihydropyridine compound (the potas-sium salt of 26-dimethyl-14-dihydropyridine-35-dicar-boxylic acid monomethyl ester) functions in biological pro-cesses through regeneration of NADH Various parametersrelated to nicotinamide coenzymes regeneration especiallyin a light of chiral compounds have been published recently[82] while Okamura et al [83] reported the use of theoxidative conversion of dihydropyridine to pyridinium ionand the metabolic trapping principle as an approach formeasuring in vivo cerebral redox states
33 Antioxidant Activity (AOA) and Antiradical Activity(ARA) of 14-Dihydropyridines Antioxidative activity of 14-DHPs was first evaluated and studied in the Latvian IOS(Tirzit and Duburs [39] Zilber et al [44] and Dubur et al[45])
Oxidative Medicine and Cellular Longevity 7
N
O O
N
O O
R R
N
O Ominuseminus minuseminusminuseminus
minusH+
minusH+minusHminus
minusH∙
R998400(H)R998400H R998400(H)
oplus
R=H
Scheme 1 Reactions of 14-dihydropyridines leading to the formation of pyridine derivatives
In the field of ARA pioneering work was made by Schel-lenberg and Westheimer [84] in 1965 In 1979 Schellenberg[85] revealed the free radical oxidation of a dihydropyridinefollowing Huyser et al [86] who reported hydroxyl radicalquenching by DHPs especially Hantzsch ester studying freeradical oxidation of DHPs in vitro in the Fenton system
AOA and ARA of various 14-DHPs were further studiedby several different methods in both in vitro and ex vivoinvivo systems [3 31 44ndash53] CA nisoldipine nimodipinenitrendipine nifedipine and nicardipine have AOA thatcorrelates with their lipophilicity (modified Buege and Austrsquosmethod of TBA determination applied in model of rat braincortex ischemiareperfusion) [87]
N-Aryl-DHPs designed as sirtuin activators were furtherreported as suitable agents for neuroprotection due to theirradical avoidance properties (Hardeland [88])
14-DHPs inhibit free radicals and consequentially thecascade of events related to lipid peroxidation They mayinfluence several stages (initiation andor propagation) of thelipid peroxidation cascade which consist of sim10 reactions[89] (detailed discussion in Section 331 (2)-(b) Scheme 2)
However considering the great number of AO com-pounds (including DHPs) and the diversity in their actionmechanisms [90] in vivo studies are not always convincingand conclusive Therefore concise in vitro models are neces-sary to screen each compound with antioxidative propertiesAntioxidants are designed to react readily with oxidizingspecies and are often extensively oxidized already duringincubations at atmospheric oxygen tension (oxidation ofsome water-soluble DHPs in water (buffer) solutions is veryfast especially in the presence of light) Even during arelatively short incubation period the concentration can dropdrastically and the real potency of the compound could beunderestimated [90]
331 Common AOA and ARA Features of Some DHPs
(1) In Vitro (in Solutions Emulsions and Liposomes) Basicmolecular principles related to antioxidative and antiradi-cal activity of various antioxidants including DHPs werepublished recently [91] These data show that DHPs reactwith various types of free radical species stable free radicals(DPPH ao) and alkyl radicals and with oxygen and nitrogenfree radicals Some derivatives of DHPs may quench a singletoxygen and may react with peroxynitrite anion [92ndash95]
Reactivity of DHPs toward alkyl radicals was studiedelectrochemically [96]
The activity against DPPH radical was found for the5-acetyl-2-alkylthio-4-aryl-6-methyl-14-dihydropyridine-3-carboxylic acid nitriles [97] structural analogues of the5-acetyl(carbamoyl)-6-methylsulfanyl-14-DHP-carbonitrile(studied as mitochondriotropic compounds see further inthe text Section 331 (2)-(b))The highest antiradical activityoccurred for a compound which contains two hydroxylgroups in the 4-phenyl substituent
DHPs were proved to decrease oxygen uptake (2-3-fold) in the heme (methemoglobin hematin hemin andcytochrome C) catalysis by oxidation of emulsions of estersof unsaturated fatty acids and liposomes of phospholipidphosphatidylcholine (Zilber et al [44] and Dubur et al [45])
Reactivity of nitrosoaryl and nitroaryl derivatives of 14-DHPs toward alkyl alkylperoxyl radicals and ABTS radicalcation was found in various LP modeling systems suitablefor determination of DHPs AOA and ARE features [98ndash104] Diludine and foridone and its analogues were shown toinhibit lipid peroxidation through inhibitory effect on lipoxy-genase in emulsions and in reversed micelles (Tsetlin et al[105] and Panek et al [106]) In addition to inhibition of ther-mally initiated oxidation of methyloleate in the solution [107](where AOA of 4-unsubstituted 35-dicarbonylderivativesof 26-dimethyl-14-DHPs is not linearly dependent onthe inhibitor concentration) DHPs derivatives containinghydroxy alkoxy or dimethylaminophenyl substituents inposition 4 were shown to prevent loss of 120573-carotene in thedisperse system of 120573-carotene and methyllinoleate (Plotnieceet al [108])
The AOA of DHPs has been detected using differentmethods in various systems where lipid free radical gen-eration (nonenzymatic Fe2+-dependent andor enzymaticNADPH-dependent) took the place [109ndash112] This activitywas further confirmed in vivo through prevention of damagecaused by renal ischemia and reperfusion as shown fordiludine [113]
Some redox properties of calcium antagonist dihydropy-ridines were revealed through electroanalytical studies [114]Competitive kinetic procedure was used for exploring theAO capacity of five (four 14-DHPs lacidipine felodipinenifedipine and amlodipine and one 12-DHP compoundGR44966) CA and one calcium ion agonist (Bay K 8644) Allbut one (amlodipine) antagonist displayed an unambiguousAO capacity (crocin test) The calcium agonist DHP revealedno reaction with peroxyl radicals Lacidipine was the mosteffective A calcium agonist Bay K 8644 is quite resistant tooxidation and does not bind H+ This could be important
8 Oxidative Medicine and Cellular Longevity
fact in the interaction with the target proteins (it should bementioned that there are no studies on LP with other Ca2+agonists)
The decreased oxidation potential correlates with AOcapacity and increased basic characterThese findings suggestthe relevance of the electron density on the DHP ring
For all the DHP compounds investigated the overalloxidation process proceeds through two consecutive one-electron releases a primary one-electron step accompaniedby a fast proton release and the formation of a neutral radical(PyH∙) undergoing a second much easier one-electron step[114]
The final product is the protonated form of the parentpyridine derivative This pattern is relevant for the antioxida-tive activity since the radical intermediate is far less prone tobe reduced than oxidized
In the case of CA DHPs the release of protons compli-cates the overall oxidation process by introducing a ldquopara-siticrdquo side reaction where a coupling between protons and thestarting species takes place
This DHP self-protonation subtracts part of the originalspecies from the electrode process because the parent cationicspecies are no longer electroactive
Conversely the calcium agonist DHP which is less proneto be oxidized turned out to be so weak base to be evenunable to undergo the self-protonation reaction
Thus the combined effect of oxidation potentials andproton binding capacity of DHPs is a key element for theredox transition relevant for their AO activity Yet opposingeffects (antagonistic versus agonistic) on protein targets ascalcium ion channels connected with protein thiol oxidationto disulfide should be also considered [114]
Kourimska et al [115] found AO effect of diludine (HEH)in edible oil Reactivity of 14-DHPs toward SIN-1-derivedperoxynitrite was shown by Lopez-Alarcon et al [116] Oleket al [117] discovered antioxidative activity of NADH and itsanalogue in vitro
Further see as referred in several subparts below Sections34 35 and 37
(2) Ex Vivo (on Lipid Peroxidation in LDL MitochondriaMicrosomes and Cells) Main chemical structures of DHPsexamined in numerous studies and reviewed in this paper arepresented in Figures 1 and 2
(a) Various DHPs Calcium Antagonists as Inhibitors of LDLPeroxidation Free radicals induce peroxidation of LDLThis process proceeds by a chain mechanism which revealsphosphatidylcholine hydroperoxides and cholesteryl esterhydroperoxides as themajor primary products [118] Calciumantagonist DHPs could act as antioxidants on LDL at leastin three ways (1) as inhibitors of isolated LDL peroxi-dation caused by various inducers (Cu2+ ions UV lightand xanthinexanthine oxidase system) (2) if preincubatedwith cells preventing against intracellular LDL oxidation (3)preventing against the harmful effect of oxidized LDL on cellsand decreasing cytotoxicity [119ndash131]
Combined application of ascorbic acid and CA DHPs(amlodipine and felodipine) has an additive (cytoprotective
and LDL antioxidant activity) effect [120] It includes acombination of peroxide-degrading and peroxyl radical scav-enging reactions thus demonstrating the importance of LPduring LDL oxidation and cytotoxicity induced by oxidizedLDL Cytoprotection is associated with inhibition of oxidant-induced increases in intracellular free calcium
Similar to the othermodel systems the recorded values ofthe tested DHPs related to AO activity on LDL LP and relatedevents [119ndash131] depend on the prooxidant model system andmethods used for activity measuring (see Tables 1ndash5)
Commercial Ca2+ antagonists (including 14-DHP deri-vatives) as well as some other 14-DHPs with less CA activitywere shown to decrease the rate of oxidation (detected asTBARS) of low-density lipoprotein (LDL) induced by Cu2+ions (CuSO
4) in two different cell lines U937 human mono-
cyte-like and J774A1 murine monocyte-macrophage cellline (Rojstaczer and Triggle [119]) The strongest effect wasrecorded for vitamin E followed by felodipine 2-Cl analogueof nifedipine nifedipine amlodipine nitrendipine vera-pamil and diltiazem
Rojstaczer and Triggle [119] found that CA from differentchemical groups had a concentration-dependent effect asantioxidants against LDL oxidation (see Table 1) Howeverthe order of potency (activity rank order ARO) of the drug(s)again depends on the oxidation system and the antioxidantassay Both CA and antioxidative effects relate to the 2- (or o-orto-) substituent of the 4-phenyl ring in the same potencyorder 119900 gt 119898 ≫ 119901 [119] On the other hand the require-ment for the 14-DHP ring is essential for both AOA andCa2+channel antagonism A charged substituent at the position C-2 of the 14-DHP ring influences the AO activity (analogousto [46ndash53]) However some other factors should not beneglected for example although amlodipine has a positivelycharged amine at this position this modificationmakes it lesslipophilic and indirectly less potent antioxidant
Similar results were obtained when testing antioxidanteffect of CA on LDL peroxidation in bovine aortic endothelialcells (BAECs) (Cominacini et al [123] see Tables 2 and 3) aswell as in HUVECs (Lupo et al [129]) (see Table 4)
Cominacini et al [123] observed antioxidant effect ofCCBs and 120572-tocopherol in BAECs The order of potency(see Tables 2 and 3) [123] was however different than inU937 human monocyte-like and J774A1 murine monocyte-macrophage cells (see Rojstaczer and Triggle [119] Table 1)The tested DHPs were lacidipine amlodipine lercanidipinenimodipine and nifedipine (in two different intracellularconcentrations 2 and 4 fmol) ROS production was signif-icantly lowered only by lacidipine (which is the compoundwith the highest lipophilicity) and lercanidipine the effectof lacidipine was much more evident than lercanidipineSurprisingly amlodipine nimodipine and nifedipine had noeffect on ROS formation suggesting that the positive effectson the earliest events of atherosclerosis are a peculiarity oflacidipine molecule through its antioxidant activity
The strong AO action of lacidipine may be related tothe lipophilic cinnamic acid side chain which favors a drugpartitioning in the membrane due to favorable physicochem-ical (hydrophobic) interactions of drug hydrophobic residues
Oxidative Medicine and Cellular Longevity 9
Table 1 Relative structure-function relationships of calcium antagonists (DHPs verapamil and diltiazem) and vitamin E Effect on oxidativemodification of isolated ex vivo human low-density lipoprotein using two various oxidation systems (copper (II) ions induced and monocyteinduced) Compiled according to data presented by Rojstaczer and Triggle [119]
Compound
Systems of LDL oxidation
Copper (II) ions induced system (comparison of three methods) Monocyte induced celloxidation system
Methods
Reduction of TBARS level of LDL(relative efficacy)
Degradation of oxidized[125I] LDL by J774
macrophages
Relative electrophoreticmobility of LDL on
agarose gel
TBARS content of LDL(in )
Relative efficacy (activity rank order (ARO) ARO = I for the most effective) effective inhibitor concentration [IC] in120583M
with polyunsaturated groups of membrane phospholipidsHowever DHPs can also reduce the oxLDL-induced ROSconcentration by affecting some intracellular ROS producerssuch as NADPH oxidases xanthine oxidase and cyclooxyge-nase enzymes The activity of these enzymes contributes tointracellular ROS elevation [125]
Preincubation of HUVECs with lacidipine inhibited anincrease of intracellular ROS caused by oxidized LDL [124]
Lupo et al [129] have studied the dose-dependent (1 510 and 50 120583M) AOA of various CA (verapamil diltiazemand DHPs nifedipine amlodipine isradipine or lacidipine)
Table 3Modulation of ROS formation in BAECs by CA (DHPs andverapamil) and vitamin E Compiled according to data presented byCominacini et al [123]
Compound
Method of flow cytometry (reduced2101584071015840-dichlorofluorescein diacetate(DCFH-DA) oxidation by ROS)
Activity rank order(ARO = I for the highest activity ARO = III for
the mindest activity)(Effective [IC] 1 5 10 50 120583M)
Lacidipine + + + (ARO = I)Lercanidipine + + (ARO = II)Amlodipine No effectNifedipine No effectNimodipine No effectVerapamil + (ARO = III)120572-Tocopherol + + + (ARO = I)
against normolipidemic human blood LDL oxidation com-pared with 120572-tocopherol by measuring the content of TBARSand the diene formation (see Table 4)
10 Oxidative Medicine and Cellular Longevity
Table 4 Normolipidemic human blood LDL (025mgmL) in vitro oxidation in the presence of 5 120583M CuSO4and CA of 3 types (DHPs
verapamil and diltiazem) and vitamin E Compiled according to Lupo et al [129]
Compound
MethodsTBARS method (fluorimetry at 515 nm533 nm 4 hours
preincubation of LDL with compounds and copper (II)ions 320 TBARS increase in control during 4 h
period)
Inhibition of conjugated diene formation (at 234 nm)expressed as prolongation of induction period (in
of control) 119905contr = 368min
Effective [IC] (in 120583M)1 120583M 10120583M 50 120583M
Activity rank order (ARO= I for the highest activity
ARO = VII for themindest activity)
Effective [IC] (in 120583M)1 120583M 5 120583M 10120583M 50 120583M
Activity rank order (ARO= I for the highest activity
ARO = VII for themindest activity)
Nifedipine 10120583M50 120583M ARO = III
5 120583M10120583M 15050 120583M 213
ARO = III
Amlodipine 50 120583M ARO = IV5 120583M
10120583M 12250120583M 138
ARO = IVndashVI
Isradipine 50 120583M ARO = VI 10120583M 15050 120583M 183 ARO = IVndashVI
Lacidipine1 120583M10120583M50 120583M
ARO = II5 120583M
10120583M 19250 120583M 283
ARO = II
Verapamil 50 120583M ARO = V 10120583M 15050 120583M 178 ARO = IVndashVI
Diltiazem No effect No effect (ARO = VII) No effect No effect (ARO = VII)
Vitamin E1 120583M
10120583M (IC50)
50 120583M (20 of control)ARO = I
5 120583M10 120583M 23050 120583M 370
ARO = I
Table 5 Antiproliferative effect (oxLDL-induced HUVSMCs proliferation) of CA DHPs and simultaneous oxLDL-induced ROS productionscavenging Comparison with N-acetyl-L-cysteine NAC (intracellular ROS scavenger) Compiled according to data presented by Zou et al2012 [130]
DHP compound
MethodsAntiproliferative effect against proproliferative effectinduced by oxLDL (50 120583gmL) (UV detection of
formazan production from tetrazolium salt)
oxLDL-induced ROS production (fluorescent DCF(2101584071015840-dichlorofluorescein) production)
Effective [IC] in120583M and I in
Amlodipine 3 120583M I = 18 3 120583M 10 120583M No effectI = 20
S(minus)-Amlodipine No effect No effect
Lacidipine 10 120583M30 120583M
I = 21I = 27 10120583M Isim23 of control
N-Acetyl-L-cysteineNAC
mdash 5000 120583M(5mM) I = 28
As presented (Table 4 according to [129]) for diltiazem(poor lipid solubility) noAOwas detected whereas the otherCA and 120572-tocopherol have demonstrated AOA at least atconcentrations of 10 and 50120583M 120572-tocopherol gt lacidipinegt nifedipine gt isradipine verapamil and amlodipine Addi-tionally120572-tocopherol and lacidipinewere able to significantlyattenuate in vitro LDL oxidation at 1 and 5120583M Theseresults have confirmed the highest activity for the stronglylipophilic DHP type CA compound lacidipine This might be
a possible antiatherogenic mechanism of CA since oxidativemodification enhances the atherogenic potential of LDL
The lipid peroxidation of LDL promoted either by UVradiation or by copper ions was inhibited (antioxidant effect)by nisoldipine in a dose-dependentmanner (IC
50values were
evaluated at around 10 120583M) nimodipine was less potent (IC50
around 50ndash100 120583M) and nicardipine almost inactive In addi-tion to this indirect protective effect CA DHPs nisoldipineand nimodipine exerted direct protective effect on lymphoid
Oxidative Medicine and Cellular Longevity 11
cells against toxicity of previously oxidized LDL The IC50
values were 6 plusmn 2 and 80 plusmn 20 120583M respectively [122] Theinhibition of the cytotoxic effect of LDL oxidized in thepresence of DHP type Ca2+ channel blockers correlated wellwith protection from oxidation by these compounds Com-plete protection cannot be obtained because the DHPs arecytotoxic themselves The potential relevance to the preven-tion of atherogenesis is envisaged
DHP typeCCBnifedipinewas themost effective inhibitorof oxidation promoted either by UV radiation or by copperions in experiments with cultured lymphoid cells LDL (2mgapoBmL) CCBs from other two CCB classes diltiazem andverapamil were only poorly active or completely ineffective[121] The protective effect of nifedipine occurs at two levelsbesides its direct antioxidant effect by inhibition of LDLoxidation it also exhibits a direct cytoprotective effect againstcytotoxicity of oxidized LDL by yet unknown mechanismsThe protective effect of CCBs was not due to an inhibitionof LDL uptake This effect seems to be independent of theinhibition of LDL oxidation per se since LDL was oxidizedin the absence of the drug before the incubation withcells Moreover this direct protective effect was observedat lower concentrations (IC
50of 1 plusmn 02 120583M) compared to
the antioxidant effect (IC50
of TBARS inhibition is around10 plusmn 2 120583M at UV promoted and 4 plusmn 05 120583M by Cu2+ ionsinitiated) The AO effect of nifedipine is also correlated withthe protection of endogenous tocopherols (IC
50= 50 120583M)
It was suggested that the AO effect of CCBs protected cellsindirectly from the cytotoxic effect of oxidized LDL [121]
A recent study has reported that beneficial vascular effectsof lercanidipine in diabetic rats depend on its antioxidantactivity related to attenuating the increase in oxidativestress and in vascular matrix metalloproteinase-2 (MMP-2) (Martinez et al [126]) Lesnik et al [127] studied theimpact of a combination of this calcium antagonist and a120573-blocker atenolol on cell- and copper-mediated oxidationof LDL and on the accumulation and efflux of cholesterolin human macrophages and murine J774 cells They realizedthat lercanidipine reduced the oxidative modification of LDLrather than diminished cholesterol accumulation in humanfoam cells
Comparing the antioxidative action of CA (DHPs amlo-dipine lacidipine nifedipine and isradipine as well as diltia-zem and semotiadil) in the copper-catalyzed oxidation oflow-density lipoprotein (LDL) with that of glycated (g)gly-coxidated (go) LDL demonstrated that the strongest AOeffects during long-term LDL glycation are seen for isradip-ine lacidipine nifedipine and semotiadil [128] Inhibitoryeffects were in the range 10minus5ndash10minus3MAuthors suggested thatdue to the increased generation of ROS by glucose-modifiedLDL the chain-breaking capacity of CA may be overriddenThe AOA of CA depends on their lipophilicity and theirability to incorporate into the LDL particle that is to reachthe site of peroxidation CA like other AOs significantlyretards advanced glycation end products (AGE) formationwhereas initial glycation reactions such as Amadori productformation are only weakly inhibited The observation thatboth oxidative changes and at least long-termglycation effectsare indeed drastically reduced by CA is corroborated by
fluorescence analysis AGE-ELISA quantitation of lipid per-oxidation and TBARS measurement of long-term ggo LDL
The effects of lipophilic DHP calcium channel blockerson oxidized LDL-induced proliferation and oxidative stressof vascular smooth muscle cells were also studied [130] (seeTable 5)
Lacidipine and amlodipine reduced carotid intima-media thickness by decreasing proliferative effect of oxLDLwhereas (S-)-amlodipine had no antiproliferative effect ROS-MAPKs (mitogen-activated protein kinases) pathway mightbe involved in the mechanism
Both 14-DHP CCBs lacidipine and nifedipine reduceplasma and LDL oxidation and formation of oxidation-specific epitopes Their application may also relate to pro-longed survival of rats independently of blood pressuremod-ifications (in the SPSHR model 1mgkg per day lacidipineand 80mgkg per day nifedipine) These results suggestedthat the protective effect of these two 14-DHP drugs invivo as shown in cerebral ischemia and stroke may in partresult from inhibition of LDL oxidative process althoughthese two drugs possess different lipophilic properties [131]Both lacidipine (03 and 10mgkg) andnifedipine (80mgkg)prolonged lag time of the conjugated diene formation inLDL isolated from arterial wall and 119905max These drugssignificantly reduced electrophoreticmobility of oxLDL fromSPSHR subjected to XXO oxidation system 14-DHP CCBsalso protected apolipoprotein B which is important for thebinding with macrophage LDL receptor lysine residues Thedoses used (gt10minus6molL for SPSHR and normotensive WKYrats) however are 2 to 3 orders of magnitude higher thanthose inhibiting vascular smooth muscle contraction in vitroand in vivo They also exceed values that are commonlyused in clinical practice The daily dose of lacidipine forhypertensive patients is 007mgkg asymp4- to 14-fold lower thanthe 2 doses used in SPSHR The maximum daily dose ofnifedipine given to hypertensive patients is 20mgkg asymp40-fold lower thanwhatwere used [131]These discrepanciesmaybe related to differences in bioavailability of CA between ratsand humans [131]
Accordingly in routine clinical use 14-DHPCCBs donotreach the concentrations required for antioxidant activity invitro [131]
Another data concerning the effect of CA DHPs on OSrelated to LDL is presented under Section 35
(b) Effect of DHPs on Isolated Rat Liver and Heart Mitochon-dria As a major cellular source of oxygen radicals (Cadenas[4 5]) mitochondria are promising targets for pharmaco-logical and toxicological actions of various membrane-activecompounds including several 14-DHP derivatives Zernig etal [132] have discovered CA binding sites associated with aninner mitochondrial membrane anion channel
More than 40-year long research onmitochondrial effectsof the DHPs (on their bioenergetics chemiosmotic proper-ties and ion fluxes) clearly points them out as mitochondri-otropic compounds
The activity of the first 35 synthesized compounds(derivatives of 14-DHP their heteroaromatic analogues
12 Oxidative Medicine and Cellular Longevity
NAD-H+ and butylated hydroxytoluene (BHT BOT)) orig-inally was examined in rat liver mitochondrial LP system inthe presence of Fe2+ ions and using the ultraweak chemilu-minescence method (Dubur et al [89])
Several 14-DHP derivatives Hantzsch ester diludine andits analogues were found to be effective antioxidants in thisexperimental system changing the kinetics of LP lengtheningthe time of the appearance of the maximum of the slowburst of the chemiluminescence (latency latent period) anddiminishing the reaction rate (the tangent of the slope angleduring the time in which the amplitude of the slow burstcharacterizing LP rate increases) and its peak value Theirpresence has influenced the reaction constant 119870
6 in relation
to a very significant reduction of lipid hydroperoxides andorinactivation of free radicals as follows
ROO∙ + ROO∙ 997888rarr P + h]lowast termination (1)
(P = molecular products) or
ROO∙ + ROO∙ +H2O 997888rarr ROH + RO∙ + 1O
2
lowast (2)
In this study diludine was one of themost active compoundsDHPs had activity similar to the standard synthetic AO-BHT(ionol) However when plotted against applied concentrationand time window diludinersquos activity profile differed from thatof BHT
There were also similar studies (using different LP rateexperimental detection system and method Hunter et al[133]) based on exploring a group of 26 26-dimethyl-35-disubstituted- and 26-dimethyl-345-trisubstituted-14-dihydropyridines (14-H
2Py=14-DHPs) and five related pyri-
dines as inhibitors of rat liver Mit swelling (Δ119860520119905) and O
2
uptake by ascorbic acid- (AsA-) dependent lipid peroxidationand as modulators of Mit swelling induced by Na+-linoleateor Na+-pyrophosphate (Velena et al [112])
Some of tested 4-DHPs (4-unsubstituted 35-dialkoxy-carbonyl-26-dimethyl-14-DHPs and 35-diamido-26-dim-ethyl-14-DHPs both 4-unsubstituted or those possessinglipophilic 4-aryl- groups) have shown significant AO andmembrane stabilizing activity These studies further revealedthat 14-DHPs preferably act as AO during the stages ofinitiation and prolongation of LP chain reactions at lowconcentrations The studied 14-DHPs had IC
50(when 119881
0119881
or 1205911205910= 2) 01 120583M to 100 120583M and the minimal activity was
scored for oxidized (heteroaromatized) derivativesAt the concentration of 100120583M 35-di-n-butyloxycarbo-
nyl-26-dimethyl-14-DHP entirely stops mitochondrialswelling in the presence of 08mM Na+-pyrophosphateAt the same concentration the following compoundsalter the mitochondrial swelling rate in the presence ofnatural protonophore Na+-linoleate 35-di-p-hydroxyphen-oxycarbonyl- and 35-di-p-tolyloxycarbonyl-26-dimethyl-14-DHPs 35-diethoxycarbonyl-26-dimethyl-pyridine (oxi-dized form of Hantzsch ester) and more lipophilic 35-diamyloxycarbonyl-26-dimethyl-pyridine The alteration ofswelling may be scored as prolonged promoted acceleratedor inhibited The type of alteration depends on the structureand concentration of 14-DHPs the type of initiators of theswelling process and the medium composition
In accord with previously published Janerorsquos results (lackof AO for Ca2+ antagonists nifedipine and nicardipine evenat 500120583M concentration in LP tests performed on heartmembrane [134]) no antioxidative activity for 4-phenyl sub-stituted derivatives of 35-dialkoxycarbonyl 14-DHP (closeanalogues of Ca2+ antagonists) was found contrary to various4-nitrophenyl 14-DHP derivatives calcium antagonists forwhich the significant antioxidant activity was reported [3146ndash53]
Studies made on phosphatidylcholine liposomes (ourunpublished data) suggest approximately three and twotimes more antioxidative activity for 100 120583M 4-unsubstitutedDHP compound diludine when compared to 4-substitutedDHPs riodipinenifedipine and nicardipine respectively atmethemoglobin-induced LP (oxygraphy)
Inhibition of mitochondrial AsA-dependent LP and sta-bilization ofmitochondriawere shown to be characteristic fora large group of 14-DHP compounds [112] showing to pos-sess the AOA in simplest in vitro systems (Tirzit andDuburs [39] Zilber et al [44] and Dubur et al [45])based on reactions with the stable free radical 11-diphenyl-2-picrylhydrazyl (DPPH) LP of fatty acid ester (linethole andmethyloleate) emulsions and phospholipid (phosphatidyl-choline) liposomes Generally these properties did not coin-cide with Ca2+ antagonism Depending on DHP structure itseems that AOA properties are less specific than Ca2+ antago-nist properties Both properties may be interrelated but notinterdependent
These data show that the presence and the nature ofa substituent in position 4 as well as 35-substituentsare important factors for 14-DHP antioxidant effects invarious systems that is AsA-dependent nonenzymatic aswell as enzymatic NADPH-dependent lipid peroxidationSometimes the efficacy of inhibition of nonenzymatic LPby 14-DHPs is higher than the inhibition of the enzymaticLP However the action may be opposite stimulation of theLP Hantzsch ester (HEH diludine) and its close analoguesexhibited significant AOA and membrane stabilizing prop-erties in both AsA-dependent nonenzymatic peroxidationof mitochondria and NADPH-dependent enzymatic LP ofmicrosomes usually at similar 10 to 100120583M concentrations[112]
The order of AOpotency (IC50
values) in vitro depends ondrug structure as well as on the experimental conditions andspecificity of the biological system Eachmethod for determi-nation of AOA and ARA has advantages and disadvantages(Karadag et al [135])
Accordingly as reported by Gubskiı et al [136] IC50
forthe AsA-dependent LP was 025 120583M and 20 120583M for 14-DHPCa2+ antagonists nitrepine (nitrendipine) and nifedipinerespectively Takei et alrsquos [137 138] studies on mitochondrialswelling induced by LP or arachidonic acid in the rat braindetermined the IC
50values of 127 105 1568 and 384 120583Mfor
efonidipine nicardipine nifedipine and nimodipine respec-tively For LDL in the copper-induced oxidation system theorder of potencywas vitamin Egt felodipinegt 2-chlorophenylanalogue of nifedipine gt nifedipine gt amlodipine nitrendip-ine verapamil and diltiazem (Rojstaczer and Triggle [119])
Oxidative Medicine and Cellular Longevity 13
It was interesting to compare the AOAofDHPswith theirsusceptibility to oxidation that is electron and hydrogendonating properties
It has been estimated that electron donor substituentsin positions 2 and 6 of 14-DHP cycle usually promoteoxidation while electron acceptor substituents promotequench oxidation Stronger electron acceptors in positions 3and 5 also significantly quench oxidation These estimationsare based on studies including chemical enzymatic andelectrochemical oxidation of 14-DHPderivatives (Dubur andUldrikis [70] Duburs et al [71] and Stradin et al [139])
On the other hand diminished AOA of 14-DHP relatesto presence of substituents in position 4 (both electron donorand electron acceptor) (Velena et al [112])
35-Dicarbamoyl substituents possess minimal quench-ing feature and are followed by benzoyl- acetyl- andalkoxycarbonyl- groups Maximal decrease was obtainedwith condensed substituents (ie oxoindeno- or oxocyclo-hexeno- groups) and a CN-group 4-Unsubstituted 35-dicar-bamoyl derivatives can be easily oxidized and consequen-tially inactivated whereas 4-substituted 35-dicarbamoyl-14-DHPs possess an oxidation potential analogous to the 4-unsubstituted 35-COOR derivatives Therefore they haveadequate electron donor properties and are considerablystableThismay be the reason for significantmembrane stabi-lization upon exposure to 4-substituted derivatives Ofimportance their AOA was usually more pronounced incomparison to 4-unsubstituted derivatives
Among them 26-dimethyl-35-difurfuryloxycarbonyl-14-DHP showed the highest antioxidative activity In thegroup of 35-dialkoxycarbonyl derivatives the strongestactivity was attributed to compounds with medium lengthalkyl chains (i-butyl- t-butyl- and i-amyl- substituents) highlevel of lipophilicity minimal electron acceptor propertiesand moderate steric hindrance as contrasted to short or longalkyl chain ester derivatives (35-dimethoxycarbonyl- 35-diethoxycarbonyl derivatives and 35-didodecyloxycarbonylderivative) These data demonstrate the bell-shaped depen-dence of AOA on alkyl chain length [112] and are in accordwith results obtained in liposomes However these datadiffer from those obtained in emulsions where diludine wasthe most active compound Finally oxidized heteroaromaticderivatives showed only minimal activity
In both LP systems studied (AsA-dependent in mito-chondria and NADPH-dependent in microsomes) some of14-DHPs showed activity similar to classical antioxidantbutylated hydroxytoluene (ionol BHT) (Velena et al [112])However there was a significant difference related to con-centration and incubation time It allowed us to postu-late that 14-dihydropyridines (InH) acting as antioxidants-reductants and scavengers of reactive oxygen species and lipidfree radicals preferably influence initiation and propagation(prolongation) of lipid peroxidation chain reactions (1)ndash(5) according to Scheme 2 The phenomenon is particularlyprominent in the presence of Fe2+ and other ions of variablevalency
Chain break and termination reactions (6)ndash(10) of theLP reaction cascade [89] were influenced by 14-DHPs in alesser degree than were initiation and propagation steps This
may be important for their therapeutic effects even in theadvanced stages of LP
Scheme 2 (stages of initiation propagation and terminationof lipid peroxidation chain reactions (1ndash10)) Initiation andpropagation reactions are as follows
(8) RO∙ + In∙minus rarr Y (Y = molecular products)(9) ROO∙ + Fe2+ rarr Fe3+ + X (X = molecular products)(10) RO∙ + RO∙minus rarr Y (Y = molecular products)
In the reversible swelling of mitochondria accompanyingLP (initiated by mixture of 5mM GSSG1mM GSH) several14-DHPs showed low or no activity manifested only as adecrease of the swelling amplitude without a rate decreaseAn addition of GSH (4mM) or ATP to swollenmitochondriacaused their contraction in both control and tested systemIt may be suggested that 14-DHPs acting as antioxidantsin mitochondria preferably influence LP reactions initiatedby ions with variable valency or their complexes with hemetype compounds methemoglobin hemin hematin and soforth (Velena et al [112]) If the peroxidation process has amaximal velocity and 50 percent of initial O
2were consumed
14-DHPs cannot completely break the chain reactions andprevent subsequent membrane damage by addition of DHPsubstance at 10 120583M concentration at the moment of 50percent oxygen consumption the subsequent oxygen uptakeproceeded unchanged This observation is important for theapplication of DHPs as inhibitors of initiation and to a lesserdegree propagation stages of LP chain reactions
The influence of 14-DHPs on Mit swelling is not strictlyassociated with their own oxidation There is the possibilitythat the labilizing (or stabilizing) effect relates to surfaceactivity (connected with substituent lipophilicity) or may bethe consequence of complexation with some -OH (or -CH
3)
group sensitive receptors at the mitochondrial membraneNamely a bathochromic shift of the absorption band maxi-mum (about 10 nm) was observed in the visible region beforeswelling However after swelling in the presence of Na+linoleate the spectrum returns to its initial value [112]
Some 14-DHPs not only protect mitochondria againstswelling caused by AsA-dependent LP salts of fatty acids
14 Oxidative Medicine and Cellular Longevity
in vitro [112] but also have beneficial effects on repairingtheir integrity in vivo after exposure to irradiation hepato-toxins ischemia hypoxia or hypothermia Some of themwere shown to normalize the process of intracellular repara-tion and physiological regeneration of ultrastructures Theywere also shown to stimulate reparative processes If pre-treated with 14-DHPs irradiatedmitochondria will not swell(Ivanov et al [140 141])
Diludine ionol and some other AOs mitochondria pro-tectors act as anti-ischemic agents If applied prophylacticallyin vivo they may prevent ischemic and reperfusion lesionsin heart kidney and other organs (Bilenko et al [113]) Theeffect is dependent on applied dose timing and way ofapplicationWhen added onto the cryoconservationmediumfor mitochondria preservation 14-DHPs prevented decreaseof membrane potential normalized facilitated respirationand prevented loss of mitochondrial Na+ and Ca2+ ionsafter thawing ([112] see citation number 36 (Subbota et alKharkov 1984) therein) Diludine was stronger protectorwhen compared to ionol
CA drug foridone (riodipine) was shown to possesscardioprotective features primarily due to is protective effecton mitochondria exposed to OS [142 143]
Similarly the DHP water-soluble antiarrhythmic com-pound glutapyrone inhibits initiation of LP by free radicalsin erythrocytes and heart mitochondria Its cardioprotectiveeffect has been experimentally shown in heart mitochondrialmembranes especially during deep hypothermia (Utno et al[144])
Cerebrocrast was effective in several translation modelsmimicking pathological situations known to be associatedwith cellular OS The potential protective action of 14-DHP derivatives (4-substituted compounds cerebrocrastgammapyrone glutapyrone and 4-unsubstituted drug dieth-one) has been studied in rat liver in experimental modelsrelevant for oxidative stress and mitochondrial bioenergetics(Fernandes et al [145]) When succinate was used as therespiratory substrate higher concentrations (gt25 120583M) ofcerebrocrast depressed respiratory control ratio (RCR) ADPto oxygen ratio (ADPO) state 3 and uncoupled respirationrates transmembrane potential (deltapsi) and the phosphatecarrier rate At the same time state 4 respiration rate wasthree times increased At concentrations lower than 25120583Mcerebrocrast inhibited mitochondrial IMAC and partiallyprevented Ca2+-induced opening of the mitochondrial PTPGammapyrone glutapyrone and diethone did not inducethese phenomena When applied at concentrations up to100 120583M cerebrocrast gammapyrone and glutapyrone didnot affect ADPFe2+-induced LP of mitochondria in rat liver(as measured by oxygen consumption and TBARS forma-tion) On the other hand low diethone concentrations (upto 5 120583M) inhibited it in a dose-dependent manner Diethonealso prevented against deltapsi dissipation induced by LPinitiated by ADPFe2+ Based on these data it may bespeculated that cerebrocrast (inhibition of the IMAC) anddiethone (acting as an AO) may provide effective protectionof mitochondria during OS Cerebrocrast has shown sometherapeutic potential for treatment of several pathologicalconditions related to cellular OS [145]
5-Acetyl(carbamoyl)-6-methylsulfanyl-14-DHP-carbo-nitriles (Figure 3) with minor differences in their molecularstructure displaying antioxidant and antiradical activitiesin vitro show different biological activities Namely 4-p-chlorophenyl derivative OSI-1146 displays AO and anti-radical activities in cardiovascular OS models whereasOSI-3701 and OSI-3761 display hepatoprotective activityThus these compounds may be potentially useful for treat-ing several pathological processes including those associatedwith OS (Fernandes et al [146]) However besides mito-chondria the cellular targets for their pharmacologicalactions have not been fully investigated [146] All these com-pounds increase the susceptibility of Mit to MPT The mostpotent is OSI-3701 although it does not affect bioenergeticparameters
Although all these compounds protected mitochondriaagainst LP induced by the oxidant pair ADPFe2+ OSI-1146was shown to be the most potent Current data point outmitochondria as potential targets for protective and toxicactions of DHPs suggesting that the potential for their use astherapeutic agents should also take into consideration theirtoxic effects on mitochondria (Fernandes et al [146])
Several structurally different DHP derivatives (antioxi-dant diludine (diethone) as a 4-unsubstituted DHP 4-substi-tuted DHPs CA foridone (bicyclic compound) and the 4-phenyldiethone compound where phenyl group is joined tothe DHP in position 4) inhibited the 1-methyl-4-phenyl-pyridinium iodide (MPP+) induced ROS production incerebellar granule cells (CGC) with a distinct potency orderforidone (26-dimethyl-35-dimethoxycarbonyl-4-(o-difluo-romethoxyphenyl)-14-dihydropyridine) gt 26-dimethyl-35-diethoxycarbonyl-4-phenyl-14-dihydropyridine gt diludineThey also reversed the MPP+-induced decrease of the mito-chondrial membrane potential in the same order (Klimavi-ciusa et al [147]) Accordingly it was postulated that theclassical two-ring (bicyclic) structure of DHP derivativesrepresents an advantage in relation to neuroprotection andROS defense and is independent on compoundrsquos propertiesrelated to calcium ions
Novel adamantane-containing 14-DHP compounds (Kli-maviciusa et al [148]) were also found to improve mitochon-drial functions (MPP+ model) (Klimaviciusa et al [148])Klusa et al [149] have discovered antineurotoxic effects of14-DHP taurine derivative tauropyrone recorded as Mitfunction improvement
Many 14-DHPs including Ca2+ antagonists and AOmodify LP processes and influencemitochondrial function invarious organs (liver heart kidney and brain) in a differentway and degree Their beneficial action oxygen or lipidfree radical scavenging antioxidative effects binding withor intercalating into phospholipid bilayer regulation of iongating and regulation of mitochondrial permeability transi-tion pores (Tirzit and Duburs [39] Zilber et al [44] andDubur et al [45]) separately or in combination with eachother depends on two strong elements (1) their individ-ual structure including nature of substituents and theirpositions and (2) the nature of the biological system Forexample the direction of LP (inhibition of promotion) wasshown to depend on structure and concentration of applied
Oxidative Medicine and Cellular Longevity 15
14-DHPs as well as stages of chain reactions Accordinglymitochondrial swelling may be prolonged (retarded) accel-erated (promoted) or inhibited (Velena et al [112])
Therefore there is a ground for 14-dihydropyridineseither Ca2+ antagonists or antioxidants to be nominated asuseful tools in development of ldquomitochondrial drugsrdquo relatedto the control of OS
(c) DHPs as AOs in Endoplasmic Reticulum (Inhibition ofNADPH-Dependent LP System) Inhibition of NADPH Oxi-dase by DHPs Elevated level of NADPH oxidase 4- (NOX4-)derived hydrogen peroxide (H
2O2) joined with concomitant
decrease of nitric oxide (NO) mediated signaling and reac-tive oxygen species scavengers are considered to be centralfactor in molecular pathogenesis of fibrosis (Sampson etal [150]) Inhibition of microsomal NADPH-dependent LPwith particular focus on NADPH oxidases (NOX1ndash5 andDUOX1) may be very important for neuro- cardio- andhepatoprotection (Velena et al [112] Leto and Geiszt [151]Griendling et al [152] and Chen et al [153]) Endoplasmicreticulum may be an important target as this is where 14-DHPs could display their antioxidative properties (Velena etal [112] Leto and Geiszt [151] Griendling et al [152] andChen et al [153])
However the initiation of LP in the NADPH-dependentmicrosomal system does not appear to involve either super-oxide or hydrogen peroxide since neither SOD nor cata-lase can inhibit it On the other hand reduced iron playsan important role in both the initiation and propaga-tion of NADPH-dependent microsomal lipid peroxidation(Hochstein and Ernster [154] and Repetto et al [111])
Many DHPs possess inhibitory activity not only towardsAsA-dependent LP in mitochondria but also towardsNADPH-dependent LP as shown in isolated rat liver micro-somes (Velena et al [112]) This means that these compoundsinteract with the shared parts (nonenzymatic and enzymatic)of LP pathways
Microcalorimetry and fluorescent probes procedureswere used for studying the interaction of alpha-tocopheroland 14-DHPs with endoplasmic reticulum membranes andmodel systems human serum albumin and phospholipidbilayers [155] Modification of microviscosity of the endo-plasmatic reticular membranes depends on localization ofantioxidants within the protein structures or phospholipidphase Increase of membrane structuralization under theinfluence of 14-DHPs blocked their antioxidant action inspontaneous and induced lipid peroxidation
Inhibition of rat heart and liver microsomal lipid perox-idation by nifedipine was observed [156] while Goncalves etal [157] found antioxidant effect of calcium antagonists onmicrosomal membranes isolated from different brain areas
Nitroaryl-14-DHPs are both calcium channel antagonistsand antioxidant agents (Letelier et al [158 159]) commonlyused for treatment of cardiovascular diseases These drugsmust be metabolized through cytochrome P450 oxidativesystem (NADPH-cytochrome P450 reductase) mainly local-ized in the hepatic endoplasmic reticulum Several lipophilicdrugs generate OS while being metabolized by this cellularsystem Thus DHP antioxidant properties may prevent the
OS associated with hepatic biotransformation of drugs Var-ious commercial and new nitro-phenyl-DHPs were studiedagainst LP using rat liver microsomes under oxidative stress[159]
Incubation of rat liver microsomes with the 41015840-nitro-4-phenyl-14-DHP compounds (26-dimethyl-4-(41015840-nitro-phenyl)-14-dihydropyridin-35-diethyl-dicarboxylate andN-ethyl-26-dimethyl-4-(41015840-nitrophenyl)-14-dihydropyri-din-35-dimethyl-dicarboxylate) results in an inhibitionof LP the UDPGT (UDP-glucuronyltransferase) oxidativeactivation and the microsomal thiol oxidation induced byFe3+ascorbate a generator system of ROS This effect wasalso produced by nitrofurantoin and naphthalene in thepresence of NADPH
Interestingly IC50
ofDHPs obtained frommicrosomal LPassays decreased to the same extent as the microsomal thiolsoxidation provoked by Fe3+ascorbate [159] Neverthelessthe AO effects of a nitrophenyl-DHP compound in whichhydrogen at position one of the DHP ring was replaced bythe ethyl groupwere significantlyweaker Authors speculatedthat DHPs can resemble NADH transferring one hydrogenatom of 4-position (Hminus) to anion superoxide and another ofthe 1-position (H+) by way of a cationic radical intermediateto generate pyridine derivatives and water [159]
The AO effects of various tested DHP derivatives (m- andp-NO
2phenyl as well as methyl or ethyl and isopropyl-DHP
35-dicarboxylate derivatives) were not significantly differentThe authors assumed that the -NH- group of the dihydropy-ridine ring could contribute both to the development ofthe calcium channel antagonism and to the antioxidativeproperties of DHPs [159]
Prevention of the membrane LP seemingly depends onthe concentration of potential antioxidants such as vitaminE or even 14-DHP in lipids However only the differencesin synthetic DHPs lipophilicity cannot explain significantvariations of DHPs concentration in microsomal membraneand cannot clarify the strength of their antioxidative activityThis work [159] has further demonstrated that 14-DHPsmay prevent the OS induced by biotransformation of somedrugs for example antibiotic nitrofurantoin Simultaneousadministration of DHPs and nitrofurantoinmay be beneficialin reducing nitrofurantoin side effects
While most of Ca antagonist 14-DHPs are metabolizedby CYP3A4 (Guengerich et al [160]) not all of them are goodinhibitors of its activity Thus nicardipine but not nifedipineand nitrendipine inhibits CYP3A4 in vitro [53] Interactionof different DHPs with various types of cytochrome P450 wasdescribed by Carosati et al [53] It was also reported thatDHP class calcium channel blockers reduce the antiplateleteffect of clopidogrel (Park et al [161])This implies themutualinteractions of both drugs with CYP3A4
(3) In Vivo Evaluation of nifedipine effects on Saccharomycescerevisiaewas recently published (Asma andReda [162]) Sur-prisingly nifedipine exercised a toxic effect on Saccharomycescerevisiae shown through measuring cellular proliferationrespiratory activity and the level of some biomarkers (CATand MDA)
16 Oxidative Medicine and Cellular Longevity
However majority of data obtained on various animalcells and tissues by other authors show the protective role ofDHPs against both LP and oxidative stress [113 163 164]
The AOA attributed to many 14-DHPs Ca2+ antag-onists and other compounds reflecting on catalytic LDLperoxidation (see Section 331 (2) and Section 35) shouldencourage their testing for treating cardiovascular diseasesandor alterations of lipid metabolism
The possibility that 14-DHP-based calcium antagonistsexert an antiatherosclerotic action (via inhibition of LDLoxidation and other mechanisms) has been proved by manyexperimental data [165] and several clinical trials Besidesantihypertensive effect nicardipine was shown to possessantioxidative and antielastase activity [165 166] These prop-erties may be useful for prevention of inflammatory reactionwhich is relevant for hypertension pathogenesis
14-DHPs administration inhibits LDL oxidation medi-ated by oxygen radicals leading to decreased carotid inti-mal media thickness and reduced progression of coronaryatherosclerosis [130] It additionally preserves Apo B-100integrity against ROS Of importance antiatherogenic mech-anisms differ between animals and humans (primarily inthe stage of conversion of aldehydes to carboxylic acids)(Parthasarathy et al [167])
For example furyl-DHP compound (FDP-1 diethyl 26-dimethyl-4-(furyl)-14-dihydropyridine-35-dicarboxylate)was shown to act as an antioxidant (decreasing MDA GOTand FFA release of ischemic myocardium and inhibiting Ca-ATPase of erythrocyte membranes) preventing against heartmyocardium ischemia-reperfusion injury and arrhythmiawhen applied (in rats) at 10mgkg (Liu et al [168])
Similarly antioxidative effects of azelnidipine andamlodipine prevented neuronal damage by CCBs aftertransient focal ischemia in rats (Lukic-Panin et al [169])
Allanore et al [170] found that both nifedipine andnicardipine significantly decrease the mean level of plasmamarkers for oxidative stress in patients suffering from sys-temic sclerosis
Antioxidants may be considered as promising neuropro-tective compounds Still while experimental data demon-strate neuroprotective effect in vitro and in animal mod-els clinical evidence is still unsatisfactory and insufficient[171]
(a) Role of Metabolism of DHPs in Their AOA Metabolicpathways and ldquobioavailabilityrdquo of the probable AOA com-pound determine antioxidant activity in vivo Antioxidantmetabolites may vary in stability and activity leading to twoopposite scenarios lack or presence of activity substantiallycontributing to the overall AOA [172] Metabolic biotransfor-mation of DHPs includes oxidation (heteroaromatization)side chain ester group cleavage (deesterification) and 4-substituent abstraction ao [160] None of the DHPs metabo-lites was shown to be more toxic than original reduced formof the compound The commonly detected metabolites ofthe DHPs do not seem to possess the AO activity (withsome exceptions as in the case of metabolites of nifedipineand its analogues including nitrosonifedipine [173 174]) (seefurther in Section 35) Due to DHPs intrinsic instability
achieving andmaintaining an adequate concentrationmay beproblematic both in vitro and in vivo
(b) Role of Concentration and Lipophilicity (MembraneWateror LipidWater Partition Coefficients) of DHPs inTheir Actionas AOs and Antiradical Compounds Antioxidative effects ofany antioxidant depend on its concentration at the site ofaction This parameter is hardly measurable especially intwo-phase systems representing one of obstacles in com-parison to AOA upon applying various compounds [172]It is often incorrectly assumed that the concentrations inthe aqueous solution and at the site of action are the sameHowever even when the concentration in the aqueous phasemay be well controlled the concentration at the site ofaction in the lipid matrix of the membranes might fluctuatebetween different test compounds depending on a differencein lipophilicity [175] The prevention of the membrane LPalso seems to be dependent on the DHP concentration in thelipidmatrix (Mason andTrumbore [46]) and its amphiphilic-ity For example AOA of diludine is associated with itslipophilicity and consequential ability to be incorporatedinto liposomes (Panasenko et al [176]) It was also foundthat diludine easily incorporates into the outer monolayer oferythrocyte membranes [176]
Membranebuffer partition coefficients (lambda) weredirectly measured in the sarcolemma and sarcoplasmicreticulum membranes for three CA DHPs The obtainedvalues were in a broad range between 5000 and 150000(Herbette et al [177])These drugs interact primarily with themembrane bilayer component but may also bind to proteinsboth nonreceptors and receptors The intrinsic forward rateconstants for DHP binding to sarcolemmal calcium channelreceptors were apparently not strongly dependent on theirmembrane partition coefficients For example nimodipine(lambda = 6300) had a forward rate constant of 68 plusmn 06 times106Ms whereas the forward rate constant for Bay P 8857
(lambda = 149000) was 14plusmn08times107Ms Since these DHPsare highly liposoluble model calculations for this bindingreaction demonstrated that these rates on lipid solubilitywould probably not be reflected in the experimental forwardrate constants In addition the intrinsic forward rate constantfor nimodipine binding to sarcolemmal calcium channelreceptors was found not to be linearly dependent on theviscosity of the buffer medium over a fivefold range The rateof drug nonspecific binding to nonreceptor protein present inhighly purified sarcoplasmic reticulum membranes appearsto be extremely fast at least 103 times faster than specificdrug binding to the receptor in the sarcolemma Authorsconcluded that partitioning into the lipid bilayer matrix ofthe sarcolemma could be a general property of CA DHPsand may be a prerequisite for their binding to sarcolemmalmembrane receptors (Herbette et al [177])
The binding of DHP calcium channel agonists and antag-onists (including those with AO properties) to receptors incardiac sarcolemmal membranes is a complex reaction thatmay involve an interaction with the lipid bilayer matrix ofthe sarcolemma (Herbette et al [178]) Belevitch et al [179]studied the binding of DHP CCBs (riodipine and nifedip-ine) and verapamil to model and biological membranes by
Oxidative Medicine and Cellular Longevity 17
fluorescence analysis The consistent location of Ca agonistBay K 8644 was determined to be within the region ofthe first few methylene segments of the fatty acyl chains ofthe membranes (Mason et al [180]) This position is nearto that observed for the DHP calcium channel antagonistsnimodipine and Bay P 8857
Themajority of studies onOSwere performedwithDHPswith various lipophilicity but only a few studies reportedamphiphilicity ofDHPderivatives AmphiphilicDHPderiva-tive K-2-11 reduced the cellular generation of ROS It alsorevealed complete reversal of multidrug resistance (MDR) ofthe resistant cells K-2-11 was more efficient than well-knownMDR inhibitor verapamil Cytotoxic effects of anticancerdrug doxorubicin were enhanced by K-2-11 in bothMDR andparental nonresistant cell line (Cindric et al [181]) K-2-11suppresses increase of ROS and consequentially prevents NF-120581B activation leading to decreased expression of MDR1 andincreased expression of antiapoptotic genes This signalingswitch is necessary for restoring the chemosensitivity ofcancer cells This phenomenon is characteristic both for14-DHPs [182] (18 novel asymmetrical DHPs bearing 3-pyridyl methyl carboxylate and alkyl carboxylate moietiesat C3 and C5 positions resp as well as nitrophenyl orheteroaromatic rings at C4) and for their oxidized formspyridine compounds (Zhou et al [183])
34 Dependence of AOA of DHPs on the Experimental SystemAO effect of DHPs depends on their structure and theexperimental system used (in vitromodel system subcellularorganelle and cells ex vivo and in vivo) Ideally for theevaluation of the profile and value of DHPs AO propertieseach compound should be tested in as many systems aspossible (Dubur et al [45])
Lipidomics studies have been traditionally explored forstudying AOA of DHPs Proteomics methods are less rep-resented and are mostly focused on the properties of DHPsrelated to scavenging of protein free radicals So far there areno studies on the role of DHPs in scavenging nitrosoperoxy-carbonate the reactive species formed out of peroxynitrite inthe presence of carbon dioxide Although it was shown thatalbumin binds diludine no studies revealed the relevance ofthis effect for the AOA of diludine
There are findings showing that dihydropyridine calciumantagonists (DHPs CA) could indirectly play a beneficialprotective role during development of atherosclerosisNamely Berkels et al [184] have studied antioxidativeproperties of four substances the DHP prototype CAnifedipine the long-acting CA lacidipine the DHP calciumchannel agonist BayK8644 and the bulkyDHPderivate BayO 5572 in three different models (1) in an in vitro superoxideanion generating system (hypoxanthinexanthine oxidase)for testing the ldquopurerdquo antioxidative effect (2) in an artificialmembrane preparation (dimyristoylphosphatidylcholine) formimicking a more physiological environment and (3) underconditions of stimulated ROS release (hyperglycemia) fromnative endothelial cells derived from porcine coronary arter-ies
The study also revealed the potential correlation betweenlipophilic and AO properties of DHPs In the first model
Bay K 8644 was significantly more effective in scavengingsuperoxide anions than lacidipine Bay O 5572 or nifedipine(micro- to millimolar concentration range) Addition of anartificial membrane preparation resulted in an enhancedAO effect with lacidipine being the most effective DHP inquenching radicals (low micromolar concentration range)In the third model mimicking hyperglycemia (30mmolL)nifedipine was significantly more potent antioxidant (ther-apeutical nanomolar concentration range) than the otherDHPs Calculated lipophilicity of these four substances(lacidipine gt Bay O 5572 gt Bay K 8644 gt nifedipine) waspositively correlated with antioxidative potential only in thesecond experimental model It has been concluded that AOproperties of DHP substances need to be tested in variousmodels for demonstrating that nifedipine exhibits ROS-quenching properties in a therapeutic concentration range[184]
341 AOA of DHPs in Isolated Cells and Cell Cultures(Comparison with Other Simplest Systems) Although DHPspossess neuromodulatory andor antimutagenic propertiesthe mechanisms of action related to these phenomena arenot entirely elucidated Borovic et al [185] have studied 14-dihydroisonicotinic acid (14-DHINA) derivatives of 14-DHP water-soluble analogues of a well-known AO diludine(diethone) 26-dimethyl-35-diethoxycarbonyl-14-dihydro-isonicotinic acid sodium 2-(26-dimethyl-35-diethoxycar-bonyl-14-dihydropyridine-4-carboxamido)glutamate gluta-pyrone and sodium 2-(26-dimethyl-35-diethoxycarbonyl-14-dihydropyridine-4-carboxamido)ethane-sulphate tauro-pyrone as AO and bioprotectors (Figure 4)
14-DHINArsquos activities were studied in comparison toTrolox by NN-diphenyl-N1015840-picrylhydrazyl (DPPH∙) deoxy-ribose degradation ABTS∙ radical scavenging and AOA(antioxidative capacity method) assays copper-induced LPof cultured rat liver cells (MDA determination by HPLCand 4-hydroxynonenal-protein conjugates by dot-blot) 3H-thymidine incorporation and trypan blue assay for liver cellsgrowth and viability Ic decreased the amount of 4-HNE-protein adducts In all assays Ia was the most potent AOable to completely abolish copper induced LP of liver cellswhile Ic only slightly decreased it Thus AOA is importantactivity principle of Ia which was even superior to Trolox intreated cell cultures Ia (and its analogues) are easily oxidizedin the Fenton system (Rubene et al [186]) exerting ARA too
35 Peculiarities Related to Antioxidative and AntiradicalActivity of Some 14-DHPs Ca Antagonists Nine commer-cialized structurally and functionally different DHPs CAwill be discussed further Their common feature is ability toprevent OS This also counts for some of their metabolitesas already discussed The comparative effects of some DHPsCA on oxidative stress-induced modification of LDL werealready reviewed in Section 331 (2)-(a) AOA of CA DHPswas discussed in Sections 331 (2)-(b) and 331 (2)-(c)
351 Nifedipine and Its Close Analogues Nifedipine vera-pamil and antiarrhythmic-antihypoxic drug stobadin wereshown to depress lipid peroxidation of phosphatidylcholine
18 Oxidative Medicine and Cellular Longevity
NH
COOH
NH
COONa
Glutapyrone
NH
Gammapyrone
NH
C 2H5OOC COOC2H5
Tauropyrone
14-DHINA
H3C H3C
H3C
H3CCH3 CH3
CH3
CH3
COOC2H5COOC2H5
COOC2H5 C2H5OOCC2H5OOCC2H5OOC
CONHCH(CH2)2COONa CONH(CH2)3COONa
CONH(CH2)2SO3Na
Figure 4 Derivatives of 14-dihydroisonicotinic acid (14-DHINA)
liposomes (Ondrias et al [187]) However data obtained insome other experimental systems are conflicting
In an in vitromodel of sarcolemmal membrane lipid per-oxidation three calcium blockers (nifedipine verapamil anddiltiazem) exhibited concentration-dependent (10ndash400 120583M)inhibitory effects [188 189] Nifedipine the most effectivecalcium blocker was more than two-fold potent compared topropranolol achieving significant effect at 10 120583M Nifedipineprotective role on LP using reduced glutathione as modelmarker was recently described (Ray et al [190]) Antiper-oxidative properties of CA nifedipine and its analogueswere explored in different systemspathogenic processesatherogenesis (Henry [165]) brain focal ischemia (Yamatoet al [191]) nephroprotection related to cyclosporine intake(Chander and Chopra [192]) and hepatoprotection relatedto intake of diethyldithiocarbamate (Gaafa et al [193])Recent data suggest that nifedipine action as protector forendothelial cells proceeds independently from its CA proper-ties
The absence of antioxidant effects of nifedipine anddiltiazemonmyocardialmembrane lipid peroxidation oppo-site to nisoldipine and propranolol was also described[194] Nisoldipine and propranolol were shown to havea concentration-dependent antiperoxidant effect with IC
50
values of 282 and 501 120583M respectively Finally nisol-dipine appeared to possess dual antiperoxidant mecha-nisms involving both preventive and chain-breaking proper-ties
These findings were confirmed in some other studiesincluding reports on the lack of antioxidative activity ofnifedipine and nicardipine even at 500120583M concentrationin heart membrane lipid peroxidation tests [134] SimilarlyROS formation in bovine aorta smooth muscle cells was notaffected by addition of amlodipine nimodipine and nife-dipine [123]
(1) Metabolites of Nifedipine and Its Analogues as Antioxidantsand Regulators of OS Antioxidant activity of nifedipine35-dimethoxycarbonyl-26-dimethyl-4-(2-nitrophenyl)-14-dihydropyridine was originally studied in vitro by Kirule etal [195] and Tirzit et al [196] According to the kinetic dataof peroxide accumulation and the ESR spectra (inhibition ofthe autoxidation of methyl oleate in presence of nifedipine)AO action was exerted by the formation of nitroso analogueof the oxidized nifedipine nitroso nifedipine 26-dimethyl-4-(2-nitrosophenyl)-35-pyridine dicarboxylate (NO-NIF)This nitroso aromatic derivative can form nitroxyl radicalsexhibiting remarkable AOA in the presence of unsaturatedfatty acids and lipids [196]
The primary species of free radicals that have beenobtained and identified were ion radicals of the nitrophenyltype (Ogle et al [76]) Such a mechanism coincides withmechanisms proposed afterwards by Nunez-Vergara et al[96] Lopez-Alarcon et al [103] Valenzuela et al [104]Fukuhara et al [174] and Yanez et al [197]
There are also data showing that nitroso compounds mayinhibit LP by direct radical trapping and subsequent forma-tion of stable nitroxide radicals It was further found that thereactivity between the synthesized 14-DHP derivatives withalkylperoxyl radicals involves electron transfer reactionsThisis documented by the presence of pyridine as a final productof the reaction and complete oxidation of the nitroso groupin the case of the nitrosoaryl 14-dihydropyridine derivatives(Valenzuela et al [104]) Tested compounds reacted fastertoward alkylperoxyl radicals and ABTS radical cation thanalkyl ones (Lopez-Alarcon et al [103])
Nitrosonifedipine a photodegradation product of nifedi-pine significantly recovers cellular damage induced by tumornecrosis factor-alpha It also prevents toxic effects of cumeneperoxide which hampers integrity of cell membranes throughoxidative stress Its positive effects are equal to Trolox-C
Oxidative Medicine and Cellular Longevity 19
As a result nitrosonifedipine was already a long time agoclaimed as a candidate for a new class of antioxidative drugs(Kirule et al [195]) cellular protectors against oxidative stressin glomerular endothelial cells [174]
Moreover Misik et al [198] Ondrias et al [199] andStasko et al [200] studied AOA of nifedipine and its oxidizednitroso analogue NO-NIF prevents the progression of type2 diabetic nephropathy associated with endothelial dysfunc-tion through selective AO effects (Ishizawa et al [201]) NO-NIF administration reduces albuminuria and proteinuriaas well as glomerular expansion without affecting glucosemetabolism or systolic blood pressure NO-NIF also sup-presses renal and systemic OS and decreases the expressionof intercellular adhesion molecule-1 (ICAM-1) a marker ofendothelial cell injury in the glomeruli of the KKAy miceSimilar effects were achieved in endothelial nitric oxide syn-thase (eNOS) knockout mice Moreover NO-NIF suppressesurinary angiotensinogen (AGT) excretion and intrarenalAGT protein expression in proximal tubular cells in theKKAy mice On the other hand hyperglycemia-inducedmitochondrial superoxide production was not attenuated byNO-NIF in cultured endothelial cells
Fujii and Berliner found EPR evidence for free radicaladducts of nifedipine in vivo [202] The nature of these rad-icals was surmised by comparing the reaction of illuminatednitrosonifedipine with polyunsaturated fatty acids Surpris-ingly identical radical spectra were detected from excisedliver doped with nonilluminated nifedipine suggesting thatthis drug can be enzymatically converted in vivo to its nitrosoanalogue without the requirement for illumination This isone of the first reports of in vivo EPR evidence for a class ofunsaturated fatty acid radical conjugates resulting from thenormal metabolism of a common drug
Dıaz-Araya et al [173] studied some 4-nitrophenyl-DHPson Fe3+ initiated LP in rat brain slices LP as measuredby MDA formation was inhibited by all the tested nitro-aryl derivatives of 14-DHP over a wide range of concen-trations On the basis of both time course and IC
50experi-
ments the tentative order of AOA on rat brain slices wasnicardipine gt nisoldipine gt (RSSR)-furnidipine gt (RRSS)-furnidipine gt nitrendipine gt nimodipine gt nifedipine14-DHP derivatives that lack a nitro group in the mole-cule (isradipine and amlodipine) also inhibited LP in ratbrain slices but at higher concentrations than that of nitro-substituted derivatives All tested compounds reduced andoxidized nitrosoaryl derivatives (26-dimethyl-4-(2-nitro-sophenyl)-35-pyridinedicarboxylic acid dimethyl ester (pho-tooxidation product of nifedipine ndash NTP) ao) and weremore potent inhibitors of LP than their parent molecules(Valenzuela et al [104])
The electrooxidation process of 4-nitrosoaromatic DHPsis a strongly pH-dependent (two-electron two-proton mech-anism) ECEC type of mechanism that is the sequenceeminusH+eminusH+ at pH gt 85 ECCE mechanism (eminusH+H+eminus)at pH lt 85 dominates Reduction reaction of nitroso groupis as follows R-NO + 2eminus + 2H+ rarr RNHOH (Bollo et al[203])
352 Lacidipine It is a generic DHP type antihypertensiveCA 35-diethyl 4-2-[(1E)-3-(tert-butoxy)-3-oxoprop-1-en-1-yl]phenyl-26-dimethyl-14-dihydropyridine-35-dicarboxy-late
Ursini [204] described redox behaviour of lacidipine andshowed its tissue protective features Cristofori et al studiedantiatherosclerotic activity in addition to lacidipinersquos CAand AO properties [205] Lacidipine reduced the extent ofatherosclerotic area in hypercholesterolemic apoE-deficientmice (these mice show widespread vascular lesions whichclosely resemble the inflammatory fibrous plaques seen inhumans in atherosclerosis) The reduction may be associatedwith the capacity of the drug to maintain endothelial NOlevels at concentrations useful to protect against vasculardamage This work suggested that DHPs modulate vascularrelaxation via increased release of NO
Herbette et al [178] remarked optimal hydrophobicity oflacidipine due to cinnamic acid substituent so membraneinteractions and facilitation of the treatment of atherosclero-sis could proceed (see also Section 331 (2)-(a))
353 Amlodipine Amlodipine (Norvasc) (RS)-3-ethyl5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-14-dihydropyridine-35-dicarboxylate (AML) hasan antioxidant effect on vessels in vitro and is a 3rd genera-tion of charged dihydropyridine CCB that is widely used forthe treatment of hypertensive patients
Amlodipine was shown to have the highest affinity(amlodipine gt verapamil ≫ diltiazem) for the membranebilayer (119870
119901= 104) It produced the significant changes in
membrane thermodynamic properties including a reductionin the thermal phase transition temperature (minus11) enthalpy(minus14) and cooperative unit size (minus59) relative to thecontrol phosphatidylcholine liposomes (Mason et al [49])
Amlodipine AOA is related to its reductant nature orhydrogen donor properties respectively Its ability for donat-ing protons and electrons to the lipid peroxide moleculesblocks the LP process
Amlodipine and even its enantiomers (Zhang et al [206])act as ROS andNOS effectors in several model systems of OSAntioxidant properties of amlodipine were recently reviewedby Vitolina et al [32] Both in vitro and in vivo studiesof amlodipine AO properties revealed inhibition of lipidsoxidative damage primarily those associated with cellularmembranes and lipoprotein particles (LDL) (Mason et al[50])
Under controlled experimental conditions in vitro amlo-dipine showed AOA and ARA by inhibition of lipid peroxideformation and trapping ROS Its scavenging activity forhydroxyl and peroxyl radicals at concentrations as low as100 nmolL (which is remarkably less compared to the classi-cal antioxidants GSH uric acid and Trolox) was shown to beindependent of the calcium channel modulation (Franzoni etal [207])
AML showed efficiency as scavenger of peroxyl radicals(TOSC assay 5945 plusmn 544 unitsmg) significantly stronger(gt50 119875 lt 0001) than GSH (2733plusmn 636 unitsmg) and 70weaker (119875 lt 00001) than uric acid (18144 plusmn 696 unitsmg)and Trolox (17522 plusmn 734 unitsmg)
20 Oxidative Medicine and Cellular Longevity
Of interest the scavenging capacity of AML towardshydroxyl radicals (1455 plusmn 154 unitsmg) was 320 higher(119875 lt 000001) than that of GSH (358 plusmn 112 unitsmg) 20higher than that of uric acid (1198plusmn121 unitsmg) and 100higher than that of Trolox (759 plusmn 143 unitsmg)
Amlodipine was shown to increase enzyme activity ofparaoxonase (PON) and glutathione peroxidase (GSH-Px)However it also decreases glutathione reductase (GSSG-R)activity and diminishes the concentration of the endogenousantioxidant 120572-tocopherol (vitamin E) Moreover AML in aconcentration of 2 ngmL decreased the content of malonicdialdehyde and activity of superoxide dismutase in the blood(Gatsura [208])
Verapamil and amlodipine produced a potent anti-ischemic effect and reduced area of myocardial infarction inrats The observed changes were accompanied by inhibitionof LP In contrast to verapamil in vitro application of AML ina dose of 50 ngmL decreased hemoglobin affinity for oxygenWhen present in a concentration of 2 ngmLAMDdecreasedthe content of MDA and activity of SOD in the blood
On the other hand amlodipine shows no activity relatedto inhibition of macrophage superoxide release and cellmigration which occurs as a consequence of decreasedTNF120572induced O
2
∙ releaseAmlodipine-induced reduction of OS in the brain is
associated with sympathoinhibitory effects in stroke-pronespontaneously hypertensive rats (SHRSP) (Hirooka et al[209]) Antihypertensive treatment with amlodipine reducedOS in all examined areas of the brain and decreased bloodpressure without a reflex increase in sympathetic nerveactivity Nicardipine another CA DHP surprisingly wassignificantly less active than amlodipine
354 Lercanidipine Tomlinson and Benzie reported AOeffect of lercanidipine [210] which is well known as anti-hypertensive drug Zanidip 2[(33-diphenylpropyl)(methyl)-amino]-11-dimethylethyl methyl 26-dimethyl-4-(3-nitro-phenyl)-14-dihydropyridine-35-dicarboxylate Compara-tive data about this drug AOA were presented in parts of thispaper about other individual CA DHPs and in the part aboutthe ex vivo DHPs effects on LDL
355 Nimodipine Nimodipine (ND) commercially knownas Nimotop is 3-(2-methoxyethyl) 5-propan-2-yl 26-dim-ethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxy-late It is centrally active CA
Treatment with glutathione blocked andwith nimodipineattenuated neuronal cell death caused by prolonged exposureof cell culture to 4-HNE (Faraqui [211])
Nascimento et al [212] found AO effect of nimodipine inyoung rats after pilocarpine- (PIL-) induced (in 400mgkg)seizures The PIL administration increased the striatal cata-lase (CAT) activity The administration of ND 30mgkg30min before PIL preserved normal value of CAT activityOn the other hand no difference was detected in the animalstreated with lower dose 10mgkg These results confirmthe neuroprotectiveantiepileptic effect of ND in young ratssuggesting that this drug acts positively on lipid peroxidation
(in both doses) Nimodipine cannot induce these effects viablockade of Ca2+ channel
Ismailoglu et al [213] studied the therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjury These beneficial effects in rats after cerebral corticalinjury seemed to be related to AOA of nimodipine
356 Benidipine Licensed in Japan and South Asia as CA(CCB) benidipine possesses AO properties Chemically it is5-methyl 3-[(3R)-1-(phenylmethyl)piperidin-3-yl] 26-dim-ethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxy-late (or its hydrochloride (4R)-rel-35-pyridinedicarboxylicacid 14-dihydro-26-dimethyl-4-(3-nitrophenyl)- 3-methyl5-[(3R)-1-(phenylmethyl)-3-piperidinyl] ester hydrochloride(1 1))
Benidipine influences processes connected with OS inseveral ways It prevents lysophosphatidylcholine- (lysoPC)-induced injury and ROS production in human aorticendothelial cells (HAECs) (Matsubara and Hasegawa [214])Matsubara et al [215] explained this effect based on stimula-tion of nitric oxide release
LysoPC is a component of oxidized low-density lipopro-teins (oxLDLs) which plays an important role in the patho-genesis of atherosclerosis Pretreatmentwith benidipine (03ndash3 120583molL) for 24 h protected against lysoPC-induced cyto-toxicity in the HAECs through inhibition of both lysoPC-stimulated ROS production and caspase-37-like activationwith a similar potency Since caspase-37 is involved inexecuting the apoptotic process the reduction of the activityof this enzyme by benidipine may explain the antiapoptoticeffect of the drug However benidipine did not suppresslysoPC-induced phosphorylation of mitogen-activated pro-tein kinases and Ca2+ influx in HAECs These results suggestthat the antioxidant properties of benidipine may be respon-sible for its ability to inhibit ROS production a possiblereason for reduced activation of caspase-37 In conclusionbenidipine suppresses lysoPC-induced endothelial dysfunc-tion through inhibition of ROS production which is due atleast in part to its antioxidant effect and not through theinhibition of L-type voltage-dependent calcium channels
Matsubara and Hasegawa [216] examined the effectsof benidipine on cytokine-induced expression of adhesionmolecules and chemokines (chemoattractants) which areimportant for the adhesion of monocytes to endotheliumPretreatment of HAECs with benidipine (03ndash10 120583molL)for 24 h significantly suppressed cytokine-induced vascularcell adhesion molecule-1 (VCAM-1) and intracellular celladhesion molecule-1 (ICAM-1) mRNA and protein expres-sion resulting in reduced adhesion of THP-1 monocytesBenidipine also suppressed induction of monocyte chemoat-tractant protein-1 (MCP-1) and interleukin-8 Benidipinealso inhibited redox-sensitive transcriptional nuclear factor-120581B (NF-120581B) pathway as determined by Western blotting ofinhibitory 120581B (I120581B) phosphorylation and luciferase reporterassay Results of analysis using optical isomers of benidip-ine and antioxidants suggest that these inhibitory effectswere dependent on pharmacological effects other than Ca2+antagonism Benidipine may thus have anti-inflammatoryproperties and benefits for the treatment of atherosclerosis
Oxidative Medicine and Cellular Longevity 21
Benidipine was also shown to inhibit ROS production inpolymorphonuclear leukocytes and oxidative stress in salt-loaded stroke-prone spontaneously hypertensive rats (Mat-subara et al [217])
It should be mentioned that other DHPs also haveendothelial AO actions [218]
357 Azelnidipine (AZL) Azelnidipine 3-[1-[di(phen-yl)methyl]azetidin-3-yl] 5-propan-2-yl 2-amino-6-methyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate(AZL) CAS number 123524-52-7 is commercially available4-nitroaryl-DHP type calcium antagonist with long-actingantihypertensive action (long-acting CA (CCB)) and a lowreported incidence of tachycardia It additionally possessesbeneficial effects in OS and diabetic conditions
Azelnidipine prevents cardiac dysfunction in strepto-zotocin-diabetic rats by reducing intracellular calcium accu-mulation (altering intracellular Ca2+ handling proteins) OSand apoptosis (Kain et al [219]) AZL can reduce the superox-ide production It exerts its protective effects by targeting theNADPH oxidase and mitochondrial redox enzymes AZL-treated diabetic rats express enhanced level of bcl-2 in thelysates of heart muscle indicating that AZL plays protectiverole in cardiac apoptosis
It has been previously observed that azelnidipine inhibitstumor necrosis factor-alpha-induced endothelial cell (EC)oxidative stress through its AO properties (Nakamura etal [220]) Azelnidipine but not nitrendipine completelyinhibits the Ang II-induced ROS generation in ECs (Matsuiet al [221])
Furthermore azelnidipine but not nitrendipine wasfound to partially restore decreased pigment epithelium-derived factor (PEDF) mRNA levels in Ang II-exposed ECsThis study suggests that AZL influence depends on its antiox-idative properties Authors concluded that upregulation ofPEDF by azelnidipine may become a therapeutic targetfor the treatment of diabetic retinopathy associated withhypertension
Antihypertensive agents with AO effects are potentiallyuseful for diabetic patients with hypertension While DHPtypeCAare among themost frequently used antihypertensivedrugs azelnidipine has been reported to have a unique AOeffect in vitro and in vivo in experimental animals (Ohmuraet al [222]) In hypertensive diabetic patients azelnidipinetreatment for 12 weeks induced a more significant decreasein erythrocyte LOOH level than amlodipine although thevalues related to blood pressure during each treatmentremained comparable These data confirm the usefulness ofLOOH level in erythrocyte membrane as a marker of OS invivo and indicate that azelnidipine has a unique antioxidativeproperty in humans
Daikuhara et al [223] reported the results of the OLCAstudy based on combination of (1) olmesartan and a calciumchannel blocker (azelnidipine) or (2) candesartan and a CCBamlodipine in two groups of diabetic hypertensive patientsPatients treated with the first combination presented highlypersistent early morning antihypertensive effect and strongerdecrease in heart rate fasting blood glucose andHbA1c levels
and microalbuminuria when compared to patients treatedwith the combination (2) Because diabetes is associated withsevere chronic OS the observed results might be at least in apart due to the AOA of azelnidipine
In favor of this are findings of Abe et al [224] who foundadditive antioxidative effects of azelnidipine on angiotensinreceptor blocker olmesartan treatment for type 2 diabeticpatients with albuminuria
Similarly the AOA of thiazolidinediones (insulin sensi-tizer) and their effect on cardiovascular function in type 2diabetic model rats and also those of some DHPs (nifedipineamlodipine or AZL commonly used antianginal and anti-hypertensive agents) in cultured human endothelial cells LPwere examined (Mizushige [225]) The AOA was evaluatedby measuring 8-iso-prostaglandine F
2120572concentration and
azelnidipine exhibited potent AOAInsulin (INS) resistance combined with hyperinsuline-
mia is involved in the generation of OS A relation-ship exists between increased production of ROS and thediverse pathogenic mechanisms involved in diabetic vascularcomplications including nephropathy Manabe et al [226]revealed that high doses of INS augmented mesangial cellproliferation through generation of intracellular ROS andactivation of redox signaling pathways Cell proliferation wasincreased in a dose-dependent manner by high doses of INS(01ndash10 120583M) but was inhibited by 01120583M AZL Namely theINS-increased phosphorylation of mitogen activated proteinkinaseextracellular signal-regulated kinase 12 (MAPKERK12) was inhibited by 01 120583MAZL The same AZL concen-tration blocked intracellular ROS production more effec-tively than 01 120583M nifedipine The NADPH oxidase inhibitorapocynin (001ndash01120583M) prevented INS-induced mesangialcell proliferation So azelnidipine inhibits insulin-inducedmesangial cell proliferation by inhibiting the productionof ROS Therefore azelnidipine may have the potential toprotect against the onset of diabetic nephropathy and slowits progression
Azelnidipine inhibited H2O2-induced cell death in
neonatal rat cardiomyocytes (Koyama et al [227]) Azelnidip-ine and nifedipine did not affect theH
2O2-induced activation
of extracellular signal-regulated protein kinases (ERK) andp38 MAPK (mitogen-activated protein kinase) In contrastazelnidipine but not nifedipine inhibited H
2O2-induced c-
Jun NH2-terminal kinases (JNK) activation Authors con-
cluded that azelnidipine has inhibited theH2O2-induced JNK
activation and cardiac cell death Therefore azelnidipine mayhave cardioprotective effects against OS
A specific atheroprotection activity of azelnidipine relatesto inhibition of TNF-120572-induced activator protein-1 activa-tion and interleukin-8 expression in human umbilical veinendothelial cells (HUVEC) through suppression of NADPHoxidase-mediated reactive oxygen species generation (Naka-mura et al [220]) TNF-120572 could play a central role in patho-genesis of insulin resistance and accelerated atherosclerosis inthe metabolic syndrome The concentration of AZL found tobe effective in these in vitro experiments is within therapeuticrange As EC do not possess voltage-operated L-type calciumchannels it is suggested that the beneficial effects of azelni-dipine are not likely due to CA property but to its unique AO
22 Oxidative Medicine and Cellular Longevity
ability Furthermore it has been recently found that serumlevels of monocyte chemoattractant protein-1 a biomarkerfor subclinical atherosclerosis were significantly decreased bythe AZL treatment in patients with essential hypertension Inthis paper [220] authors hypothesize that due to its uniqueTNF-120572 signalmodulatory activity and antioxidative propertyazelnidipine may be a promising DHP for targeting diabetesand cardiovascular diseases in hypertensive patients withmetabolic syndrome
Shinomiya et al [228] evaluated its AOA in culturedhuman arterial EC under OS Azelnidipine has shown apotent antioxidative effect that could be of significant clinicalbenefit when combined with its long-lasting antihypertensiveaction and low incidence of tachycardia
Azelnidipine inhibited TGF-1205731 and angiotensin II- (AngII-) activated 1205721(I) collagen mRNA expression in hepaticstellate cells (HSCs) (Ohyama et al [229]) FurthermoreTGF-1205731- and Ang II-induced OS and TGF-1205731-induced p38and JNK phosphorylation were reduced inHSCs treated withAZL Azelnidipine significantly decreased inflammatory cellinfiltration profibrotic genes expression HSC activation LPoxidative DNA damage and fibrosis in liver of CCl
4- or
TAA-treated mice Finally AZL prevented decrease of theexpression of some AO enzymes and accelerated regressionof liver fibrosis in CCl
4-treated mice Hence the antifibrotic
mechanism of AZL against CCl4-induced liver fibrosis in
mice may have been due to an increased level of AO defenseAs azelnidipine is widely used in clinical practice withoutserious adverse effects it may provide an effective newstrategy for antifibrotic therapy
358 Manidipine Manidipine (2-[4-(diphenylmethyl)pip-erazin-1-yl]ethyl methyl 26-dimethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate) is a DHP CCB withreported nephroprotective properties Calo et al [230] stud-ied effect of manidipine on gene expression and proteinlevel of OS related proteins p22(phox) (human neutrophilcytochrome b light chain (CYBA)) and heme oxygenase-1HO-1 Relevance for antihypertensive effects was revealedThe study assessed the effect of manidipine on normalsubjectsrsquo monocyte gene and protein expression of OS relatedproteins such as p22phox a NADPH oxidase system subunitcritical in generating O
2
∙minus and HO-1 induced by and pro-tective against OS Manidipine was compared with the ACEinhibitor captopril and the CCB nifedipine in the presenceand in the absence of sodiumarsenite (NaAsO
2) as an inducer
of OS Monocyte p22phox (CYBA) mRNA production wasreduced by both manidipine and captopril while no changeswere induced by nifedipine Manidipine increased monocyteHO-1 mRNA production while nifedipine and captoprilshowed no effect The effects of manidipine on p22phoxand HO-1 gene expression in the presence of OS were alsoconfirmed at the protein level Thus manidipine seems tosuppress p22phox and to increase the HO-1 mRNA produc-tion and protein level The manidipine-induced increase ofHO-1 gene and protein expression seems to be a peculiareffect of this drug since it is not observed with captopriland nifedipine This effect together with the reduction of
p22phoxmRNAproduction could play a role in its protectivemechanism against OS
359 Mebudipine The protective effect of mebudipine (14-dihydro-26-dimethyl-4-(3-nitrophenyl)-35-pyridinedicar-boxylic acid 3-methyl-5-tert-butyl ester BAY-n-6391) wasrevealed on OS and LP (MDA decrease SOD GPX andcatalase increase) in myocardial ischemic-reperfusion injuryin male rats (Ghyasi et al [231])
There are articles about other commercial and experi-mental DHPs on OS but we have reviewed only the mostcommonly studied compounds Effects of other commercialCA DHPs on OS are also mentioned in several parts of thisreview
36 14-DHPs Ca Agonists andTheir AOA and ARA For themost popular calcium agonist DHP Bay K 8644 no reactionwith peroxyl radicals was registered (Toniolo et al [114])However interactionwith other compounds possessing AOAand ARA (quercetin) was found
Opposite to that AON-acetylcysteine (NAC) diminishedincrease in Ca2+ transient amplitude and cell shorteninginduced by ISO and forskolin whereas NAC had no effecton the (S)-(minus)-methyl-14-dihydro-26-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylatemdash(minus)-BayK 8644-induced increases (Andersson et al [232])
Increased vasoconstriction responses to Bay K 8644 (3 times10minus7ndash3times 10minus5M)were significantly decreased by pyridoindoleantioxidant stobadine treatment in diabetes (Ceylan-Isik etal [233])
The functional interaction between two L-type Ca2+channel activators quercetin and Bay K 8644 has beeninvestigated in vascular smooth muscle cells Biological ARAcompound quercetin at nutritionally meaningful concen-trations limited the responsiveness of vascular L-type Ca2+channels to the pharmacological stimulation operated by BayK 8644 These data contribute to a better understanding ofquercetin effects on experimental in vivo cardioprotection(Saponara et al [234]) Thus these findings indicated thatalthough Bay K 8644 does not exert potent and direct AOAyet acting as calcium agonist it may affect efficiency of AOsubstances and vice versa
Interaction of grapefruit juice (containing quercetin andits analogues) with DHPs CA diminished effectiveness of CAaction of DHPs (Sica [235])
37 Interpretations of the Mechanism(s) of RadicalScavenging and AOA by DHPs
371 Molecular Mechanism(s) of Radical Scavenging andAOA of DHPs in the Model Systems 35-Dicarbonyl-14-di-hydropyridine derivatives possess powerful bis-120573-carbony-lvinyl-amino conjugation and for that reason cannot be con-sidered as ordinary amino antioxidants The electron andorH donation from DHPs ensures their reductant role andresults in AOA and ARA Oxidation reaction from DHPsresults in production of corresponding heteroaromatic pyri-dine derivatives
Oxidative Medicine and Cellular Longevity 23
Detailed studies were made about substituent in DHPring positions 14- namely 4-unsubstituted- 4-substituted4-alkyl- 4-aryl- 4-alkylaryl- ao 26- 35- (diacetyl ordialkoxycarbonyl chain ao) electronic and steric effects onAOA and ARA of DHPs [44 45 51] see Sections 331and 35 The bell-shaped dependence of DHPs AOA onthe 35-dialkoxycarbonyl- chain length was observed [4445 107 109 112] with the maximum activity at C
2H5ndash
C4H9 Decrease of AOA and incorporation into liposomes for
DHPs with alkyl chains longer than R gt C4H9further were
clarified as probable tendency to self-aggregation of thesecompounds ([51] and citation number 245 therein) Electronacceptorelectron donor properties are relevant for expres-sion of AOA or ARA of 35-disubstituted DHPs 35-Diacyl-substituted and 35-dicarbanilido- and 35-dipyridylamido-substituted DHPs are more active as AOs as their 35-dicyano-substituted analogues which have electron acceptorproperties [186]
Dubur et al [89] observed overwhelming steric influenceof substituents in position 4 of the DHP ring Gaviraghiet al [163 164] proposed that AO activity of DHPs ispartly dependent on capacity of the 14-DHP ring to donateelectrons to the propagating radical (ROO∙ or RO∙) and toreduce it to a less reactive form The abstraction (donation)of electron andor H in the oxidation and LP reactionstakes place from all 35-dicarbonyl-14-DHP systems andresults in the formation of corresponding pyridine derivatives(Augustyniak et al [51]) The physicochemical mechanism ofARA and AOA of 14-DHP has been extensively studied anddiscussed (Mulder et al [236]) but precise mechanisms oftheir activity need further clarification
The reactivity of C-4 substituted 14-DHPs possessingeither secondary or tertiary nitrogen atom in the DHP ringtoward alkyl alkylperoxyl radicals and ABTS radical cationwas determined in aqueous media at pH 74 [103] Thesecompounds reacted faster toward alkylperoxyl radicals andABTS radical cation than alkyl ones N-Ethyl-substitutedDHPs showed the lowest reactivity
The 4-methyl substituted DHP was the most reac-tive compound in previously mentioned reactions (Lopez-Alarcon et al [103]) However it was less active (068versus 10) than Trolox-C DHPs having electron-donatingsubstituents (4-Me-DHP and p-MeO-Phe-DHP) showed thehighest kinetic rate constants toward ABTS radical cation p-nitro-Phe-DHP a compound with an electron-withdrawingsubstituent showed a lower kinetic rate constant and N-alkyl-DHP compounds show kinetic rate constants lowerthan the -NH-DHP
Hydrogen at the 1-position of the DHP ring was revealedaccording to the deuteriumkinetic isotope effect studies to beinvolved in the proposedARAmechanismThis fact ismostlynoticeable in the case of alkyl radicals N-Ethyl-substitutedDHPs show the lowest reactivity when compared to Troloxor nisoldipine In all cases the respective pyridine derivativewas detected as the main product of the reaction (Lopez-Alarcon et al [103]) Authors indicate that the kinetic rateconstants toward alkyl alkylperoxyl andABTS radical cationdepend on the nature of the substituents in the C-4 positionof DHP and the presence of the secondary amine group in the
dihydropyridine ring that is the presence of the hydrogen in1-position
Yanez et al [197] have studied the reactivity of 11derivatives of 14-DHPs (including commercial CA) withalkylperoxyl radicals and ABTS radical cation The tested14-DHPs were 83-fold more reactive towards alkylperoxylradicals than to the ABTS cation radical All commercial14-DHP type CCBs were weaker than Trolox-C The par-ticipation of the hydrogen atom in the 1-position appearsto be very relevant for exhibited reactivity Hantzsch ester(diludine)was again found to be themost active compound inthe reaction with alkylperoxyl radicals 23-fold more activethan Trolox The photodegradation product of nifedipine(nitrosophenyl derivative of pyridine) also showed a highactivity Kinetic rate constants for the reaction between 14-DHP compounds and alkylperoxyl radicals exhibited a fairlygood linear correlation with the oxidation peak potentialof DHP derivatives However the activity of tested 14-DHPs towards ABTS radical cation showed an independencebetween kinetic rate constants and oxidation peak potentials
Kirule et al [195] andTirzit et al [196] studiedmechanismof AOA of 4-nitrophenyl-14-DHPs nifedipine and its ana-logues involving formation of 4-(21015840-nitrosophenyl)-pyridinederivative (as active principle) as a result of intramolecularredox reaction using chemical electrochemical and bio-chemical approaches (see Sections 331 and 351)
Nunez-Vergara et al [237] reported the electrochemicaloxidation of C4-hydroxyphenyl-substituted 14-DHP deriva-tives The oxidation proceeds via formation of the unstabledihydropyridyl radical as confirmed by controlled-potentialelectrolysis (CPE) and ESR experiments This type of 14-DHPs has significant activity towards the radicals even whencompared with commercial 14-DHP drugs with well-knownantioxidant ability
It was observed that nicardipine preferentially targets RO∙radicals and is inactive against ROO∙ Lacidipine on theother hand is equally active towards both types of radicals(Gaviraghi et al [164]) The cytoprotective effect againstexposure to H
2O2was more significant for lacidipine (ID
50=
14 nM its log119875 = 54 membrane partition = 136000 assumesposition located 7 A near to the membrane center otherless lipophilic DHPs located 12ndash16 A far from the center)as compared to amlodipine nifedipine and nicardipine insmooth muscle cell culture (Gaviraghi et al [164]) Oxidativeeffect of H
2O2shifts the Ca channel toward an open state
Thus the redox property of CCBs DHPs may augment theirCCB properties
Oxidation of pharmacologically active Hantzsch 14-dihydropyridines was found by electrogenerated superoxideusing a voltammetric approach in DMSO solutions (Ortiz etal [238] and Ortiz et al [239]) Raghuvanshi and Singh [240]have also reported oxidative aromatization of these DHPsinduced by superoxide
Chemiluminescence (CL) was used in the studies ana-lyzing the antioxidant activity of 12 various 4-flavonil-14-dihydropyridine derivatives (Kruk et al [241]) on a chemicalsystem involving a superoxide radical anion These deriva-tives showed structural similarity to flavonoids with respectto the presence of rings A B and C The results obtained in
24 Oxidative Medicine and Cellular Longevity
this study indicate that the tested derivatives may catalyzeconversion of superoxide radicals through mimicking theactivity of superoxide dismutase by delivering H+ for reac-tion
O2
minus∙+O2
minus∙+ 2H+ 997888rarr H
2O2+1O2
(3)
The enhanced emission of the light in the presence oftested compounds was significant and related to stimulatedproduction ofH
2O2and 1O
2fromO
2
∙The latter specieswereremoved from the reactionmixture by the following sequenceof reactions
H+
O2
minus∙997888rarr HO
2
∙
HO2
∙+O2
∙minus997888rarr HO
2
minus+1O2
2HO2
∙997888rarr H
2O2+1O2
2 (1O2) 997888rarr (O
2)2+ h]lowast
(4)
or to take part in spontaneous dismutation of H2O2
2H2O2997888rarr 2H
2O + 1O
2(5)
The authors have offered an original concept of action for 4-flavonil-14-dihydropyridine derivatives unrelated to that ofO2
∙ radical-trapping chain-breaking antioxidants Insteadthey showed that these compounds act similar to superoxidedismutases converting O
2
∙ to H2O2 Hydrogen peroxide
is less toxic for cells than O2
∙ because it is predominantlyremoved by peroxidases and catalases Finally AO effect ofthese DHPs differed from those mediated by flavonoids witha catechol structure of ring B which are well-known 1O
2
quenchersMulder and collaborators came to similar conclusions
especially related to molecular mechanisms of antioxidativeactivity of DHPs [236]TheAOproperties of Hantzsch 14-di-hydropyridine esters and two dibenzo-14-dihydropyridines910-dihydroacridine (DHAC) and N-methyl-910-dihydro-acridine (N-Me-DHAC) have been explored by determin-ing the autoxidation of styrene or cumene at 30∘C Theseexperiments showed that Hantzsch esters are virtually inac-tive as chain-breaking antioxidants (CB-AOs) contrary tothe findings observed by Lopez-Alarcon et al [103] whoused CB-AOA in aqueous media at pH 74 Their reactivitytoward peroxyl radicals was shown to be some 5 orders ofmagnitude lower than that of the excellent CB-AO 22578-pentamethyl-6-hydroxy-chroman (PMHC)
DHAC was found to be sim10 times less reactive thanPMHC kinetic measurements using DHAC N-deuterio-DHAC and N-Me-DHAC pointing out the abstraction ofN-H hydrogen in DHAC by peroxyl radicals despite the factthat the calculated C-H bond dissociation enthalpy (BDE) inDHAC is about 11 kcalmol lower than the N-H BDE Therates of hydrogen atom abstraction by the 22-diphenyl-1-picrylhydrazyl radical (DPPH∙) have also been determined
for the same series of compounds The trends in the peroxyl∙and DPPH∙ rate constants were found to be similar [236]
Tirzit et al [242] have observed quenching of singletoxygen by DHPs This observation paved the ground forfurther research related to reactions of DHPs with hydroxylradicals (Tirzit et al [243]) singlet oxygen (Kazush etal [94]) and mechanisms of action A series of 14-DHPderivatives in NAD-H-Cu2+-H
2O2system inhibited forming
of the hydroxyl radical (HO∙) while 14-DHP derivativeswith electron donor substituents in the molecule were shownto be capable themselves of generating HO∙ in the presenceof Cu2+ and H
2O2 Rubene et al [186] also described
interaction of 14-DHP derivatives with Fentonrsquos reagentwhich produces hydroxyl radical (HO∙) Rate constants ofthe DHPs reaction (1st order) with HO∙ radical were highin the range 109 L times mol times secminus1 close to that of NADHcysteine and thiourea 35-Diacetyl- derivatives reacted fastercompared to 35-dialkoxycarbonyl- ones The reaction ratedecrease was observed in the case of substitution at position4 as compared to 4-unsubstituted DHPs Some DHPs havingelectron donor -COOminus groups in the 35- or 26- positionsof DHP ring reacted immediately (having rate constantshigher as 109 L times mol times secminus1) Rate constants with HO
2
∙
and O2
∙minus radicals were of lower degree Thus DHPs actingas oxygen radical scavengers could effectively inhibit ROSrelated reactions of LP initiation stage
Nifedipine and nitrendipine reactivity toward singletoxygen was also studied [244] Nifedipine was shown tobe a good scavenger of excited oxygen mainly via physicaldeactivation with values of the total rate constant rangingfrom 208 times 105Mminus1 sminus1 (in dioxane) to 930 times 105Mminus1 sminus1(in propylene carbonate)The less reactive pathway generateda photooxidation product For that reason a mechanisminvolving a perepoxide-like encounter complex in the firststep of the reaction path was proposed (see [244] Figures8 and 9 therein) The dependence was observed on solventmicroscopic parameters of the total rate constant for the reac-tion between singlet oxygen and 14-DHPs These findingsshow that nifedipine possesses stronger protective activity inbiological systems than nitrendipine
Density-functional-theory (DFT) calculations made byWang et al [245] confirmed the former experimental obser-vations that Hantzsch ester diludine is potent antioxi-dant with high H atom-donating ability and relatively lowprooxidant activity Possible reaction pathways for radicalsderived from 14-dihydropyridine and the resonance modesfor radical species were given [245]
Moreover two ethoxycarbonyl (EtOCO) substituentsat C(2) and C(6) should further enhance Hantzsch esterdiludine H-atom-donating ability due to resonance effectsHowever DHPs should be used in nonpolar rather than inpolar solvents since in the latter not H-atom but electrontransfer is preferred in the radical scavenging process [245]
Mulder et al [246] proposed that quantum-thermochem-ical calculations must be used with caution to indicate ldquoapromising lead antioxidantrdquo as they criticized the density-functional-theory (DFT) calculations made by Wang et al[245]
Oxidative Medicine and Cellular Longevity 25
372 Possible Mechanisms of DHPs ARA and AOA in the Bio-logical Systems Interaction with Other OSModifiers Some ofthese mechanisms were already described (Sections 331 (2)-(b) 331 (2)-(c) 331 (3)-(b) 35)
Enzymatic sources of ROSwith confirmed functional rolein hypertension are NADPH oxidase NO synthase (NOS)xanthine oxidase and cyclooxygenase Godfraind [3] hasreviewed AO effects and protective action of calcium channelblockers (CCBs) Yao et al [247] observed antioxidant effects(as inhibition of LP) for cardio- and neuroprotective CCBs(3ndash300 120583molL) including 7 DHPs in homogenates of ratbrain IC
50values (120583M) were as follows nifedipine (515) gt
barnidipine (586) gt benidipine (712) gt nicardipine (1293)gt amlodipine (1355) gt nilvadipine (1673) gt nitrendipine(2521) gt diltiazem (gt300) = verapamil (gt300) There arealso research articles describing the AO properties of CCBsthrough direct scavenging effect or through preservationof the endogenous SOD activity These findings indicatethat CCBs may also act by reducing the production ofvasoconstrictors angiotensin and endothelin
When present in concentrations that can be achievedin plasma CCBs may inhibit LP formation [3] This AOactivity seems to be typical for high lipophilic CCBs becausetheir chemical structure facilitates proton-donating andresonance-stabilization mechanisms that quench the freeradical reaction Their insertion in the membrane nearpolyunsaturated fatty acids at relatively high concentrationspotentiates proton donation (or atomary H) to lipid peroxidemolecules thereby blocking the peroxidation process Theremaining unpaired free electron associated with the CCBmolecule can be stabilized in well-defined resonance struc-tures associated with the DHP ring (Mason et al [48])
The radical reaction (according to Godfraind [3]) thatdescribes the AO effects of a DHP CCBs is LOOlowast + DHPrarr LOOH + DHPlowast (where LOOlowast is lipid peroxide radical)which in general is reaction (7) of the LP reaction cascadeconsisting of sim10 reactions (Scheme 2) [89]
As the rate constants of in vitro interaction of 4-substituted DHPs with peroxyl radicals are three ordersof magnitude lower than that of the vitamin E derivativethese DHPs must be considered as weak AO (Ursini [204])However due to partition coefficient of DHPs in membranesand in case of specific binding high local concentration ofDHPs may be obtained
DHPs without CCB properties for instance Bay w 9798although structurally related to nifedipine inhibit TNF-120572-induced vascular cell adhesion molecule-1 expression inendothelial cells by suppressing reactive oxygen speciesgeneration [248]
Mitrega et al [249] have discovered that antiarrhythmicand hemodynamic effects of oxidized heteroaromatic DHPsoxy nifedipine oxy nimodipine oxy nitrendipine and oxynisoldipine suggest that CCB DHPs and their metabolitescould act at least in two ways targeting OS related eventsas reductants (see Section 351 (1)) andor bypassing OSrelatedmetabolic routes Authors postulated that contrary tocurrent belief NIF metabolites are pharmacologically activeATP sensitive potassium channels were mentioned as a tar-get
38 DHPs Anti- or Prooxidants Several substances (ascorbicacid being the most commonly studied) can serve either asantioxidants or as prooxidants depending on given condi-tions (Herbert [250]) Therefore Halliwell [251] has reporteddilemma related to polyphenols as possible antioxidantsand prooxidants causing experimental artifacts (about 25)by oxidation of antioxidant compounds in the cell culturemedia Nevertheless it is generally accepted opinion thatpolyphenols act as antioxidants in vivo Studies on DHPs alsoface such a dilemmaThe exact roles (anti- or prooxidative) ofany specific DHP depend on its structure appliedachievedconcentration and specificity of the targetexperimentaltesting system
This situation resembles the case of antioxidative effectsof tocopherol which depends on the fate of the secondaryradical as proposed by Winterbourn [252] The question wasldquoVitamin E - Pro- or Antioxidantrdquo
997888rarr chain termination of lipid peroxidation
(6)
Prooxidant
Toc∙ + Lipid-H 997888rarr Lipid∙ (in LDL particles) (7)
This example shows that generally speaking any AO mustfulfil several criteria to be considered as an effective com-pound physiologically
(i) It must be able to functionally interact with endoge-nous scavengers even at low concentrations
(ii) It must affect endogenous pathways of OS(iii) It should not have undesirable adverse effect(iv) It should manifest the antioxidant efficacy dependent
on the oxidant(v) It must discriminate among different strategies
needed for 1-electron and 2-electron processes(vi) Radical scavengers can be prooxidant unless linked to
a radical sink (Winterbourn [252])
According to these statements DHPs could be effective asAO under physiological conditions in vivo (Godfraind [3]and others [30 31 38]) and in vitro in various experimentalsystems (cell and tissue) (see Sections 33 34 35)
Hence calcium antagonists appeared to disrupt thefine balance between the production and scavenging ofROS Nifedipine verapamil and diltiazem were shown toinduce significant oxidative stress in the epididymal sperm(increased MDA and decreased catalase and superoxidedismutase activity) This may be the reason for the inductionof male infertility [253]
The dualism of 14-DHP effects has been recorded asinhibition or promotion of LP as quenching or initiating
26 Oxidative Medicine and Cellular Longevity
oxygen and nitrogen free radical chain reactions radiopro-tecting or radiosensitizing antagonizing or synergizing Ca2+in electromechanical coupling as well as in the membranestabilization or labilization
39 Could DHPs Be Involved in Antioxidative Stress Beforebeing applied in vivo the optimal dose and optimal timeintervals forDHPs applicationmust be knownNamely whileROS have been traditionally considered as toxic byproductsof aerobic metabolism we know nowadays that ROS may actas essential signaling molecules needed for the control ofmany different physiological processes Whether the role ofROS will be damaging protective or signaling depends onthe delicate equilibrium between time- and location-specificROS production and scavenging Accordingly the imbalanceof the increased AO potential so-called antioxidative stresscould be dangerous similar to chronic OS in particular incase of extended exposure Inappropriate interventions inthe oxidative homeostasis by excessive antioxidants especiallyin case of chronic exposure to antioxidants might havevery negative effects as was published in the ATBC studyshowing an increased cancer incidence in smokers treatedby excessive beta-carotene [254] Therefore overconsump-tion of any natural or synthetic AO including DHPs asdietary supplements or drugs must be avoided in order tosuppress oxidative damage and must not disrupt the well-integrated antioxidant defense network (Poljsak [255] andPoljsak and Milisav [256]) This is especially important whenadministrating lipid-soluble antioxidants that can be storedin biomembranes thus not only attenuating or preventing LPbut also affecting physiological effects of the natural antiox-idants in particular tocopherol The interrelationship withthe status of endogenous antioxidantsprooxidants should befollowed
DHPs primarily suppress the initiation stages of LPprocessThey do not entirely stop the LP propagation Actingsynergistically with tocopherol diludine may prevent patho-logical excess of ROS production within the lipid moiety ofthe cellular membranes and LDL However due to its lowsolubility and fast metabolism its concentration in the cellsis low For that reason it cannot cause antioxidative stresseven if used for an extended period of time Thus diludine(diethone) could be only a mild antioxidant it has potentialfor restoring the pool of natural antioxidants (as synergist of120572-tocopherol and polyphenols) in the cells
Moreover DHPs CA used for cardioprotection andvasodilatation as commercial drugs in low concentrationsare fast metabolized via CYP3A4 and for that reason theirapplication does not induce cellular AO stress [53 160]However Godfraind and Salomone [257] have postulated noevidence that allows recommending dietary supplementationwith antioxidants for the primary or secondary prevention ofcardiovascular disease
So far there are no reports on antioxidative stress causedby some DHPs diludine and its analogues Diludine andits analogues therefore could act as adaptogens supportinghormetic effects of mild oxidative stress These compoundsmay act as potential multisided modulators of Yin-Yang
cycles of redox and cell functions (the electroplasmic cycle)(Wagner et al [258])
4 Conclusions
14-Dihydropyridines (14-DHPs) have broad spectrum ofOS modulating activities DHPs have reducing and lipidperoxidation inhibitor properties act as reductants in simplechemical systems and stabilize various biological systems(LDL mitochondria microsomes cells and tissues) againstOS Examples and peculiarities and mechanisms of antiox-idant activity (AOA) and antiradical activity (ARA) as wellas stress-protective effect of DHPs including commercialcalcium antagonists (CA) were highlighted These activitiesdepend on various structural parameters related to DHPs(presence and character of substituents) lipophilicity anddepth of the incorporation in the biologicalmembranesTheyalso depend on the experimental model system for exploringthe lipid peroxidation or oxidative stress Stress-protectiveeffect of some metabolites of CA (nifedipine) is reviewedAlthough some DHPs including CA have prooxidant prop-erties (on epididymal sperm cells) they can generally beconsidered as potent antioxidants Therefore comparisonof the AOA and ARA of different DHPs (mutually andwith other AOs) was described in detail According to thedata presented the DHPs might be considered as bellwetheramong synthetic compounds targeting OS and as a kind ofpharmacological measure for respective field of organic andmedicinal chemistry
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
Authors from Latvian IOS acknowledge ESF 201300021DP1112013APIAVIAA011 and National Research Pro-gramme PUBLIC HEALTHBiomedicine of the Republicof Latvia for financial support administration of the Insti-tute for technical support and Rufus Smits PhD for con-sultations in English The support of Cooperation in Euro-pean System of Science and Technology (COST) Domain ofChemistry Molecular Sciences and Technologies (CMST)was of highest importance for preparation of this paper
[2] D J Triggle ldquo14-Dihydropyridines as calcium channel ligandsand privileged structuresrdquoCellular andMolecular Neurobiologyvol 23 no 3 pp 293ndash303 2003
[3] T Godfraind ldquoAntioxidant effects and the therapeutic modeof action of calcium channel blockers in hypertension andatherosclerosisrdquo Philosophical Transactions of the Royal SocietyB Biological Sciences vol 360 no 1464 pp 2259ndash2272 2005
[4] E Cadenas ldquoMitochondrial free radical production and cellsignalingrdquoMolecular Aspects of Medicine vol 25 no 1-2 pp 17ndash26 2004
[5] E Cadenas ldquoFree radicals oxidative stress and diseasesrdquo inLecture PSC 616 p 38 Missouri University of Science andTechnology Rolla Mo USA httpwwwcarnicominstituteorgarticlesenrique cadenaspdf
[6] K Rahman ldquoStudies on free radicals antioxidants and co-fac-torsrdquo Clinical Interventions in Aging vol 2 no 2 pp 219ndash2362007
[7] V Bocci and G Valacchi ldquoFree radicals and antioxidants howto reestablish redox homeostasis in chronic diseasesrdquo CurrentMedicinal Chemistry vol 20 no 27 pp 3397ndash3415 2013
[8] M Valko C J Rhodes J Moncol M Izakovic and M MazurldquoFree radicals metals and antioxidants in oxidative stress-induced cancerrdquo Chemico-Biological Interactions vol 160 no 1pp 1ndash40 2006
[9] G Bartosz ldquoReactive oxygen species destroyers or messen-gersrdquo Biochemical Pharmacology vol 77 no 8 pp 1303ndash13152009
[10] R Visconti and D Grieco ldquoNew insights on oxidative stress incancerrdquo Current Opinion in Drug Discovery and Developmentvol 12 no 2 pp 240ndash245 2009
[11] R N Kujundzic N Zarkovic and K G Troselj ldquoPyridinenucleotides in regulation of cell death and survival by redoxand non-redox reactionsrdquo Critical Reviews in Eukaryotic GeneExpression vol 24 no 4 pp 287ndash309 2014
[12] B Halliwell and J M C Gutteridge ldquoThe definition and mea-surement of antioxidants in biological systemsrdquo Free RadicalBiology and Medicine vol 18 no 1 pp 125ndash126 1995
[13] V D Kancheva and O T Kasaikina ldquoBio-antioxidantsmdashachemical base of their antioxidant activity and beneficial effect
on human healthrdquo Current Medicinal Chemistry vol 20 no 37pp 4784ndash4805 2013
[14] H V Panglossi Ed Frontiers in Antioxidants Research NovaScience Publishers New York NY USA 2006
[15] E B Burlakova E M Molochkina and G A NikiforovldquoHybrid antioxidantsrdquo Oxidation Communications vol 31 no4 pp 739ndash757 2008 httpmembraneustceducnpaperpdfHybrid20Antioxidantspdf
[16] A Bast and G R M M Haenen ldquoTen misconceptions aboutantioxidantsrdquo Trends in Pharmacological Sciences vol 34 no 8pp 430ndash436 2013
[17] E B Burlakova A V 0lesenko E M Molochkina N PPalmina and N G Khrapova Bioantioxidants for RadiationDamage and Malignant Growth Nauka Moscow Russia 1975(Russian)
[18] J Fang T Seki and H Maeda ldquoTherapeutic strategies by mod-ulating oxygen stress in cancer and inflammationrdquo AdvancedDrug Delivery Reviews vol 61 no 4 pp 290ndash302 2009
[19] M Valko D Leibfritz J Moncol M T D Cronin M Mazurand J Telser ldquoFree radicals and antioxidants in normal physi-ological functions and human diseaserdquo International Journal ofBiochemistry and Cell Biology vol 39 no 1 pp 44ndash84 2007
[20] M Jimenez-Del-Rio and C Velez-Pardo ldquoThe bad the goodand the ugly about oxidative stressrdquo Oxidative Medicine andCellular Longevity vol 2012 Article ID 163913 13 pages 2012
[21] C D Kamat S Gadal M Mhatre K S Williamson Q N Pyeand K Hensley ldquoAntioxidants in central nervous system dis-eases preclinical promise and translational challengesrdquo Journalof Alzheimerrsquos Disease vol 15 no 3 pp 473ndash493 2008
[22] A Pompella H Sies R Wacker et al ldquoThe use of totalantioxidant capacity as surrogate marker for food quality andits effect on health is to be discouragedrdquo Nutrition vol 30 no7-8 pp 791ndash793 2014
[23] Z Ye and H Song ldquoAntioxidant vitamins intake and the risk ofcoronary heart disease meta-analysis of cohort studiesrdquo Euro-pean Journal of Cardiovascular Prevention and Rehabilitationvol 15 no 1 pp 26ndash34 2008
[24] P Knekt J Ritz M A Pereira et al ldquoAntioxidant vitamins andcoronary heart disease risk a pooled analysis of 9 cohortsrdquoTheAmerican Journal of Clinical Nutrition vol 80 no 6 pp 1508ndash1520 2004
[25] A C Carr and M C M Vissers ldquoSynthetic or food-derivedvitamin Cmdashare they equally bioavailablerdquo Nutrients vol 5 no11 pp 4284ndash4304 2013
[26] R Tabrizchi ldquoEdaravoneMitsubishi-TokyordquoCurrentOpinion inInvestigational Drugs vol 1 no 3 pp 347ndash354 2000
[27] K Kikuchi S Tancharoen N Takeshige et al ldquoThe efficacy ofedaravone (radicut) a free radical scavenger for cardiovasculardiseaserdquo International Journal of Molecular Sciences vol 14 no7 pp 13909ndash13930 2013
[28] D Mauzerall and F H Westheimer ldquo1-Benzyldihydronicoti-namidemdasha model for reduced DPNrdquo Journal of the AmericanChemical Society vol 77 no 8 pp 2261ndash2264 1955 ChemicalAbstracts vol 50 Article ID 2588i 1956
[29] F Bossert and W Vater ldquo14-Dihydropyridinesmdasha basis fordeveloping new drugsrdquo Medicinal Research Reviews vol 9 no3 pp 291ndash324 1989
[30] G Swarnalatha G Prasanthi N Sirisha and CMadhusudhanaChetty ldquo14-Dihydropyridines a multtifunctional moleculemdash areviewrdquo International Journal of ChemTech Research vol 3 no1 pp 75ndash89 2011
28 Oxidative Medicine and Cellular Longevity
[31] M Cataldi and F Bruno ldquo14-Dihydropyridines the multiplepersonalities of a blockbuster drug familyrdquo Translational Medi-cine UniSa vol 4 no 2 pp 12ndash26 2012 httpwwwncbinlmnihgovpmcarticlesPMC3728803
[32] R Vitolina A Krauze G Duburs and A Velena ldquoAspects ofthe amlodipine pleiotropy in biochemistry pharmacology andclinicsrdquo International Journal of Pharmaceutical Sciences andResearch vol 3 no 5 pp 1215ndash1232 2012
[33] D Grover S N Mokale and M T Shete ldquoDihydropyridinea novel pharmacophorerdquo International Journal of Pharmaceu-tical Erudition vol 1 no 2 pp 16ndash29 2011 httppharmaeru-ditionorgContentPaper20111-RV-320Final2016-29pdf
[34] A M Vijesh A M Isloor S K Peethambar K N ShivanandaT Arulmoli and N A Isloor ldquoHantzsch reaction synthesis andcharacterization of somenew 14-dihydropyridine derivatives aspotent antimicrobial and antioxidant agentsrdquo European Journalof Medicinal Chemistry vol 46 no 11 pp 5591ndash5597 2011
[35] P Mehta and P Verma ldquoAntimicrobial activity of some deriva-tives of 14-dihydropyridinesrdquo Journal of Chemistry vol 2013Article ID 865128 4 pages 2013
[36] P Olejnıkova L Svorc D Olsovska et al ldquoAntimicrobialactivity of novel C2-substituted 14-dihydropyridine analoguesrdquoScientia Pharmaceutica vol 82 no 2 pp 221ndash232 2014
[37] S Sepehri H Perez Sanchez and A Fassihi ldquoHantzsch-typedihydropyridines and biginelli-type tetra-hydropyrimidinesa review of their chemotherapeutic activitiesrdquo Journal of Phar-macy amp Pharmaceutical Sciences vol 18 no 1 pp 1ndash52 2015httpsejournalslibraryualbertacaindexphpJPPSarticleview2383617863
[38] S A Khedkar and P B Auti ldquo14-Dihydropyridines a classof pharmacologically important moleculesrdquo Mini-Reviews inMedicinal Chemistry vol 14 no 3 pp 282ndash290 2014
[39] G D Tirzit and G Ya Duburs ldquo14-dihydropyridines as inhi-bitors of free-radical reactionsrdquo Chemistry of Heterocyclic Com-pounds vol 8 no 1 pp 126ndash127 1972 Translated from KhimiyaGeterotsiklicheskikh Soedinenii no1 pp 133ndash134 1972 (Rus-sian)
[40] I Bogeski R Kappl C Kummerow R Gulaboski M Hothand B A Niemeyer ldquoRedox regulation of calcium ion channelschemical and physiological aspectsrdquoCell Calcium vol 50 no 5pp 407ndash423 2011
[41] S A Giller G Y Dubur Y R Uldrikis et al ldquoDiludine [Themethod to obtain 35-dicarbonylderivatives of 26-dimethyl-14-dihydropyridines]rdquo Authors certificate of USSR no 3004651971 [Byull Izobret no13 p 95 1971] and following patentsPatent of England no 1294650 1973 Patent of France no2055458 1971 Patent of Japan no 702883 1973 Patent ofHolland no 149787 1976 Patent of Italy no 969022 1974 Patentof FRG no 2036403 1978 US Patent no 3883673 1975 USPatent no 3948924 1976
[42] S A Giller G Y Dubur Y R Uldrikis et al ldquoImprovementsin or relating to the stabilization of carotenerdquo GB Patent no1294650 1972
[43] S A Giller G Y Dubur Y R Uldrikis et al ldquoStabilization ofcarotenerdquo US Patent no 3883673 1975 Chemical Abstracts vol83 Article ID 95193 1975
[44] Yu A Zilber G Ya Dubur K K Kumsar and A Kh VelenaldquoThe effect of antioxidants on the peroxidation of bimole-cular phospholipid membranesrdquo Latvijas PSR ZA Vestis Izves-tia Akademii Nauk Latviyskoy SSR vol 6 pp 80ndash82 1971(Russian) translated from the original Russian Doc Accesion
No AD0771751 distributed by NTIS US Department of Com-merce httpwwwdticmildtictrfulltextu2771751pdf
[45] G Ya Dubur Yu A Zilbers A Kh Velena A O Kumerovaand G D Tirzitis ldquoMultistage study of regulation of peroxida-tion processes in biological membranes by antioxidants of 14-dihydropyridine grouprdquo Izvestiya Akademii Nauk LatviyskoySSR vol 336 no 7 pp 65ndash68 1975 (Russian)
[46] R P Mason and M W Trumbore ldquoDifferential membraneinteractions of calcium channel blockers Implications forantioxidant activityrdquo Biochemical Pharmacology vol 51 no 5pp 653ndash660 1996
[47] R P Mason M F Walter M W Trumbore E G Olmstead Jrand P E Mason ldquoMembrane antioxidant effects of the chargeddihydropyridine calcium antagonist amlodipinerdquo Journal ofMolecular and Cellular Cardiology vol 31 no 1 pp 275ndash2811999
[48] R PMason I T MakMW Trumbore and P EMason ldquoAnti-oxidant properties of calcium antagonists related to membranebiophysical interactionsrdquo American Journal of Cardiology vol84 no 4 pp 16ndash22 1999
[49] R PMasonMW Trumbore and P EMason ldquoMembrane bio-physical interaction of amlodipine and antioxidant propertiesrdquoDrugs vol 59 no 2 pp 9ndash16 2000 (French)
[50] R P Mason P Marche and T H Hintze ldquoNovel vascularbiology of third-generation L-type calcium channel antagonistsAncillary actions of amlodipinerdquo Arteriosclerosis Thrombosisand Vascular Biology vol 23 no 12 pp 2155ndash2163 2003
[51] A Augustyniak G Bartosz A Cipak et al ldquoNatural andsynthetic antioxidants an updated overviewrdquo Free RadicalResearch vol 44 no 10 pp 1216ndash1262 2010
[52] T Grune N Zarkovic and K Kostelidou ldquoLipid peroxidationresearch in Europe and the COST B35 action lsquoLipid Peroxida-tion Associated Disordersrsquordquo Free Radical Research vol 44 no10 pp 1095ndash1097 2010
[53] E Carosati P Ioan M Micucci et al ldquo14-Dihydropyridinescaffold in medicinal chemistry the story so far and perspec-tives (part 2) action in other targets and antitargetsrdquo CurrentMedicinal Chemistry vol 19 no 25 pp 4306ndash4323 2012
[54] U Eisner and J Kuthan ldquoThe chemistry of dihydropyridinesrdquoChemical Reviews vol 72 no 1 pp 1ndash42 1972 httpwwwsci-encemadnessorgtalkfilesphppid=138742ampaid=6475
[55] J Kuthan and A Kurfurst ldquoDevelopment in dihydropyri-dine chemistryrdquo Industrial amp Engineering Chemistry ProductResearch and Development vol 21 no 2 pp 191ndash261 1982
[56] A Sausins and G Duburs ldquoSynthesis of 14-dihydropyridinesby cyclocondensation reactionsrdquo Heterocycles vol 27 no 1 pp269ndash289 1988
[57] A E Sausins and G Y Duburs ldquoSynthesis of 14-dihydro-pyridines in cyclocondensation reactions (review)rdquo Chemistryof Heterocyclic Compounds vol 28 no 4 pp 363ndash391 1992Translated from Khimiya Geterotsiklicheskikh Soedinenii no 4pp 435ndash467 1992 (Russian)
[58] S Kazda ldquoTwenty years of dihydropyridinesrdquo in Dihydropy-ridines Progress in Pharmacology and Therapy W-D Busse BGarthoff and F Seuter Eds pp 1ndash12 Springer Verlag BerlinGermany 1993
[59] J-P Wan and Y Liu ldquoRecent advances in new multicomponentsynthesis of structurally diversified 14-dihydropyridinesrdquo RSCAdvances vol 2 no 26 pp 9763ndash9777 2012
[61] Reaxys Database[62] J Tuttle ldquoStructure mechanism and reactivity of hantzsch
estersrdquo in MacMillan Lab Group Meeting (082504) p 332004 httpwwwprincetoneduchemistrymacmillangroup-meetingsJBT20Hantzschpdf
[63] A Saini S Kumar and J S Sandhu ldquoHantzsch reaction recentadvances in Hantzsch 14-dihydropyridinesrdquo Journal of Sci-entific amp Industrial Research vol 67 pp 95ndash111 2008
[64] L LW Cheung S A Styler and A P Dicks ldquoRapid and conve-nient synthesis of the 14-dihydropyridine privileged structurerdquoJournal of Chemical Education vol 87 no 6 pp 628ndash630 2010
[65] A Kumar R A Maurya S Sharma M Kumar and G BhatialdquoSynthesis and biological evaluation of N-aryl-14-dihydro-pyridines as novel antidyslipidemic and antioxidant agentsrdquoEuropean Journal of Medicinal Chemistry vol 45 no 2 pp 501ndash509 2010
[66] R S Kumar A Idhayadhulla A J Abdul Nasser and J SelvinldquoSynthesis and anticoagulant activity of a new series of 14-dihydropyridine derivativesrdquo European Journal of MedicinalChemistry vol 46 no 2 pp 804ndash810 2011
[67] H A Stefani C B Oliveira R B Almeida et al ldquoDihydro-pyrimidin-(2H)-ones obtained by ultrasound irradiation anew class of potential antioxidant agentsrdquo European Journal ofMedicinal Chemistry vol 41 no 4 pp 513ndash518 2006
[68] H Sun C Shang L Jin and J Zhang ldquoSynthesis and antiox-idant activity of a series of novel 3-chalcone-substituted 14-dihydropyridine derivativesrdquoHeterocyclic Communications vol18 no 5-6 pp 239ndash243 2012
[69] D B Tikhonov and B S Zhorov ldquoStructural model for dihy-dropyridine binding to L-type calcium channelsrdquo The Journalof Biological Chemistry vol 284 no 28 pp 19006ndash19017 2009
[70] G Y Dubur and Y R Uldrikis ldquoThe oxidation of 14-dihydro-pyridinesrdquo Chemistry of Heterocyclic Compounds vol 6 no 1pp 80ndash84 1970 Translated from Khimiya GeterotsiklicheskikhSoedinenii no 1 pp 83ndash88 1970 (Russian)
[71] G Ya Duburs A O Kumerova and Ya R Uldrikis ldquoEnzymicoxidation of hydrogenated pyridines with peroxidase-hydrogenperoxide systemrdquoLatvijas PSRZAVestis vol 73 no 7 pp 73ndash771970 (Russian) Chemical Abstracts vol 73 Article ID 94913g1970
[72] K Xie Y-C Liu Y Cui J-GWang Y Fu andT CWMak ldquoN-methyl-(R)-3-(tert-butyl)-sulfinyl-14-dihydropyridine a novelNADHmodel compoundrdquoMolecules vol 12 no 3 pp 415ndash4222007
[73] S Tamagaki T Mimura and W Tagaki ldquoMetal-ion-facilitatedoxidations of dihydropyridines with molecular oxygen andhydrogen peroxiderdquo Journal of the Chemical Society PerkinTransactions 2 no 10 pp 1645ndash1650 1990
[74] D Tirzite G Tirzitis andD Antipova ldquoReductive ability of 14-dihydropyridine derivatives in relation to ions of trivalent ironrdquoChemistry of Heterocyclic Compounds vol 35 no 5 pp 592ndash594 1999
[76] J Ogle J Stradins and L Baumane ldquoFormation and decay offree cation-radicals in the course of electro-oxidation of 12- and14-dihydropyridines (Hantzsch esters)rdquo Electrochimica Actavol 39 no 1 pp 73ndash79 1994
[77] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for the
synthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts C Wittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Berlin Germany 2010
[78] WDu and Zh Yu ldquoBiomimetic in situ regeneration of cofactorsNAD(P)+ and NAD(P)H models hantzsch esters and dihy-drophenanthridinerdquo Synlett vol 23 no 9 pp 1300ndash1304 2012
[79] H K Chenault and G M Whitesides ldquoRegeneration ofnicotinamide cofactors for use in organic synthesisrdquo AppliedBiochemistry and Biotechnology vol 14 no 2 pp 147ndash197 1987
[80] Y R Uldrikis A A Zidermane E A Biseniex I E Preisa GY Dubur and G D Tirzit ldquoEsters of 26-dimethyl-14-dihydro-pyridine-35-dicarboxylic acid and method of obtainingthereofrdquo WO 8000345 A1 1978 httpworldwideespacenetcompublicationDetailsbiblioDB=EPODOCampII=1ampND=3ampadjacent=trueamplocale=en EPampFT=Dampdate=19800306ampCC=WOampNR=8000345A1ampKC=A1
[81] Y Sambongi H Nitta K Ichihashi M Futai and I Ueda ldquoAnovel water-soluble Hantzsch 14-dihydropyridine compoundthat functions in biological processes through NADH regener-ationrdquo Journal of Organic Chemistry vol 67 no 10 pp 3499ndash3501 2002
[82] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for thesynthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts ChWittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Verlag Berlin Germany 2010
[83] T Okamura T Kikuchi A Nagamine et al ldquoAn approach formeasuring in vivo cerebral redox states using the oxidative con-version of dihydropyridine to pyridinium ion and themetabolictrapping principlerdquo Free Radical Biology and Medicine vol 38no 9 pp 1197ndash1205 2005
[84] K A Schellenberg and F H Westheimer ldquoA free-radicaloxidation of a dihydropyridine1ardquo The Journal of OrganicChemistry vol 30 no 6 pp 1859ndash1862 1965
[85] K A Schellenberg ldquoReaction of hydroxyl radical with thymi-dine Scavenging by a dihydropyridinerdquo Federation Proceedingsvol 38 no 3 I p 1433 1979
[86] E S Huyser J A K Harmony and F L McMillian ldquoPeroxideoxidations of dihydropyridine derivativesrdquo Journal of the Amer-ican Chemical Society vol 94 no 9 pp 3176ndash3180 1972
[87] A Sakamoto S T Ohnishi and R Ogawa ldquoInhibition of lipidperoxidation by some dihydropyridine derivativesrdquo Journal ofAnesthesia vol 7 no 2 pp 193ndash197 1993
[88] R Hardeland ldquoReview Neuroprotection by radical avoidancesearch for suitable agentsrdquo Molecules vol 14 no 12 pp 5054ndash5102 2009
[89] G Ya Dubur A Kh Velena V M Gukasov and Yu AVladimirov ldquoRegulation of peroxidation of mitochondrialmembrane lipids initiated by Fe2+ ions by antoxidants of the14-dihydropyridine series in experiments in vitrordquo Biomed-itsinskaya Khimiya vol 22 no 5 pp 665ndash673 1976 (Russian)Chemical Abstracts vol 88 Article ID 2640 1977
[90] G RMMHaenenM J T J Arts A Bast andMD ColemanldquoStructure and activity in assessing antioxidant activity in vitroand in vivo a critical appraisal illustrated with the flavonoidsrdquoEnvironmental Toxicology and Pharmacology vol 21 no 2 pp191ndash198 2006
[91] G Tirzitis and G Bartosz ldquoDetermination of antiradical andantioxidant activity basic principles and new insightsrdquo ActaBiochimica Polonica vol 57 no 2 pp 139ndash142 2010
30 Oxidative Medicine and Cellular Longevity
[92] G R Buettner and R P Mason ldquoSpin-trapping methods fordetecting superoxide and hydroxyl free radicals in vitro and invivordquo inCritical Reviews of Oxidative Stress and Aging Advancesin Basic Science Diagnostics and Intervention R G Cutler andH Rodriguez Eds vol 1 chapter 2 pp 27ndash38World ScientificLondon UK 2003
[93] M M Tarpey and I Fridovich ldquoMethods of detection ofvascular reactive species Nitric oxide superoxide hydrogenperoxide and peroxynitriterdquo Circulation Research vol 89 no3 pp 224ndash236 2001
[94] E Y Kazush E I Sagun G D Tirzit and G Y DaburldquoQuenching of singlet oxygen by electron donating derivativesof 14-dihydropyridinerdquo Chemistry of Heterocyclic Compoundsvol 30 no 5 pp 562ndash563 1994
[95] G Tirzitis E Kazush and G Duburs ldquoReaction of 14-dihydropyridine derivatives with peroxynitrite anionrdquo Chem-istry of Heterocyclic Compounds vol 34 no 3 pp 321ndash3231998 (Russian) Translated from Khimiya GeterotsiklicheskikhSoedinenii no 3 pp 355ndash357 1998
[96] L J Nunez-Vergara C Lopez-Alarcon P A Navarrete-EncinaA M Atria C Camargo and J A Squella ldquoElectrochemicaland EPR characterization of 14-dihydropyridines Reactivitytowards alkyl radicalsrdquo Free Radical Research vol 37 no 1 pp109ndash120 2003
[97] D Tirzite A Krauze A Zubareva G Tirzitis and G DubursldquoSynthesis and antiradical activity of 5-acetyl-2-alkylthio-4-aryl-6-methyl-14-dihydropyridine-3-carboxylic acid nitrilesrdquoChemistry of Heterocyclic Compounds vol 38 no 7 pp 795ndash800 2002
[98] H Ohkawa N Ohishi and K Yagi ldquoAssay for lipid peroxidesin animal tissues by thiobarbituric acid reactionrdquo AnalyticalBiochemistry vol 95 no 2 pp 351ndash358 1979
[99] N Zarkovic ldquo4-Hydroxynonenal as a bioactive marker ofpathophysiological processesrdquo Molecular Aspects of Medicinevol 24 no 4-5 pp 281ndash291 2003
[100] M Parola G Bellomo G Robino G Barrera and M UDianzani ldquo4-Hydroxynonenal as a biological signal molecularbasis and pathophysiological implicationsrdquo Antioxidants andRedox Signaling vol 1 no 3 pp 255ndash284 1999
[101] T Lovakovic M Poljak-Blazi G Duburs et al ldquoGrowthmodulation of human cells in vitro by mild oxidative stressand 14-dihydropyridine derivative antioxidantsrdquo CollegiumAntropologicum vol 35 no 1 pp 137ndash141 2011
[102] R van den Berg G R M M Haenen H van den Bergand A Bast ldquoApplicability of an improved Trolox equivalentantioxidant capacity (TEAC) assay for evaluation of antioxidantcapacity measurements of mixturesrdquo Food Chemistry vol 66no 4 pp 511ndash517 1999
[103] C Lopez-Alarcon P Navarrete C Camargo J A Squella andL J Nunez-Vergara ldquoReactivity of 14-dihydropyridines towardalkyl alkylperoxyl radicals and ABTS radical cationrdquo ChemicalResearch in Toxicology vol 16 no 2 pp 208ndash215 2003
[104] V Valenzuela P Santander C Camargo J A Squella C Lopez-Alarcon and L J Nunez-Vergara ldquo14-Dihydropyridines reac-tivity of nitrosoaryl and nitroaryl derivatives with alkylperoxylradicals andABTS radical cationrdquo Free Radical Research vol 38no 7 pp 715ndash727 2004
[105] L G Tsetlin N A Chebotareva B I Kurganov A K VelenaG Y Dubur and V Z Lankin ldquoStudy of 14-dihydropyridinesas lipoxygenase inhibitors with the use of hydrated reversedmicellesrdquo Pharmaceutical Chemistry Journal vol 22 no 6 pp425ndash428 1988 (Russian)
[106] J Panek Z Reblova L Kocirkova et al ldquoAntioxidant activityof dihydropyridine derivativesrdquo Czech Journal of Food Sciencesvol 18 pp 144ndash145 2000
[107] G Tirzitis I Kirule and G Duburs ldquoAntioxidationsaktivitatder 35-dicarbonylderivate des 26-demethyl-14-dihydropyri-dinsrdquo Fett Wissenschaft TechnologieFat Science Technology vol90 no 10 pp 411ndash413 1988
[108] M Plotniece G Tirzitis Y Uldrikis et al ldquoSynthesis of 14-dihydropyridine derivatives having an oxy- alkoxy- or dimeth-ylaminophenyl substituent in the 4 position their antioxidantactivity and their binding to phospholipid membranesrdquo Chem-istry of Heterocyclic Compounds vol 32 no 10 pp 1166ndash11721996 Translated from Khimiya Geterotsiklicheskikh Soedineniino 10(352) pp 1358ndash1365 1996 (Russian)
[109] D Y Rubene V S Sharov V I Olenev G D Tirzit G Y Duburand Y A Vladimirov ldquoUse of chemiluminescent method forthe evaluation of antioxidant activity of some derivatives of 14-dihydropyridinerdquo Russian Journal of Physical Chemistry A vol55 no 2 pp 511ndash512 1981 (Russian)
[110] M C R Symons and JM C Gutteridge Free Radicals and IronChemistry Biology and Medicine Oxford Science PublicationsOxford University Press Oxford UK 1998
[111] M Repetto J Semprine and A Boveris ldquoLipid peroxidationchemical mechanism biological implications and analyticaldeterminationrdquo in Lipid Peroxidation A Catala Ed Section ILipid Peroxidation Chemical Mechanisms Antioxidants Bio-logical Implications of Biochemistry Genetics and MolecularBiology chapter 1 pp 3ndash30 InTech Rijeka Croatia 2012
[112] A Velena J Zilbers and G Duburs ldquoDerivatives of 14-dihydropyridines asmodulators of ascorbate-induced lipid per-oxidation and high-amplitude swelling ofmitochondria causedby ascorbate sodium linoleate and sodiumpyrophosphaterdquoCellBiochemistry and Function vol 17 no 4 pp 237ndash252 1999
[113] M V Bilenko L N Shelenkova G Y Dubur and A K VelenaldquoUse of antioxidants to prevent renal damage during acuteischemia and reperfusionrdquo Bulletin of Experimental Biology andMedicine vol 96 no 3 pp 1195ndash1198 1983 Translated fromByulletenrsquo Eksperimentalrsquonoi Biologii i Meditsiny vol 96 no 9pp 8ndash11 1983 (Russian)
[114] R Toniolo F Tubaro F Ursini and G Bontempelli ldquoAn elec-troanalytical investigation on the redox properties of calciumantagonist dihydropyridinesrdquo Electroanalysis vol 15 no 10 pp855ndash861 2003
[115] L Kourimska J Pokorny and G Tirzitis ldquoThe antioxidant aci-tivity of 26-dimethyl-35-diethoxycarbonyl-14-dihydropyri-dine in edible oilsrdquo Nahrung vol 37 no 1 pp 91ndash93 1993
[116] C Lopez-Alarcon H Speisky J A Squella C Olea-Azar CCamargo and L J Nunez-Vergara ldquoReactivity of 14-dihydro-pyridines toward SIN-1-derived peroxynitriterdquo PharmaceuticalResearch vol 21 no 10 pp 1750ndash1757 2004
[117] R A Olek W Ziolkowski J J Kaczor L Greci J Popinigisand J Antosiewicz ldquoAntioxidant activity of NADH and its ana-loguemdashan in vitro studyrdquo Journal of Biochemistry andMolecularBiology vol 37 no 4 pp 416ndash421 2004
[118] E Niki N Noguchi and N Gotoh ldquoInhibition of oxidativemodification of low density lipoprotein by antioxidantsrdquo Jour-nal of Nutritional Science andVitaminology vol 39 supplementpp S1ndashS8 1993
[119] N Rojstaczer and D J Triggle ldquoStructure-function relation-ships of calcium antagonists effect on oxidative modificationof low density lipoproteinrdquo Biochemical Pharmacology vol 51no 2 pp 141ndash150 1996
Oxidative Medicine and Cellular Longevity 31
[120] A Sevanian L Shen and FUrsini ldquoInhibition of LDLoxidationand oxidized LDL-induced cytotoxicity by dihydropyridinecalcium antagonistsrdquo Pharmaceutical Research vol 17 no 8 pp999ndash1006 2000
[121] A Negre-Salvayre and R Salvayre ldquoProtection by Ca2+ channelblockers (nifedipine diltiazem and verapamil) against the tox-icity of oxidized low density lipoprotein to cultured lymphoidcellsrdquo British Journal of Pharmacology vol 107 no 3 pp 738ndash744 1992
[122] A Negre-Salvayre G FitoussiM Troly and R Salvayre ldquoCom-parative cytoprotective effect of dihydropyridine calcium chan-nel blockers against the toxicity of oxidized low density lipopro-tein for cultured lymphoid cellsrdquo Biochemical Pharmacologyvol 44 no 12 pp 2379ndash2386 1992
[123] L Cominacini A F Pasini U Garbin et al ldquoAntioxidant activ-ity of different dihydropyridinesrdquo Biochemical and BiophysicalResearch Communications vol 302 no 4 pp 679ndash684 2003
[124] L Cominacini U Garbin A Fratta Pasini et al ldquoOxidized low-density lipoprotein increases the production of intracellularreactive oxygen species in endothelial cells inhibitory effect oflacidipinerdquo Journal of Hypertension vol 16 no 12 part 2 pp1913ndash1919 1998
[125] H M Lander ldquoAn essential role for free radicals and derivedspecies in signal transductionrdquo The FASEB Journal vol 11 no2 pp 118ndash124 1997
[126] M L L Martinez E Rizzi M M Castro et al ldquoLercanidipinedecreases vascular matrix metalloproteinase-2 activity andprotects against vascular dysfunction in diabetic ratsrdquo EuropeanJournal of Pharmacology vol 599 no 1ndash3 pp 110ndash116 2008
[127] P Lesnik C Dachet L Petit et al ldquoImpact of a combinationof a calcium antagonist and a 120573-blocker on cell- and copper-mediated oxidation of LDL and on the accumulation and effluxof cholesterol in human macrophages and murine J774 cellsrdquoArteriosclerosis Thrombosis and Vascular Biology vol 17 no 5pp 979ndash988 1997
[128] G Sobal E J Menzel and H Sinzinger ldquoCalcium antagonistsas inhibitors of in vitro low density lipoprotein oxidation andglycationrdquoBiochemical Pharmacology vol 61 no 3 pp 373ndash3792001
[129] E Lupo R Locher B Weisser and W Vetter ldquoIn vitro antiox-idant activity of calcium antagonists against LDL oxidationcompared with 120572-tocopherolrdquo Biochemical and BiophysicalResearch Communications vol 203 no 3 pp 1803ndash1808 1994
[130] J Zou Y Li H-Q Fan and J-G Wang ldquoEffects of dihydropy-ridine calcium channel blockers on oxidized low-density lipo-protein induced proliferation and oxidative stress of vascularsmooth muscle cellsrdquo BMC Research Notes vol 5 article 1682012
[131] C Napoli S Salomone T Godfraind et al ldquo14-Dihydro-pyridine calcium channel blockers inhibit plasma and LDL oxi-dation and formation of oxidation-specific epitopes in the arte-rial wall and prolong survival in stroke-prone spontaneouslyhypertensive ratsrdquo Stroke vol 30 no 9 pp 1907ndash1915 1999
[132] G Zernig I Graziadei T Moshammer C Zech N Reider andH Glossmann ldquoMitochondrial Ca2+ antagonist binding sitesare associated with an inner mitochondrial membrane anionchannelrdquo Molecular Pharmacology vol 38 no 3 pp 362ndash3691990
[133] F E Hunter Jr A Scott P E Hochstein et al ldquoStudies of themechanism of ascorbate-induced swelling and lysis of isolatedliver mitochondriardquo The Journal of Biological Chemistry vol239 pp 604ndash613 1964
[134] D R Janero B Burghardt and R Lopez ldquoProtection of cardiacmembrane phospholipid against oxidative injury by calciumantagonistsrdquoBiochemical Pharmacology vol 37 no 21 pp 4197ndash4203 1988
[135] A Karadag B Ozcelik and S S Saner ldquoReview of methods todetermine antioxidant capacitiesrdquo FoodAnalyticalMethods vol2 no 1 pp 41ndash60 2009
[136] Y I Gubskiı N V Litvinova and E V Shnurko-TabakovaldquoAntioxidant and antiradical activity of various classes of antiox-idantsrdquo Ukrainskiı Biokhimicheskiı Zhurnal vol 66 no 4 pp114ndash116 1994 (Russian)
[137] M Takei M Hiramatsu and A Mori ldquoInhibitory effects ofcalcium antagonists onmitochondrial swelling induced by lipidperoxidation or arachidonic acid in the rat brain in vitrordquoNeurochemical Research vol 19 no 9 pp 1199ndash1206 1994
[138] M Takei M Hiramatsu R Edamatsu and A Mori ldquoFreeradical scavenging by calcium antagonistsrdquo Neurosciences vol20 no 2 pp 75ndash82 1994
[139] Ya P Stradin G Ya Dubur Yu A Beilis Ya R Uldrikis andA F Korotkova ldquoVoltammetry of 14-dihydropyridine deriva-tives I Potentials of electrochemical oxidation of 35-diacyl-and 35-di(alkoxycarbonyl)-14-dihydropyridines in acetoni-trilerdquo Chemistry of Heterocyclic Compounds no 1 pp 84ndash871972 (Russian)
[140] E V Ivanov T V Ponomarjova G N Merkusev et al ldquoEinneuer Haut-Radioprotektor Diethon (experimentelle Unter-suchung)rdquo Radiobiologia Radiotherapia vol 31 no 1 pp 69ndash78 1990
[141] E V Ivanov T V Ponomareva G N Merkushev et al ldquoRadia-tion modulating properties of derivates of 14-dihydropyridineand 12345678910-decahydroacridine-18 dionerdquo Radiat-sionnaia Biologiia Radioecologiia vol 44 no 5 pp 550ndash5592004 (Russian)
[142] R O Vitolinia D A Berzinia A K Velena I A Vutsina A AKimenis and G Y Duburs ldquoThe protective effects of the cal-cium antagonist foridon in acute myocardial ischaemiardquo Kardi-ologiya vol 27 no 3 pp 90ndash93 1987 (Russian)
[143] A H Velena G Ya Duburs R O Vitolina et al ldquoEffect ofryodipine on electromechanical parameters of heart and vesselscAMP phosphodiesterase activity and swelling-contractioncycle of mitochondriardquo Arzneimittelforschung vol 35 no 6 pp907ndash914 1985
[144] L I Utno Z E Lipsberga A A Silova M I Girgensone EA Bisenieks and G I Ia ldquoCardioprotective properties of a 14-dihydropyridine derivative glutapyrone in deep hypothermiardquoBiulletenrsquo Eksperimentalrsquonoı Biologii i Meditsiny vol 108 no 11pp 558ndash561 1989 (Russian)
[145] M A S FernandesM S Santos J A F Vicente et al ldquoEffects of14-dihydropyridine derivatives (cerebrocrast gammapyroneglutapyrone and diethone) onmitochondrial bioenergetics andoxidative stress a comparative studyrdquoMitochondrion vol 3 no1 pp 47ndash59 2003
[146] M A S Fernandes M S Santos A J M Moreno et al ldquoEffectsof 5-acetyl(carbamoyl)-6-methylsulfanyl-14-dihydropyridine-5-carbonitriles on rat liver mitochondrial functionrdquo Toxicologyin Vitro vol 23 no 7 pp 1333ndash1341 2009
[147] L Klimaviciusa A Kalda A Kaasik et al ldquoNeuroprotectiveactivity of 14-dihydropyridine derivatives structure determi-nantsrdquo Proceedings of the Latvian Academy of Sciences BNatural Exact and Applied Sciences vol 61 no 1-2 pp 33ndash372007
32 Oxidative Medicine and Cellular Longevity
[148] L Klimaviciusa M A S Fernandes N Lencberga et alldquoTargeting the mitochondria by novel adamantane-containing14-dihydropyridine compoundsrdquo in Bioenergetics K B ClarkEd pp 257ndash272 InTech 2012
[149] V Klusa L Klimaviciusa G Duburs J Poikans and AZharkovsky ldquoAnti-neurotoxic effects of tauropyrone a taurineanaloguerdquo Advances in Experimental Medicine and Biology vol583 pp 499ndash508 2006
[150] N Sampson P Berger and Ch Zenzmaier ldquoRedox signalingas a therapeutic target to inhibit myofibroblast activation indegenerative fibrotic diseaserdquo BioMed Research Internationalvol 2014 Article ID 131737 14 pages 2014
[151] T L Leto and M Geiszt ldquoRole of Nox family NADPH oxidasesin host defenserdquoAntioxidantsampRedox Signaling vol 8 no 9-10pp 1549ndash1561 2006
[152] K K Griendling D Sorescu and M Ushio-Fukai ldquoNAD(P)Hoxidase role in cardiovascular biology and diseaserdquo CirculationResearch vol 86 no 5 pp 494ndash501 2000
[153] H Chen Y S Song and P H Chan ldquoInhibition of NADPHoxi-dase is neuroprotective after ischemia-reperfusionrdquo Journal ofCerebral Blood Flow and Metabolism vol 29 no 7 pp 1262ndash1272 2009
[154] P Hochstein and L Ernster ldquoADP-activated lipid peroxidationcoupled to the TPNH oxidase system of microsomesrdquo Biochem-ical and Biophysical Research Communications vol 12 no 5 pp388ndash394 1963
[155] I I Gubskiı AGGoriushkoNV Litvinova et al ldquoAntioxidantproperties and membranotropic effect of certain derivatives of14-dihydropyridinerdquo Ukrainskiı Biokhimicheskiı Zhurnal vol71 no 4 pp 35ndash39 1999 (Russian)
[156] F Engineer and R Sridhar ldquoInhibition of rat heart andliver microsomal lipid peroxidation by nifedipinerdquo BiochemicalPharmacology vol 38 no 8 pp 1279ndash1285 1989
[157] T Goncalves A P Carvalho and C R Oliveira ldquoAntioxidanteffect of calcium antagonists on microsomai membranes iso-lated from different brain areasrdquo European Journal of Pharma-cology vol 204 no 3 pp 315ndash322 1991
[158] M E Letelier P Izquierdo L Godoy A M Lepe and MFaundez ldquoLiver microsomal biotransformation of nitro-aryldrugs mechanism for potential oxidative stress inductionrdquoJournal of Applied Toxicology vol 24 no 6 pp 519ndash525 2004
[159] M E Letelier P Entrala C Lopez-Alarcon et al ldquoNitroaryl-14-dihydropyridines as antioxidants against rat liver microsomesoxidation induced by ironascorbate Nitrofurantoin and naph-thalenerdquo Toxicology in Vitro vol 21 no 8 pp 1610ndash1618 2007
[160] F P Guengerich W R Brian M Iwasaki M-A Sari CBaarnhielm and P Berntsson ldquoOxidation of dihydropyridinecalcium channel blockers and analogues by human liver cyto-chrome P-450 IIIA4rdquo Journal of Medicinal Chemistry vol 34no 6 pp 1838ndash1844 1991
[161] S H Park S-W RhaW-Y Shin et al ldquoAS-160 Calcium channelblockers of dihydropyridine class reduce the antiplatelet effectof Clopidogrel what is clinical impactrdquo The American Journalof Cardiology vol 107 no 8 supplement p 47A 2011
[162] C Asma and D M Reda ldquoEvaluation of dihydropyridinecalcium antagonist effects on the stress bioindicator orga-nism Saccharomyces cerevisiaerdquo Annals of Biological Researchvol 4 no 10 pp 40ndash46 2013 httpscholarsresearchlibrarycomABR-vol4-iss10ABR-2013-4-10-40-46pdf
[163] G Gaviraghi A M Pastorino E Ratti and D G TristldquoCalcium channel blockers with antioxidant activityrdquo in Free
Radicals Lipoprotein Oxidation andAtherosclerosis G BellomoG Finardi E Maggi and E Rice-Evans Eds pp 431ndash456Richelieu Press London UK 1995
[164] G Gaviraghi AM Pastorino E Ratti and D G Trist ldquoAntiox-idant dihydropyridines a new and comprehensive therapy forfree radical-induced cardiovascular diseasesrdquo in Free Radicalsin Biology and Environment F Minisci Ed vol 27 of NATOASI Series pp 193ndash221 Springer Dordrecht The Netherlands1997
[165] P D Henry ldquoAntiperoxidative actions of calcium antagonistsand atherogenesisrdquo Journal of Cardiovascular Pharmacologyvol 18 supplement 1 pp S6ndashS10 1991
[166] F Kouoh B Gressier T Dine et al ldquoAntioxidant effects andanti-elastase activity of the calcium antagonist nicardipine onactivated human and rabbit neutrophilsmdasha potential antiath-erosclerotic property of calcium antagonistsrdquo CardiovascularDrugs andTherapy vol 16 no 6 pp 515ndash520 2002
[167] S Parthasarathy D Litvinov K Selvarajan and M GarelnabildquoLipid peroxidation and decompositionmdashconflicting roles inplaque vulnerability and stabilityrdquo Biochimica et BiophysicaActa vol 1781 no 5 pp 221ndash231 2008
[168] D-Q Liu Z-Q Pang D-H Zhao and B-H Sheng ldquoEffects offuryl-dihydropyridines I on lipid peroxides of ischemic myo-cardium and ATPases activity of erythrocyte membranes inratsrdquo Acta Pharmacologica Sinica vol 12 no 3 pp 253ndash2561991
[169] V Lukic-Panin T Kamiya H Zhang et al ldquoPrevention of neu-ronal damage by calcium channel blockers with antioxidativeeffects after transient focal ischemia in ratsrdquo Brain Research vol1176 no 1 pp 143ndash150 2007
[170] Y Allanore D Borderie H Lemarechal O G Ekindjian andA Kahan ldquoAcute and sustained effects of dihydropyridine-typecalcium channel antagonists on oxidative stress in systemicsclerosisrdquo American Journal of Medicine vol 116 no 9 pp 595ndash600 2004
[171] I Casetta V Govoni and E Granieri ldquoOxidative stress antioxi-dants and neurodegenerative diseasesrdquo Current PharmaceuticalDesign vol 11 no 16 pp 2033ndash2052 2005
[172] M J T J Arts Assessing antioxidant activity [PhD the-sis] Maastricht University Maastricht The Netherlands 2007httparnounimaasnlshowcgifid=8676
[173] G Dıaz-Araya L Godoy L Naranjo A Squella M E Letelierand L J Nunez-Vergara ldquoAntioxidant effects of 14-dihydro-pyridine and nitroso aryl derivatives on the Fe+3ascorbate-stimulated lipid peroxidation in rat brain slicesrdquo General Phar-macology The Vascular System vol 31 no 3 pp 385ndash391 1998
[174] Y Fukuhara K Tsuchiya Y Horinouchi et al ldquoProtectiveeffect of photodegradation product of nifedipine against tumornecrosis factor 120572-induced oxidative stress in human glomerularendothelial cellsrdquo Journal of Medical Investigation vol 58 no1-2 pp 118ndash126 2011
[175] W Stengel M Jainz and K Andreas ldquoDifferent potencies ofdihydropyridine derivatives in blocking T-type but not L-typeCa2+ channels in neuroblastoma-glioma hybrid cellsrdquo EuropeanJournal of Pharmacology vol 342 no 2-3 pp 339ndash345 1998
[176] O M Panasenko D J Tirzite G D Tirzitis and G J DubursldquoEffect of some 14-dihydropyridine derivatives on structuralorganization of erythrocyte membranesrdquo Biologicheskie Mem-brany (Biochemistry (Moscow) Series A Membrane and CellBiology) vol 1 pp 919ndash925 1984 (Russian)
[177] L G Herbette Y M H Vant Erve and D G Rhodes ldquoInter-action of 14 dihydropyridine calcium channel antagonists with
Oxidative Medicine and Cellular Longevity 33
biological membranes lipid bilayer partitioning could occurbefore drug binding to receptorsrdquo Journal of Molecular andCellular Cardiology vol 21 no 2 pp 187ndash201 1989
[178] L G Herbette P E Mason G Gaviraghi T N Tulenko andR P Mason ldquoThe molecular basis for lacidipinersquos unique phar-macokinetics optimal hydrophobicity results in membraneinteractions that may facilitate the treatment of atherosclerosisrdquoJournal of Cardiovascular Pharmacology vol 23 supplement 5pp S16ndashS25 1994
[179] G V Belevitch G Y Dubur G E Dobretsov N K Kurek andM M Spirin ldquoCalcium antagonists riodipine nifedipine andverapamil binding to model and biological membranes fluore-scence analysisrdquo Biologicheskie Membrany (Biochemistry(Moscow) Series A Membrane and Cell Biology) vol 5 pp768ndash776 1988 (Russian)
[180] R P Mason G E Gonye D W Chester and L G HerbetteldquoPartitioning and location of Bay K 8644 14-dihydropyridinecalcium channel agonist in model and biological membranesrdquoBiophysical Journal vol 55 no 4 pp 769ndash778 1989
[181] M Cindric A Cipak J Serly et al ldquoReversal of multidrugresistance inmurine lymphoma cells by amphiphilic dihydropy-ridine antioxidant derivativerdquo Anticancer Research vol 30 no10 pp 4063ndash4070 2010
[182] F Shekari H Sadeghpour K Javidnia et al ldquoCytotoxic andmultidrug resistance reversal activities of novel 14-dihydro-pyridines against human cancer cellsrdquo European Journal ofPharmacology vol 746 no 1 pp 233ndash244 2015
[183] X-F Zhou Q Shao R A Coburn and M E Morris ldquoQuanti-tative structure-activity relationship and quantitative structure-pharmacokinetics relationship of 14-dihydropyridines andpyridines as multidrug resistance modulatorsrdquo PharmaceuticalResearch vol 22 no 12 pp 1989ndash1996 2005
[184] R Berkels T Breitenbach H Bartels et al ldquoDifferent antioxida-tive potencies of dihydropyridine calcium channel modulatorsin various modelsrdquo Vascular Pharmacology vol 42 no 4 pp145ndash152 2005
[185] S Borovic G Tirzitis D Tirzite et al ldquoBioactive 14-dihydro-isonicotinic acid derivatives prevent oxidative damage of livercellsrdquo European Journal of Pharmacology vol 537 no 1ndash3 pp12ndash19 2006
[186] D Ya Rubene G D Tirzitis and G Ya Duburs ldquoInteractionof some 14-dihydropyridine derivatives with Fentonrsquos reagentrdquoLatvijas PSRZinatnuAkademijas Vestis Kimijas Serija Proceed-ings of the Latvian SSR Academy of Sciences Chemistry Seriespp 212ndash216 1982 (Russian)
[187] K Ondrias V Misık D Gergel and A Stasko ldquoLipid per-oxidation of phosphatidylcholine liposomes depressed by thecalcium channel blockers nifedipine and verapamil and bythe antiarrhythmic-antihypoxic drug stobadinerdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1003 no 3pp 238ndash245 1989
[188] I T Mak and W B Weglicki ldquoComparative antioxidant acti-vities of propranolol nifedipine verapamil and diltiazemagainst sarcolemmal membrane lipid peroxidationrdquoCirculationResearch vol 66 no 5 pp 1449ndash1452 1990
[189] I T Mak P Boehme and W B Weglicki ldquoProtective effects ofcalcium channel blockers against free radical-impaired endo-thelial cell proliferationrdquo Biochemical Pharmacology vol 50 no9 pp 1531ndash1534 1995
[190] S Ray S Mondal and N Dana ldquoEvaluation of protective roleof nifedipine on lipid peroxidation using reduced glutathione as
model markerrdquo Oxidants and Antioxidants in Medical Sciencevol 1 no 2 pp 97ndash100 2012
[191] M Yamato T Shiba T Ide Y Honda K-I Yamada andH Tsutsui ldquoNifedipine treatment reduces brain damage aftertransient focal ischemia possibly through its antioxidativeeffectsrdquoHypertension Research vol 34 no 7 pp 840ndash845 2011
[192] V Chander and K Chopra ldquoNifedipine attenuates changes innitric oxide levels renal oxidative stress and nephrotoxicityinduced by cyclosporinerdquo Renal Failure vol 27 no 4 pp 441ndash450 2005
[193] K M Gaafa M M Badawy and A A Hamza ldquoThe protectiveeffects of ascorbic acid cimetidine and nifedipine on diethyl-dithiocarbamate-induced hepatic toxicity in albino ratsrdquo Drugand Chemical Toxicology vol 34 no 4 pp 405ndash419 2011
[194] H Sugawara K Tobise and S Onodera ldquoAbsence of antiox-idant effects of nifedipine and diltiazem on myocardial mem-brane lipid peroxidation in contrast with those of nisoldipineand propranololrdquo Biochemical Pharmacology vol 47 no 5 pp887ndash892 1994
[195] I E Kirule D Y Rubene E A Bisenieks G D Tirzit and GY Dubur ldquo4-Nitrophenyl-14-dihydropyridinesmdasha new groupof inhibitors of peroxide oxidationrdquo Chemistry of HeterocyclicCompounds vol 18 no 3 p 316 1982
[196] G D Tirzit I E Kirule L K Baumane R A Gavar Y PStradynrsquo andG YDubur ldquoMechanism of the antioxidant actionof 26-dimethyl-35-dimethoxy-carbonyl-4-(2-nitrophenyl)14-dihydropyridinerdquoChemistry ofHeterocyclic Compounds vol 20no 8 pp 915ndash918 1984
[197] C Yanez C Lopez-Alarcon C Camargo V Valenzuela J ASquella and L J Nunez-Vergara ldquoStructural effects on thereactivity 14-dihydropyridines with alkylperoxyl radicals andABTS radical cationrdquo Bioorganic and Medicinal Chemistry vol12 no 9 pp 2459ndash2468 2004
[198] VMisik A J Stasko D Gergel and K Ondrias ldquoSpin-trappingand antioxidant properties of illuminated and nonilluminatednifedipine and nimodipine in heart homogenate and modelsystemrdquo Molecular Pharmacology vol 40 no 3 pp 435ndash4391991
[199] K Ondrias V Misık A Stasko D Gergelrsquo and M HromadovaldquoComparison of antioxidant properties of nifedipine and illu-minated nifedipine with nitroso spin traps in low densitylipoproteins and phosphatidylcholine liposomesrdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1211 no 1pp 114ndash119 1994
[200] A Stasko V Brezova S Biskupic K Ondrias and V MisıkldquoReactive radical intermediates formed from illuminated nife-dipinerdquoFree Radical Biology andMedicine vol 17 no 6 pp 545ndash556 1994
[201] K Ishizawa Y Izawa-Ishizawa N Yamano et al ldquoNitrosoni-fedipine ameliorates the progression of type 2 diabetic nephro-pathy by exerting antioxidative effectsrdquo PLoS ONE vol 9 no 1Article ID e86335 2014
[202] H Fujii and L J Berliner ldquoIn vivo EPR evidence for free radicaladducts of nifedipinerdquoMagnetic Resonance in Medicine vol 42no 4 pp 691ndash694 1999
[203] S Bollo S Finger J C Sturm L J Nunez-Vergara and JA Squella ldquoCyclic voltammetry and scanning electrochemicalmicroscopy studies of the heterogeneous electron transferreaction of some nitrosoaromatic compoundsrdquo ElectrochimicaActa vol 52 no 15 pp 4892ndash4898 2007
34 Oxidative Medicine and Cellular Longevity
[204] F Ursini ldquoTissue protection by lacidipine insight from redoxbehaviorrdquo Journal of Cardiovascular Pharmacology vol 30supplement 2 pp S28ndashS30 1997
[205] P G Cristofori F A Crivellente I Faustinelli et al ldquoInvolve-ment of the nitric oxide system in the anti-atheroscleroticpotential of lacidipine in the apoE-deficient mouse a mor-phological functional and electrochemical studyrdquo ToxicologicPathology vol 32 no 4 pp 493ndash499 2004
[206] X-P Zhang E L Kit S Mital S Chahwala and T HHintze ldquoParadoxical release of nitric oxide by an L-type calciumchannel antagonist the R+ enantiomer of amlodipinerdquo Journalof Cardiovascular Pharmacology vol 39 no 2 pp 208ndash2142002
[207] F Franzoni G Santoro F Regoli et al ldquoAn in vitro study of theperoxyl and hydroxyl radical scavenging capacity of the calciumantagonist amlodipinerdquo Biomedicine and Pharmacotherapy vol58 no 8 pp 423ndash426 2004
[208] S V Gatsura ldquoOxygen-dependent mechanisms underlying theantiischemic effect of verapamil and amlodipinerdquo Bulletin ofExperimental Biology and Medicine vol 137 no 1 pp 40ndash422004
[209] Y Hirooka Y Kimura M Nozoe Y Sagara K Ito and KSunagawa ldquoAmlodipine-induced reduction of oxidative stressin the brain is associated with sympatho-inhibitory effects instroke-prone spontaneously hypertensive ratsrdquo HypertensionResearch vol 29 no 1 pp 49ndash56 2006
[210] B Tomlinson and I F F Benzie ldquoAntioxidant effect of lercani-dipine (note)rdquo Hypertension vol 42 no 4 pp e10ndashe11 2003
[211] A A Faraqui ldquoNeurochemical aspects of 4-hydroxynonenalrdquoin Lipid Mediators and Their Metabolism in the Brain A AFaraqui Ed chapter 6 pp 159ndash191 Springer New York NYUSA 2011
[212] V S NascimentoM S DrsquoAlva A AOliveira et al ldquoAntioxidanteffect of nimodipine in young rats after pilocarpine-inducedseizuresrdquo Pharmacology Biochemistry and Behavior vol 82 no1 pp 11ndash16 2005
[213] O Ismailoglu P Atilla S Palaoglu et al ldquoThe therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjuryrdquo Turkish Neurosurgery vol 22 no 6 pp 740ndash746 2012
[214] M Matsubara and K Hasegawa ldquoBenidipine a dihydropy-ridine-calcium channel blocker prevents lysophosphatidyl-choline-induced injury and reactive oxygen species productionin human aortic endothelial cellsrdquo Atherosclerosis vol 178 no1 pp 57ndash66 2005
[215] M Matsubara K Yao and K Hasegawa ldquoBenidipine adihydropyridine-calcium channel blocker inhibits lysophos-phatidylcholine-induced endothelial injury via stimulation ofnitric oxide releaserdquo Pharmacological Research vol 53 no 1 pp35ndash43 2006
[216] MMatsubara and K Hasegawa ldquoEffects of benidipine a dihyd-ropyridine-Ca2+ channel blocker on expression of cytokine-induced adhesion molecules and chemoattractants in humanaortic endothelial cellsrdquo European Journal of Pharmacology vol498 no 1ndash3 pp 303ndash314 2004
[217] M Matsubara O Akizuki J-I Ikeda K Saeki K Yao and KSasaki ldquoBenidipine an anti-hypertensive drug inhibits reactiveoxygen species production in polymorphonuclear leukocytesand oxidative stress in salt-loaded stroke-prone spontaneouslyhypertensive ratsrdquo European Journal of Pharmacology vol 580no 1-2 pp 201ndash213 2008
[218] A C Rosenkranz H Lob T Breitenbach R Berkels and RRoesen ldquoEndothelial antioxidant actions of dihydropyridines
and angiotensin converting enzyme inhibitorsrdquo European Jour-nal of Pharmacology vol 529 no 1ndash3 pp 55ndash62 2006
[219] V Kain S Kumar and S L Sitasawad ldquoAzelnidipine preventscardiac dysfunction in streptozotocin-diabetic rats by reducingintracellular calcium accumulation oxidative stress and apop-tosisrdquo Cardiovascular Diabetology vol 10 article 97 2011
[220] K Nakamura S Yamagishi and H Inoue ldquoUnique atheropro-tective property of azelnidipine a dihydropyridine-based cal-cium antagonistrdquoMedical Hypotheses vol 65 no 1 pp 155ndash1572005
[221] TMatsui S Yamagishi K Nakamura S Kikuchi andH InoueldquoAzelnidipine a dihydropyridine-based calcium antagonistinhibits angiotensin II-induced oxidative stress generation anddownregulation of pigment epithelium-derived factor mRNAlevels in microvascular endothelial cellsrdquo Drugs under Experi-mental and Clinical Research vol 31 no 5-6 pp 215ndash219 2005
[222] C Ohmura H Watada T Shimizu et al ldquoCalcium channelblocker azelnidipine reduces lipid hydroperoxides in patientswith type 2 diabetes independent of blood pressurerdquo EndocrineJournal vol 54 no 5 pp 805ndash811 2007
[223] H Daikuhara F Kikuchi and T Ishida ldquoThe combination ofOLmesartan and a CAlcium channel blocker (azelnidipine) orcandesartan and a calcium channel blocker (amlodipine) intype 2 diabetic hypertensive patients theOLCA studyrdquoDiabetesand Vascular Disease Research vol 9 no 4 pp 280ndash286 2012
[224] MAbe NMaruyama KOkada SMatsumoto KMatsumotoand M Soma ldquoAdditive antioxidative effects of azelnidipine onangiotensin receptor blocker olmesartan treatment for type 2diabetic patients with albuminuriardquoHypertension Research vol34 no 8 pp 935ndash941 2011
[225] K Mizushige ldquoAntioxidative activities of thiazolidinedionesand dihydropyridine-type calcium antagonistsrdquo IRYOmdashJapa-nese Journal of National Medical Services vol 59 no 11 pp 581ndash592 2005
[226] S Manabe T Okura T Fukuoka and J Higaki ldquoAntioxidativeeffects of azelnidipine on mesangial cell proliferation inducedby highly concentrated insulinrdquo European Journal of Pharma-cology vol 567 no 3 pp 252ndash257 2007
[227] Y Koyama Y Takeishi H Takahashi et al ldquoAzelnidipine inhi-bits H
2O2-induced cell death in neonatal rat cardiomyocytesrdquo
CardiovascularDrugs andTherapy vol 21 no 1 pp 69ndash72 2007[228] K Shinomiya K Mizushige M Fukunaga et al ldquoAntioxidant
effect of a new calcium antagonist azelnipidine in culturedhuman arterial endothelial cellsrdquo Journal of International Med-ical Research vol 32 no 2 pp 170ndash175 2004
[229] T Ohyama K Sato K Kishimoto et al ldquoAzelnidipine is acalcium blocker that attenuates liver fibrosis and may increaseantioxidant defencerdquo British Journal of Pharmacology vol 165no 4 pp 1173ndash1187 2012
[230] L A Calo F Zaghetto E Pagnin P A Davis A Sempliciniand A C Pessina ldquoEffect of manidipine on gene expressionand protein level of oxidative stress-related proteins p22phoxand HO-1 Relevance for antihypertensive and anti-remodelingeffectsrdquo Journal of Cardiovascular Pharmacology vol 43 no 4pp 531ndash538 2004
[231] R Ghyasi G Sepehri M Mohammadi R Badalzadeh and AGhyasi ldquoEffect of mebudipine on oxidative stress and lipid per-oxidation in myocardial ischemic-reperfusion injury in maleratrdquo Journal of Research in Medical Sciences vol 17 no 12 pp1150ndash1155 2012
Oxidative Medicine and Cellular Longevity 35
[232] DCAndersson J Fauconnier T Yamada et al ldquoMitochondrialproduction of reactive oxygen species contributes to the 120573-adrenergic stimulation of mouse cardiomycytesrdquoThe Journal ofPhysiology vol 589 no 7 pp 1791ndash1801 2011
[233] A F Ceylan-Isik N Ari M Stefek et al ldquoEffects of a long-term treatment with an antioxidant pyridoindole on vascularresponsiveness in diabetes-induced aging ratsrdquo Current AgingScience vol 4 no 2 pp 150ndash157 2011
[234] S Saponara G Sgaragli and F Fusi ldquoQuercetin antagonismof Bay K 8644 effects on rat tail artery L-type Ca2+ channelsrdquoEuropean Journal of Pharmacology vol 598 no 1ndash3 pp 75ndash802008
[235] D A Sica ldquoInteraction of grapefruit juice and calcium channelblockersrdquo American Journal of Hypertension vol 19 no 7 pp768ndash773 2006
[236] P Mulder G Litwinienko S Lin P D MacLean L R CBarclay and K U Ingold ldquoThe L-type calcium channel block-ers Hantzsch 14-dihydropyridines are not peroxyl radical-trapping chain-breaking antioxidantsrdquo Chemical Research inToxicology vol 19 no 1 pp 79ndash85 2006
[237] L J Nunez-Vergara R Salazar C Camargo et al ldquoOxidation ofC4-hydroxyphenyl 14-dihydropyridines in dimethylsulfoxideand its reactivity towards alkylperoxyl radicals in aqueousmediumrdquo Bioorganic and Medicinal Chemistry vol 15 no 12pp 4318ndash4326 2007
[238] M E Ortiz L J Nunez-Vergara and J A Squella ldquoRelativereactivity of dihydropyridine derivatives to electrogeneratedsuperoxide ion in DMSO solutions a voltammetric approachrdquoPharmaceutical Research vol 20 no 2 pp 292ndash296 2003
[239] M E Ortiz L J Nunez-Vergara C Camargo and J A SquellaldquoOxidation of Hantzsch 14-dihydropyridines of pharmacolog-ical significance by electrogenerated superoxiderdquo Pharmaceuti-cal Research vol 21 no 3 pp 428ndash435 2004
[240] R S Raghuvanshi and K N Singh ldquoSuperoxide induced oxida-tive aromatization of Hantzsch 14-dihydropyridinesrdquo IndianJournal of Chemistry Section B Organic and Medicinal Chem-istry vol 47 no 11 pp 1735ndash1738 2008
[241] I Kruk A Kladna K Lichszteld et al ldquoAntioxidant activityof 4-flavonil-14-dihydropyridine derivativesrdquo Biopolymers vol62 no 3 pp 163ndash167 2001
[242] G D Tirzit I M Byteva K I Salokhiddinov G P Gurinovichand G Y Dubur ldquo14-Dihydropyridine derivatives as deactiva-tors of singlet oxygenrdquo Chemistry of Heterocyclic Compoundsvol 17 no 7 pp 682ndash684 1981
[243] G D Tirzit E Y Kazush and G Y Dubur ldquoInfluence of14-dihydropyridine derivatives on the generation of hydroxylradicalsrdquo Chemistry of Heterocyclic Compounds vol 28 no 4pp 435ndash437 1992
[244] N A Pizarro-Urzua and L J Nunez-Vergara ldquoNifedipine andnitrendipine reactivity toward singlet oxygenrdquo Journal of Photo-chemistry and Photobiology A Chemistry vol 175 no 2-3 pp129ndash137 2005
[245] L-F Wang H-Y Zhang L Konga Z-W Chena and J-G ShildquoDFT calculations indicate that 14-dihydropyridine is a promis-ing lead antioxidantrdquo Helvetica Chimica Acta vol 87 no 6 pp1515ndash1521 2004
[246] P Mulder H-G Korth and K U Ingold ldquoWhy quantum-thermochemical calculations must be used with caution toindicate lsquoa promising lead antioxidantrsquordquoHelvetica Chimica Actavol 88 no 2 pp 370ndash374 2005
[247] K Yao Y Ina K Nagashima K Ohmori and T Ohno ldquoAntiox-idant effects of calcium antagonists in rat brain homogenatesrdquo
Biological and Pharmaceutical Bulletin vol 23 no 6 pp 766ndash769 2000
[248] T Matsui S-I Yamagishi K Nakamura and H Inoue ldquoBayw 9798 a dihydropyridine structurally related to nifedipinewith no calcium channel-blocking properties inhibits tumournecrosis factor-120572-induced vascular cell adhesion molecule-1expression in endothelial cells by suppressing reactive oxygenspecies generationrdquo Journal of International Medical Researchvol 35 no 6 pp 886ndash891 2007
[249] K AMitrega B VargheseM Porc and T F Krzeminski ldquoAnti-arrhythmic and hemodynamic effects of oxy nifedipine oxynimodipine oxy nitrendipine and oxy nisoldipinerdquo Pharmaco-logical Research vol 66 no 4 pp 300ndash308 2012
[250] V Herbert ldquoSymposium prooxidant effects of antioxidantvitamins Introductionrdquo The Journal of Nutrition vol 126 no4 supplement pp 1197Sndash1200S 1996 httpjnnutritionorgcontent1264 Suppl1197Sfullpdf
[251] B Halliwell ldquoAre polyphenols antioxidants or pro-oxidantsWhat do we learn from cell culture and in vivo studiesrdquoArchives of Biochemistry and Biophysics vol 476 no 2 pp 107ndash112 2008
[252] C Winterbourn Pro-Oxidants or Antioxidants ChristchurchSchool of Medicine Depatment of Pathology Free RadicalSchool SFRBMUniversity of Otago San Francisco Calif USA2009 httpwwwsfrbmorgfrsWinterbournpdf
[253] A Morakinyo B Iranloye and O Adegoke ldquoCalcium antag-onists modulate oxidative stress and acrosomal reaction in ratspermatozoardquo Archives of Medical Science vol 7 no 4 pp 613ndash618 2011
[254] The Alpha-Tocopherol Beta Carotene Cancer Prevention StudyGroup ldquoThe effect of vitamin E and beta carotene on theincidence of lung cancer and other cancers in male smokersrdquoTheNew England Journal of Medicine vol 330 no 15 pp 1029ndash1035 1994
[255] B Poljsak ldquoStrategies for reducing or preventing the generationof oxidative stressrdquo Oxidative Medicine and Cellular Longevityvol 2011 Article ID 194586 15 pages 2011
[256] B Poljsak and I Milisav ldquoThe neglected significance of lsquoanti-oxidative stressrsquordquoOxidativeMedicine and Cellular Longevity vol2012 Article ID 480895 12 pages 2012
[257] T Godfraind and S Salomone ldquoAmbiguities in dietary antiox-idant supplementation compared to calcium channel blockerstherapyrdquo Frontiers in Pharmacology vol 6 article 10 2015
[258] H Wagner H Norr and H Winterhoff ldquoDrugs with adap-togenic effects for strengthening the powers of resistancerdquoZeitschrift fur Phytotherapie vol 13 no 2 pp 42ndash54 1992
6 Oxidative Medicine and Cellular Longevity
NH
SCH3
CN
Cl
O
NH
SCH3 SCH3 SCH3
CN
O
NH
CN
O
NH
CN
OCl OCHF2 OCHF2
OSI-3701OSI-9642OSI-3761OSI-1146
H3C
H3C H3C
H3C H3C H2N
H3C H3C
Figure 3 Molecular structures of OSI-1146 OSI-3701 OSI-3761 and OSI-9642 (according to [146])
blocks media and reactions routes Water and ionic liquidsas reaction media microwave and infrared irradiation newcatalysts solid phase synthesis and biotechnology based andgreen chemistry approaches were also proposed as attractiveoptions for syntheses of DHPs [62ndash66]
Furthermore several new dihydropyrimidin-(2H)-ones(DHPMs) close analogues of DHPs were prepared in theBiginelli reaction under ultrasound irradiation and in thepresence of NH
4Cl Some of these compounds when tested
in vitro at concentrations higher than 100 120583M [67] showedAOAs manifested as inhibition of LPO induced by complexFe + EDTA and reduction of ROS levels
Recently Sun et al [68] reported about the synthesis andantioxidant activity of a series of novel 3-chalcone-substituted14-dihydropyridine derivatives based on dimethyl or diethyl26-dimethyl-4-phenyl-14-DHP-35-dicarboxylate
32 14-Dihydropyridines as Hydrogen Donors Steric elec-trostatic and hydrophobic descriptors in DHP moleculecould serve as its potential pharmacophores [2] In caseof Hantzsch ester this implies partly hydrogenated N-heteroaromatic DHP nucleus itself or its fragments that isNH group or C-4 H- atom as hydrogen donors necessaryfor the AO activity andor carboxylic ester side groups (itsC=O group and O atom as hydrogen bond acceptors) inpositions 3- and 5- and alkyl side groups in positions 2-and 6- (as hydrophobic features) (Grover et al [33] andTikhonov and Zhorov [69]) The presence of labile hydrogenatoms (mainly in positions 14-) in DHPs molecule assignssignificant hydrogen donating ability to these compounds
DHPs (26-dimethyl-14-dihydropyridine-35-dicarboxy-lic acid esters) can be oxidized in chemical (Dubur andUldrikis [70]) electrochemical enzymatic (Duburs et al[71]) and biological (including metabolism and biotransfor-mation) systems As already stated dihydropyridines (espe-cially unsubstituted in position 4) may transfer the hydro-gen similar to the reduced diphosphopyridine nucleotidesNADH and NADPH (Scheme 1) (Mauzerall and Westheimer[28]) while HEH hydrogen transfer studies and search fornovel NADHmodel compounds are continuously developing(Xie et al [72])
Tamagaki et al [73] observedmetal-ion-facilitated oxida-tions ofDHPswithmolecular oxygen andhydrogenperoxideOn the other side Tirzite et al [74] studied some 14-DHP derivatives as reductants in relation to trivalent iron
Hantzsch esters have been extensively utilized as stoichio-metric biomimetic reducing agents Recent summarized lit-erature about DHPs as reducing agents including referenceson diludine may be found on specialized websites httpwwworganic-chemistryorgchemicalsreductions [75]
DHPs form free radicals in chemical electrochemicaland biological oxidation processes The kinetic parametersand pathways of decay of the cationic radicals formed asprimary products in the course of electrooxidation of theesters of 12- and 14-dihydropyridine have been extensivelystudied [76]
The regenerative system of nicotinamide cofactors mayinvolve oxidizing or reducing reagents regulating enzymesand photochemical reactions Thus in situ regenerationof the consumed cofactors was observed in the biosys-tems engineering which create superior biocatalysts by thereduction of NAD(P)+ which can lead to the 14-DHPproduct (which is the only active form) and to the 16-DHP compound [77] The NADPH models of HEHs can beregenerated in situ as biomimetic hydrogen sources bymeansof transition metalBroslashnsted acid catalyzed relay asymmetrichydrogenation [78] General regeneration strategies werereviewed by Chenault and Whitesides [79] Based on thesestrategies particularly related to methods of preparation andpractical use of esters of 26-dimethyl-14-dihydropyridine-35-dicarboxylic acid as antioxidants that might be probablyapplicable for radioprotection and adjuvant treatment againstmetastases several patents were prepared [80]
Sambongi et al [81] have found that the novel water-soluble Hantzsch 14-dihydropyridine compound (the potas-sium salt of 26-dimethyl-14-dihydropyridine-35-dicar-boxylic acid monomethyl ester) functions in biological pro-cesses through regeneration of NADH Various parametersrelated to nicotinamide coenzymes regeneration especiallyin a light of chiral compounds have been published recently[82] while Okamura et al [83] reported the use of theoxidative conversion of dihydropyridine to pyridinium ionand the metabolic trapping principle as an approach formeasuring in vivo cerebral redox states
33 Antioxidant Activity (AOA) and Antiradical Activity(ARA) of 14-Dihydropyridines Antioxidative activity of 14-DHPs was first evaluated and studied in the Latvian IOS(Tirzit and Duburs [39] Zilber et al [44] and Dubur et al[45])
Oxidative Medicine and Cellular Longevity 7
N
O O
N
O O
R R
N
O Ominuseminus minuseminusminuseminus
minusH+
minusH+minusHminus
minusH∙
R998400(H)R998400H R998400(H)
oplus
R=H
Scheme 1 Reactions of 14-dihydropyridines leading to the formation of pyridine derivatives
In the field of ARA pioneering work was made by Schel-lenberg and Westheimer [84] in 1965 In 1979 Schellenberg[85] revealed the free radical oxidation of a dihydropyridinefollowing Huyser et al [86] who reported hydroxyl radicalquenching by DHPs especially Hantzsch ester studying freeradical oxidation of DHPs in vitro in the Fenton system
AOA and ARA of various 14-DHPs were further studiedby several different methods in both in vitro and ex vivoinvivo systems [3 31 44ndash53] CA nisoldipine nimodipinenitrendipine nifedipine and nicardipine have AOA thatcorrelates with their lipophilicity (modified Buege and Austrsquosmethod of TBA determination applied in model of rat braincortex ischemiareperfusion) [87]
N-Aryl-DHPs designed as sirtuin activators were furtherreported as suitable agents for neuroprotection due to theirradical avoidance properties (Hardeland [88])
14-DHPs inhibit free radicals and consequentially thecascade of events related to lipid peroxidation They mayinfluence several stages (initiation andor propagation) of thelipid peroxidation cascade which consist of sim10 reactions[89] (detailed discussion in Section 331 (2)-(b) Scheme 2)
However considering the great number of AO com-pounds (including DHPs) and the diversity in their actionmechanisms [90] in vivo studies are not always convincingand conclusive Therefore concise in vitro models are neces-sary to screen each compound with antioxidative propertiesAntioxidants are designed to react readily with oxidizingspecies and are often extensively oxidized already duringincubations at atmospheric oxygen tension (oxidation ofsome water-soluble DHPs in water (buffer) solutions is veryfast especially in the presence of light) Even during arelatively short incubation period the concentration can dropdrastically and the real potency of the compound could beunderestimated [90]
331 Common AOA and ARA Features of Some DHPs
(1) In Vitro (in Solutions Emulsions and Liposomes) Basicmolecular principles related to antioxidative and antiradi-cal activity of various antioxidants including DHPs werepublished recently [91] These data show that DHPs reactwith various types of free radical species stable free radicals(DPPH ao) and alkyl radicals and with oxygen and nitrogenfree radicals Some derivatives of DHPs may quench a singletoxygen and may react with peroxynitrite anion [92ndash95]
Reactivity of DHPs toward alkyl radicals was studiedelectrochemically [96]
The activity against DPPH radical was found for the5-acetyl-2-alkylthio-4-aryl-6-methyl-14-dihydropyridine-3-carboxylic acid nitriles [97] structural analogues of the5-acetyl(carbamoyl)-6-methylsulfanyl-14-DHP-carbonitrile(studied as mitochondriotropic compounds see further inthe text Section 331 (2)-(b))The highest antiradical activityoccurred for a compound which contains two hydroxylgroups in the 4-phenyl substituent
DHPs were proved to decrease oxygen uptake (2-3-fold) in the heme (methemoglobin hematin hemin andcytochrome C) catalysis by oxidation of emulsions of estersof unsaturated fatty acids and liposomes of phospholipidphosphatidylcholine (Zilber et al [44] and Dubur et al [45])
Reactivity of nitrosoaryl and nitroaryl derivatives of 14-DHPs toward alkyl alkylperoxyl radicals and ABTS radicalcation was found in various LP modeling systems suitablefor determination of DHPs AOA and ARE features [98ndash104] Diludine and foridone and its analogues were shown toinhibit lipid peroxidation through inhibitory effect on lipoxy-genase in emulsions and in reversed micelles (Tsetlin et al[105] and Panek et al [106]) In addition to inhibition of ther-mally initiated oxidation of methyloleate in the solution [107](where AOA of 4-unsubstituted 35-dicarbonylderivativesof 26-dimethyl-14-DHPs is not linearly dependent onthe inhibitor concentration) DHPs derivatives containinghydroxy alkoxy or dimethylaminophenyl substituents inposition 4 were shown to prevent loss of 120573-carotene in thedisperse system of 120573-carotene and methyllinoleate (Plotnieceet al [108])
The AOA of DHPs has been detected using differentmethods in various systems where lipid free radical gen-eration (nonenzymatic Fe2+-dependent andor enzymaticNADPH-dependent) took the place [109ndash112] This activitywas further confirmed in vivo through prevention of damagecaused by renal ischemia and reperfusion as shown fordiludine [113]
Some redox properties of calcium antagonist dihydropy-ridines were revealed through electroanalytical studies [114]Competitive kinetic procedure was used for exploring theAO capacity of five (four 14-DHPs lacidipine felodipinenifedipine and amlodipine and one 12-DHP compoundGR44966) CA and one calcium ion agonist (Bay K 8644) Allbut one (amlodipine) antagonist displayed an unambiguousAO capacity (crocin test) The calcium agonist DHP revealedno reaction with peroxyl radicals Lacidipine was the mosteffective A calcium agonist Bay K 8644 is quite resistant tooxidation and does not bind H+ This could be important
8 Oxidative Medicine and Cellular Longevity
fact in the interaction with the target proteins (it should bementioned that there are no studies on LP with other Ca2+agonists)
The decreased oxidation potential correlates with AOcapacity and increased basic characterThese findings suggestthe relevance of the electron density on the DHP ring
For all the DHP compounds investigated the overalloxidation process proceeds through two consecutive one-electron releases a primary one-electron step accompaniedby a fast proton release and the formation of a neutral radical(PyH∙) undergoing a second much easier one-electron step[114]
The final product is the protonated form of the parentpyridine derivative This pattern is relevant for the antioxida-tive activity since the radical intermediate is far less prone tobe reduced than oxidized
In the case of CA DHPs the release of protons compli-cates the overall oxidation process by introducing a ldquopara-siticrdquo side reaction where a coupling between protons and thestarting species takes place
This DHP self-protonation subtracts part of the originalspecies from the electrode process because the parent cationicspecies are no longer electroactive
Conversely the calcium agonist DHP which is less proneto be oxidized turned out to be so weak base to be evenunable to undergo the self-protonation reaction
Thus the combined effect of oxidation potentials andproton binding capacity of DHPs is a key element for theredox transition relevant for their AO activity Yet opposingeffects (antagonistic versus agonistic) on protein targets ascalcium ion channels connected with protein thiol oxidationto disulfide should be also considered [114]
Kourimska et al [115] found AO effect of diludine (HEH)in edible oil Reactivity of 14-DHPs toward SIN-1-derivedperoxynitrite was shown by Lopez-Alarcon et al [116] Oleket al [117] discovered antioxidative activity of NADH and itsanalogue in vitro
Further see as referred in several subparts below Sections34 35 and 37
(2) Ex Vivo (on Lipid Peroxidation in LDL MitochondriaMicrosomes and Cells) Main chemical structures of DHPsexamined in numerous studies and reviewed in this paper arepresented in Figures 1 and 2
(a) Various DHPs Calcium Antagonists as Inhibitors of LDLPeroxidation Free radicals induce peroxidation of LDLThis process proceeds by a chain mechanism which revealsphosphatidylcholine hydroperoxides and cholesteryl esterhydroperoxides as themajor primary products [118] Calciumantagonist DHPs could act as antioxidants on LDL at leastin three ways (1) as inhibitors of isolated LDL peroxi-dation caused by various inducers (Cu2+ ions UV lightand xanthinexanthine oxidase system) (2) if preincubatedwith cells preventing against intracellular LDL oxidation (3)preventing against the harmful effect of oxidized LDL on cellsand decreasing cytotoxicity [119ndash131]
Combined application of ascorbic acid and CA DHPs(amlodipine and felodipine) has an additive (cytoprotective
and LDL antioxidant activity) effect [120] It includes acombination of peroxide-degrading and peroxyl radical scav-enging reactions thus demonstrating the importance of LPduring LDL oxidation and cytotoxicity induced by oxidizedLDL Cytoprotection is associated with inhibition of oxidant-induced increases in intracellular free calcium
Similar to the othermodel systems the recorded values ofthe tested DHPs related to AO activity on LDL LP and relatedevents [119ndash131] depend on the prooxidant model system andmethods used for activity measuring (see Tables 1ndash5)
Commercial Ca2+ antagonists (including 14-DHP deri-vatives) as well as some other 14-DHPs with less CA activitywere shown to decrease the rate of oxidation (detected asTBARS) of low-density lipoprotein (LDL) induced by Cu2+ions (CuSO
4) in two different cell lines U937 human mono-
cyte-like and J774A1 murine monocyte-macrophage cellline (Rojstaczer and Triggle [119]) The strongest effect wasrecorded for vitamin E followed by felodipine 2-Cl analogueof nifedipine nifedipine amlodipine nitrendipine vera-pamil and diltiazem
Rojstaczer and Triggle [119] found that CA from differentchemical groups had a concentration-dependent effect asantioxidants against LDL oxidation (see Table 1) Howeverthe order of potency (activity rank order ARO) of the drug(s)again depends on the oxidation system and the antioxidantassay Both CA and antioxidative effects relate to the 2- (or o-orto-) substituent of the 4-phenyl ring in the same potencyorder 119900 gt 119898 ≫ 119901 [119] On the other hand the require-ment for the 14-DHP ring is essential for both AOA andCa2+channel antagonism A charged substituent at the position C-2 of the 14-DHP ring influences the AO activity (analogousto [46ndash53]) However some other factors should not beneglected for example although amlodipine has a positivelycharged amine at this position this modificationmakes it lesslipophilic and indirectly less potent antioxidant
Similar results were obtained when testing antioxidanteffect of CA on LDL peroxidation in bovine aortic endothelialcells (BAECs) (Cominacini et al [123] see Tables 2 and 3) aswell as in HUVECs (Lupo et al [129]) (see Table 4)
Cominacini et al [123] observed antioxidant effect ofCCBs and 120572-tocopherol in BAECs The order of potency(see Tables 2 and 3) [123] was however different than inU937 human monocyte-like and J774A1 murine monocyte-macrophage cells (see Rojstaczer and Triggle [119] Table 1)The tested DHPs were lacidipine amlodipine lercanidipinenimodipine and nifedipine (in two different intracellularconcentrations 2 and 4 fmol) ROS production was signif-icantly lowered only by lacidipine (which is the compoundwith the highest lipophilicity) and lercanidipine the effectof lacidipine was much more evident than lercanidipineSurprisingly amlodipine nimodipine and nifedipine had noeffect on ROS formation suggesting that the positive effectson the earliest events of atherosclerosis are a peculiarity oflacidipine molecule through its antioxidant activity
The strong AO action of lacidipine may be related tothe lipophilic cinnamic acid side chain which favors a drugpartitioning in the membrane due to favorable physicochem-ical (hydrophobic) interactions of drug hydrophobic residues
Oxidative Medicine and Cellular Longevity 9
Table 1 Relative structure-function relationships of calcium antagonists (DHPs verapamil and diltiazem) and vitamin E Effect on oxidativemodification of isolated ex vivo human low-density lipoprotein using two various oxidation systems (copper (II) ions induced and monocyteinduced) Compiled according to data presented by Rojstaczer and Triggle [119]
Compound
Systems of LDL oxidation
Copper (II) ions induced system (comparison of three methods) Monocyte induced celloxidation system
Methods
Reduction of TBARS level of LDL(relative efficacy)
Degradation of oxidized[125I] LDL by J774
macrophages
Relative electrophoreticmobility of LDL on
agarose gel
TBARS content of LDL(in )
Relative efficacy (activity rank order (ARO) ARO = I for the most effective) effective inhibitor concentration [IC] in120583M
with polyunsaturated groups of membrane phospholipidsHowever DHPs can also reduce the oxLDL-induced ROSconcentration by affecting some intracellular ROS producerssuch as NADPH oxidases xanthine oxidase and cyclooxyge-nase enzymes The activity of these enzymes contributes tointracellular ROS elevation [125]
Preincubation of HUVECs with lacidipine inhibited anincrease of intracellular ROS caused by oxidized LDL [124]
Lupo et al [129] have studied the dose-dependent (1 510 and 50 120583M) AOA of various CA (verapamil diltiazemand DHPs nifedipine amlodipine isradipine or lacidipine)
Table 3Modulation of ROS formation in BAECs by CA (DHPs andverapamil) and vitamin E Compiled according to data presented byCominacini et al [123]
Compound
Method of flow cytometry (reduced2101584071015840-dichlorofluorescein diacetate(DCFH-DA) oxidation by ROS)
Activity rank order(ARO = I for the highest activity ARO = III for
the mindest activity)(Effective [IC] 1 5 10 50 120583M)
Lacidipine + + + (ARO = I)Lercanidipine + + (ARO = II)Amlodipine No effectNifedipine No effectNimodipine No effectVerapamil + (ARO = III)120572-Tocopherol + + + (ARO = I)
against normolipidemic human blood LDL oxidation com-pared with 120572-tocopherol by measuring the content of TBARSand the diene formation (see Table 4)
10 Oxidative Medicine and Cellular Longevity
Table 4 Normolipidemic human blood LDL (025mgmL) in vitro oxidation in the presence of 5 120583M CuSO4and CA of 3 types (DHPs
verapamil and diltiazem) and vitamin E Compiled according to Lupo et al [129]
Compound
MethodsTBARS method (fluorimetry at 515 nm533 nm 4 hours
preincubation of LDL with compounds and copper (II)ions 320 TBARS increase in control during 4 h
period)
Inhibition of conjugated diene formation (at 234 nm)expressed as prolongation of induction period (in
of control) 119905contr = 368min
Effective [IC] (in 120583M)1 120583M 10120583M 50 120583M
Activity rank order (ARO= I for the highest activity
ARO = VII for themindest activity)
Effective [IC] (in 120583M)1 120583M 5 120583M 10120583M 50 120583M
Activity rank order (ARO= I for the highest activity
ARO = VII for themindest activity)
Nifedipine 10120583M50 120583M ARO = III
5 120583M10120583M 15050 120583M 213
ARO = III
Amlodipine 50 120583M ARO = IV5 120583M
10120583M 12250120583M 138
ARO = IVndashVI
Isradipine 50 120583M ARO = VI 10120583M 15050 120583M 183 ARO = IVndashVI
Lacidipine1 120583M10120583M50 120583M
ARO = II5 120583M
10120583M 19250 120583M 283
ARO = II
Verapamil 50 120583M ARO = V 10120583M 15050 120583M 178 ARO = IVndashVI
Diltiazem No effect No effect (ARO = VII) No effect No effect (ARO = VII)
Vitamin E1 120583M
10120583M (IC50)
50 120583M (20 of control)ARO = I
5 120583M10 120583M 23050 120583M 370
ARO = I
Table 5 Antiproliferative effect (oxLDL-induced HUVSMCs proliferation) of CA DHPs and simultaneous oxLDL-induced ROS productionscavenging Comparison with N-acetyl-L-cysteine NAC (intracellular ROS scavenger) Compiled according to data presented by Zou et al2012 [130]
DHP compound
MethodsAntiproliferative effect against proproliferative effectinduced by oxLDL (50 120583gmL) (UV detection of
formazan production from tetrazolium salt)
oxLDL-induced ROS production (fluorescent DCF(2101584071015840-dichlorofluorescein) production)
Effective [IC] in120583M and I in
Amlodipine 3 120583M I = 18 3 120583M 10 120583M No effectI = 20
S(minus)-Amlodipine No effect No effect
Lacidipine 10 120583M30 120583M
I = 21I = 27 10120583M Isim23 of control
N-Acetyl-L-cysteineNAC
mdash 5000 120583M(5mM) I = 28
As presented (Table 4 according to [129]) for diltiazem(poor lipid solubility) noAOwas detected whereas the otherCA and 120572-tocopherol have demonstrated AOA at least atconcentrations of 10 and 50120583M 120572-tocopherol gt lacidipinegt nifedipine gt isradipine verapamil and amlodipine Addi-tionally120572-tocopherol and lacidipinewere able to significantlyattenuate in vitro LDL oxidation at 1 and 5120583M Theseresults have confirmed the highest activity for the stronglylipophilic DHP type CA compound lacidipine This might be
a possible antiatherogenic mechanism of CA since oxidativemodification enhances the atherogenic potential of LDL
The lipid peroxidation of LDL promoted either by UVradiation or by copper ions was inhibited (antioxidant effect)by nisoldipine in a dose-dependentmanner (IC
50values were
evaluated at around 10 120583M) nimodipine was less potent (IC50
around 50ndash100 120583M) and nicardipine almost inactive In addi-tion to this indirect protective effect CA DHPs nisoldipineand nimodipine exerted direct protective effect on lymphoid
Oxidative Medicine and Cellular Longevity 11
cells against toxicity of previously oxidized LDL The IC50
values were 6 plusmn 2 and 80 plusmn 20 120583M respectively [122] Theinhibition of the cytotoxic effect of LDL oxidized in thepresence of DHP type Ca2+ channel blockers correlated wellwith protection from oxidation by these compounds Com-plete protection cannot be obtained because the DHPs arecytotoxic themselves The potential relevance to the preven-tion of atherogenesis is envisaged
DHP typeCCBnifedipinewas themost effective inhibitorof oxidation promoted either by UV radiation or by copperions in experiments with cultured lymphoid cells LDL (2mgapoBmL) CCBs from other two CCB classes diltiazem andverapamil were only poorly active or completely ineffective[121] The protective effect of nifedipine occurs at two levelsbesides its direct antioxidant effect by inhibition of LDLoxidation it also exhibits a direct cytoprotective effect againstcytotoxicity of oxidized LDL by yet unknown mechanismsThe protective effect of CCBs was not due to an inhibitionof LDL uptake This effect seems to be independent of theinhibition of LDL oxidation per se since LDL was oxidizedin the absence of the drug before the incubation withcells Moreover this direct protective effect was observedat lower concentrations (IC
50of 1 plusmn 02 120583M) compared to
the antioxidant effect (IC50
of TBARS inhibition is around10 plusmn 2 120583M at UV promoted and 4 plusmn 05 120583M by Cu2+ ionsinitiated) The AO effect of nifedipine is also correlated withthe protection of endogenous tocopherols (IC
50= 50 120583M)
It was suggested that the AO effect of CCBs protected cellsindirectly from the cytotoxic effect of oxidized LDL [121]
A recent study has reported that beneficial vascular effectsof lercanidipine in diabetic rats depend on its antioxidantactivity related to attenuating the increase in oxidativestress and in vascular matrix metalloproteinase-2 (MMP-2) (Martinez et al [126]) Lesnik et al [127] studied theimpact of a combination of this calcium antagonist and a120573-blocker atenolol on cell- and copper-mediated oxidationof LDL and on the accumulation and efflux of cholesterolin human macrophages and murine J774 cells They realizedthat lercanidipine reduced the oxidative modification of LDLrather than diminished cholesterol accumulation in humanfoam cells
Comparing the antioxidative action of CA (DHPs amlo-dipine lacidipine nifedipine and isradipine as well as diltia-zem and semotiadil) in the copper-catalyzed oxidation oflow-density lipoprotein (LDL) with that of glycated (g)gly-coxidated (go) LDL demonstrated that the strongest AOeffects during long-term LDL glycation are seen for isradip-ine lacidipine nifedipine and semotiadil [128] Inhibitoryeffects were in the range 10minus5ndash10minus3MAuthors suggested thatdue to the increased generation of ROS by glucose-modifiedLDL the chain-breaking capacity of CA may be overriddenThe AOA of CA depends on their lipophilicity and theirability to incorporate into the LDL particle that is to reachthe site of peroxidation CA like other AOs significantlyretards advanced glycation end products (AGE) formationwhereas initial glycation reactions such as Amadori productformation are only weakly inhibited The observation thatboth oxidative changes and at least long-termglycation effectsare indeed drastically reduced by CA is corroborated by
fluorescence analysis AGE-ELISA quantitation of lipid per-oxidation and TBARS measurement of long-term ggo LDL
The effects of lipophilic DHP calcium channel blockerson oxidized LDL-induced proliferation and oxidative stressof vascular smooth muscle cells were also studied [130] (seeTable 5)
Lacidipine and amlodipine reduced carotid intima-media thickness by decreasing proliferative effect of oxLDLwhereas (S-)-amlodipine had no antiproliferative effect ROS-MAPKs (mitogen-activated protein kinases) pathway mightbe involved in the mechanism
Both 14-DHP CCBs lacidipine and nifedipine reduceplasma and LDL oxidation and formation of oxidation-specific epitopes Their application may also relate to pro-longed survival of rats independently of blood pressuremod-ifications (in the SPSHR model 1mgkg per day lacidipineand 80mgkg per day nifedipine) These results suggestedthat the protective effect of these two 14-DHP drugs invivo as shown in cerebral ischemia and stroke may in partresult from inhibition of LDL oxidative process althoughthese two drugs possess different lipophilic properties [131]Both lacidipine (03 and 10mgkg) andnifedipine (80mgkg)prolonged lag time of the conjugated diene formation inLDL isolated from arterial wall and 119905max These drugssignificantly reduced electrophoreticmobility of oxLDL fromSPSHR subjected to XXO oxidation system 14-DHP CCBsalso protected apolipoprotein B which is important for thebinding with macrophage LDL receptor lysine residues Thedoses used (gt10minus6molL for SPSHR and normotensive WKYrats) however are 2 to 3 orders of magnitude higher thanthose inhibiting vascular smooth muscle contraction in vitroand in vivo They also exceed values that are commonlyused in clinical practice The daily dose of lacidipine forhypertensive patients is 007mgkg asymp4- to 14-fold lower thanthe 2 doses used in SPSHR The maximum daily dose ofnifedipine given to hypertensive patients is 20mgkg asymp40-fold lower thanwhatwere used [131]These discrepanciesmaybe related to differences in bioavailability of CA between ratsand humans [131]
Accordingly in routine clinical use 14-DHPCCBs donotreach the concentrations required for antioxidant activity invitro [131]
Another data concerning the effect of CA DHPs on OSrelated to LDL is presented under Section 35
(b) Effect of DHPs on Isolated Rat Liver and Heart Mitochon-dria As a major cellular source of oxygen radicals (Cadenas[4 5]) mitochondria are promising targets for pharmaco-logical and toxicological actions of various membrane-activecompounds including several 14-DHP derivatives Zernig etal [132] have discovered CA binding sites associated with aninner mitochondrial membrane anion channel
More than 40-year long research onmitochondrial effectsof the DHPs (on their bioenergetics chemiosmotic proper-ties and ion fluxes) clearly points them out as mitochondri-otropic compounds
The activity of the first 35 synthesized compounds(derivatives of 14-DHP their heteroaromatic analogues
12 Oxidative Medicine and Cellular Longevity
NAD-H+ and butylated hydroxytoluene (BHT BOT)) orig-inally was examined in rat liver mitochondrial LP system inthe presence of Fe2+ ions and using the ultraweak chemilu-minescence method (Dubur et al [89])
Several 14-DHP derivatives Hantzsch ester diludine andits analogues were found to be effective antioxidants in thisexperimental system changing the kinetics of LP lengtheningthe time of the appearance of the maximum of the slowburst of the chemiluminescence (latency latent period) anddiminishing the reaction rate (the tangent of the slope angleduring the time in which the amplitude of the slow burstcharacterizing LP rate increases) and its peak value Theirpresence has influenced the reaction constant 119870
6 in relation
to a very significant reduction of lipid hydroperoxides andorinactivation of free radicals as follows
ROO∙ + ROO∙ 997888rarr P + h]lowast termination (1)
(P = molecular products) or
ROO∙ + ROO∙ +H2O 997888rarr ROH + RO∙ + 1O
2
lowast (2)
In this study diludine was one of themost active compoundsDHPs had activity similar to the standard synthetic AO-BHT(ionol) However when plotted against applied concentrationand time window diludinersquos activity profile differed from thatof BHT
There were also similar studies (using different LP rateexperimental detection system and method Hunter et al[133]) based on exploring a group of 26 26-dimethyl-35-disubstituted- and 26-dimethyl-345-trisubstituted-14-dihydropyridines (14-H
2Py=14-DHPs) and five related pyri-
dines as inhibitors of rat liver Mit swelling (Δ119860520119905) and O
2
uptake by ascorbic acid- (AsA-) dependent lipid peroxidationand as modulators of Mit swelling induced by Na+-linoleateor Na+-pyrophosphate (Velena et al [112])
Some of tested 4-DHPs (4-unsubstituted 35-dialkoxy-carbonyl-26-dimethyl-14-DHPs and 35-diamido-26-dim-ethyl-14-DHPs both 4-unsubstituted or those possessinglipophilic 4-aryl- groups) have shown significant AO andmembrane stabilizing activity These studies further revealedthat 14-DHPs preferably act as AO during the stages ofinitiation and prolongation of LP chain reactions at lowconcentrations The studied 14-DHPs had IC
50(when 119881
0119881
or 1205911205910= 2) 01 120583M to 100 120583M and the minimal activity was
scored for oxidized (heteroaromatized) derivativesAt the concentration of 100120583M 35-di-n-butyloxycarbo-
nyl-26-dimethyl-14-DHP entirely stops mitochondrialswelling in the presence of 08mM Na+-pyrophosphateAt the same concentration the following compoundsalter the mitochondrial swelling rate in the presence ofnatural protonophore Na+-linoleate 35-di-p-hydroxyphen-oxycarbonyl- and 35-di-p-tolyloxycarbonyl-26-dimethyl-14-DHPs 35-diethoxycarbonyl-26-dimethyl-pyridine (oxi-dized form of Hantzsch ester) and more lipophilic 35-diamyloxycarbonyl-26-dimethyl-pyridine The alteration ofswelling may be scored as prolonged promoted acceleratedor inhibited The type of alteration depends on the structureand concentration of 14-DHPs the type of initiators of theswelling process and the medium composition
In accord with previously published Janerorsquos results (lackof AO for Ca2+ antagonists nifedipine and nicardipine evenat 500120583M concentration in LP tests performed on heartmembrane [134]) no antioxidative activity for 4-phenyl sub-stituted derivatives of 35-dialkoxycarbonyl 14-DHP (closeanalogues of Ca2+ antagonists) was found contrary to various4-nitrophenyl 14-DHP derivatives calcium antagonists forwhich the significant antioxidant activity was reported [3146ndash53]
Studies made on phosphatidylcholine liposomes (ourunpublished data) suggest approximately three and twotimes more antioxidative activity for 100 120583M 4-unsubstitutedDHP compound diludine when compared to 4-substitutedDHPs riodipinenifedipine and nicardipine respectively atmethemoglobin-induced LP (oxygraphy)
Inhibition of mitochondrial AsA-dependent LP and sta-bilization ofmitochondriawere shown to be characteristic fora large group of 14-DHP compounds [112] showing to pos-sess the AOA in simplest in vitro systems (Tirzit andDuburs [39] Zilber et al [44] and Dubur et al [45])based on reactions with the stable free radical 11-diphenyl-2-picrylhydrazyl (DPPH) LP of fatty acid ester (linethole andmethyloleate) emulsions and phospholipid (phosphatidyl-choline) liposomes Generally these properties did not coin-cide with Ca2+ antagonism Depending on DHP structure itseems that AOA properties are less specific than Ca2+ antago-nist properties Both properties may be interrelated but notinterdependent
These data show that the presence and the nature ofa substituent in position 4 as well as 35-substituentsare important factors for 14-DHP antioxidant effects invarious systems that is AsA-dependent nonenzymatic aswell as enzymatic NADPH-dependent lipid peroxidationSometimes the efficacy of inhibition of nonenzymatic LPby 14-DHPs is higher than the inhibition of the enzymaticLP However the action may be opposite stimulation of theLP Hantzsch ester (HEH diludine) and its close analoguesexhibited significant AOA and membrane stabilizing prop-erties in both AsA-dependent nonenzymatic peroxidationof mitochondria and NADPH-dependent enzymatic LP ofmicrosomes usually at similar 10 to 100120583M concentrations[112]
The order of AOpotency (IC50
values) in vitro depends ondrug structure as well as on the experimental conditions andspecificity of the biological system Eachmethod for determi-nation of AOA and ARA has advantages and disadvantages(Karadag et al [135])
Accordingly as reported by Gubskiı et al [136] IC50
forthe AsA-dependent LP was 025 120583M and 20 120583M for 14-DHPCa2+ antagonists nitrepine (nitrendipine) and nifedipinerespectively Takei et alrsquos [137 138] studies on mitochondrialswelling induced by LP or arachidonic acid in the rat braindetermined the IC
50values of 127 105 1568 and 384 120583Mfor
efonidipine nicardipine nifedipine and nimodipine respec-tively For LDL in the copper-induced oxidation system theorder of potencywas vitamin Egt felodipinegt 2-chlorophenylanalogue of nifedipine gt nifedipine gt amlodipine nitrendip-ine verapamil and diltiazem (Rojstaczer and Triggle [119])
Oxidative Medicine and Cellular Longevity 13
It was interesting to compare the AOAofDHPswith theirsusceptibility to oxidation that is electron and hydrogendonating properties
It has been estimated that electron donor substituentsin positions 2 and 6 of 14-DHP cycle usually promoteoxidation while electron acceptor substituents promotequench oxidation Stronger electron acceptors in positions 3and 5 also significantly quench oxidation These estimationsare based on studies including chemical enzymatic andelectrochemical oxidation of 14-DHPderivatives (Dubur andUldrikis [70] Duburs et al [71] and Stradin et al [139])
On the other hand diminished AOA of 14-DHP relatesto presence of substituents in position 4 (both electron donorand electron acceptor) (Velena et al [112])
35-Dicarbamoyl substituents possess minimal quench-ing feature and are followed by benzoyl- acetyl- andalkoxycarbonyl- groups Maximal decrease was obtainedwith condensed substituents (ie oxoindeno- or oxocyclo-hexeno- groups) and a CN-group 4-Unsubstituted 35-dicar-bamoyl derivatives can be easily oxidized and consequen-tially inactivated whereas 4-substituted 35-dicarbamoyl-14-DHPs possess an oxidation potential analogous to the 4-unsubstituted 35-COOR derivatives Therefore they haveadequate electron donor properties and are considerablystableThismay be the reason for significantmembrane stabi-lization upon exposure to 4-substituted derivatives Ofimportance their AOA was usually more pronounced incomparison to 4-unsubstituted derivatives
Among them 26-dimethyl-35-difurfuryloxycarbonyl-14-DHP showed the highest antioxidative activity In thegroup of 35-dialkoxycarbonyl derivatives the strongestactivity was attributed to compounds with medium lengthalkyl chains (i-butyl- t-butyl- and i-amyl- substituents) highlevel of lipophilicity minimal electron acceptor propertiesand moderate steric hindrance as contrasted to short or longalkyl chain ester derivatives (35-dimethoxycarbonyl- 35-diethoxycarbonyl derivatives and 35-didodecyloxycarbonylderivative) These data demonstrate the bell-shaped depen-dence of AOA on alkyl chain length [112] and are in accordwith results obtained in liposomes However these datadiffer from those obtained in emulsions where diludine wasthe most active compound Finally oxidized heteroaromaticderivatives showed only minimal activity
In both LP systems studied (AsA-dependent in mito-chondria and NADPH-dependent in microsomes) some of14-DHPs showed activity similar to classical antioxidantbutylated hydroxytoluene (ionol BHT) (Velena et al [112])However there was a significant difference related to con-centration and incubation time It allowed us to postu-late that 14-dihydropyridines (InH) acting as antioxidants-reductants and scavengers of reactive oxygen species and lipidfree radicals preferably influence initiation and propagation(prolongation) of lipid peroxidation chain reactions (1)ndash(5) according to Scheme 2 The phenomenon is particularlyprominent in the presence of Fe2+ and other ions of variablevalency
Chain break and termination reactions (6)ndash(10) of theLP reaction cascade [89] were influenced by 14-DHPs in alesser degree than were initiation and propagation steps This
may be important for their therapeutic effects even in theadvanced stages of LP
Scheme 2 (stages of initiation propagation and terminationof lipid peroxidation chain reactions (1ndash10)) Initiation andpropagation reactions are as follows
(8) RO∙ + In∙minus rarr Y (Y = molecular products)(9) ROO∙ + Fe2+ rarr Fe3+ + X (X = molecular products)(10) RO∙ + RO∙minus rarr Y (Y = molecular products)
In the reversible swelling of mitochondria accompanyingLP (initiated by mixture of 5mM GSSG1mM GSH) several14-DHPs showed low or no activity manifested only as adecrease of the swelling amplitude without a rate decreaseAn addition of GSH (4mM) or ATP to swollenmitochondriacaused their contraction in both control and tested systemIt may be suggested that 14-DHPs acting as antioxidantsin mitochondria preferably influence LP reactions initiatedby ions with variable valency or their complexes with hemetype compounds methemoglobin hemin hematin and soforth (Velena et al [112]) If the peroxidation process has amaximal velocity and 50 percent of initial O
2were consumed
14-DHPs cannot completely break the chain reactions andprevent subsequent membrane damage by addition of DHPsubstance at 10 120583M concentration at the moment of 50percent oxygen consumption the subsequent oxygen uptakeproceeded unchanged This observation is important for theapplication of DHPs as inhibitors of initiation and to a lesserdegree propagation stages of LP chain reactions
The influence of 14-DHPs on Mit swelling is not strictlyassociated with their own oxidation There is the possibilitythat the labilizing (or stabilizing) effect relates to surfaceactivity (connected with substituent lipophilicity) or may bethe consequence of complexation with some -OH (or -CH
3)
group sensitive receptors at the mitochondrial membraneNamely a bathochromic shift of the absorption band maxi-mum (about 10 nm) was observed in the visible region beforeswelling However after swelling in the presence of Na+linoleate the spectrum returns to its initial value [112]
Some 14-DHPs not only protect mitochondria againstswelling caused by AsA-dependent LP salts of fatty acids
14 Oxidative Medicine and Cellular Longevity
in vitro [112] but also have beneficial effects on repairingtheir integrity in vivo after exposure to irradiation hepato-toxins ischemia hypoxia or hypothermia Some of themwere shown to normalize the process of intracellular repara-tion and physiological regeneration of ultrastructures Theywere also shown to stimulate reparative processes If pre-treated with 14-DHPs irradiatedmitochondria will not swell(Ivanov et al [140 141])
Diludine ionol and some other AOs mitochondria pro-tectors act as anti-ischemic agents If applied prophylacticallyin vivo they may prevent ischemic and reperfusion lesionsin heart kidney and other organs (Bilenko et al [113]) Theeffect is dependent on applied dose timing and way ofapplicationWhen added onto the cryoconservationmediumfor mitochondria preservation 14-DHPs prevented decreaseof membrane potential normalized facilitated respirationand prevented loss of mitochondrial Na+ and Ca2+ ionsafter thawing ([112] see citation number 36 (Subbota et alKharkov 1984) therein) Diludine was stronger protectorwhen compared to ionol
CA drug foridone (riodipine) was shown to possesscardioprotective features primarily due to is protective effecton mitochondria exposed to OS [142 143]
Similarly the DHP water-soluble antiarrhythmic com-pound glutapyrone inhibits initiation of LP by free radicalsin erythrocytes and heart mitochondria Its cardioprotectiveeffect has been experimentally shown in heart mitochondrialmembranes especially during deep hypothermia (Utno et al[144])
Cerebrocrast was effective in several translation modelsmimicking pathological situations known to be associatedwith cellular OS The potential protective action of 14-DHP derivatives (4-substituted compounds cerebrocrastgammapyrone glutapyrone and 4-unsubstituted drug dieth-one) has been studied in rat liver in experimental modelsrelevant for oxidative stress and mitochondrial bioenergetics(Fernandes et al [145]) When succinate was used as therespiratory substrate higher concentrations (gt25 120583M) ofcerebrocrast depressed respiratory control ratio (RCR) ADPto oxygen ratio (ADPO) state 3 and uncoupled respirationrates transmembrane potential (deltapsi) and the phosphatecarrier rate At the same time state 4 respiration rate wasthree times increased At concentrations lower than 25120583Mcerebrocrast inhibited mitochondrial IMAC and partiallyprevented Ca2+-induced opening of the mitochondrial PTPGammapyrone glutapyrone and diethone did not inducethese phenomena When applied at concentrations up to100 120583M cerebrocrast gammapyrone and glutapyrone didnot affect ADPFe2+-induced LP of mitochondria in rat liver(as measured by oxygen consumption and TBARS forma-tion) On the other hand low diethone concentrations (upto 5 120583M) inhibited it in a dose-dependent manner Diethonealso prevented against deltapsi dissipation induced by LPinitiated by ADPFe2+ Based on these data it may bespeculated that cerebrocrast (inhibition of the IMAC) anddiethone (acting as an AO) may provide effective protectionof mitochondria during OS Cerebrocrast has shown sometherapeutic potential for treatment of several pathologicalconditions related to cellular OS [145]
5-Acetyl(carbamoyl)-6-methylsulfanyl-14-DHP-carbo-nitriles (Figure 3) with minor differences in their molecularstructure displaying antioxidant and antiradical activitiesin vitro show different biological activities Namely 4-p-chlorophenyl derivative OSI-1146 displays AO and anti-radical activities in cardiovascular OS models whereasOSI-3701 and OSI-3761 display hepatoprotective activityThus these compounds may be potentially useful for treat-ing several pathological processes including those associatedwith OS (Fernandes et al [146]) However besides mito-chondria the cellular targets for their pharmacologicalactions have not been fully investigated [146] All these com-pounds increase the susceptibility of Mit to MPT The mostpotent is OSI-3701 although it does not affect bioenergeticparameters
Although all these compounds protected mitochondriaagainst LP induced by the oxidant pair ADPFe2+ OSI-1146was shown to be the most potent Current data point outmitochondria as potential targets for protective and toxicactions of DHPs suggesting that the potential for their use astherapeutic agents should also take into consideration theirtoxic effects on mitochondria (Fernandes et al [146])
Several structurally different DHP derivatives (antioxi-dant diludine (diethone) as a 4-unsubstituted DHP 4-substi-tuted DHPs CA foridone (bicyclic compound) and the 4-phenyldiethone compound where phenyl group is joined tothe DHP in position 4) inhibited the 1-methyl-4-phenyl-pyridinium iodide (MPP+) induced ROS production incerebellar granule cells (CGC) with a distinct potency orderforidone (26-dimethyl-35-dimethoxycarbonyl-4-(o-difluo-romethoxyphenyl)-14-dihydropyridine) gt 26-dimethyl-35-diethoxycarbonyl-4-phenyl-14-dihydropyridine gt diludineThey also reversed the MPP+-induced decrease of the mito-chondrial membrane potential in the same order (Klimavi-ciusa et al [147]) Accordingly it was postulated that theclassical two-ring (bicyclic) structure of DHP derivativesrepresents an advantage in relation to neuroprotection andROS defense and is independent on compoundrsquos propertiesrelated to calcium ions
Novel adamantane-containing 14-DHP compounds (Kli-maviciusa et al [148]) were also found to improve mitochon-drial functions (MPP+ model) (Klimaviciusa et al [148])Klusa et al [149] have discovered antineurotoxic effects of14-DHP taurine derivative tauropyrone recorded as Mitfunction improvement
Many 14-DHPs including Ca2+ antagonists and AOmodify LP processes and influencemitochondrial function invarious organs (liver heart kidney and brain) in a differentway and degree Their beneficial action oxygen or lipidfree radical scavenging antioxidative effects binding withor intercalating into phospholipid bilayer regulation of iongating and regulation of mitochondrial permeability transi-tion pores (Tirzit and Duburs [39] Zilber et al [44] andDubur et al [45]) separately or in combination with eachother depends on two strong elements (1) their individ-ual structure including nature of substituents and theirpositions and (2) the nature of the biological system Forexample the direction of LP (inhibition of promotion) wasshown to depend on structure and concentration of applied
Oxidative Medicine and Cellular Longevity 15
14-DHPs as well as stages of chain reactions Accordinglymitochondrial swelling may be prolonged (retarded) accel-erated (promoted) or inhibited (Velena et al [112])
Therefore there is a ground for 14-dihydropyridineseither Ca2+ antagonists or antioxidants to be nominated asuseful tools in development of ldquomitochondrial drugsrdquo relatedto the control of OS
(c) DHPs as AOs in Endoplasmic Reticulum (Inhibition ofNADPH-Dependent LP System) Inhibition of NADPH Oxi-dase by DHPs Elevated level of NADPH oxidase 4- (NOX4-)derived hydrogen peroxide (H
2O2) joined with concomitant
decrease of nitric oxide (NO) mediated signaling and reac-tive oxygen species scavengers are considered to be centralfactor in molecular pathogenesis of fibrosis (Sampson etal [150]) Inhibition of microsomal NADPH-dependent LPwith particular focus on NADPH oxidases (NOX1ndash5 andDUOX1) may be very important for neuro- cardio- andhepatoprotection (Velena et al [112] Leto and Geiszt [151]Griendling et al [152] and Chen et al [153]) Endoplasmicreticulum may be an important target as this is where 14-DHPs could display their antioxidative properties (Velena etal [112] Leto and Geiszt [151] Griendling et al [152] andChen et al [153])
However the initiation of LP in the NADPH-dependentmicrosomal system does not appear to involve either super-oxide or hydrogen peroxide since neither SOD nor cata-lase can inhibit it On the other hand reduced iron playsan important role in both the initiation and propaga-tion of NADPH-dependent microsomal lipid peroxidation(Hochstein and Ernster [154] and Repetto et al [111])
Many DHPs possess inhibitory activity not only towardsAsA-dependent LP in mitochondria but also towardsNADPH-dependent LP as shown in isolated rat liver micro-somes (Velena et al [112]) This means that these compoundsinteract with the shared parts (nonenzymatic and enzymatic)of LP pathways
Microcalorimetry and fluorescent probes procedureswere used for studying the interaction of alpha-tocopheroland 14-DHPs with endoplasmic reticulum membranes andmodel systems human serum albumin and phospholipidbilayers [155] Modification of microviscosity of the endo-plasmatic reticular membranes depends on localization ofantioxidants within the protein structures or phospholipidphase Increase of membrane structuralization under theinfluence of 14-DHPs blocked their antioxidant action inspontaneous and induced lipid peroxidation
Inhibition of rat heart and liver microsomal lipid perox-idation by nifedipine was observed [156] while Goncalves etal [157] found antioxidant effect of calcium antagonists onmicrosomal membranes isolated from different brain areas
Nitroaryl-14-DHPs are both calcium channel antagonistsand antioxidant agents (Letelier et al [158 159]) commonlyused for treatment of cardiovascular diseases These drugsmust be metabolized through cytochrome P450 oxidativesystem (NADPH-cytochrome P450 reductase) mainly local-ized in the hepatic endoplasmic reticulum Several lipophilicdrugs generate OS while being metabolized by this cellularsystem Thus DHP antioxidant properties may prevent the
OS associated with hepatic biotransformation of drugs Var-ious commercial and new nitro-phenyl-DHPs were studiedagainst LP using rat liver microsomes under oxidative stress[159]
Incubation of rat liver microsomes with the 41015840-nitro-4-phenyl-14-DHP compounds (26-dimethyl-4-(41015840-nitro-phenyl)-14-dihydropyridin-35-diethyl-dicarboxylate andN-ethyl-26-dimethyl-4-(41015840-nitrophenyl)-14-dihydropyri-din-35-dimethyl-dicarboxylate) results in an inhibitionof LP the UDPGT (UDP-glucuronyltransferase) oxidativeactivation and the microsomal thiol oxidation induced byFe3+ascorbate a generator system of ROS This effect wasalso produced by nitrofurantoin and naphthalene in thepresence of NADPH
Interestingly IC50
ofDHPs obtained frommicrosomal LPassays decreased to the same extent as the microsomal thiolsoxidation provoked by Fe3+ascorbate [159] Neverthelessthe AO effects of a nitrophenyl-DHP compound in whichhydrogen at position one of the DHP ring was replaced bythe ethyl groupwere significantlyweaker Authors speculatedthat DHPs can resemble NADH transferring one hydrogenatom of 4-position (Hminus) to anion superoxide and another ofthe 1-position (H+) by way of a cationic radical intermediateto generate pyridine derivatives and water [159]
The AO effects of various tested DHP derivatives (m- andp-NO
2phenyl as well as methyl or ethyl and isopropyl-DHP
35-dicarboxylate derivatives) were not significantly differentThe authors assumed that the -NH- group of the dihydropy-ridine ring could contribute both to the development ofthe calcium channel antagonism and to the antioxidativeproperties of DHPs [159]
Prevention of the membrane LP seemingly depends onthe concentration of potential antioxidants such as vitaminE or even 14-DHP in lipids However only the differencesin synthetic DHPs lipophilicity cannot explain significantvariations of DHPs concentration in microsomal membraneand cannot clarify the strength of their antioxidative activityThis work [159] has further demonstrated that 14-DHPsmay prevent the OS induced by biotransformation of somedrugs for example antibiotic nitrofurantoin Simultaneousadministration of DHPs and nitrofurantoinmay be beneficialin reducing nitrofurantoin side effects
While most of Ca antagonist 14-DHPs are metabolizedby CYP3A4 (Guengerich et al [160]) not all of them are goodinhibitors of its activity Thus nicardipine but not nifedipineand nitrendipine inhibits CYP3A4 in vitro [53] Interactionof different DHPs with various types of cytochrome P450 wasdescribed by Carosati et al [53] It was also reported thatDHP class calcium channel blockers reduce the antiplateleteffect of clopidogrel (Park et al [161])This implies themutualinteractions of both drugs with CYP3A4
(3) In Vivo Evaluation of nifedipine effects on Saccharomycescerevisiaewas recently published (Asma andReda [162]) Sur-prisingly nifedipine exercised a toxic effect on Saccharomycescerevisiae shown through measuring cellular proliferationrespiratory activity and the level of some biomarkers (CATand MDA)
16 Oxidative Medicine and Cellular Longevity
However majority of data obtained on various animalcells and tissues by other authors show the protective role ofDHPs against both LP and oxidative stress [113 163 164]
The AOA attributed to many 14-DHPs Ca2+ antag-onists and other compounds reflecting on catalytic LDLperoxidation (see Section 331 (2) and Section 35) shouldencourage their testing for treating cardiovascular diseasesandor alterations of lipid metabolism
The possibility that 14-DHP-based calcium antagonistsexert an antiatherosclerotic action (via inhibition of LDLoxidation and other mechanisms) has been proved by manyexperimental data [165] and several clinical trials Besidesantihypertensive effect nicardipine was shown to possessantioxidative and antielastase activity [165 166] These prop-erties may be useful for prevention of inflammatory reactionwhich is relevant for hypertension pathogenesis
14-DHPs administration inhibits LDL oxidation medi-ated by oxygen radicals leading to decreased carotid inti-mal media thickness and reduced progression of coronaryatherosclerosis [130] It additionally preserves Apo B-100integrity against ROS Of importance antiatherogenic mech-anisms differ between animals and humans (primarily inthe stage of conversion of aldehydes to carboxylic acids)(Parthasarathy et al [167])
For example furyl-DHP compound (FDP-1 diethyl 26-dimethyl-4-(furyl)-14-dihydropyridine-35-dicarboxylate)was shown to act as an antioxidant (decreasing MDA GOTand FFA release of ischemic myocardium and inhibiting Ca-ATPase of erythrocyte membranes) preventing against heartmyocardium ischemia-reperfusion injury and arrhythmiawhen applied (in rats) at 10mgkg (Liu et al [168])
Similarly antioxidative effects of azelnidipine andamlodipine prevented neuronal damage by CCBs aftertransient focal ischemia in rats (Lukic-Panin et al [169])
Allanore et al [170] found that both nifedipine andnicardipine significantly decrease the mean level of plasmamarkers for oxidative stress in patients suffering from sys-temic sclerosis
Antioxidants may be considered as promising neuropro-tective compounds Still while experimental data demon-strate neuroprotective effect in vitro and in animal mod-els clinical evidence is still unsatisfactory and insufficient[171]
(a) Role of Metabolism of DHPs in Their AOA Metabolicpathways and ldquobioavailabilityrdquo of the probable AOA com-pound determine antioxidant activity in vivo Antioxidantmetabolites may vary in stability and activity leading to twoopposite scenarios lack or presence of activity substantiallycontributing to the overall AOA [172] Metabolic biotransfor-mation of DHPs includes oxidation (heteroaromatization)side chain ester group cleavage (deesterification) and 4-substituent abstraction ao [160] None of the DHPs metabo-lites was shown to be more toxic than original reduced formof the compound The commonly detected metabolites ofthe DHPs do not seem to possess the AO activity (withsome exceptions as in the case of metabolites of nifedipineand its analogues including nitrosonifedipine [173 174]) (seefurther in Section 35) Due to DHPs intrinsic instability
achieving andmaintaining an adequate concentrationmay beproblematic both in vitro and in vivo
(b) Role of Concentration and Lipophilicity (MembraneWateror LipidWater Partition Coefficients) of DHPs inTheir Actionas AOs and Antiradical Compounds Antioxidative effects ofany antioxidant depend on its concentration at the site ofaction This parameter is hardly measurable especially intwo-phase systems representing one of obstacles in com-parison to AOA upon applying various compounds [172]It is often incorrectly assumed that the concentrations inthe aqueous solution and at the site of action are the sameHowever even when the concentration in the aqueous phasemay be well controlled the concentration at the site ofaction in the lipid matrix of the membranes might fluctuatebetween different test compounds depending on a differencein lipophilicity [175] The prevention of the membrane LPalso seems to be dependent on the DHP concentration in thelipidmatrix (Mason andTrumbore [46]) and its amphiphilic-ity For example AOA of diludine is associated with itslipophilicity and consequential ability to be incorporatedinto liposomes (Panasenko et al [176]) It was also foundthat diludine easily incorporates into the outer monolayer oferythrocyte membranes [176]
Membranebuffer partition coefficients (lambda) weredirectly measured in the sarcolemma and sarcoplasmicreticulum membranes for three CA DHPs The obtainedvalues were in a broad range between 5000 and 150000(Herbette et al [177])These drugs interact primarily with themembrane bilayer component but may also bind to proteinsboth nonreceptors and receptors The intrinsic forward rateconstants for DHP binding to sarcolemmal calcium channelreceptors were apparently not strongly dependent on theirmembrane partition coefficients For example nimodipine(lambda = 6300) had a forward rate constant of 68 plusmn 06 times106Ms whereas the forward rate constant for Bay P 8857
(lambda = 149000) was 14plusmn08times107Ms Since these DHPsare highly liposoluble model calculations for this bindingreaction demonstrated that these rates on lipid solubilitywould probably not be reflected in the experimental forwardrate constants In addition the intrinsic forward rate constantfor nimodipine binding to sarcolemmal calcium channelreceptors was found not to be linearly dependent on theviscosity of the buffer medium over a fivefold range The rateof drug nonspecific binding to nonreceptor protein present inhighly purified sarcoplasmic reticulum membranes appearsto be extremely fast at least 103 times faster than specificdrug binding to the receptor in the sarcolemma Authorsconcluded that partitioning into the lipid bilayer matrix ofthe sarcolemma could be a general property of CA DHPsand may be a prerequisite for their binding to sarcolemmalmembrane receptors (Herbette et al [177])
The binding of DHP calcium channel agonists and antag-onists (including those with AO properties) to receptors incardiac sarcolemmal membranes is a complex reaction thatmay involve an interaction with the lipid bilayer matrix ofthe sarcolemma (Herbette et al [178]) Belevitch et al [179]studied the binding of DHP CCBs (riodipine and nifedip-ine) and verapamil to model and biological membranes by
Oxidative Medicine and Cellular Longevity 17
fluorescence analysis The consistent location of Ca agonistBay K 8644 was determined to be within the region ofthe first few methylene segments of the fatty acyl chains ofthe membranes (Mason et al [180]) This position is nearto that observed for the DHP calcium channel antagonistsnimodipine and Bay P 8857
Themajority of studies onOSwere performedwithDHPswith various lipophilicity but only a few studies reportedamphiphilicity ofDHPderivatives AmphiphilicDHPderiva-tive K-2-11 reduced the cellular generation of ROS It alsorevealed complete reversal of multidrug resistance (MDR) ofthe resistant cells K-2-11 was more efficient than well-knownMDR inhibitor verapamil Cytotoxic effects of anticancerdrug doxorubicin were enhanced by K-2-11 in bothMDR andparental nonresistant cell line (Cindric et al [181]) K-2-11suppresses increase of ROS and consequentially prevents NF-120581B activation leading to decreased expression of MDR1 andincreased expression of antiapoptotic genes This signalingswitch is necessary for restoring the chemosensitivity ofcancer cells This phenomenon is characteristic both for14-DHPs [182] (18 novel asymmetrical DHPs bearing 3-pyridyl methyl carboxylate and alkyl carboxylate moietiesat C3 and C5 positions resp as well as nitrophenyl orheteroaromatic rings at C4) and for their oxidized formspyridine compounds (Zhou et al [183])
34 Dependence of AOA of DHPs on the Experimental SystemAO effect of DHPs depends on their structure and theexperimental system used (in vitromodel system subcellularorganelle and cells ex vivo and in vivo) Ideally for theevaluation of the profile and value of DHPs AO propertieseach compound should be tested in as many systems aspossible (Dubur et al [45])
Lipidomics studies have been traditionally explored forstudying AOA of DHPs Proteomics methods are less rep-resented and are mostly focused on the properties of DHPsrelated to scavenging of protein free radicals So far there areno studies on the role of DHPs in scavenging nitrosoperoxy-carbonate the reactive species formed out of peroxynitrite inthe presence of carbon dioxide Although it was shown thatalbumin binds diludine no studies revealed the relevance ofthis effect for the AOA of diludine
There are findings showing that dihydropyridine calciumantagonists (DHPs CA) could indirectly play a beneficialprotective role during development of atherosclerosisNamely Berkels et al [184] have studied antioxidativeproperties of four substances the DHP prototype CAnifedipine the long-acting CA lacidipine the DHP calciumchannel agonist BayK8644 and the bulkyDHPderivate BayO 5572 in three different models (1) in an in vitro superoxideanion generating system (hypoxanthinexanthine oxidase)for testing the ldquopurerdquo antioxidative effect (2) in an artificialmembrane preparation (dimyristoylphosphatidylcholine) formimicking a more physiological environment and (3) underconditions of stimulated ROS release (hyperglycemia) fromnative endothelial cells derived from porcine coronary arter-ies
The study also revealed the potential correlation betweenlipophilic and AO properties of DHPs In the first model
Bay K 8644 was significantly more effective in scavengingsuperoxide anions than lacidipine Bay O 5572 or nifedipine(micro- to millimolar concentration range) Addition of anartificial membrane preparation resulted in an enhancedAO effect with lacidipine being the most effective DHP inquenching radicals (low micromolar concentration range)In the third model mimicking hyperglycemia (30mmolL)nifedipine was significantly more potent antioxidant (ther-apeutical nanomolar concentration range) than the otherDHPs Calculated lipophilicity of these four substances(lacidipine gt Bay O 5572 gt Bay K 8644 gt nifedipine) waspositively correlated with antioxidative potential only in thesecond experimental model It has been concluded that AOproperties of DHP substances need to be tested in variousmodels for demonstrating that nifedipine exhibits ROS-quenching properties in a therapeutic concentration range[184]
341 AOA of DHPs in Isolated Cells and Cell Cultures(Comparison with Other Simplest Systems) Although DHPspossess neuromodulatory andor antimutagenic propertiesthe mechanisms of action related to these phenomena arenot entirely elucidated Borovic et al [185] have studied 14-dihydroisonicotinic acid (14-DHINA) derivatives of 14-DHP water-soluble analogues of a well-known AO diludine(diethone) 26-dimethyl-35-diethoxycarbonyl-14-dihydro-isonicotinic acid sodium 2-(26-dimethyl-35-diethoxycar-bonyl-14-dihydropyridine-4-carboxamido)glutamate gluta-pyrone and sodium 2-(26-dimethyl-35-diethoxycarbonyl-14-dihydropyridine-4-carboxamido)ethane-sulphate tauro-pyrone as AO and bioprotectors (Figure 4)
14-DHINArsquos activities were studied in comparison toTrolox by NN-diphenyl-N1015840-picrylhydrazyl (DPPH∙) deoxy-ribose degradation ABTS∙ radical scavenging and AOA(antioxidative capacity method) assays copper-induced LPof cultured rat liver cells (MDA determination by HPLCand 4-hydroxynonenal-protein conjugates by dot-blot) 3H-thymidine incorporation and trypan blue assay for liver cellsgrowth and viability Ic decreased the amount of 4-HNE-protein adducts In all assays Ia was the most potent AOable to completely abolish copper induced LP of liver cellswhile Ic only slightly decreased it Thus AOA is importantactivity principle of Ia which was even superior to Trolox intreated cell cultures Ia (and its analogues) are easily oxidizedin the Fenton system (Rubene et al [186]) exerting ARA too
35 Peculiarities Related to Antioxidative and AntiradicalActivity of Some 14-DHPs Ca Antagonists Nine commer-cialized structurally and functionally different DHPs CAwill be discussed further Their common feature is ability toprevent OS This also counts for some of their metabolitesas already discussed The comparative effects of some DHPsCA on oxidative stress-induced modification of LDL werealready reviewed in Section 331 (2)-(a) AOA of CA DHPswas discussed in Sections 331 (2)-(b) and 331 (2)-(c)
351 Nifedipine and Its Close Analogues Nifedipine vera-pamil and antiarrhythmic-antihypoxic drug stobadin wereshown to depress lipid peroxidation of phosphatidylcholine
18 Oxidative Medicine and Cellular Longevity
NH
COOH
NH
COONa
Glutapyrone
NH
Gammapyrone
NH
C 2H5OOC COOC2H5
Tauropyrone
14-DHINA
H3C H3C
H3C
H3CCH3 CH3
CH3
CH3
COOC2H5COOC2H5
COOC2H5 C2H5OOCC2H5OOCC2H5OOC
CONHCH(CH2)2COONa CONH(CH2)3COONa
CONH(CH2)2SO3Na
Figure 4 Derivatives of 14-dihydroisonicotinic acid (14-DHINA)
liposomes (Ondrias et al [187]) However data obtained insome other experimental systems are conflicting
In an in vitromodel of sarcolemmal membrane lipid per-oxidation three calcium blockers (nifedipine verapamil anddiltiazem) exhibited concentration-dependent (10ndash400 120583M)inhibitory effects [188 189] Nifedipine the most effectivecalcium blocker was more than two-fold potent compared topropranolol achieving significant effect at 10 120583M Nifedipineprotective role on LP using reduced glutathione as modelmarker was recently described (Ray et al [190]) Antiper-oxidative properties of CA nifedipine and its analogueswere explored in different systemspathogenic processesatherogenesis (Henry [165]) brain focal ischemia (Yamatoet al [191]) nephroprotection related to cyclosporine intake(Chander and Chopra [192]) and hepatoprotection relatedto intake of diethyldithiocarbamate (Gaafa et al [193])Recent data suggest that nifedipine action as protector forendothelial cells proceeds independently from its CA proper-ties
The absence of antioxidant effects of nifedipine anddiltiazemonmyocardialmembrane lipid peroxidation oppo-site to nisoldipine and propranolol was also described[194] Nisoldipine and propranolol were shown to havea concentration-dependent antiperoxidant effect with IC
50
values of 282 and 501 120583M respectively Finally nisol-dipine appeared to possess dual antiperoxidant mecha-nisms involving both preventive and chain-breaking proper-ties
These findings were confirmed in some other studiesincluding reports on the lack of antioxidative activity ofnifedipine and nicardipine even at 500120583M concentrationin heart membrane lipid peroxidation tests [134] SimilarlyROS formation in bovine aorta smooth muscle cells was notaffected by addition of amlodipine nimodipine and nife-dipine [123]
(1) Metabolites of Nifedipine and Its Analogues as Antioxidantsand Regulators of OS Antioxidant activity of nifedipine35-dimethoxycarbonyl-26-dimethyl-4-(2-nitrophenyl)-14-dihydropyridine was originally studied in vitro by Kirule etal [195] and Tirzit et al [196] According to the kinetic dataof peroxide accumulation and the ESR spectra (inhibition ofthe autoxidation of methyl oleate in presence of nifedipine)AO action was exerted by the formation of nitroso analogueof the oxidized nifedipine nitroso nifedipine 26-dimethyl-4-(2-nitrosophenyl)-35-pyridine dicarboxylate (NO-NIF)This nitroso aromatic derivative can form nitroxyl radicalsexhibiting remarkable AOA in the presence of unsaturatedfatty acids and lipids [196]
The primary species of free radicals that have beenobtained and identified were ion radicals of the nitrophenyltype (Ogle et al [76]) Such a mechanism coincides withmechanisms proposed afterwards by Nunez-Vergara et al[96] Lopez-Alarcon et al [103] Valenzuela et al [104]Fukuhara et al [174] and Yanez et al [197]
There are also data showing that nitroso compounds mayinhibit LP by direct radical trapping and subsequent forma-tion of stable nitroxide radicals It was further found that thereactivity between the synthesized 14-DHP derivatives withalkylperoxyl radicals involves electron transfer reactionsThisis documented by the presence of pyridine as a final productof the reaction and complete oxidation of the nitroso groupin the case of the nitrosoaryl 14-dihydropyridine derivatives(Valenzuela et al [104]) Tested compounds reacted fastertoward alkylperoxyl radicals and ABTS radical cation thanalkyl ones (Lopez-Alarcon et al [103])
Nitrosonifedipine a photodegradation product of nifedi-pine significantly recovers cellular damage induced by tumornecrosis factor-alpha It also prevents toxic effects of cumeneperoxide which hampers integrity of cell membranes throughoxidative stress Its positive effects are equal to Trolox-C
Oxidative Medicine and Cellular Longevity 19
As a result nitrosonifedipine was already a long time agoclaimed as a candidate for a new class of antioxidative drugs(Kirule et al [195]) cellular protectors against oxidative stressin glomerular endothelial cells [174]
Moreover Misik et al [198] Ondrias et al [199] andStasko et al [200] studied AOA of nifedipine and its oxidizednitroso analogue NO-NIF prevents the progression of type2 diabetic nephropathy associated with endothelial dysfunc-tion through selective AO effects (Ishizawa et al [201]) NO-NIF administration reduces albuminuria and proteinuriaas well as glomerular expansion without affecting glucosemetabolism or systolic blood pressure NO-NIF also sup-presses renal and systemic OS and decreases the expressionof intercellular adhesion molecule-1 (ICAM-1) a marker ofendothelial cell injury in the glomeruli of the KKAy miceSimilar effects were achieved in endothelial nitric oxide syn-thase (eNOS) knockout mice Moreover NO-NIF suppressesurinary angiotensinogen (AGT) excretion and intrarenalAGT protein expression in proximal tubular cells in theKKAy mice On the other hand hyperglycemia-inducedmitochondrial superoxide production was not attenuated byNO-NIF in cultured endothelial cells
Fujii and Berliner found EPR evidence for free radicaladducts of nifedipine in vivo [202] The nature of these rad-icals was surmised by comparing the reaction of illuminatednitrosonifedipine with polyunsaturated fatty acids Surpris-ingly identical radical spectra were detected from excisedliver doped with nonilluminated nifedipine suggesting thatthis drug can be enzymatically converted in vivo to its nitrosoanalogue without the requirement for illumination This isone of the first reports of in vivo EPR evidence for a class ofunsaturated fatty acid radical conjugates resulting from thenormal metabolism of a common drug
Dıaz-Araya et al [173] studied some 4-nitrophenyl-DHPson Fe3+ initiated LP in rat brain slices LP as measuredby MDA formation was inhibited by all the tested nitro-aryl derivatives of 14-DHP over a wide range of concen-trations On the basis of both time course and IC
50experi-
ments the tentative order of AOA on rat brain slices wasnicardipine gt nisoldipine gt (RSSR)-furnidipine gt (RRSS)-furnidipine gt nitrendipine gt nimodipine gt nifedipine14-DHP derivatives that lack a nitro group in the mole-cule (isradipine and amlodipine) also inhibited LP in ratbrain slices but at higher concentrations than that of nitro-substituted derivatives All tested compounds reduced andoxidized nitrosoaryl derivatives (26-dimethyl-4-(2-nitro-sophenyl)-35-pyridinedicarboxylic acid dimethyl ester (pho-tooxidation product of nifedipine ndash NTP) ao) and weremore potent inhibitors of LP than their parent molecules(Valenzuela et al [104])
The electrooxidation process of 4-nitrosoaromatic DHPsis a strongly pH-dependent (two-electron two-proton mech-anism) ECEC type of mechanism that is the sequenceeminusH+eminusH+ at pH gt 85 ECCE mechanism (eminusH+H+eminus)at pH lt 85 dominates Reduction reaction of nitroso groupis as follows R-NO + 2eminus + 2H+ rarr RNHOH (Bollo et al[203])
352 Lacidipine It is a generic DHP type antihypertensiveCA 35-diethyl 4-2-[(1E)-3-(tert-butoxy)-3-oxoprop-1-en-1-yl]phenyl-26-dimethyl-14-dihydropyridine-35-dicarboxy-late
Ursini [204] described redox behaviour of lacidipine andshowed its tissue protective features Cristofori et al studiedantiatherosclerotic activity in addition to lacidipinersquos CAand AO properties [205] Lacidipine reduced the extent ofatherosclerotic area in hypercholesterolemic apoE-deficientmice (these mice show widespread vascular lesions whichclosely resemble the inflammatory fibrous plaques seen inhumans in atherosclerosis) The reduction may be associatedwith the capacity of the drug to maintain endothelial NOlevels at concentrations useful to protect against vasculardamage This work suggested that DHPs modulate vascularrelaxation via increased release of NO
Herbette et al [178] remarked optimal hydrophobicity oflacidipine due to cinnamic acid substituent so membraneinteractions and facilitation of the treatment of atherosclero-sis could proceed (see also Section 331 (2)-(a))
353 Amlodipine Amlodipine (Norvasc) (RS)-3-ethyl5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-14-dihydropyridine-35-dicarboxylate (AML) hasan antioxidant effect on vessels in vitro and is a 3rd genera-tion of charged dihydropyridine CCB that is widely used forthe treatment of hypertensive patients
Amlodipine was shown to have the highest affinity(amlodipine gt verapamil ≫ diltiazem) for the membranebilayer (119870
119901= 104) It produced the significant changes in
membrane thermodynamic properties including a reductionin the thermal phase transition temperature (minus11) enthalpy(minus14) and cooperative unit size (minus59) relative to thecontrol phosphatidylcholine liposomes (Mason et al [49])
Amlodipine AOA is related to its reductant nature orhydrogen donor properties respectively Its ability for donat-ing protons and electrons to the lipid peroxide moleculesblocks the LP process
Amlodipine and even its enantiomers (Zhang et al [206])act as ROS andNOS effectors in several model systems of OSAntioxidant properties of amlodipine were recently reviewedby Vitolina et al [32] Both in vitro and in vivo studiesof amlodipine AO properties revealed inhibition of lipidsoxidative damage primarily those associated with cellularmembranes and lipoprotein particles (LDL) (Mason et al[50])
Under controlled experimental conditions in vitro amlo-dipine showed AOA and ARA by inhibition of lipid peroxideformation and trapping ROS Its scavenging activity forhydroxyl and peroxyl radicals at concentrations as low as100 nmolL (which is remarkably less compared to the classi-cal antioxidants GSH uric acid and Trolox) was shown to beindependent of the calcium channel modulation (Franzoni etal [207])
AML showed efficiency as scavenger of peroxyl radicals(TOSC assay 5945 plusmn 544 unitsmg) significantly stronger(gt50 119875 lt 0001) than GSH (2733plusmn 636 unitsmg) and 70weaker (119875 lt 00001) than uric acid (18144 plusmn 696 unitsmg)and Trolox (17522 plusmn 734 unitsmg)
20 Oxidative Medicine and Cellular Longevity
Of interest the scavenging capacity of AML towardshydroxyl radicals (1455 plusmn 154 unitsmg) was 320 higher(119875 lt 000001) than that of GSH (358 plusmn 112 unitsmg) 20higher than that of uric acid (1198plusmn121 unitsmg) and 100higher than that of Trolox (759 plusmn 143 unitsmg)
Amlodipine was shown to increase enzyme activity ofparaoxonase (PON) and glutathione peroxidase (GSH-Px)However it also decreases glutathione reductase (GSSG-R)activity and diminishes the concentration of the endogenousantioxidant 120572-tocopherol (vitamin E) Moreover AML in aconcentration of 2 ngmL decreased the content of malonicdialdehyde and activity of superoxide dismutase in the blood(Gatsura [208])
Verapamil and amlodipine produced a potent anti-ischemic effect and reduced area of myocardial infarction inrats The observed changes were accompanied by inhibitionof LP In contrast to verapamil in vitro application of AML ina dose of 50 ngmL decreased hemoglobin affinity for oxygenWhen present in a concentration of 2 ngmLAMDdecreasedthe content of MDA and activity of SOD in the blood
On the other hand amlodipine shows no activity relatedto inhibition of macrophage superoxide release and cellmigration which occurs as a consequence of decreasedTNF120572induced O
2
∙ releaseAmlodipine-induced reduction of OS in the brain is
associated with sympathoinhibitory effects in stroke-pronespontaneously hypertensive rats (SHRSP) (Hirooka et al[209]) Antihypertensive treatment with amlodipine reducedOS in all examined areas of the brain and decreased bloodpressure without a reflex increase in sympathetic nerveactivity Nicardipine another CA DHP surprisingly wassignificantly less active than amlodipine
354 Lercanidipine Tomlinson and Benzie reported AOeffect of lercanidipine [210] which is well known as anti-hypertensive drug Zanidip 2[(33-diphenylpropyl)(methyl)-amino]-11-dimethylethyl methyl 26-dimethyl-4-(3-nitro-phenyl)-14-dihydropyridine-35-dicarboxylate Compara-tive data about this drug AOA were presented in parts of thispaper about other individual CA DHPs and in the part aboutthe ex vivo DHPs effects on LDL
355 Nimodipine Nimodipine (ND) commercially knownas Nimotop is 3-(2-methoxyethyl) 5-propan-2-yl 26-dim-ethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxy-late It is centrally active CA
Treatment with glutathione blocked andwith nimodipineattenuated neuronal cell death caused by prolonged exposureof cell culture to 4-HNE (Faraqui [211])
Nascimento et al [212] found AO effect of nimodipine inyoung rats after pilocarpine- (PIL-) induced (in 400mgkg)seizures The PIL administration increased the striatal cata-lase (CAT) activity The administration of ND 30mgkg30min before PIL preserved normal value of CAT activityOn the other hand no difference was detected in the animalstreated with lower dose 10mgkg These results confirmthe neuroprotectiveantiepileptic effect of ND in young ratssuggesting that this drug acts positively on lipid peroxidation
(in both doses) Nimodipine cannot induce these effects viablockade of Ca2+ channel
Ismailoglu et al [213] studied the therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjury These beneficial effects in rats after cerebral corticalinjury seemed to be related to AOA of nimodipine
356 Benidipine Licensed in Japan and South Asia as CA(CCB) benidipine possesses AO properties Chemically it is5-methyl 3-[(3R)-1-(phenylmethyl)piperidin-3-yl] 26-dim-ethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxy-late (or its hydrochloride (4R)-rel-35-pyridinedicarboxylicacid 14-dihydro-26-dimethyl-4-(3-nitrophenyl)- 3-methyl5-[(3R)-1-(phenylmethyl)-3-piperidinyl] ester hydrochloride(1 1))
Benidipine influences processes connected with OS inseveral ways It prevents lysophosphatidylcholine- (lysoPC)-induced injury and ROS production in human aorticendothelial cells (HAECs) (Matsubara and Hasegawa [214])Matsubara et al [215] explained this effect based on stimula-tion of nitric oxide release
LysoPC is a component of oxidized low-density lipopro-teins (oxLDLs) which plays an important role in the patho-genesis of atherosclerosis Pretreatmentwith benidipine (03ndash3 120583molL) for 24 h protected against lysoPC-induced cyto-toxicity in the HAECs through inhibition of both lysoPC-stimulated ROS production and caspase-37-like activationwith a similar potency Since caspase-37 is involved inexecuting the apoptotic process the reduction of the activityof this enzyme by benidipine may explain the antiapoptoticeffect of the drug However benidipine did not suppresslysoPC-induced phosphorylation of mitogen-activated pro-tein kinases and Ca2+ influx in HAECs These results suggestthat the antioxidant properties of benidipine may be respon-sible for its ability to inhibit ROS production a possiblereason for reduced activation of caspase-37 In conclusionbenidipine suppresses lysoPC-induced endothelial dysfunc-tion through inhibition of ROS production which is due atleast in part to its antioxidant effect and not through theinhibition of L-type voltage-dependent calcium channels
Matsubara and Hasegawa [216] examined the effectsof benidipine on cytokine-induced expression of adhesionmolecules and chemokines (chemoattractants) which areimportant for the adhesion of monocytes to endotheliumPretreatment of HAECs with benidipine (03ndash10 120583molL)for 24 h significantly suppressed cytokine-induced vascularcell adhesion molecule-1 (VCAM-1) and intracellular celladhesion molecule-1 (ICAM-1) mRNA and protein expres-sion resulting in reduced adhesion of THP-1 monocytesBenidipine also suppressed induction of monocyte chemoat-tractant protein-1 (MCP-1) and interleukin-8 Benidipinealso inhibited redox-sensitive transcriptional nuclear factor-120581B (NF-120581B) pathway as determined by Western blotting ofinhibitory 120581B (I120581B) phosphorylation and luciferase reporterassay Results of analysis using optical isomers of benidip-ine and antioxidants suggest that these inhibitory effectswere dependent on pharmacological effects other than Ca2+antagonism Benidipine may thus have anti-inflammatoryproperties and benefits for the treatment of atherosclerosis
Oxidative Medicine and Cellular Longevity 21
Benidipine was also shown to inhibit ROS production inpolymorphonuclear leukocytes and oxidative stress in salt-loaded stroke-prone spontaneously hypertensive rats (Mat-subara et al [217])
It should be mentioned that other DHPs also haveendothelial AO actions [218]
357 Azelnidipine (AZL) Azelnidipine 3-[1-[di(phen-yl)methyl]azetidin-3-yl] 5-propan-2-yl 2-amino-6-methyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate(AZL) CAS number 123524-52-7 is commercially available4-nitroaryl-DHP type calcium antagonist with long-actingantihypertensive action (long-acting CA (CCB)) and a lowreported incidence of tachycardia It additionally possessesbeneficial effects in OS and diabetic conditions
Azelnidipine prevents cardiac dysfunction in strepto-zotocin-diabetic rats by reducing intracellular calcium accu-mulation (altering intracellular Ca2+ handling proteins) OSand apoptosis (Kain et al [219]) AZL can reduce the superox-ide production It exerts its protective effects by targeting theNADPH oxidase and mitochondrial redox enzymes AZL-treated diabetic rats express enhanced level of bcl-2 in thelysates of heart muscle indicating that AZL plays protectiverole in cardiac apoptosis
It has been previously observed that azelnidipine inhibitstumor necrosis factor-alpha-induced endothelial cell (EC)oxidative stress through its AO properties (Nakamura etal [220]) Azelnidipine but not nitrendipine completelyinhibits the Ang II-induced ROS generation in ECs (Matsuiet al [221])
Furthermore azelnidipine but not nitrendipine wasfound to partially restore decreased pigment epithelium-derived factor (PEDF) mRNA levels in Ang II-exposed ECsThis study suggests that AZL influence depends on its antiox-idative properties Authors concluded that upregulation ofPEDF by azelnidipine may become a therapeutic targetfor the treatment of diabetic retinopathy associated withhypertension
Antihypertensive agents with AO effects are potentiallyuseful for diabetic patients with hypertension While DHPtypeCAare among themost frequently used antihypertensivedrugs azelnidipine has been reported to have a unique AOeffect in vitro and in vivo in experimental animals (Ohmuraet al [222]) In hypertensive diabetic patients azelnidipinetreatment for 12 weeks induced a more significant decreasein erythrocyte LOOH level than amlodipine although thevalues related to blood pressure during each treatmentremained comparable These data confirm the usefulness ofLOOH level in erythrocyte membrane as a marker of OS invivo and indicate that azelnidipine has a unique antioxidativeproperty in humans
Daikuhara et al [223] reported the results of the OLCAstudy based on combination of (1) olmesartan and a calciumchannel blocker (azelnidipine) or (2) candesartan and a CCBamlodipine in two groups of diabetic hypertensive patientsPatients treated with the first combination presented highlypersistent early morning antihypertensive effect and strongerdecrease in heart rate fasting blood glucose andHbA1c levels
and microalbuminuria when compared to patients treatedwith the combination (2) Because diabetes is associated withsevere chronic OS the observed results might be at least in apart due to the AOA of azelnidipine
In favor of this are findings of Abe et al [224] who foundadditive antioxidative effects of azelnidipine on angiotensinreceptor blocker olmesartan treatment for type 2 diabeticpatients with albuminuria
Similarly the AOA of thiazolidinediones (insulin sensi-tizer) and their effect on cardiovascular function in type 2diabetic model rats and also those of some DHPs (nifedipineamlodipine or AZL commonly used antianginal and anti-hypertensive agents) in cultured human endothelial cells LPwere examined (Mizushige [225]) The AOA was evaluatedby measuring 8-iso-prostaglandine F
2120572concentration and
azelnidipine exhibited potent AOAInsulin (INS) resistance combined with hyperinsuline-
mia is involved in the generation of OS A relation-ship exists between increased production of ROS and thediverse pathogenic mechanisms involved in diabetic vascularcomplications including nephropathy Manabe et al [226]revealed that high doses of INS augmented mesangial cellproliferation through generation of intracellular ROS andactivation of redox signaling pathways Cell proliferation wasincreased in a dose-dependent manner by high doses of INS(01ndash10 120583M) but was inhibited by 01120583M AZL Namely theINS-increased phosphorylation of mitogen activated proteinkinaseextracellular signal-regulated kinase 12 (MAPKERK12) was inhibited by 01 120583MAZL The same AZL concen-tration blocked intracellular ROS production more effec-tively than 01 120583M nifedipine The NADPH oxidase inhibitorapocynin (001ndash01120583M) prevented INS-induced mesangialcell proliferation So azelnidipine inhibits insulin-inducedmesangial cell proliferation by inhibiting the productionof ROS Therefore azelnidipine may have the potential toprotect against the onset of diabetic nephropathy and slowits progression
Azelnidipine inhibited H2O2-induced cell death in
neonatal rat cardiomyocytes (Koyama et al [227]) Azelnidip-ine and nifedipine did not affect theH
2O2-induced activation
of extracellular signal-regulated protein kinases (ERK) andp38 MAPK (mitogen-activated protein kinase) In contrastazelnidipine but not nifedipine inhibited H
2O2-induced c-
Jun NH2-terminal kinases (JNK) activation Authors con-
cluded that azelnidipine has inhibited theH2O2-induced JNK
activation and cardiac cell death Therefore azelnidipine mayhave cardioprotective effects against OS
A specific atheroprotection activity of azelnidipine relatesto inhibition of TNF-120572-induced activator protein-1 activa-tion and interleukin-8 expression in human umbilical veinendothelial cells (HUVEC) through suppression of NADPHoxidase-mediated reactive oxygen species generation (Naka-mura et al [220]) TNF-120572 could play a central role in patho-genesis of insulin resistance and accelerated atherosclerosis inthe metabolic syndrome The concentration of AZL found tobe effective in these in vitro experiments is within therapeuticrange As EC do not possess voltage-operated L-type calciumchannels it is suggested that the beneficial effects of azelni-dipine are not likely due to CA property but to its unique AO
22 Oxidative Medicine and Cellular Longevity
ability Furthermore it has been recently found that serumlevels of monocyte chemoattractant protein-1 a biomarkerfor subclinical atherosclerosis were significantly decreased bythe AZL treatment in patients with essential hypertension Inthis paper [220] authors hypothesize that due to its uniqueTNF-120572 signalmodulatory activity and antioxidative propertyazelnidipine may be a promising DHP for targeting diabetesand cardiovascular diseases in hypertensive patients withmetabolic syndrome
Shinomiya et al [228] evaluated its AOA in culturedhuman arterial EC under OS Azelnidipine has shown apotent antioxidative effect that could be of significant clinicalbenefit when combined with its long-lasting antihypertensiveaction and low incidence of tachycardia
Azelnidipine inhibited TGF-1205731 and angiotensin II- (AngII-) activated 1205721(I) collagen mRNA expression in hepaticstellate cells (HSCs) (Ohyama et al [229]) FurthermoreTGF-1205731- and Ang II-induced OS and TGF-1205731-induced p38and JNK phosphorylation were reduced inHSCs treated withAZL Azelnidipine significantly decreased inflammatory cellinfiltration profibrotic genes expression HSC activation LPoxidative DNA damage and fibrosis in liver of CCl
4- or
TAA-treated mice Finally AZL prevented decrease of theexpression of some AO enzymes and accelerated regressionof liver fibrosis in CCl
4-treated mice Hence the antifibrotic
mechanism of AZL against CCl4-induced liver fibrosis in
mice may have been due to an increased level of AO defenseAs azelnidipine is widely used in clinical practice withoutserious adverse effects it may provide an effective newstrategy for antifibrotic therapy
358 Manidipine Manidipine (2-[4-(diphenylmethyl)pip-erazin-1-yl]ethyl methyl 26-dimethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate) is a DHP CCB withreported nephroprotective properties Calo et al [230] stud-ied effect of manidipine on gene expression and proteinlevel of OS related proteins p22(phox) (human neutrophilcytochrome b light chain (CYBA)) and heme oxygenase-1HO-1 Relevance for antihypertensive effects was revealedThe study assessed the effect of manidipine on normalsubjectsrsquo monocyte gene and protein expression of OS relatedproteins such as p22phox a NADPH oxidase system subunitcritical in generating O
2
∙minus and HO-1 induced by and pro-tective against OS Manidipine was compared with the ACEinhibitor captopril and the CCB nifedipine in the presenceand in the absence of sodiumarsenite (NaAsO
2) as an inducer
of OS Monocyte p22phox (CYBA) mRNA production wasreduced by both manidipine and captopril while no changeswere induced by nifedipine Manidipine increased monocyteHO-1 mRNA production while nifedipine and captoprilshowed no effect The effects of manidipine on p22phoxand HO-1 gene expression in the presence of OS were alsoconfirmed at the protein level Thus manidipine seems tosuppress p22phox and to increase the HO-1 mRNA produc-tion and protein level The manidipine-induced increase ofHO-1 gene and protein expression seems to be a peculiareffect of this drug since it is not observed with captopriland nifedipine This effect together with the reduction of
p22phoxmRNAproduction could play a role in its protectivemechanism against OS
359 Mebudipine The protective effect of mebudipine (14-dihydro-26-dimethyl-4-(3-nitrophenyl)-35-pyridinedicar-boxylic acid 3-methyl-5-tert-butyl ester BAY-n-6391) wasrevealed on OS and LP (MDA decrease SOD GPX andcatalase increase) in myocardial ischemic-reperfusion injuryin male rats (Ghyasi et al [231])
There are articles about other commercial and experi-mental DHPs on OS but we have reviewed only the mostcommonly studied compounds Effects of other commercialCA DHPs on OS are also mentioned in several parts of thisreview
36 14-DHPs Ca Agonists andTheir AOA and ARA For themost popular calcium agonist DHP Bay K 8644 no reactionwith peroxyl radicals was registered (Toniolo et al [114])However interactionwith other compounds possessing AOAand ARA (quercetin) was found
Opposite to that AON-acetylcysteine (NAC) diminishedincrease in Ca2+ transient amplitude and cell shorteninginduced by ISO and forskolin whereas NAC had no effecton the (S)-(minus)-methyl-14-dihydro-26-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylatemdash(minus)-BayK 8644-induced increases (Andersson et al [232])
Increased vasoconstriction responses to Bay K 8644 (3 times10minus7ndash3times 10minus5M)were significantly decreased by pyridoindoleantioxidant stobadine treatment in diabetes (Ceylan-Isik etal [233])
The functional interaction between two L-type Ca2+channel activators quercetin and Bay K 8644 has beeninvestigated in vascular smooth muscle cells Biological ARAcompound quercetin at nutritionally meaningful concen-trations limited the responsiveness of vascular L-type Ca2+channels to the pharmacological stimulation operated by BayK 8644 These data contribute to a better understanding ofquercetin effects on experimental in vivo cardioprotection(Saponara et al [234]) Thus these findings indicated thatalthough Bay K 8644 does not exert potent and direct AOAyet acting as calcium agonist it may affect efficiency of AOsubstances and vice versa
Interaction of grapefruit juice (containing quercetin andits analogues) with DHPs CA diminished effectiveness of CAaction of DHPs (Sica [235])
37 Interpretations of the Mechanism(s) of RadicalScavenging and AOA by DHPs
371 Molecular Mechanism(s) of Radical Scavenging andAOA of DHPs in the Model Systems 35-Dicarbonyl-14-di-hydropyridine derivatives possess powerful bis-120573-carbony-lvinyl-amino conjugation and for that reason cannot be con-sidered as ordinary amino antioxidants The electron andorH donation from DHPs ensures their reductant role andresults in AOA and ARA Oxidation reaction from DHPsresults in production of corresponding heteroaromatic pyri-dine derivatives
Oxidative Medicine and Cellular Longevity 23
Detailed studies were made about substituent in DHPring positions 14- namely 4-unsubstituted- 4-substituted4-alkyl- 4-aryl- 4-alkylaryl- ao 26- 35- (diacetyl ordialkoxycarbonyl chain ao) electronic and steric effects onAOA and ARA of DHPs [44 45 51] see Sections 331and 35 The bell-shaped dependence of DHPs AOA onthe 35-dialkoxycarbonyl- chain length was observed [4445 107 109 112] with the maximum activity at C
2H5ndash
C4H9 Decrease of AOA and incorporation into liposomes for
DHPs with alkyl chains longer than R gt C4H9further were
clarified as probable tendency to self-aggregation of thesecompounds ([51] and citation number 245 therein) Electronacceptorelectron donor properties are relevant for expres-sion of AOA or ARA of 35-disubstituted DHPs 35-Diacyl-substituted and 35-dicarbanilido- and 35-dipyridylamido-substituted DHPs are more active as AOs as their 35-dicyano-substituted analogues which have electron acceptorproperties [186]
Dubur et al [89] observed overwhelming steric influenceof substituents in position 4 of the DHP ring Gaviraghiet al [163 164] proposed that AO activity of DHPs ispartly dependent on capacity of the 14-DHP ring to donateelectrons to the propagating radical (ROO∙ or RO∙) and toreduce it to a less reactive form The abstraction (donation)of electron andor H in the oxidation and LP reactionstakes place from all 35-dicarbonyl-14-DHP systems andresults in the formation of corresponding pyridine derivatives(Augustyniak et al [51]) The physicochemical mechanism ofARA and AOA of 14-DHP has been extensively studied anddiscussed (Mulder et al [236]) but precise mechanisms oftheir activity need further clarification
The reactivity of C-4 substituted 14-DHPs possessingeither secondary or tertiary nitrogen atom in the DHP ringtoward alkyl alkylperoxyl radicals and ABTS radical cationwas determined in aqueous media at pH 74 [103] Thesecompounds reacted faster toward alkylperoxyl radicals andABTS radical cation than alkyl ones N-Ethyl-substitutedDHPs showed the lowest reactivity
The 4-methyl substituted DHP was the most reac-tive compound in previously mentioned reactions (Lopez-Alarcon et al [103]) However it was less active (068versus 10) than Trolox-C DHPs having electron-donatingsubstituents (4-Me-DHP and p-MeO-Phe-DHP) showed thehighest kinetic rate constants toward ABTS radical cation p-nitro-Phe-DHP a compound with an electron-withdrawingsubstituent showed a lower kinetic rate constant and N-alkyl-DHP compounds show kinetic rate constants lowerthan the -NH-DHP
Hydrogen at the 1-position of the DHP ring was revealedaccording to the deuteriumkinetic isotope effect studies to beinvolved in the proposedARAmechanismThis fact ismostlynoticeable in the case of alkyl radicals N-Ethyl-substitutedDHPs show the lowest reactivity when compared to Troloxor nisoldipine In all cases the respective pyridine derivativewas detected as the main product of the reaction (Lopez-Alarcon et al [103]) Authors indicate that the kinetic rateconstants toward alkyl alkylperoxyl andABTS radical cationdepend on the nature of the substituents in the C-4 positionof DHP and the presence of the secondary amine group in the
dihydropyridine ring that is the presence of the hydrogen in1-position
Yanez et al [197] have studied the reactivity of 11derivatives of 14-DHPs (including commercial CA) withalkylperoxyl radicals and ABTS radical cation The tested14-DHPs were 83-fold more reactive towards alkylperoxylradicals than to the ABTS cation radical All commercial14-DHP type CCBs were weaker than Trolox-C The par-ticipation of the hydrogen atom in the 1-position appearsto be very relevant for exhibited reactivity Hantzsch ester(diludine)was again found to be themost active compound inthe reaction with alkylperoxyl radicals 23-fold more activethan Trolox The photodegradation product of nifedipine(nitrosophenyl derivative of pyridine) also showed a highactivity Kinetic rate constants for the reaction between 14-DHP compounds and alkylperoxyl radicals exhibited a fairlygood linear correlation with the oxidation peak potentialof DHP derivatives However the activity of tested 14-DHPs towards ABTS radical cation showed an independencebetween kinetic rate constants and oxidation peak potentials
Kirule et al [195] andTirzit et al [196] studiedmechanismof AOA of 4-nitrophenyl-14-DHPs nifedipine and its ana-logues involving formation of 4-(21015840-nitrosophenyl)-pyridinederivative (as active principle) as a result of intramolecularredox reaction using chemical electrochemical and bio-chemical approaches (see Sections 331 and 351)
Nunez-Vergara et al [237] reported the electrochemicaloxidation of C4-hydroxyphenyl-substituted 14-DHP deriva-tives The oxidation proceeds via formation of the unstabledihydropyridyl radical as confirmed by controlled-potentialelectrolysis (CPE) and ESR experiments This type of 14-DHPs has significant activity towards the radicals even whencompared with commercial 14-DHP drugs with well-knownantioxidant ability
It was observed that nicardipine preferentially targets RO∙radicals and is inactive against ROO∙ Lacidipine on theother hand is equally active towards both types of radicals(Gaviraghi et al [164]) The cytoprotective effect againstexposure to H
2O2was more significant for lacidipine (ID
50=
14 nM its log119875 = 54 membrane partition = 136000 assumesposition located 7 A near to the membrane center otherless lipophilic DHPs located 12ndash16 A far from the center)as compared to amlodipine nifedipine and nicardipine insmooth muscle cell culture (Gaviraghi et al [164]) Oxidativeeffect of H
2O2shifts the Ca channel toward an open state
Thus the redox property of CCBs DHPs may augment theirCCB properties
Oxidation of pharmacologically active Hantzsch 14-dihydropyridines was found by electrogenerated superoxideusing a voltammetric approach in DMSO solutions (Ortiz etal [238] and Ortiz et al [239]) Raghuvanshi and Singh [240]have also reported oxidative aromatization of these DHPsinduced by superoxide
Chemiluminescence (CL) was used in the studies ana-lyzing the antioxidant activity of 12 various 4-flavonil-14-dihydropyridine derivatives (Kruk et al [241]) on a chemicalsystem involving a superoxide radical anion These deriva-tives showed structural similarity to flavonoids with respectto the presence of rings A B and C The results obtained in
24 Oxidative Medicine and Cellular Longevity
this study indicate that the tested derivatives may catalyzeconversion of superoxide radicals through mimicking theactivity of superoxide dismutase by delivering H+ for reac-tion
O2
minus∙+O2
minus∙+ 2H+ 997888rarr H
2O2+1O2
(3)
The enhanced emission of the light in the presence oftested compounds was significant and related to stimulatedproduction ofH
2O2and 1O
2fromO
2
∙The latter specieswereremoved from the reactionmixture by the following sequenceof reactions
H+
O2
minus∙997888rarr HO
2
∙
HO2
∙+O2
∙minus997888rarr HO
2
minus+1O2
2HO2
∙997888rarr H
2O2+1O2
2 (1O2) 997888rarr (O
2)2+ h]lowast
(4)
or to take part in spontaneous dismutation of H2O2
2H2O2997888rarr 2H
2O + 1O
2(5)
The authors have offered an original concept of action for 4-flavonil-14-dihydropyridine derivatives unrelated to that ofO2
∙ radical-trapping chain-breaking antioxidants Insteadthey showed that these compounds act similar to superoxidedismutases converting O
2
∙ to H2O2 Hydrogen peroxide
is less toxic for cells than O2
∙ because it is predominantlyremoved by peroxidases and catalases Finally AO effect ofthese DHPs differed from those mediated by flavonoids witha catechol structure of ring B which are well-known 1O
2
quenchersMulder and collaborators came to similar conclusions
especially related to molecular mechanisms of antioxidativeactivity of DHPs [236]TheAOproperties of Hantzsch 14-di-hydropyridine esters and two dibenzo-14-dihydropyridines910-dihydroacridine (DHAC) and N-methyl-910-dihydro-acridine (N-Me-DHAC) have been explored by determin-ing the autoxidation of styrene or cumene at 30∘C Theseexperiments showed that Hantzsch esters are virtually inac-tive as chain-breaking antioxidants (CB-AOs) contrary tothe findings observed by Lopez-Alarcon et al [103] whoused CB-AOA in aqueous media at pH 74 Their reactivitytoward peroxyl radicals was shown to be some 5 orders ofmagnitude lower than that of the excellent CB-AO 22578-pentamethyl-6-hydroxy-chroman (PMHC)
DHAC was found to be sim10 times less reactive thanPMHC kinetic measurements using DHAC N-deuterio-DHAC and N-Me-DHAC pointing out the abstraction ofN-H hydrogen in DHAC by peroxyl radicals despite the factthat the calculated C-H bond dissociation enthalpy (BDE) inDHAC is about 11 kcalmol lower than the N-H BDE Therates of hydrogen atom abstraction by the 22-diphenyl-1-picrylhydrazyl radical (DPPH∙) have also been determined
for the same series of compounds The trends in the peroxyl∙and DPPH∙ rate constants were found to be similar [236]
Tirzit et al [242] have observed quenching of singletoxygen by DHPs This observation paved the ground forfurther research related to reactions of DHPs with hydroxylradicals (Tirzit et al [243]) singlet oxygen (Kazush etal [94]) and mechanisms of action A series of 14-DHPderivatives in NAD-H-Cu2+-H
2O2system inhibited forming
of the hydroxyl radical (HO∙) while 14-DHP derivativeswith electron donor substituents in the molecule were shownto be capable themselves of generating HO∙ in the presenceof Cu2+ and H
2O2 Rubene et al [186] also described
interaction of 14-DHP derivatives with Fentonrsquos reagentwhich produces hydroxyl radical (HO∙) Rate constants ofthe DHPs reaction (1st order) with HO∙ radical were highin the range 109 L times mol times secminus1 close to that of NADHcysteine and thiourea 35-Diacetyl- derivatives reacted fastercompared to 35-dialkoxycarbonyl- ones The reaction ratedecrease was observed in the case of substitution at position4 as compared to 4-unsubstituted DHPs Some DHPs havingelectron donor -COOminus groups in the 35- or 26- positionsof DHP ring reacted immediately (having rate constantshigher as 109 L times mol times secminus1) Rate constants with HO
2
∙
and O2
∙minus radicals were of lower degree Thus DHPs actingas oxygen radical scavengers could effectively inhibit ROSrelated reactions of LP initiation stage
Nifedipine and nitrendipine reactivity toward singletoxygen was also studied [244] Nifedipine was shown tobe a good scavenger of excited oxygen mainly via physicaldeactivation with values of the total rate constant rangingfrom 208 times 105Mminus1 sminus1 (in dioxane) to 930 times 105Mminus1 sminus1(in propylene carbonate)The less reactive pathway generateda photooxidation product For that reason a mechanisminvolving a perepoxide-like encounter complex in the firststep of the reaction path was proposed (see [244] Figures8 and 9 therein) The dependence was observed on solventmicroscopic parameters of the total rate constant for the reac-tion between singlet oxygen and 14-DHPs These findingsshow that nifedipine possesses stronger protective activity inbiological systems than nitrendipine
Density-functional-theory (DFT) calculations made byWang et al [245] confirmed the former experimental obser-vations that Hantzsch ester diludine is potent antioxi-dant with high H atom-donating ability and relatively lowprooxidant activity Possible reaction pathways for radicalsderived from 14-dihydropyridine and the resonance modesfor radical species were given [245]
Moreover two ethoxycarbonyl (EtOCO) substituentsat C(2) and C(6) should further enhance Hantzsch esterdiludine H-atom-donating ability due to resonance effectsHowever DHPs should be used in nonpolar rather than inpolar solvents since in the latter not H-atom but electrontransfer is preferred in the radical scavenging process [245]
Mulder et al [246] proposed that quantum-thermochem-ical calculations must be used with caution to indicate ldquoapromising lead antioxidantrdquo as they criticized the density-functional-theory (DFT) calculations made by Wang et al[245]
Oxidative Medicine and Cellular Longevity 25
372 Possible Mechanisms of DHPs ARA and AOA in the Bio-logical Systems Interaction with Other OSModifiers Some ofthese mechanisms were already described (Sections 331 (2)-(b) 331 (2)-(c) 331 (3)-(b) 35)
Enzymatic sources of ROSwith confirmed functional rolein hypertension are NADPH oxidase NO synthase (NOS)xanthine oxidase and cyclooxygenase Godfraind [3] hasreviewed AO effects and protective action of calcium channelblockers (CCBs) Yao et al [247] observed antioxidant effects(as inhibition of LP) for cardio- and neuroprotective CCBs(3ndash300 120583molL) including 7 DHPs in homogenates of ratbrain IC
50values (120583M) were as follows nifedipine (515) gt
barnidipine (586) gt benidipine (712) gt nicardipine (1293)gt amlodipine (1355) gt nilvadipine (1673) gt nitrendipine(2521) gt diltiazem (gt300) = verapamil (gt300) There arealso research articles describing the AO properties of CCBsthrough direct scavenging effect or through preservationof the endogenous SOD activity These findings indicatethat CCBs may also act by reducing the production ofvasoconstrictors angiotensin and endothelin
When present in concentrations that can be achievedin plasma CCBs may inhibit LP formation [3] This AOactivity seems to be typical for high lipophilic CCBs becausetheir chemical structure facilitates proton-donating andresonance-stabilization mechanisms that quench the freeradical reaction Their insertion in the membrane nearpolyunsaturated fatty acids at relatively high concentrationspotentiates proton donation (or atomary H) to lipid peroxidemolecules thereby blocking the peroxidation process Theremaining unpaired free electron associated with the CCBmolecule can be stabilized in well-defined resonance struc-tures associated with the DHP ring (Mason et al [48])
The radical reaction (according to Godfraind [3]) thatdescribes the AO effects of a DHP CCBs is LOOlowast + DHPrarr LOOH + DHPlowast (where LOOlowast is lipid peroxide radical)which in general is reaction (7) of the LP reaction cascadeconsisting of sim10 reactions (Scheme 2) [89]
As the rate constants of in vitro interaction of 4-substituted DHPs with peroxyl radicals are three ordersof magnitude lower than that of the vitamin E derivativethese DHPs must be considered as weak AO (Ursini [204])However due to partition coefficient of DHPs in membranesand in case of specific binding high local concentration ofDHPs may be obtained
DHPs without CCB properties for instance Bay w 9798although structurally related to nifedipine inhibit TNF-120572-induced vascular cell adhesion molecule-1 expression inendothelial cells by suppressing reactive oxygen speciesgeneration [248]
Mitrega et al [249] have discovered that antiarrhythmicand hemodynamic effects of oxidized heteroaromatic DHPsoxy nifedipine oxy nimodipine oxy nitrendipine and oxynisoldipine suggest that CCB DHPs and their metabolitescould act at least in two ways targeting OS related eventsas reductants (see Section 351 (1)) andor bypassing OSrelatedmetabolic routes Authors postulated that contrary tocurrent belief NIF metabolites are pharmacologically activeATP sensitive potassium channels were mentioned as a tar-get
38 DHPs Anti- or Prooxidants Several substances (ascorbicacid being the most commonly studied) can serve either asantioxidants or as prooxidants depending on given condi-tions (Herbert [250]) Therefore Halliwell [251] has reporteddilemma related to polyphenols as possible antioxidantsand prooxidants causing experimental artifacts (about 25)by oxidation of antioxidant compounds in the cell culturemedia Nevertheless it is generally accepted opinion thatpolyphenols act as antioxidants in vivo Studies on DHPs alsoface such a dilemmaThe exact roles (anti- or prooxidative) ofany specific DHP depend on its structure appliedachievedconcentration and specificity of the targetexperimentaltesting system
This situation resembles the case of antioxidative effectsof tocopherol which depends on the fate of the secondaryradical as proposed by Winterbourn [252] The question wasldquoVitamin E - Pro- or Antioxidantrdquo
997888rarr chain termination of lipid peroxidation
(6)
Prooxidant
Toc∙ + Lipid-H 997888rarr Lipid∙ (in LDL particles) (7)
This example shows that generally speaking any AO mustfulfil several criteria to be considered as an effective com-pound physiologically
(i) It must be able to functionally interact with endoge-nous scavengers even at low concentrations
(ii) It must affect endogenous pathways of OS(iii) It should not have undesirable adverse effect(iv) It should manifest the antioxidant efficacy dependent
on the oxidant(v) It must discriminate among different strategies
needed for 1-electron and 2-electron processes(vi) Radical scavengers can be prooxidant unless linked to
a radical sink (Winterbourn [252])
According to these statements DHPs could be effective asAO under physiological conditions in vivo (Godfraind [3]and others [30 31 38]) and in vitro in various experimentalsystems (cell and tissue) (see Sections 33 34 35)
Hence calcium antagonists appeared to disrupt thefine balance between the production and scavenging ofROS Nifedipine verapamil and diltiazem were shown toinduce significant oxidative stress in the epididymal sperm(increased MDA and decreased catalase and superoxidedismutase activity) This may be the reason for the inductionof male infertility [253]
The dualism of 14-DHP effects has been recorded asinhibition or promotion of LP as quenching or initiating
26 Oxidative Medicine and Cellular Longevity
oxygen and nitrogen free radical chain reactions radiopro-tecting or radiosensitizing antagonizing or synergizing Ca2+in electromechanical coupling as well as in the membranestabilization or labilization
39 Could DHPs Be Involved in Antioxidative Stress Beforebeing applied in vivo the optimal dose and optimal timeintervals forDHPs applicationmust be knownNamely whileROS have been traditionally considered as toxic byproductsof aerobic metabolism we know nowadays that ROS may actas essential signaling molecules needed for the control ofmany different physiological processes Whether the role ofROS will be damaging protective or signaling depends onthe delicate equilibrium between time- and location-specificROS production and scavenging Accordingly the imbalanceof the increased AO potential so-called antioxidative stresscould be dangerous similar to chronic OS in particular incase of extended exposure Inappropriate interventions inthe oxidative homeostasis by excessive antioxidants especiallyin case of chronic exposure to antioxidants might havevery negative effects as was published in the ATBC studyshowing an increased cancer incidence in smokers treatedby excessive beta-carotene [254] Therefore overconsump-tion of any natural or synthetic AO including DHPs asdietary supplements or drugs must be avoided in order tosuppress oxidative damage and must not disrupt the well-integrated antioxidant defense network (Poljsak [255] andPoljsak and Milisav [256]) This is especially important whenadministrating lipid-soluble antioxidants that can be storedin biomembranes thus not only attenuating or preventing LPbut also affecting physiological effects of the natural antiox-idants in particular tocopherol The interrelationship withthe status of endogenous antioxidantsprooxidants should befollowed
DHPs primarily suppress the initiation stages of LPprocessThey do not entirely stop the LP propagation Actingsynergistically with tocopherol diludine may prevent patho-logical excess of ROS production within the lipid moiety ofthe cellular membranes and LDL However due to its lowsolubility and fast metabolism its concentration in the cellsis low For that reason it cannot cause antioxidative stresseven if used for an extended period of time Thus diludine(diethone) could be only a mild antioxidant it has potentialfor restoring the pool of natural antioxidants (as synergist of120572-tocopherol and polyphenols) in the cells
Moreover DHPs CA used for cardioprotection andvasodilatation as commercial drugs in low concentrationsare fast metabolized via CYP3A4 and for that reason theirapplication does not induce cellular AO stress [53 160]However Godfraind and Salomone [257] have postulated noevidence that allows recommending dietary supplementationwith antioxidants for the primary or secondary prevention ofcardiovascular disease
So far there are no reports on antioxidative stress causedby some DHPs diludine and its analogues Diludine andits analogues therefore could act as adaptogens supportinghormetic effects of mild oxidative stress These compoundsmay act as potential multisided modulators of Yin-Yang
cycles of redox and cell functions (the electroplasmic cycle)(Wagner et al [258])
4 Conclusions
14-Dihydropyridines (14-DHPs) have broad spectrum ofOS modulating activities DHPs have reducing and lipidperoxidation inhibitor properties act as reductants in simplechemical systems and stabilize various biological systems(LDL mitochondria microsomes cells and tissues) againstOS Examples and peculiarities and mechanisms of antiox-idant activity (AOA) and antiradical activity (ARA) as wellas stress-protective effect of DHPs including commercialcalcium antagonists (CA) were highlighted These activitiesdepend on various structural parameters related to DHPs(presence and character of substituents) lipophilicity anddepth of the incorporation in the biologicalmembranesTheyalso depend on the experimental model system for exploringthe lipid peroxidation or oxidative stress Stress-protectiveeffect of some metabolites of CA (nifedipine) is reviewedAlthough some DHPs including CA have prooxidant prop-erties (on epididymal sperm cells) they can generally beconsidered as potent antioxidants Therefore comparisonof the AOA and ARA of different DHPs (mutually andwith other AOs) was described in detail According to thedata presented the DHPs might be considered as bellwetheramong synthetic compounds targeting OS and as a kind ofpharmacological measure for respective field of organic andmedicinal chemistry
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
Authors from Latvian IOS acknowledge ESF 201300021DP1112013APIAVIAA011 and National Research Pro-gramme PUBLIC HEALTHBiomedicine of the Republicof Latvia for financial support administration of the Insti-tute for technical support and Rufus Smits PhD for con-sultations in English The support of Cooperation in Euro-pean System of Science and Technology (COST) Domain ofChemistry Molecular Sciences and Technologies (CMST)was of highest importance for preparation of this paper
[2] D J Triggle ldquo14-Dihydropyridines as calcium channel ligandsand privileged structuresrdquoCellular andMolecular Neurobiologyvol 23 no 3 pp 293ndash303 2003
[3] T Godfraind ldquoAntioxidant effects and the therapeutic modeof action of calcium channel blockers in hypertension andatherosclerosisrdquo Philosophical Transactions of the Royal SocietyB Biological Sciences vol 360 no 1464 pp 2259ndash2272 2005
[4] E Cadenas ldquoMitochondrial free radical production and cellsignalingrdquoMolecular Aspects of Medicine vol 25 no 1-2 pp 17ndash26 2004
[5] E Cadenas ldquoFree radicals oxidative stress and diseasesrdquo inLecture PSC 616 p 38 Missouri University of Science andTechnology Rolla Mo USA httpwwwcarnicominstituteorgarticlesenrique cadenaspdf
[6] K Rahman ldquoStudies on free radicals antioxidants and co-fac-torsrdquo Clinical Interventions in Aging vol 2 no 2 pp 219ndash2362007
[7] V Bocci and G Valacchi ldquoFree radicals and antioxidants howto reestablish redox homeostasis in chronic diseasesrdquo CurrentMedicinal Chemistry vol 20 no 27 pp 3397ndash3415 2013
[8] M Valko C J Rhodes J Moncol M Izakovic and M MazurldquoFree radicals metals and antioxidants in oxidative stress-induced cancerrdquo Chemico-Biological Interactions vol 160 no 1pp 1ndash40 2006
[9] G Bartosz ldquoReactive oxygen species destroyers or messen-gersrdquo Biochemical Pharmacology vol 77 no 8 pp 1303ndash13152009
[10] R Visconti and D Grieco ldquoNew insights on oxidative stress incancerrdquo Current Opinion in Drug Discovery and Developmentvol 12 no 2 pp 240ndash245 2009
[11] R N Kujundzic N Zarkovic and K G Troselj ldquoPyridinenucleotides in regulation of cell death and survival by redoxand non-redox reactionsrdquo Critical Reviews in Eukaryotic GeneExpression vol 24 no 4 pp 287ndash309 2014
[12] B Halliwell and J M C Gutteridge ldquoThe definition and mea-surement of antioxidants in biological systemsrdquo Free RadicalBiology and Medicine vol 18 no 1 pp 125ndash126 1995
[13] V D Kancheva and O T Kasaikina ldquoBio-antioxidantsmdashachemical base of their antioxidant activity and beneficial effect
on human healthrdquo Current Medicinal Chemistry vol 20 no 37pp 4784ndash4805 2013
[14] H V Panglossi Ed Frontiers in Antioxidants Research NovaScience Publishers New York NY USA 2006
[15] E B Burlakova E M Molochkina and G A NikiforovldquoHybrid antioxidantsrdquo Oxidation Communications vol 31 no4 pp 739ndash757 2008 httpmembraneustceducnpaperpdfHybrid20Antioxidantspdf
[16] A Bast and G R M M Haenen ldquoTen misconceptions aboutantioxidantsrdquo Trends in Pharmacological Sciences vol 34 no 8pp 430ndash436 2013
[17] E B Burlakova A V 0lesenko E M Molochkina N PPalmina and N G Khrapova Bioantioxidants for RadiationDamage and Malignant Growth Nauka Moscow Russia 1975(Russian)
[18] J Fang T Seki and H Maeda ldquoTherapeutic strategies by mod-ulating oxygen stress in cancer and inflammationrdquo AdvancedDrug Delivery Reviews vol 61 no 4 pp 290ndash302 2009
[19] M Valko D Leibfritz J Moncol M T D Cronin M Mazurand J Telser ldquoFree radicals and antioxidants in normal physi-ological functions and human diseaserdquo International Journal ofBiochemistry and Cell Biology vol 39 no 1 pp 44ndash84 2007
[20] M Jimenez-Del-Rio and C Velez-Pardo ldquoThe bad the goodand the ugly about oxidative stressrdquo Oxidative Medicine andCellular Longevity vol 2012 Article ID 163913 13 pages 2012
[21] C D Kamat S Gadal M Mhatre K S Williamson Q N Pyeand K Hensley ldquoAntioxidants in central nervous system dis-eases preclinical promise and translational challengesrdquo Journalof Alzheimerrsquos Disease vol 15 no 3 pp 473ndash493 2008
[22] A Pompella H Sies R Wacker et al ldquoThe use of totalantioxidant capacity as surrogate marker for food quality andits effect on health is to be discouragedrdquo Nutrition vol 30 no7-8 pp 791ndash793 2014
[23] Z Ye and H Song ldquoAntioxidant vitamins intake and the risk ofcoronary heart disease meta-analysis of cohort studiesrdquo Euro-pean Journal of Cardiovascular Prevention and Rehabilitationvol 15 no 1 pp 26ndash34 2008
[24] P Knekt J Ritz M A Pereira et al ldquoAntioxidant vitamins andcoronary heart disease risk a pooled analysis of 9 cohortsrdquoTheAmerican Journal of Clinical Nutrition vol 80 no 6 pp 1508ndash1520 2004
[25] A C Carr and M C M Vissers ldquoSynthetic or food-derivedvitamin Cmdashare they equally bioavailablerdquo Nutrients vol 5 no11 pp 4284ndash4304 2013
[26] R Tabrizchi ldquoEdaravoneMitsubishi-TokyordquoCurrentOpinion inInvestigational Drugs vol 1 no 3 pp 347ndash354 2000
[27] K Kikuchi S Tancharoen N Takeshige et al ldquoThe efficacy ofedaravone (radicut) a free radical scavenger for cardiovasculardiseaserdquo International Journal of Molecular Sciences vol 14 no7 pp 13909ndash13930 2013
[28] D Mauzerall and F H Westheimer ldquo1-Benzyldihydronicoti-namidemdasha model for reduced DPNrdquo Journal of the AmericanChemical Society vol 77 no 8 pp 2261ndash2264 1955 ChemicalAbstracts vol 50 Article ID 2588i 1956
[29] F Bossert and W Vater ldquo14-Dihydropyridinesmdasha basis fordeveloping new drugsrdquo Medicinal Research Reviews vol 9 no3 pp 291ndash324 1989
[30] G Swarnalatha G Prasanthi N Sirisha and CMadhusudhanaChetty ldquo14-Dihydropyridines a multtifunctional moleculemdash areviewrdquo International Journal of ChemTech Research vol 3 no1 pp 75ndash89 2011
28 Oxidative Medicine and Cellular Longevity
[31] M Cataldi and F Bruno ldquo14-Dihydropyridines the multiplepersonalities of a blockbuster drug familyrdquo Translational Medi-cine UniSa vol 4 no 2 pp 12ndash26 2012 httpwwwncbinlmnihgovpmcarticlesPMC3728803
[32] R Vitolina A Krauze G Duburs and A Velena ldquoAspects ofthe amlodipine pleiotropy in biochemistry pharmacology andclinicsrdquo International Journal of Pharmaceutical Sciences andResearch vol 3 no 5 pp 1215ndash1232 2012
[33] D Grover S N Mokale and M T Shete ldquoDihydropyridinea novel pharmacophorerdquo International Journal of Pharmaceu-tical Erudition vol 1 no 2 pp 16ndash29 2011 httppharmaeru-ditionorgContentPaper20111-RV-320Final2016-29pdf
[34] A M Vijesh A M Isloor S K Peethambar K N ShivanandaT Arulmoli and N A Isloor ldquoHantzsch reaction synthesis andcharacterization of somenew 14-dihydropyridine derivatives aspotent antimicrobial and antioxidant agentsrdquo European Journalof Medicinal Chemistry vol 46 no 11 pp 5591ndash5597 2011
[35] P Mehta and P Verma ldquoAntimicrobial activity of some deriva-tives of 14-dihydropyridinesrdquo Journal of Chemistry vol 2013Article ID 865128 4 pages 2013
[36] P Olejnıkova L Svorc D Olsovska et al ldquoAntimicrobialactivity of novel C2-substituted 14-dihydropyridine analoguesrdquoScientia Pharmaceutica vol 82 no 2 pp 221ndash232 2014
[37] S Sepehri H Perez Sanchez and A Fassihi ldquoHantzsch-typedihydropyridines and biginelli-type tetra-hydropyrimidinesa review of their chemotherapeutic activitiesrdquo Journal of Phar-macy amp Pharmaceutical Sciences vol 18 no 1 pp 1ndash52 2015httpsejournalslibraryualbertacaindexphpJPPSarticleview2383617863
[38] S A Khedkar and P B Auti ldquo14-Dihydropyridines a classof pharmacologically important moleculesrdquo Mini-Reviews inMedicinal Chemistry vol 14 no 3 pp 282ndash290 2014
[39] G D Tirzit and G Ya Duburs ldquo14-dihydropyridines as inhi-bitors of free-radical reactionsrdquo Chemistry of Heterocyclic Com-pounds vol 8 no 1 pp 126ndash127 1972 Translated from KhimiyaGeterotsiklicheskikh Soedinenii no1 pp 133ndash134 1972 (Rus-sian)
[40] I Bogeski R Kappl C Kummerow R Gulaboski M Hothand B A Niemeyer ldquoRedox regulation of calcium ion channelschemical and physiological aspectsrdquoCell Calcium vol 50 no 5pp 407ndash423 2011
[41] S A Giller G Y Dubur Y R Uldrikis et al ldquoDiludine [Themethod to obtain 35-dicarbonylderivatives of 26-dimethyl-14-dihydropyridines]rdquo Authors certificate of USSR no 3004651971 [Byull Izobret no13 p 95 1971] and following patentsPatent of England no 1294650 1973 Patent of France no2055458 1971 Patent of Japan no 702883 1973 Patent ofHolland no 149787 1976 Patent of Italy no 969022 1974 Patentof FRG no 2036403 1978 US Patent no 3883673 1975 USPatent no 3948924 1976
[42] S A Giller G Y Dubur Y R Uldrikis et al ldquoImprovementsin or relating to the stabilization of carotenerdquo GB Patent no1294650 1972
[43] S A Giller G Y Dubur Y R Uldrikis et al ldquoStabilization ofcarotenerdquo US Patent no 3883673 1975 Chemical Abstracts vol83 Article ID 95193 1975
[44] Yu A Zilber G Ya Dubur K K Kumsar and A Kh VelenaldquoThe effect of antioxidants on the peroxidation of bimole-cular phospholipid membranesrdquo Latvijas PSR ZA Vestis Izves-tia Akademii Nauk Latviyskoy SSR vol 6 pp 80ndash82 1971(Russian) translated from the original Russian Doc Accesion
No AD0771751 distributed by NTIS US Department of Com-merce httpwwwdticmildtictrfulltextu2771751pdf
[45] G Ya Dubur Yu A Zilbers A Kh Velena A O Kumerovaand G D Tirzitis ldquoMultistage study of regulation of peroxida-tion processes in biological membranes by antioxidants of 14-dihydropyridine grouprdquo Izvestiya Akademii Nauk LatviyskoySSR vol 336 no 7 pp 65ndash68 1975 (Russian)
[46] R P Mason and M W Trumbore ldquoDifferential membraneinteractions of calcium channel blockers Implications forantioxidant activityrdquo Biochemical Pharmacology vol 51 no 5pp 653ndash660 1996
[47] R P Mason M F Walter M W Trumbore E G Olmstead Jrand P E Mason ldquoMembrane antioxidant effects of the chargeddihydropyridine calcium antagonist amlodipinerdquo Journal ofMolecular and Cellular Cardiology vol 31 no 1 pp 275ndash2811999
[48] R PMason I T MakMW Trumbore and P EMason ldquoAnti-oxidant properties of calcium antagonists related to membranebiophysical interactionsrdquo American Journal of Cardiology vol84 no 4 pp 16ndash22 1999
[49] R PMasonMW Trumbore and P EMason ldquoMembrane bio-physical interaction of amlodipine and antioxidant propertiesrdquoDrugs vol 59 no 2 pp 9ndash16 2000 (French)
[50] R P Mason P Marche and T H Hintze ldquoNovel vascularbiology of third-generation L-type calcium channel antagonistsAncillary actions of amlodipinerdquo Arteriosclerosis Thrombosisand Vascular Biology vol 23 no 12 pp 2155ndash2163 2003
[51] A Augustyniak G Bartosz A Cipak et al ldquoNatural andsynthetic antioxidants an updated overviewrdquo Free RadicalResearch vol 44 no 10 pp 1216ndash1262 2010
[52] T Grune N Zarkovic and K Kostelidou ldquoLipid peroxidationresearch in Europe and the COST B35 action lsquoLipid Peroxida-tion Associated Disordersrsquordquo Free Radical Research vol 44 no10 pp 1095ndash1097 2010
[53] E Carosati P Ioan M Micucci et al ldquo14-Dihydropyridinescaffold in medicinal chemistry the story so far and perspec-tives (part 2) action in other targets and antitargetsrdquo CurrentMedicinal Chemistry vol 19 no 25 pp 4306ndash4323 2012
[54] U Eisner and J Kuthan ldquoThe chemistry of dihydropyridinesrdquoChemical Reviews vol 72 no 1 pp 1ndash42 1972 httpwwwsci-encemadnessorgtalkfilesphppid=138742ampaid=6475
[55] J Kuthan and A Kurfurst ldquoDevelopment in dihydropyri-dine chemistryrdquo Industrial amp Engineering Chemistry ProductResearch and Development vol 21 no 2 pp 191ndash261 1982
[56] A Sausins and G Duburs ldquoSynthesis of 14-dihydropyridinesby cyclocondensation reactionsrdquo Heterocycles vol 27 no 1 pp269ndash289 1988
[57] A E Sausins and G Y Duburs ldquoSynthesis of 14-dihydro-pyridines in cyclocondensation reactions (review)rdquo Chemistryof Heterocyclic Compounds vol 28 no 4 pp 363ndash391 1992Translated from Khimiya Geterotsiklicheskikh Soedinenii no 4pp 435ndash467 1992 (Russian)
[58] S Kazda ldquoTwenty years of dihydropyridinesrdquo in Dihydropy-ridines Progress in Pharmacology and Therapy W-D Busse BGarthoff and F Seuter Eds pp 1ndash12 Springer Verlag BerlinGermany 1993
[59] J-P Wan and Y Liu ldquoRecent advances in new multicomponentsynthesis of structurally diversified 14-dihydropyridinesrdquo RSCAdvances vol 2 no 26 pp 9763ndash9777 2012
[61] Reaxys Database[62] J Tuttle ldquoStructure mechanism and reactivity of hantzsch
estersrdquo in MacMillan Lab Group Meeting (082504) p 332004 httpwwwprincetoneduchemistrymacmillangroup-meetingsJBT20Hantzschpdf
[63] A Saini S Kumar and J S Sandhu ldquoHantzsch reaction recentadvances in Hantzsch 14-dihydropyridinesrdquo Journal of Sci-entific amp Industrial Research vol 67 pp 95ndash111 2008
[64] L LW Cheung S A Styler and A P Dicks ldquoRapid and conve-nient synthesis of the 14-dihydropyridine privileged structurerdquoJournal of Chemical Education vol 87 no 6 pp 628ndash630 2010
[65] A Kumar R A Maurya S Sharma M Kumar and G BhatialdquoSynthesis and biological evaluation of N-aryl-14-dihydro-pyridines as novel antidyslipidemic and antioxidant agentsrdquoEuropean Journal of Medicinal Chemistry vol 45 no 2 pp 501ndash509 2010
[66] R S Kumar A Idhayadhulla A J Abdul Nasser and J SelvinldquoSynthesis and anticoagulant activity of a new series of 14-dihydropyridine derivativesrdquo European Journal of MedicinalChemistry vol 46 no 2 pp 804ndash810 2011
[67] H A Stefani C B Oliveira R B Almeida et al ldquoDihydro-pyrimidin-(2H)-ones obtained by ultrasound irradiation anew class of potential antioxidant agentsrdquo European Journal ofMedicinal Chemistry vol 41 no 4 pp 513ndash518 2006
[68] H Sun C Shang L Jin and J Zhang ldquoSynthesis and antiox-idant activity of a series of novel 3-chalcone-substituted 14-dihydropyridine derivativesrdquoHeterocyclic Communications vol18 no 5-6 pp 239ndash243 2012
[69] D B Tikhonov and B S Zhorov ldquoStructural model for dihy-dropyridine binding to L-type calcium channelsrdquo The Journalof Biological Chemistry vol 284 no 28 pp 19006ndash19017 2009
[70] G Y Dubur and Y R Uldrikis ldquoThe oxidation of 14-dihydro-pyridinesrdquo Chemistry of Heterocyclic Compounds vol 6 no 1pp 80ndash84 1970 Translated from Khimiya GeterotsiklicheskikhSoedinenii no 1 pp 83ndash88 1970 (Russian)
[71] G Ya Duburs A O Kumerova and Ya R Uldrikis ldquoEnzymicoxidation of hydrogenated pyridines with peroxidase-hydrogenperoxide systemrdquoLatvijas PSRZAVestis vol 73 no 7 pp 73ndash771970 (Russian) Chemical Abstracts vol 73 Article ID 94913g1970
[72] K Xie Y-C Liu Y Cui J-GWang Y Fu andT CWMak ldquoN-methyl-(R)-3-(tert-butyl)-sulfinyl-14-dihydropyridine a novelNADHmodel compoundrdquoMolecules vol 12 no 3 pp 415ndash4222007
[73] S Tamagaki T Mimura and W Tagaki ldquoMetal-ion-facilitatedoxidations of dihydropyridines with molecular oxygen andhydrogen peroxiderdquo Journal of the Chemical Society PerkinTransactions 2 no 10 pp 1645ndash1650 1990
[74] D Tirzite G Tirzitis andD Antipova ldquoReductive ability of 14-dihydropyridine derivatives in relation to ions of trivalent ironrdquoChemistry of Heterocyclic Compounds vol 35 no 5 pp 592ndash594 1999
[76] J Ogle J Stradins and L Baumane ldquoFormation and decay offree cation-radicals in the course of electro-oxidation of 12- and14-dihydropyridines (Hantzsch esters)rdquo Electrochimica Actavol 39 no 1 pp 73ndash79 1994
[77] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for the
synthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts C Wittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Berlin Germany 2010
[78] WDu and Zh Yu ldquoBiomimetic in situ regeneration of cofactorsNAD(P)+ and NAD(P)H models hantzsch esters and dihy-drophenanthridinerdquo Synlett vol 23 no 9 pp 1300ndash1304 2012
[79] H K Chenault and G M Whitesides ldquoRegeneration ofnicotinamide cofactors for use in organic synthesisrdquo AppliedBiochemistry and Biotechnology vol 14 no 2 pp 147ndash197 1987
[80] Y R Uldrikis A A Zidermane E A Biseniex I E Preisa GY Dubur and G D Tirzit ldquoEsters of 26-dimethyl-14-dihydro-pyridine-35-dicarboxylic acid and method of obtainingthereofrdquo WO 8000345 A1 1978 httpworldwideespacenetcompublicationDetailsbiblioDB=EPODOCampII=1ampND=3ampadjacent=trueamplocale=en EPampFT=Dampdate=19800306ampCC=WOampNR=8000345A1ampKC=A1
[81] Y Sambongi H Nitta K Ichihashi M Futai and I Ueda ldquoAnovel water-soluble Hantzsch 14-dihydropyridine compoundthat functions in biological processes through NADH regener-ationrdquo Journal of Organic Chemistry vol 67 no 10 pp 3499ndash3501 2002
[82] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for thesynthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts ChWittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Verlag Berlin Germany 2010
[83] T Okamura T Kikuchi A Nagamine et al ldquoAn approach formeasuring in vivo cerebral redox states using the oxidative con-version of dihydropyridine to pyridinium ion and themetabolictrapping principlerdquo Free Radical Biology and Medicine vol 38no 9 pp 1197ndash1205 2005
[84] K A Schellenberg and F H Westheimer ldquoA free-radicaloxidation of a dihydropyridine1ardquo The Journal of OrganicChemistry vol 30 no 6 pp 1859ndash1862 1965
[85] K A Schellenberg ldquoReaction of hydroxyl radical with thymi-dine Scavenging by a dihydropyridinerdquo Federation Proceedingsvol 38 no 3 I p 1433 1979
[86] E S Huyser J A K Harmony and F L McMillian ldquoPeroxideoxidations of dihydropyridine derivativesrdquo Journal of the Amer-ican Chemical Society vol 94 no 9 pp 3176ndash3180 1972
[87] A Sakamoto S T Ohnishi and R Ogawa ldquoInhibition of lipidperoxidation by some dihydropyridine derivativesrdquo Journal ofAnesthesia vol 7 no 2 pp 193ndash197 1993
[88] R Hardeland ldquoReview Neuroprotection by radical avoidancesearch for suitable agentsrdquo Molecules vol 14 no 12 pp 5054ndash5102 2009
[89] G Ya Dubur A Kh Velena V M Gukasov and Yu AVladimirov ldquoRegulation of peroxidation of mitochondrialmembrane lipids initiated by Fe2+ ions by antoxidants of the14-dihydropyridine series in experiments in vitrordquo Biomed-itsinskaya Khimiya vol 22 no 5 pp 665ndash673 1976 (Russian)Chemical Abstracts vol 88 Article ID 2640 1977
[90] G RMMHaenenM J T J Arts A Bast andMD ColemanldquoStructure and activity in assessing antioxidant activity in vitroand in vivo a critical appraisal illustrated with the flavonoidsrdquoEnvironmental Toxicology and Pharmacology vol 21 no 2 pp191ndash198 2006
[91] G Tirzitis and G Bartosz ldquoDetermination of antiradical andantioxidant activity basic principles and new insightsrdquo ActaBiochimica Polonica vol 57 no 2 pp 139ndash142 2010
30 Oxidative Medicine and Cellular Longevity
[92] G R Buettner and R P Mason ldquoSpin-trapping methods fordetecting superoxide and hydroxyl free radicals in vitro and invivordquo inCritical Reviews of Oxidative Stress and Aging Advancesin Basic Science Diagnostics and Intervention R G Cutler andH Rodriguez Eds vol 1 chapter 2 pp 27ndash38World ScientificLondon UK 2003
[93] M M Tarpey and I Fridovich ldquoMethods of detection ofvascular reactive species Nitric oxide superoxide hydrogenperoxide and peroxynitriterdquo Circulation Research vol 89 no3 pp 224ndash236 2001
[94] E Y Kazush E I Sagun G D Tirzit and G Y DaburldquoQuenching of singlet oxygen by electron donating derivativesof 14-dihydropyridinerdquo Chemistry of Heterocyclic Compoundsvol 30 no 5 pp 562ndash563 1994
[95] G Tirzitis E Kazush and G Duburs ldquoReaction of 14-dihydropyridine derivatives with peroxynitrite anionrdquo Chem-istry of Heterocyclic Compounds vol 34 no 3 pp 321ndash3231998 (Russian) Translated from Khimiya GeterotsiklicheskikhSoedinenii no 3 pp 355ndash357 1998
[96] L J Nunez-Vergara C Lopez-Alarcon P A Navarrete-EncinaA M Atria C Camargo and J A Squella ldquoElectrochemicaland EPR characterization of 14-dihydropyridines Reactivitytowards alkyl radicalsrdquo Free Radical Research vol 37 no 1 pp109ndash120 2003
[97] D Tirzite A Krauze A Zubareva G Tirzitis and G DubursldquoSynthesis and antiradical activity of 5-acetyl-2-alkylthio-4-aryl-6-methyl-14-dihydropyridine-3-carboxylic acid nitrilesrdquoChemistry of Heterocyclic Compounds vol 38 no 7 pp 795ndash800 2002
[98] H Ohkawa N Ohishi and K Yagi ldquoAssay for lipid peroxidesin animal tissues by thiobarbituric acid reactionrdquo AnalyticalBiochemistry vol 95 no 2 pp 351ndash358 1979
[99] N Zarkovic ldquo4-Hydroxynonenal as a bioactive marker ofpathophysiological processesrdquo Molecular Aspects of Medicinevol 24 no 4-5 pp 281ndash291 2003
[100] M Parola G Bellomo G Robino G Barrera and M UDianzani ldquo4-Hydroxynonenal as a biological signal molecularbasis and pathophysiological implicationsrdquo Antioxidants andRedox Signaling vol 1 no 3 pp 255ndash284 1999
[101] T Lovakovic M Poljak-Blazi G Duburs et al ldquoGrowthmodulation of human cells in vitro by mild oxidative stressand 14-dihydropyridine derivative antioxidantsrdquo CollegiumAntropologicum vol 35 no 1 pp 137ndash141 2011
[102] R van den Berg G R M M Haenen H van den Bergand A Bast ldquoApplicability of an improved Trolox equivalentantioxidant capacity (TEAC) assay for evaluation of antioxidantcapacity measurements of mixturesrdquo Food Chemistry vol 66no 4 pp 511ndash517 1999
[103] C Lopez-Alarcon P Navarrete C Camargo J A Squella andL J Nunez-Vergara ldquoReactivity of 14-dihydropyridines towardalkyl alkylperoxyl radicals and ABTS radical cationrdquo ChemicalResearch in Toxicology vol 16 no 2 pp 208ndash215 2003
[104] V Valenzuela P Santander C Camargo J A Squella C Lopez-Alarcon and L J Nunez-Vergara ldquo14-Dihydropyridines reac-tivity of nitrosoaryl and nitroaryl derivatives with alkylperoxylradicals andABTS radical cationrdquo Free Radical Research vol 38no 7 pp 715ndash727 2004
[105] L G Tsetlin N A Chebotareva B I Kurganov A K VelenaG Y Dubur and V Z Lankin ldquoStudy of 14-dihydropyridinesas lipoxygenase inhibitors with the use of hydrated reversedmicellesrdquo Pharmaceutical Chemistry Journal vol 22 no 6 pp425ndash428 1988 (Russian)
[106] J Panek Z Reblova L Kocirkova et al ldquoAntioxidant activityof dihydropyridine derivativesrdquo Czech Journal of Food Sciencesvol 18 pp 144ndash145 2000
[107] G Tirzitis I Kirule and G Duburs ldquoAntioxidationsaktivitatder 35-dicarbonylderivate des 26-demethyl-14-dihydropyri-dinsrdquo Fett Wissenschaft TechnologieFat Science Technology vol90 no 10 pp 411ndash413 1988
[108] M Plotniece G Tirzitis Y Uldrikis et al ldquoSynthesis of 14-dihydropyridine derivatives having an oxy- alkoxy- or dimeth-ylaminophenyl substituent in the 4 position their antioxidantactivity and their binding to phospholipid membranesrdquo Chem-istry of Heterocyclic Compounds vol 32 no 10 pp 1166ndash11721996 Translated from Khimiya Geterotsiklicheskikh Soedineniino 10(352) pp 1358ndash1365 1996 (Russian)
[109] D Y Rubene V S Sharov V I Olenev G D Tirzit G Y Duburand Y A Vladimirov ldquoUse of chemiluminescent method forthe evaluation of antioxidant activity of some derivatives of 14-dihydropyridinerdquo Russian Journal of Physical Chemistry A vol55 no 2 pp 511ndash512 1981 (Russian)
[110] M C R Symons and JM C Gutteridge Free Radicals and IronChemistry Biology and Medicine Oxford Science PublicationsOxford University Press Oxford UK 1998
[111] M Repetto J Semprine and A Boveris ldquoLipid peroxidationchemical mechanism biological implications and analyticaldeterminationrdquo in Lipid Peroxidation A Catala Ed Section ILipid Peroxidation Chemical Mechanisms Antioxidants Bio-logical Implications of Biochemistry Genetics and MolecularBiology chapter 1 pp 3ndash30 InTech Rijeka Croatia 2012
[112] A Velena J Zilbers and G Duburs ldquoDerivatives of 14-dihydropyridines asmodulators of ascorbate-induced lipid per-oxidation and high-amplitude swelling ofmitochondria causedby ascorbate sodium linoleate and sodiumpyrophosphaterdquoCellBiochemistry and Function vol 17 no 4 pp 237ndash252 1999
[113] M V Bilenko L N Shelenkova G Y Dubur and A K VelenaldquoUse of antioxidants to prevent renal damage during acuteischemia and reperfusionrdquo Bulletin of Experimental Biology andMedicine vol 96 no 3 pp 1195ndash1198 1983 Translated fromByulletenrsquo Eksperimentalrsquonoi Biologii i Meditsiny vol 96 no 9pp 8ndash11 1983 (Russian)
[114] R Toniolo F Tubaro F Ursini and G Bontempelli ldquoAn elec-troanalytical investigation on the redox properties of calciumantagonist dihydropyridinesrdquo Electroanalysis vol 15 no 10 pp855ndash861 2003
[115] L Kourimska J Pokorny and G Tirzitis ldquoThe antioxidant aci-tivity of 26-dimethyl-35-diethoxycarbonyl-14-dihydropyri-dine in edible oilsrdquo Nahrung vol 37 no 1 pp 91ndash93 1993
[116] C Lopez-Alarcon H Speisky J A Squella C Olea-Azar CCamargo and L J Nunez-Vergara ldquoReactivity of 14-dihydro-pyridines toward SIN-1-derived peroxynitriterdquo PharmaceuticalResearch vol 21 no 10 pp 1750ndash1757 2004
[117] R A Olek W Ziolkowski J J Kaczor L Greci J Popinigisand J Antosiewicz ldquoAntioxidant activity of NADH and its ana-loguemdashan in vitro studyrdquo Journal of Biochemistry andMolecularBiology vol 37 no 4 pp 416ndash421 2004
[118] E Niki N Noguchi and N Gotoh ldquoInhibition of oxidativemodification of low density lipoprotein by antioxidantsrdquo Jour-nal of Nutritional Science andVitaminology vol 39 supplementpp S1ndashS8 1993
[119] N Rojstaczer and D J Triggle ldquoStructure-function relation-ships of calcium antagonists effect on oxidative modificationof low density lipoproteinrdquo Biochemical Pharmacology vol 51no 2 pp 141ndash150 1996
Oxidative Medicine and Cellular Longevity 31
[120] A Sevanian L Shen and FUrsini ldquoInhibition of LDLoxidationand oxidized LDL-induced cytotoxicity by dihydropyridinecalcium antagonistsrdquo Pharmaceutical Research vol 17 no 8 pp999ndash1006 2000
[121] A Negre-Salvayre and R Salvayre ldquoProtection by Ca2+ channelblockers (nifedipine diltiazem and verapamil) against the tox-icity of oxidized low density lipoprotein to cultured lymphoidcellsrdquo British Journal of Pharmacology vol 107 no 3 pp 738ndash744 1992
[122] A Negre-Salvayre G FitoussiM Troly and R Salvayre ldquoCom-parative cytoprotective effect of dihydropyridine calcium chan-nel blockers against the toxicity of oxidized low density lipopro-tein for cultured lymphoid cellsrdquo Biochemical Pharmacologyvol 44 no 12 pp 2379ndash2386 1992
[123] L Cominacini A F Pasini U Garbin et al ldquoAntioxidant activ-ity of different dihydropyridinesrdquo Biochemical and BiophysicalResearch Communications vol 302 no 4 pp 679ndash684 2003
[124] L Cominacini U Garbin A Fratta Pasini et al ldquoOxidized low-density lipoprotein increases the production of intracellularreactive oxygen species in endothelial cells inhibitory effect oflacidipinerdquo Journal of Hypertension vol 16 no 12 part 2 pp1913ndash1919 1998
[125] H M Lander ldquoAn essential role for free radicals and derivedspecies in signal transductionrdquo The FASEB Journal vol 11 no2 pp 118ndash124 1997
[126] M L L Martinez E Rizzi M M Castro et al ldquoLercanidipinedecreases vascular matrix metalloproteinase-2 activity andprotects against vascular dysfunction in diabetic ratsrdquo EuropeanJournal of Pharmacology vol 599 no 1ndash3 pp 110ndash116 2008
[127] P Lesnik C Dachet L Petit et al ldquoImpact of a combinationof a calcium antagonist and a 120573-blocker on cell- and copper-mediated oxidation of LDL and on the accumulation and effluxof cholesterol in human macrophages and murine J774 cellsrdquoArteriosclerosis Thrombosis and Vascular Biology vol 17 no 5pp 979ndash988 1997
[128] G Sobal E J Menzel and H Sinzinger ldquoCalcium antagonistsas inhibitors of in vitro low density lipoprotein oxidation andglycationrdquoBiochemical Pharmacology vol 61 no 3 pp 373ndash3792001
[129] E Lupo R Locher B Weisser and W Vetter ldquoIn vitro antiox-idant activity of calcium antagonists against LDL oxidationcompared with 120572-tocopherolrdquo Biochemical and BiophysicalResearch Communications vol 203 no 3 pp 1803ndash1808 1994
[130] J Zou Y Li H-Q Fan and J-G Wang ldquoEffects of dihydropy-ridine calcium channel blockers on oxidized low-density lipo-protein induced proliferation and oxidative stress of vascularsmooth muscle cellsrdquo BMC Research Notes vol 5 article 1682012
[131] C Napoli S Salomone T Godfraind et al ldquo14-Dihydro-pyridine calcium channel blockers inhibit plasma and LDL oxi-dation and formation of oxidation-specific epitopes in the arte-rial wall and prolong survival in stroke-prone spontaneouslyhypertensive ratsrdquo Stroke vol 30 no 9 pp 1907ndash1915 1999
[132] G Zernig I Graziadei T Moshammer C Zech N Reider andH Glossmann ldquoMitochondrial Ca2+ antagonist binding sitesare associated with an inner mitochondrial membrane anionchannelrdquo Molecular Pharmacology vol 38 no 3 pp 362ndash3691990
[133] F E Hunter Jr A Scott P E Hochstein et al ldquoStudies of themechanism of ascorbate-induced swelling and lysis of isolatedliver mitochondriardquo The Journal of Biological Chemistry vol239 pp 604ndash613 1964
[134] D R Janero B Burghardt and R Lopez ldquoProtection of cardiacmembrane phospholipid against oxidative injury by calciumantagonistsrdquoBiochemical Pharmacology vol 37 no 21 pp 4197ndash4203 1988
[135] A Karadag B Ozcelik and S S Saner ldquoReview of methods todetermine antioxidant capacitiesrdquo FoodAnalyticalMethods vol2 no 1 pp 41ndash60 2009
[136] Y I Gubskiı N V Litvinova and E V Shnurko-TabakovaldquoAntioxidant and antiradical activity of various classes of antiox-idantsrdquo Ukrainskiı Biokhimicheskiı Zhurnal vol 66 no 4 pp114ndash116 1994 (Russian)
[137] M Takei M Hiramatsu and A Mori ldquoInhibitory effects ofcalcium antagonists onmitochondrial swelling induced by lipidperoxidation or arachidonic acid in the rat brain in vitrordquoNeurochemical Research vol 19 no 9 pp 1199ndash1206 1994
[138] M Takei M Hiramatsu R Edamatsu and A Mori ldquoFreeradical scavenging by calcium antagonistsrdquo Neurosciences vol20 no 2 pp 75ndash82 1994
[139] Ya P Stradin G Ya Dubur Yu A Beilis Ya R Uldrikis andA F Korotkova ldquoVoltammetry of 14-dihydropyridine deriva-tives I Potentials of electrochemical oxidation of 35-diacyl-and 35-di(alkoxycarbonyl)-14-dihydropyridines in acetoni-trilerdquo Chemistry of Heterocyclic Compounds no 1 pp 84ndash871972 (Russian)
[140] E V Ivanov T V Ponomarjova G N Merkusev et al ldquoEinneuer Haut-Radioprotektor Diethon (experimentelle Unter-suchung)rdquo Radiobiologia Radiotherapia vol 31 no 1 pp 69ndash78 1990
[141] E V Ivanov T V Ponomareva G N Merkushev et al ldquoRadia-tion modulating properties of derivates of 14-dihydropyridineand 12345678910-decahydroacridine-18 dionerdquo Radiat-sionnaia Biologiia Radioecologiia vol 44 no 5 pp 550ndash5592004 (Russian)
[142] R O Vitolinia D A Berzinia A K Velena I A Vutsina A AKimenis and G Y Duburs ldquoThe protective effects of the cal-cium antagonist foridon in acute myocardial ischaemiardquo Kardi-ologiya vol 27 no 3 pp 90ndash93 1987 (Russian)
[143] A H Velena G Ya Duburs R O Vitolina et al ldquoEffect ofryodipine on electromechanical parameters of heart and vesselscAMP phosphodiesterase activity and swelling-contractioncycle of mitochondriardquo Arzneimittelforschung vol 35 no 6 pp907ndash914 1985
[144] L I Utno Z E Lipsberga A A Silova M I Girgensone EA Bisenieks and G I Ia ldquoCardioprotective properties of a 14-dihydropyridine derivative glutapyrone in deep hypothermiardquoBiulletenrsquo Eksperimentalrsquonoı Biologii i Meditsiny vol 108 no 11pp 558ndash561 1989 (Russian)
[145] M A S FernandesM S Santos J A F Vicente et al ldquoEffects of14-dihydropyridine derivatives (cerebrocrast gammapyroneglutapyrone and diethone) onmitochondrial bioenergetics andoxidative stress a comparative studyrdquoMitochondrion vol 3 no1 pp 47ndash59 2003
[146] M A S Fernandes M S Santos A J M Moreno et al ldquoEffectsof 5-acetyl(carbamoyl)-6-methylsulfanyl-14-dihydropyridine-5-carbonitriles on rat liver mitochondrial functionrdquo Toxicologyin Vitro vol 23 no 7 pp 1333ndash1341 2009
[147] L Klimaviciusa A Kalda A Kaasik et al ldquoNeuroprotectiveactivity of 14-dihydropyridine derivatives structure determi-nantsrdquo Proceedings of the Latvian Academy of Sciences BNatural Exact and Applied Sciences vol 61 no 1-2 pp 33ndash372007
32 Oxidative Medicine and Cellular Longevity
[148] L Klimaviciusa M A S Fernandes N Lencberga et alldquoTargeting the mitochondria by novel adamantane-containing14-dihydropyridine compoundsrdquo in Bioenergetics K B ClarkEd pp 257ndash272 InTech 2012
[149] V Klusa L Klimaviciusa G Duburs J Poikans and AZharkovsky ldquoAnti-neurotoxic effects of tauropyrone a taurineanaloguerdquo Advances in Experimental Medicine and Biology vol583 pp 499ndash508 2006
[150] N Sampson P Berger and Ch Zenzmaier ldquoRedox signalingas a therapeutic target to inhibit myofibroblast activation indegenerative fibrotic diseaserdquo BioMed Research Internationalvol 2014 Article ID 131737 14 pages 2014
[151] T L Leto and M Geiszt ldquoRole of Nox family NADPH oxidasesin host defenserdquoAntioxidantsampRedox Signaling vol 8 no 9-10pp 1549ndash1561 2006
[152] K K Griendling D Sorescu and M Ushio-Fukai ldquoNAD(P)Hoxidase role in cardiovascular biology and diseaserdquo CirculationResearch vol 86 no 5 pp 494ndash501 2000
[153] H Chen Y S Song and P H Chan ldquoInhibition of NADPHoxi-dase is neuroprotective after ischemia-reperfusionrdquo Journal ofCerebral Blood Flow and Metabolism vol 29 no 7 pp 1262ndash1272 2009
[154] P Hochstein and L Ernster ldquoADP-activated lipid peroxidationcoupled to the TPNH oxidase system of microsomesrdquo Biochem-ical and Biophysical Research Communications vol 12 no 5 pp388ndash394 1963
[155] I I Gubskiı AGGoriushkoNV Litvinova et al ldquoAntioxidantproperties and membranotropic effect of certain derivatives of14-dihydropyridinerdquo Ukrainskiı Biokhimicheskiı Zhurnal vol71 no 4 pp 35ndash39 1999 (Russian)
[156] F Engineer and R Sridhar ldquoInhibition of rat heart andliver microsomal lipid peroxidation by nifedipinerdquo BiochemicalPharmacology vol 38 no 8 pp 1279ndash1285 1989
[157] T Goncalves A P Carvalho and C R Oliveira ldquoAntioxidanteffect of calcium antagonists on microsomai membranes iso-lated from different brain areasrdquo European Journal of Pharma-cology vol 204 no 3 pp 315ndash322 1991
[158] M E Letelier P Izquierdo L Godoy A M Lepe and MFaundez ldquoLiver microsomal biotransformation of nitro-aryldrugs mechanism for potential oxidative stress inductionrdquoJournal of Applied Toxicology vol 24 no 6 pp 519ndash525 2004
[159] M E Letelier P Entrala C Lopez-Alarcon et al ldquoNitroaryl-14-dihydropyridines as antioxidants against rat liver microsomesoxidation induced by ironascorbate Nitrofurantoin and naph-thalenerdquo Toxicology in Vitro vol 21 no 8 pp 1610ndash1618 2007
[160] F P Guengerich W R Brian M Iwasaki M-A Sari CBaarnhielm and P Berntsson ldquoOxidation of dihydropyridinecalcium channel blockers and analogues by human liver cyto-chrome P-450 IIIA4rdquo Journal of Medicinal Chemistry vol 34no 6 pp 1838ndash1844 1991
[161] S H Park S-W RhaW-Y Shin et al ldquoAS-160 Calcium channelblockers of dihydropyridine class reduce the antiplatelet effectof Clopidogrel what is clinical impactrdquo The American Journalof Cardiology vol 107 no 8 supplement p 47A 2011
[162] C Asma and D M Reda ldquoEvaluation of dihydropyridinecalcium antagonist effects on the stress bioindicator orga-nism Saccharomyces cerevisiaerdquo Annals of Biological Researchvol 4 no 10 pp 40ndash46 2013 httpscholarsresearchlibrarycomABR-vol4-iss10ABR-2013-4-10-40-46pdf
[163] G Gaviraghi A M Pastorino E Ratti and D G TristldquoCalcium channel blockers with antioxidant activityrdquo in Free
Radicals Lipoprotein Oxidation andAtherosclerosis G BellomoG Finardi E Maggi and E Rice-Evans Eds pp 431ndash456Richelieu Press London UK 1995
[164] G Gaviraghi AM Pastorino E Ratti and D G Trist ldquoAntiox-idant dihydropyridines a new and comprehensive therapy forfree radical-induced cardiovascular diseasesrdquo in Free Radicalsin Biology and Environment F Minisci Ed vol 27 of NATOASI Series pp 193ndash221 Springer Dordrecht The Netherlands1997
[165] P D Henry ldquoAntiperoxidative actions of calcium antagonistsand atherogenesisrdquo Journal of Cardiovascular Pharmacologyvol 18 supplement 1 pp S6ndashS10 1991
[166] F Kouoh B Gressier T Dine et al ldquoAntioxidant effects andanti-elastase activity of the calcium antagonist nicardipine onactivated human and rabbit neutrophilsmdasha potential antiath-erosclerotic property of calcium antagonistsrdquo CardiovascularDrugs andTherapy vol 16 no 6 pp 515ndash520 2002
[167] S Parthasarathy D Litvinov K Selvarajan and M GarelnabildquoLipid peroxidation and decompositionmdashconflicting roles inplaque vulnerability and stabilityrdquo Biochimica et BiophysicaActa vol 1781 no 5 pp 221ndash231 2008
[168] D-Q Liu Z-Q Pang D-H Zhao and B-H Sheng ldquoEffects offuryl-dihydropyridines I on lipid peroxides of ischemic myo-cardium and ATPases activity of erythrocyte membranes inratsrdquo Acta Pharmacologica Sinica vol 12 no 3 pp 253ndash2561991
[169] V Lukic-Panin T Kamiya H Zhang et al ldquoPrevention of neu-ronal damage by calcium channel blockers with antioxidativeeffects after transient focal ischemia in ratsrdquo Brain Research vol1176 no 1 pp 143ndash150 2007
[170] Y Allanore D Borderie H Lemarechal O G Ekindjian andA Kahan ldquoAcute and sustained effects of dihydropyridine-typecalcium channel antagonists on oxidative stress in systemicsclerosisrdquo American Journal of Medicine vol 116 no 9 pp 595ndash600 2004
[171] I Casetta V Govoni and E Granieri ldquoOxidative stress antioxi-dants and neurodegenerative diseasesrdquo Current PharmaceuticalDesign vol 11 no 16 pp 2033ndash2052 2005
[172] M J T J Arts Assessing antioxidant activity [PhD the-sis] Maastricht University Maastricht The Netherlands 2007httparnounimaasnlshowcgifid=8676
[173] G Dıaz-Araya L Godoy L Naranjo A Squella M E Letelierand L J Nunez-Vergara ldquoAntioxidant effects of 14-dihydro-pyridine and nitroso aryl derivatives on the Fe+3ascorbate-stimulated lipid peroxidation in rat brain slicesrdquo General Phar-macology The Vascular System vol 31 no 3 pp 385ndash391 1998
[174] Y Fukuhara K Tsuchiya Y Horinouchi et al ldquoProtectiveeffect of photodegradation product of nifedipine against tumornecrosis factor 120572-induced oxidative stress in human glomerularendothelial cellsrdquo Journal of Medical Investigation vol 58 no1-2 pp 118ndash126 2011
[175] W Stengel M Jainz and K Andreas ldquoDifferent potencies ofdihydropyridine derivatives in blocking T-type but not L-typeCa2+ channels in neuroblastoma-glioma hybrid cellsrdquo EuropeanJournal of Pharmacology vol 342 no 2-3 pp 339ndash345 1998
[176] O M Panasenko D J Tirzite G D Tirzitis and G J DubursldquoEffect of some 14-dihydropyridine derivatives on structuralorganization of erythrocyte membranesrdquo Biologicheskie Mem-brany (Biochemistry (Moscow) Series A Membrane and CellBiology) vol 1 pp 919ndash925 1984 (Russian)
[177] L G Herbette Y M H Vant Erve and D G Rhodes ldquoInter-action of 14 dihydropyridine calcium channel antagonists with
Oxidative Medicine and Cellular Longevity 33
biological membranes lipid bilayer partitioning could occurbefore drug binding to receptorsrdquo Journal of Molecular andCellular Cardiology vol 21 no 2 pp 187ndash201 1989
[178] L G Herbette P E Mason G Gaviraghi T N Tulenko andR P Mason ldquoThe molecular basis for lacidipinersquos unique phar-macokinetics optimal hydrophobicity results in membraneinteractions that may facilitate the treatment of atherosclerosisrdquoJournal of Cardiovascular Pharmacology vol 23 supplement 5pp S16ndashS25 1994
[179] G V Belevitch G Y Dubur G E Dobretsov N K Kurek andM M Spirin ldquoCalcium antagonists riodipine nifedipine andverapamil binding to model and biological membranes fluore-scence analysisrdquo Biologicheskie Membrany (Biochemistry(Moscow) Series A Membrane and Cell Biology) vol 5 pp768ndash776 1988 (Russian)
[180] R P Mason G E Gonye D W Chester and L G HerbetteldquoPartitioning and location of Bay K 8644 14-dihydropyridinecalcium channel agonist in model and biological membranesrdquoBiophysical Journal vol 55 no 4 pp 769ndash778 1989
[181] M Cindric A Cipak J Serly et al ldquoReversal of multidrugresistance inmurine lymphoma cells by amphiphilic dihydropy-ridine antioxidant derivativerdquo Anticancer Research vol 30 no10 pp 4063ndash4070 2010
[182] F Shekari H Sadeghpour K Javidnia et al ldquoCytotoxic andmultidrug resistance reversal activities of novel 14-dihydro-pyridines against human cancer cellsrdquo European Journal ofPharmacology vol 746 no 1 pp 233ndash244 2015
[183] X-F Zhou Q Shao R A Coburn and M E Morris ldquoQuanti-tative structure-activity relationship and quantitative structure-pharmacokinetics relationship of 14-dihydropyridines andpyridines as multidrug resistance modulatorsrdquo PharmaceuticalResearch vol 22 no 12 pp 1989ndash1996 2005
[184] R Berkels T Breitenbach H Bartels et al ldquoDifferent antioxida-tive potencies of dihydropyridine calcium channel modulatorsin various modelsrdquo Vascular Pharmacology vol 42 no 4 pp145ndash152 2005
[185] S Borovic G Tirzitis D Tirzite et al ldquoBioactive 14-dihydro-isonicotinic acid derivatives prevent oxidative damage of livercellsrdquo European Journal of Pharmacology vol 537 no 1ndash3 pp12ndash19 2006
[186] D Ya Rubene G D Tirzitis and G Ya Duburs ldquoInteractionof some 14-dihydropyridine derivatives with Fentonrsquos reagentrdquoLatvijas PSRZinatnuAkademijas Vestis Kimijas Serija Proceed-ings of the Latvian SSR Academy of Sciences Chemistry Seriespp 212ndash216 1982 (Russian)
[187] K Ondrias V Misık D Gergel and A Stasko ldquoLipid per-oxidation of phosphatidylcholine liposomes depressed by thecalcium channel blockers nifedipine and verapamil and bythe antiarrhythmic-antihypoxic drug stobadinerdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1003 no 3pp 238ndash245 1989
[188] I T Mak and W B Weglicki ldquoComparative antioxidant acti-vities of propranolol nifedipine verapamil and diltiazemagainst sarcolemmal membrane lipid peroxidationrdquoCirculationResearch vol 66 no 5 pp 1449ndash1452 1990
[189] I T Mak P Boehme and W B Weglicki ldquoProtective effects ofcalcium channel blockers against free radical-impaired endo-thelial cell proliferationrdquo Biochemical Pharmacology vol 50 no9 pp 1531ndash1534 1995
[190] S Ray S Mondal and N Dana ldquoEvaluation of protective roleof nifedipine on lipid peroxidation using reduced glutathione as
model markerrdquo Oxidants and Antioxidants in Medical Sciencevol 1 no 2 pp 97ndash100 2012
[191] M Yamato T Shiba T Ide Y Honda K-I Yamada andH Tsutsui ldquoNifedipine treatment reduces brain damage aftertransient focal ischemia possibly through its antioxidativeeffectsrdquoHypertension Research vol 34 no 7 pp 840ndash845 2011
[192] V Chander and K Chopra ldquoNifedipine attenuates changes innitric oxide levels renal oxidative stress and nephrotoxicityinduced by cyclosporinerdquo Renal Failure vol 27 no 4 pp 441ndash450 2005
[193] K M Gaafa M M Badawy and A A Hamza ldquoThe protectiveeffects of ascorbic acid cimetidine and nifedipine on diethyl-dithiocarbamate-induced hepatic toxicity in albino ratsrdquo Drugand Chemical Toxicology vol 34 no 4 pp 405ndash419 2011
[194] H Sugawara K Tobise and S Onodera ldquoAbsence of antiox-idant effects of nifedipine and diltiazem on myocardial mem-brane lipid peroxidation in contrast with those of nisoldipineand propranololrdquo Biochemical Pharmacology vol 47 no 5 pp887ndash892 1994
[195] I E Kirule D Y Rubene E A Bisenieks G D Tirzit and GY Dubur ldquo4-Nitrophenyl-14-dihydropyridinesmdasha new groupof inhibitors of peroxide oxidationrdquo Chemistry of HeterocyclicCompounds vol 18 no 3 p 316 1982
[196] G D Tirzit I E Kirule L K Baumane R A Gavar Y PStradynrsquo andG YDubur ldquoMechanism of the antioxidant actionof 26-dimethyl-35-dimethoxy-carbonyl-4-(2-nitrophenyl)14-dihydropyridinerdquoChemistry ofHeterocyclic Compounds vol 20no 8 pp 915ndash918 1984
[197] C Yanez C Lopez-Alarcon C Camargo V Valenzuela J ASquella and L J Nunez-Vergara ldquoStructural effects on thereactivity 14-dihydropyridines with alkylperoxyl radicals andABTS radical cationrdquo Bioorganic and Medicinal Chemistry vol12 no 9 pp 2459ndash2468 2004
[198] VMisik A J Stasko D Gergel and K Ondrias ldquoSpin-trappingand antioxidant properties of illuminated and nonilluminatednifedipine and nimodipine in heart homogenate and modelsystemrdquo Molecular Pharmacology vol 40 no 3 pp 435ndash4391991
[199] K Ondrias V Misık A Stasko D Gergelrsquo and M HromadovaldquoComparison of antioxidant properties of nifedipine and illu-minated nifedipine with nitroso spin traps in low densitylipoproteins and phosphatidylcholine liposomesrdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1211 no 1pp 114ndash119 1994
[200] A Stasko V Brezova S Biskupic K Ondrias and V MisıkldquoReactive radical intermediates formed from illuminated nife-dipinerdquoFree Radical Biology andMedicine vol 17 no 6 pp 545ndash556 1994
[201] K Ishizawa Y Izawa-Ishizawa N Yamano et al ldquoNitrosoni-fedipine ameliorates the progression of type 2 diabetic nephro-pathy by exerting antioxidative effectsrdquo PLoS ONE vol 9 no 1Article ID e86335 2014
[202] H Fujii and L J Berliner ldquoIn vivo EPR evidence for free radicaladducts of nifedipinerdquoMagnetic Resonance in Medicine vol 42no 4 pp 691ndash694 1999
[203] S Bollo S Finger J C Sturm L J Nunez-Vergara and JA Squella ldquoCyclic voltammetry and scanning electrochemicalmicroscopy studies of the heterogeneous electron transferreaction of some nitrosoaromatic compoundsrdquo ElectrochimicaActa vol 52 no 15 pp 4892ndash4898 2007
34 Oxidative Medicine and Cellular Longevity
[204] F Ursini ldquoTissue protection by lacidipine insight from redoxbehaviorrdquo Journal of Cardiovascular Pharmacology vol 30supplement 2 pp S28ndashS30 1997
[205] P G Cristofori F A Crivellente I Faustinelli et al ldquoInvolve-ment of the nitric oxide system in the anti-atheroscleroticpotential of lacidipine in the apoE-deficient mouse a mor-phological functional and electrochemical studyrdquo ToxicologicPathology vol 32 no 4 pp 493ndash499 2004
[206] X-P Zhang E L Kit S Mital S Chahwala and T HHintze ldquoParadoxical release of nitric oxide by an L-type calciumchannel antagonist the R+ enantiomer of amlodipinerdquo Journalof Cardiovascular Pharmacology vol 39 no 2 pp 208ndash2142002
[207] F Franzoni G Santoro F Regoli et al ldquoAn in vitro study of theperoxyl and hydroxyl radical scavenging capacity of the calciumantagonist amlodipinerdquo Biomedicine and Pharmacotherapy vol58 no 8 pp 423ndash426 2004
[208] S V Gatsura ldquoOxygen-dependent mechanisms underlying theantiischemic effect of verapamil and amlodipinerdquo Bulletin ofExperimental Biology and Medicine vol 137 no 1 pp 40ndash422004
[209] Y Hirooka Y Kimura M Nozoe Y Sagara K Ito and KSunagawa ldquoAmlodipine-induced reduction of oxidative stressin the brain is associated with sympatho-inhibitory effects instroke-prone spontaneously hypertensive ratsrdquo HypertensionResearch vol 29 no 1 pp 49ndash56 2006
[210] B Tomlinson and I F F Benzie ldquoAntioxidant effect of lercani-dipine (note)rdquo Hypertension vol 42 no 4 pp e10ndashe11 2003
[211] A A Faraqui ldquoNeurochemical aspects of 4-hydroxynonenalrdquoin Lipid Mediators and Their Metabolism in the Brain A AFaraqui Ed chapter 6 pp 159ndash191 Springer New York NYUSA 2011
[212] V S NascimentoM S DrsquoAlva A AOliveira et al ldquoAntioxidanteffect of nimodipine in young rats after pilocarpine-inducedseizuresrdquo Pharmacology Biochemistry and Behavior vol 82 no1 pp 11ndash16 2005
[213] O Ismailoglu P Atilla S Palaoglu et al ldquoThe therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjuryrdquo Turkish Neurosurgery vol 22 no 6 pp 740ndash746 2012
[214] M Matsubara and K Hasegawa ldquoBenidipine a dihydropy-ridine-calcium channel blocker prevents lysophosphatidyl-choline-induced injury and reactive oxygen species productionin human aortic endothelial cellsrdquo Atherosclerosis vol 178 no1 pp 57ndash66 2005
[215] M Matsubara K Yao and K Hasegawa ldquoBenidipine adihydropyridine-calcium channel blocker inhibits lysophos-phatidylcholine-induced endothelial injury via stimulation ofnitric oxide releaserdquo Pharmacological Research vol 53 no 1 pp35ndash43 2006
[216] MMatsubara and K Hasegawa ldquoEffects of benidipine a dihyd-ropyridine-Ca2+ channel blocker on expression of cytokine-induced adhesion molecules and chemoattractants in humanaortic endothelial cellsrdquo European Journal of Pharmacology vol498 no 1ndash3 pp 303ndash314 2004
[217] M Matsubara O Akizuki J-I Ikeda K Saeki K Yao and KSasaki ldquoBenidipine an anti-hypertensive drug inhibits reactiveoxygen species production in polymorphonuclear leukocytesand oxidative stress in salt-loaded stroke-prone spontaneouslyhypertensive ratsrdquo European Journal of Pharmacology vol 580no 1-2 pp 201ndash213 2008
[218] A C Rosenkranz H Lob T Breitenbach R Berkels and RRoesen ldquoEndothelial antioxidant actions of dihydropyridines
and angiotensin converting enzyme inhibitorsrdquo European Jour-nal of Pharmacology vol 529 no 1ndash3 pp 55ndash62 2006
[219] V Kain S Kumar and S L Sitasawad ldquoAzelnidipine preventscardiac dysfunction in streptozotocin-diabetic rats by reducingintracellular calcium accumulation oxidative stress and apop-tosisrdquo Cardiovascular Diabetology vol 10 article 97 2011
[220] K Nakamura S Yamagishi and H Inoue ldquoUnique atheropro-tective property of azelnidipine a dihydropyridine-based cal-cium antagonistrdquoMedical Hypotheses vol 65 no 1 pp 155ndash1572005
[221] TMatsui S Yamagishi K Nakamura S Kikuchi andH InoueldquoAzelnidipine a dihydropyridine-based calcium antagonistinhibits angiotensin II-induced oxidative stress generation anddownregulation of pigment epithelium-derived factor mRNAlevels in microvascular endothelial cellsrdquo Drugs under Experi-mental and Clinical Research vol 31 no 5-6 pp 215ndash219 2005
[222] C Ohmura H Watada T Shimizu et al ldquoCalcium channelblocker azelnidipine reduces lipid hydroperoxides in patientswith type 2 diabetes independent of blood pressurerdquo EndocrineJournal vol 54 no 5 pp 805ndash811 2007
[223] H Daikuhara F Kikuchi and T Ishida ldquoThe combination ofOLmesartan and a CAlcium channel blocker (azelnidipine) orcandesartan and a calcium channel blocker (amlodipine) intype 2 diabetic hypertensive patients theOLCA studyrdquoDiabetesand Vascular Disease Research vol 9 no 4 pp 280ndash286 2012
[224] MAbe NMaruyama KOkada SMatsumoto KMatsumotoand M Soma ldquoAdditive antioxidative effects of azelnidipine onangiotensin receptor blocker olmesartan treatment for type 2diabetic patients with albuminuriardquoHypertension Research vol34 no 8 pp 935ndash941 2011
[225] K Mizushige ldquoAntioxidative activities of thiazolidinedionesand dihydropyridine-type calcium antagonistsrdquo IRYOmdashJapa-nese Journal of National Medical Services vol 59 no 11 pp 581ndash592 2005
[226] S Manabe T Okura T Fukuoka and J Higaki ldquoAntioxidativeeffects of azelnidipine on mesangial cell proliferation inducedby highly concentrated insulinrdquo European Journal of Pharma-cology vol 567 no 3 pp 252ndash257 2007
[227] Y Koyama Y Takeishi H Takahashi et al ldquoAzelnidipine inhi-bits H
2O2-induced cell death in neonatal rat cardiomyocytesrdquo
CardiovascularDrugs andTherapy vol 21 no 1 pp 69ndash72 2007[228] K Shinomiya K Mizushige M Fukunaga et al ldquoAntioxidant
effect of a new calcium antagonist azelnipidine in culturedhuman arterial endothelial cellsrdquo Journal of International Med-ical Research vol 32 no 2 pp 170ndash175 2004
[229] T Ohyama K Sato K Kishimoto et al ldquoAzelnidipine is acalcium blocker that attenuates liver fibrosis and may increaseantioxidant defencerdquo British Journal of Pharmacology vol 165no 4 pp 1173ndash1187 2012
[230] L A Calo F Zaghetto E Pagnin P A Davis A Sempliciniand A C Pessina ldquoEffect of manidipine on gene expressionand protein level of oxidative stress-related proteins p22phoxand HO-1 Relevance for antihypertensive and anti-remodelingeffectsrdquo Journal of Cardiovascular Pharmacology vol 43 no 4pp 531ndash538 2004
[231] R Ghyasi G Sepehri M Mohammadi R Badalzadeh and AGhyasi ldquoEffect of mebudipine on oxidative stress and lipid per-oxidation in myocardial ischemic-reperfusion injury in maleratrdquo Journal of Research in Medical Sciences vol 17 no 12 pp1150ndash1155 2012
Oxidative Medicine and Cellular Longevity 35
[232] DCAndersson J Fauconnier T Yamada et al ldquoMitochondrialproduction of reactive oxygen species contributes to the 120573-adrenergic stimulation of mouse cardiomycytesrdquoThe Journal ofPhysiology vol 589 no 7 pp 1791ndash1801 2011
[233] A F Ceylan-Isik N Ari M Stefek et al ldquoEffects of a long-term treatment with an antioxidant pyridoindole on vascularresponsiveness in diabetes-induced aging ratsrdquo Current AgingScience vol 4 no 2 pp 150ndash157 2011
[234] S Saponara G Sgaragli and F Fusi ldquoQuercetin antagonismof Bay K 8644 effects on rat tail artery L-type Ca2+ channelsrdquoEuropean Journal of Pharmacology vol 598 no 1ndash3 pp 75ndash802008
[235] D A Sica ldquoInteraction of grapefruit juice and calcium channelblockersrdquo American Journal of Hypertension vol 19 no 7 pp768ndash773 2006
[236] P Mulder G Litwinienko S Lin P D MacLean L R CBarclay and K U Ingold ldquoThe L-type calcium channel block-ers Hantzsch 14-dihydropyridines are not peroxyl radical-trapping chain-breaking antioxidantsrdquo Chemical Research inToxicology vol 19 no 1 pp 79ndash85 2006
[237] L J Nunez-Vergara R Salazar C Camargo et al ldquoOxidation ofC4-hydroxyphenyl 14-dihydropyridines in dimethylsulfoxideand its reactivity towards alkylperoxyl radicals in aqueousmediumrdquo Bioorganic and Medicinal Chemistry vol 15 no 12pp 4318ndash4326 2007
[238] M E Ortiz L J Nunez-Vergara and J A Squella ldquoRelativereactivity of dihydropyridine derivatives to electrogeneratedsuperoxide ion in DMSO solutions a voltammetric approachrdquoPharmaceutical Research vol 20 no 2 pp 292ndash296 2003
[239] M E Ortiz L J Nunez-Vergara C Camargo and J A SquellaldquoOxidation of Hantzsch 14-dihydropyridines of pharmacolog-ical significance by electrogenerated superoxiderdquo Pharmaceuti-cal Research vol 21 no 3 pp 428ndash435 2004
[240] R S Raghuvanshi and K N Singh ldquoSuperoxide induced oxida-tive aromatization of Hantzsch 14-dihydropyridinesrdquo IndianJournal of Chemistry Section B Organic and Medicinal Chem-istry vol 47 no 11 pp 1735ndash1738 2008
[241] I Kruk A Kladna K Lichszteld et al ldquoAntioxidant activityof 4-flavonil-14-dihydropyridine derivativesrdquo Biopolymers vol62 no 3 pp 163ndash167 2001
[242] G D Tirzit I M Byteva K I Salokhiddinov G P Gurinovichand G Y Dubur ldquo14-Dihydropyridine derivatives as deactiva-tors of singlet oxygenrdquo Chemistry of Heterocyclic Compoundsvol 17 no 7 pp 682ndash684 1981
[243] G D Tirzit E Y Kazush and G Y Dubur ldquoInfluence of14-dihydropyridine derivatives on the generation of hydroxylradicalsrdquo Chemistry of Heterocyclic Compounds vol 28 no 4pp 435ndash437 1992
[244] N A Pizarro-Urzua and L J Nunez-Vergara ldquoNifedipine andnitrendipine reactivity toward singlet oxygenrdquo Journal of Photo-chemistry and Photobiology A Chemistry vol 175 no 2-3 pp129ndash137 2005
[245] L-F Wang H-Y Zhang L Konga Z-W Chena and J-G ShildquoDFT calculations indicate that 14-dihydropyridine is a promis-ing lead antioxidantrdquo Helvetica Chimica Acta vol 87 no 6 pp1515ndash1521 2004
[246] P Mulder H-G Korth and K U Ingold ldquoWhy quantum-thermochemical calculations must be used with caution toindicate lsquoa promising lead antioxidantrsquordquoHelvetica Chimica Actavol 88 no 2 pp 370ndash374 2005
[247] K Yao Y Ina K Nagashima K Ohmori and T Ohno ldquoAntiox-idant effects of calcium antagonists in rat brain homogenatesrdquo
Biological and Pharmaceutical Bulletin vol 23 no 6 pp 766ndash769 2000
[248] T Matsui S-I Yamagishi K Nakamura and H Inoue ldquoBayw 9798 a dihydropyridine structurally related to nifedipinewith no calcium channel-blocking properties inhibits tumournecrosis factor-120572-induced vascular cell adhesion molecule-1expression in endothelial cells by suppressing reactive oxygenspecies generationrdquo Journal of International Medical Researchvol 35 no 6 pp 886ndash891 2007
[249] K AMitrega B VargheseM Porc and T F Krzeminski ldquoAnti-arrhythmic and hemodynamic effects of oxy nifedipine oxynimodipine oxy nitrendipine and oxy nisoldipinerdquo Pharmaco-logical Research vol 66 no 4 pp 300ndash308 2012
[250] V Herbert ldquoSymposium prooxidant effects of antioxidantvitamins Introductionrdquo The Journal of Nutrition vol 126 no4 supplement pp 1197Sndash1200S 1996 httpjnnutritionorgcontent1264 Suppl1197Sfullpdf
[251] B Halliwell ldquoAre polyphenols antioxidants or pro-oxidantsWhat do we learn from cell culture and in vivo studiesrdquoArchives of Biochemistry and Biophysics vol 476 no 2 pp 107ndash112 2008
[252] C Winterbourn Pro-Oxidants or Antioxidants ChristchurchSchool of Medicine Depatment of Pathology Free RadicalSchool SFRBMUniversity of Otago San Francisco Calif USA2009 httpwwwsfrbmorgfrsWinterbournpdf
[253] A Morakinyo B Iranloye and O Adegoke ldquoCalcium antag-onists modulate oxidative stress and acrosomal reaction in ratspermatozoardquo Archives of Medical Science vol 7 no 4 pp 613ndash618 2011
[254] The Alpha-Tocopherol Beta Carotene Cancer Prevention StudyGroup ldquoThe effect of vitamin E and beta carotene on theincidence of lung cancer and other cancers in male smokersrdquoTheNew England Journal of Medicine vol 330 no 15 pp 1029ndash1035 1994
[255] B Poljsak ldquoStrategies for reducing or preventing the generationof oxidative stressrdquo Oxidative Medicine and Cellular Longevityvol 2011 Article ID 194586 15 pages 2011
[256] B Poljsak and I Milisav ldquoThe neglected significance of lsquoanti-oxidative stressrsquordquoOxidativeMedicine and Cellular Longevity vol2012 Article ID 480895 12 pages 2012
[257] T Godfraind and S Salomone ldquoAmbiguities in dietary antiox-idant supplementation compared to calcium channel blockerstherapyrdquo Frontiers in Pharmacology vol 6 article 10 2015
[258] H Wagner H Norr and H Winterhoff ldquoDrugs with adap-togenic effects for strengthening the powers of resistancerdquoZeitschrift fur Phytotherapie vol 13 no 2 pp 42ndash54 1992
Oxidative Medicine and Cellular Longevity 7
N
O O
N
O O
R R
N
O Ominuseminus minuseminusminuseminus
minusH+
minusH+minusHminus
minusH∙
R998400(H)R998400H R998400(H)
oplus
R=H
Scheme 1 Reactions of 14-dihydropyridines leading to the formation of pyridine derivatives
In the field of ARA pioneering work was made by Schel-lenberg and Westheimer [84] in 1965 In 1979 Schellenberg[85] revealed the free radical oxidation of a dihydropyridinefollowing Huyser et al [86] who reported hydroxyl radicalquenching by DHPs especially Hantzsch ester studying freeradical oxidation of DHPs in vitro in the Fenton system
AOA and ARA of various 14-DHPs were further studiedby several different methods in both in vitro and ex vivoinvivo systems [3 31 44ndash53] CA nisoldipine nimodipinenitrendipine nifedipine and nicardipine have AOA thatcorrelates with their lipophilicity (modified Buege and Austrsquosmethod of TBA determination applied in model of rat braincortex ischemiareperfusion) [87]
N-Aryl-DHPs designed as sirtuin activators were furtherreported as suitable agents for neuroprotection due to theirradical avoidance properties (Hardeland [88])
14-DHPs inhibit free radicals and consequentially thecascade of events related to lipid peroxidation They mayinfluence several stages (initiation andor propagation) of thelipid peroxidation cascade which consist of sim10 reactions[89] (detailed discussion in Section 331 (2)-(b) Scheme 2)
However considering the great number of AO com-pounds (including DHPs) and the diversity in their actionmechanisms [90] in vivo studies are not always convincingand conclusive Therefore concise in vitro models are neces-sary to screen each compound with antioxidative propertiesAntioxidants are designed to react readily with oxidizingspecies and are often extensively oxidized already duringincubations at atmospheric oxygen tension (oxidation ofsome water-soluble DHPs in water (buffer) solutions is veryfast especially in the presence of light) Even during arelatively short incubation period the concentration can dropdrastically and the real potency of the compound could beunderestimated [90]
331 Common AOA and ARA Features of Some DHPs
(1) In Vitro (in Solutions Emulsions and Liposomes) Basicmolecular principles related to antioxidative and antiradi-cal activity of various antioxidants including DHPs werepublished recently [91] These data show that DHPs reactwith various types of free radical species stable free radicals(DPPH ao) and alkyl radicals and with oxygen and nitrogenfree radicals Some derivatives of DHPs may quench a singletoxygen and may react with peroxynitrite anion [92ndash95]
Reactivity of DHPs toward alkyl radicals was studiedelectrochemically [96]
The activity against DPPH radical was found for the5-acetyl-2-alkylthio-4-aryl-6-methyl-14-dihydropyridine-3-carboxylic acid nitriles [97] structural analogues of the5-acetyl(carbamoyl)-6-methylsulfanyl-14-DHP-carbonitrile(studied as mitochondriotropic compounds see further inthe text Section 331 (2)-(b))The highest antiradical activityoccurred for a compound which contains two hydroxylgroups in the 4-phenyl substituent
DHPs were proved to decrease oxygen uptake (2-3-fold) in the heme (methemoglobin hematin hemin andcytochrome C) catalysis by oxidation of emulsions of estersof unsaturated fatty acids and liposomes of phospholipidphosphatidylcholine (Zilber et al [44] and Dubur et al [45])
Reactivity of nitrosoaryl and nitroaryl derivatives of 14-DHPs toward alkyl alkylperoxyl radicals and ABTS radicalcation was found in various LP modeling systems suitablefor determination of DHPs AOA and ARE features [98ndash104] Diludine and foridone and its analogues were shown toinhibit lipid peroxidation through inhibitory effect on lipoxy-genase in emulsions and in reversed micelles (Tsetlin et al[105] and Panek et al [106]) In addition to inhibition of ther-mally initiated oxidation of methyloleate in the solution [107](where AOA of 4-unsubstituted 35-dicarbonylderivativesof 26-dimethyl-14-DHPs is not linearly dependent onthe inhibitor concentration) DHPs derivatives containinghydroxy alkoxy or dimethylaminophenyl substituents inposition 4 were shown to prevent loss of 120573-carotene in thedisperse system of 120573-carotene and methyllinoleate (Plotnieceet al [108])
The AOA of DHPs has been detected using differentmethods in various systems where lipid free radical gen-eration (nonenzymatic Fe2+-dependent andor enzymaticNADPH-dependent) took the place [109ndash112] This activitywas further confirmed in vivo through prevention of damagecaused by renal ischemia and reperfusion as shown fordiludine [113]
Some redox properties of calcium antagonist dihydropy-ridines were revealed through electroanalytical studies [114]Competitive kinetic procedure was used for exploring theAO capacity of five (four 14-DHPs lacidipine felodipinenifedipine and amlodipine and one 12-DHP compoundGR44966) CA and one calcium ion agonist (Bay K 8644) Allbut one (amlodipine) antagonist displayed an unambiguousAO capacity (crocin test) The calcium agonist DHP revealedno reaction with peroxyl radicals Lacidipine was the mosteffective A calcium agonist Bay K 8644 is quite resistant tooxidation and does not bind H+ This could be important
8 Oxidative Medicine and Cellular Longevity
fact in the interaction with the target proteins (it should bementioned that there are no studies on LP with other Ca2+agonists)
The decreased oxidation potential correlates with AOcapacity and increased basic characterThese findings suggestthe relevance of the electron density on the DHP ring
For all the DHP compounds investigated the overalloxidation process proceeds through two consecutive one-electron releases a primary one-electron step accompaniedby a fast proton release and the formation of a neutral radical(PyH∙) undergoing a second much easier one-electron step[114]
The final product is the protonated form of the parentpyridine derivative This pattern is relevant for the antioxida-tive activity since the radical intermediate is far less prone tobe reduced than oxidized
In the case of CA DHPs the release of protons compli-cates the overall oxidation process by introducing a ldquopara-siticrdquo side reaction where a coupling between protons and thestarting species takes place
This DHP self-protonation subtracts part of the originalspecies from the electrode process because the parent cationicspecies are no longer electroactive
Conversely the calcium agonist DHP which is less proneto be oxidized turned out to be so weak base to be evenunable to undergo the self-protonation reaction
Thus the combined effect of oxidation potentials andproton binding capacity of DHPs is a key element for theredox transition relevant for their AO activity Yet opposingeffects (antagonistic versus agonistic) on protein targets ascalcium ion channels connected with protein thiol oxidationto disulfide should be also considered [114]
Kourimska et al [115] found AO effect of diludine (HEH)in edible oil Reactivity of 14-DHPs toward SIN-1-derivedperoxynitrite was shown by Lopez-Alarcon et al [116] Oleket al [117] discovered antioxidative activity of NADH and itsanalogue in vitro
Further see as referred in several subparts below Sections34 35 and 37
(2) Ex Vivo (on Lipid Peroxidation in LDL MitochondriaMicrosomes and Cells) Main chemical structures of DHPsexamined in numerous studies and reviewed in this paper arepresented in Figures 1 and 2
(a) Various DHPs Calcium Antagonists as Inhibitors of LDLPeroxidation Free radicals induce peroxidation of LDLThis process proceeds by a chain mechanism which revealsphosphatidylcholine hydroperoxides and cholesteryl esterhydroperoxides as themajor primary products [118] Calciumantagonist DHPs could act as antioxidants on LDL at leastin three ways (1) as inhibitors of isolated LDL peroxi-dation caused by various inducers (Cu2+ ions UV lightand xanthinexanthine oxidase system) (2) if preincubatedwith cells preventing against intracellular LDL oxidation (3)preventing against the harmful effect of oxidized LDL on cellsand decreasing cytotoxicity [119ndash131]
Combined application of ascorbic acid and CA DHPs(amlodipine and felodipine) has an additive (cytoprotective
and LDL antioxidant activity) effect [120] It includes acombination of peroxide-degrading and peroxyl radical scav-enging reactions thus demonstrating the importance of LPduring LDL oxidation and cytotoxicity induced by oxidizedLDL Cytoprotection is associated with inhibition of oxidant-induced increases in intracellular free calcium
Similar to the othermodel systems the recorded values ofthe tested DHPs related to AO activity on LDL LP and relatedevents [119ndash131] depend on the prooxidant model system andmethods used for activity measuring (see Tables 1ndash5)
Commercial Ca2+ antagonists (including 14-DHP deri-vatives) as well as some other 14-DHPs with less CA activitywere shown to decrease the rate of oxidation (detected asTBARS) of low-density lipoprotein (LDL) induced by Cu2+ions (CuSO
4) in two different cell lines U937 human mono-
cyte-like and J774A1 murine monocyte-macrophage cellline (Rojstaczer and Triggle [119]) The strongest effect wasrecorded for vitamin E followed by felodipine 2-Cl analogueof nifedipine nifedipine amlodipine nitrendipine vera-pamil and diltiazem
Rojstaczer and Triggle [119] found that CA from differentchemical groups had a concentration-dependent effect asantioxidants against LDL oxidation (see Table 1) Howeverthe order of potency (activity rank order ARO) of the drug(s)again depends on the oxidation system and the antioxidantassay Both CA and antioxidative effects relate to the 2- (or o-orto-) substituent of the 4-phenyl ring in the same potencyorder 119900 gt 119898 ≫ 119901 [119] On the other hand the require-ment for the 14-DHP ring is essential for both AOA andCa2+channel antagonism A charged substituent at the position C-2 of the 14-DHP ring influences the AO activity (analogousto [46ndash53]) However some other factors should not beneglected for example although amlodipine has a positivelycharged amine at this position this modificationmakes it lesslipophilic and indirectly less potent antioxidant
Similar results were obtained when testing antioxidanteffect of CA on LDL peroxidation in bovine aortic endothelialcells (BAECs) (Cominacini et al [123] see Tables 2 and 3) aswell as in HUVECs (Lupo et al [129]) (see Table 4)
Cominacini et al [123] observed antioxidant effect ofCCBs and 120572-tocopherol in BAECs The order of potency(see Tables 2 and 3) [123] was however different than inU937 human monocyte-like and J774A1 murine monocyte-macrophage cells (see Rojstaczer and Triggle [119] Table 1)The tested DHPs were lacidipine amlodipine lercanidipinenimodipine and nifedipine (in two different intracellularconcentrations 2 and 4 fmol) ROS production was signif-icantly lowered only by lacidipine (which is the compoundwith the highest lipophilicity) and lercanidipine the effectof lacidipine was much more evident than lercanidipineSurprisingly amlodipine nimodipine and nifedipine had noeffect on ROS formation suggesting that the positive effectson the earliest events of atherosclerosis are a peculiarity oflacidipine molecule through its antioxidant activity
The strong AO action of lacidipine may be related tothe lipophilic cinnamic acid side chain which favors a drugpartitioning in the membrane due to favorable physicochem-ical (hydrophobic) interactions of drug hydrophobic residues
Oxidative Medicine and Cellular Longevity 9
Table 1 Relative structure-function relationships of calcium antagonists (DHPs verapamil and diltiazem) and vitamin E Effect on oxidativemodification of isolated ex vivo human low-density lipoprotein using two various oxidation systems (copper (II) ions induced and monocyteinduced) Compiled according to data presented by Rojstaczer and Triggle [119]
Compound
Systems of LDL oxidation
Copper (II) ions induced system (comparison of three methods) Monocyte induced celloxidation system
Methods
Reduction of TBARS level of LDL(relative efficacy)
Degradation of oxidized[125I] LDL by J774
macrophages
Relative electrophoreticmobility of LDL on
agarose gel
TBARS content of LDL(in )
Relative efficacy (activity rank order (ARO) ARO = I for the most effective) effective inhibitor concentration [IC] in120583M
with polyunsaturated groups of membrane phospholipidsHowever DHPs can also reduce the oxLDL-induced ROSconcentration by affecting some intracellular ROS producerssuch as NADPH oxidases xanthine oxidase and cyclooxyge-nase enzymes The activity of these enzymes contributes tointracellular ROS elevation [125]
Preincubation of HUVECs with lacidipine inhibited anincrease of intracellular ROS caused by oxidized LDL [124]
Lupo et al [129] have studied the dose-dependent (1 510 and 50 120583M) AOA of various CA (verapamil diltiazemand DHPs nifedipine amlodipine isradipine or lacidipine)
Table 3Modulation of ROS formation in BAECs by CA (DHPs andverapamil) and vitamin E Compiled according to data presented byCominacini et al [123]
Compound
Method of flow cytometry (reduced2101584071015840-dichlorofluorescein diacetate(DCFH-DA) oxidation by ROS)
Activity rank order(ARO = I for the highest activity ARO = III for
the mindest activity)(Effective [IC] 1 5 10 50 120583M)
Lacidipine + + + (ARO = I)Lercanidipine + + (ARO = II)Amlodipine No effectNifedipine No effectNimodipine No effectVerapamil + (ARO = III)120572-Tocopherol + + + (ARO = I)
against normolipidemic human blood LDL oxidation com-pared with 120572-tocopherol by measuring the content of TBARSand the diene formation (see Table 4)
10 Oxidative Medicine and Cellular Longevity
Table 4 Normolipidemic human blood LDL (025mgmL) in vitro oxidation in the presence of 5 120583M CuSO4and CA of 3 types (DHPs
verapamil and diltiazem) and vitamin E Compiled according to Lupo et al [129]
Compound
MethodsTBARS method (fluorimetry at 515 nm533 nm 4 hours
preincubation of LDL with compounds and copper (II)ions 320 TBARS increase in control during 4 h
period)
Inhibition of conjugated diene formation (at 234 nm)expressed as prolongation of induction period (in
of control) 119905contr = 368min
Effective [IC] (in 120583M)1 120583M 10120583M 50 120583M
Activity rank order (ARO= I for the highest activity
ARO = VII for themindest activity)
Effective [IC] (in 120583M)1 120583M 5 120583M 10120583M 50 120583M
Activity rank order (ARO= I for the highest activity
ARO = VII for themindest activity)
Nifedipine 10120583M50 120583M ARO = III
5 120583M10120583M 15050 120583M 213
ARO = III
Amlodipine 50 120583M ARO = IV5 120583M
10120583M 12250120583M 138
ARO = IVndashVI
Isradipine 50 120583M ARO = VI 10120583M 15050 120583M 183 ARO = IVndashVI
Lacidipine1 120583M10120583M50 120583M
ARO = II5 120583M
10120583M 19250 120583M 283
ARO = II
Verapamil 50 120583M ARO = V 10120583M 15050 120583M 178 ARO = IVndashVI
Diltiazem No effect No effect (ARO = VII) No effect No effect (ARO = VII)
Vitamin E1 120583M
10120583M (IC50)
50 120583M (20 of control)ARO = I
5 120583M10 120583M 23050 120583M 370
ARO = I
Table 5 Antiproliferative effect (oxLDL-induced HUVSMCs proliferation) of CA DHPs and simultaneous oxLDL-induced ROS productionscavenging Comparison with N-acetyl-L-cysteine NAC (intracellular ROS scavenger) Compiled according to data presented by Zou et al2012 [130]
DHP compound
MethodsAntiproliferative effect against proproliferative effectinduced by oxLDL (50 120583gmL) (UV detection of
formazan production from tetrazolium salt)
oxLDL-induced ROS production (fluorescent DCF(2101584071015840-dichlorofluorescein) production)
Effective [IC] in120583M and I in
Amlodipine 3 120583M I = 18 3 120583M 10 120583M No effectI = 20
S(minus)-Amlodipine No effect No effect
Lacidipine 10 120583M30 120583M
I = 21I = 27 10120583M Isim23 of control
N-Acetyl-L-cysteineNAC
mdash 5000 120583M(5mM) I = 28
As presented (Table 4 according to [129]) for diltiazem(poor lipid solubility) noAOwas detected whereas the otherCA and 120572-tocopherol have demonstrated AOA at least atconcentrations of 10 and 50120583M 120572-tocopherol gt lacidipinegt nifedipine gt isradipine verapamil and amlodipine Addi-tionally120572-tocopherol and lacidipinewere able to significantlyattenuate in vitro LDL oxidation at 1 and 5120583M Theseresults have confirmed the highest activity for the stronglylipophilic DHP type CA compound lacidipine This might be
a possible antiatherogenic mechanism of CA since oxidativemodification enhances the atherogenic potential of LDL
The lipid peroxidation of LDL promoted either by UVradiation or by copper ions was inhibited (antioxidant effect)by nisoldipine in a dose-dependentmanner (IC
50values were
evaluated at around 10 120583M) nimodipine was less potent (IC50
around 50ndash100 120583M) and nicardipine almost inactive In addi-tion to this indirect protective effect CA DHPs nisoldipineand nimodipine exerted direct protective effect on lymphoid
Oxidative Medicine and Cellular Longevity 11
cells against toxicity of previously oxidized LDL The IC50
values were 6 plusmn 2 and 80 plusmn 20 120583M respectively [122] Theinhibition of the cytotoxic effect of LDL oxidized in thepresence of DHP type Ca2+ channel blockers correlated wellwith protection from oxidation by these compounds Com-plete protection cannot be obtained because the DHPs arecytotoxic themselves The potential relevance to the preven-tion of atherogenesis is envisaged
DHP typeCCBnifedipinewas themost effective inhibitorof oxidation promoted either by UV radiation or by copperions in experiments with cultured lymphoid cells LDL (2mgapoBmL) CCBs from other two CCB classes diltiazem andverapamil were only poorly active or completely ineffective[121] The protective effect of nifedipine occurs at two levelsbesides its direct antioxidant effect by inhibition of LDLoxidation it also exhibits a direct cytoprotective effect againstcytotoxicity of oxidized LDL by yet unknown mechanismsThe protective effect of CCBs was not due to an inhibitionof LDL uptake This effect seems to be independent of theinhibition of LDL oxidation per se since LDL was oxidizedin the absence of the drug before the incubation withcells Moreover this direct protective effect was observedat lower concentrations (IC
50of 1 plusmn 02 120583M) compared to
the antioxidant effect (IC50
of TBARS inhibition is around10 plusmn 2 120583M at UV promoted and 4 plusmn 05 120583M by Cu2+ ionsinitiated) The AO effect of nifedipine is also correlated withthe protection of endogenous tocopherols (IC
50= 50 120583M)
It was suggested that the AO effect of CCBs protected cellsindirectly from the cytotoxic effect of oxidized LDL [121]
A recent study has reported that beneficial vascular effectsof lercanidipine in diabetic rats depend on its antioxidantactivity related to attenuating the increase in oxidativestress and in vascular matrix metalloproteinase-2 (MMP-2) (Martinez et al [126]) Lesnik et al [127] studied theimpact of a combination of this calcium antagonist and a120573-blocker atenolol on cell- and copper-mediated oxidationof LDL and on the accumulation and efflux of cholesterolin human macrophages and murine J774 cells They realizedthat lercanidipine reduced the oxidative modification of LDLrather than diminished cholesterol accumulation in humanfoam cells
Comparing the antioxidative action of CA (DHPs amlo-dipine lacidipine nifedipine and isradipine as well as diltia-zem and semotiadil) in the copper-catalyzed oxidation oflow-density lipoprotein (LDL) with that of glycated (g)gly-coxidated (go) LDL demonstrated that the strongest AOeffects during long-term LDL glycation are seen for isradip-ine lacidipine nifedipine and semotiadil [128] Inhibitoryeffects were in the range 10minus5ndash10minus3MAuthors suggested thatdue to the increased generation of ROS by glucose-modifiedLDL the chain-breaking capacity of CA may be overriddenThe AOA of CA depends on their lipophilicity and theirability to incorporate into the LDL particle that is to reachthe site of peroxidation CA like other AOs significantlyretards advanced glycation end products (AGE) formationwhereas initial glycation reactions such as Amadori productformation are only weakly inhibited The observation thatboth oxidative changes and at least long-termglycation effectsare indeed drastically reduced by CA is corroborated by
fluorescence analysis AGE-ELISA quantitation of lipid per-oxidation and TBARS measurement of long-term ggo LDL
The effects of lipophilic DHP calcium channel blockerson oxidized LDL-induced proliferation and oxidative stressof vascular smooth muscle cells were also studied [130] (seeTable 5)
Lacidipine and amlodipine reduced carotid intima-media thickness by decreasing proliferative effect of oxLDLwhereas (S-)-amlodipine had no antiproliferative effect ROS-MAPKs (mitogen-activated protein kinases) pathway mightbe involved in the mechanism
Both 14-DHP CCBs lacidipine and nifedipine reduceplasma and LDL oxidation and formation of oxidation-specific epitopes Their application may also relate to pro-longed survival of rats independently of blood pressuremod-ifications (in the SPSHR model 1mgkg per day lacidipineand 80mgkg per day nifedipine) These results suggestedthat the protective effect of these two 14-DHP drugs invivo as shown in cerebral ischemia and stroke may in partresult from inhibition of LDL oxidative process althoughthese two drugs possess different lipophilic properties [131]Both lacidipine (03 and 10mgkg) andnifedipine (80mgkg)prolonged lag time of the conjugated diene formation inLDL isolated from arterial wall and 119905max These drugssignificantly reduced electrophoreticmobility of oxLDL fromSPSHR subjected to XXO oxidation system 14-DHP CCBsalso protected apolipoprotein B which is important for thebinding with macrophage LDL receptor lysine residues Thedoses used (gt10minus6molL for SPSHR and normotensive WKYrats) however are 2 to 3 orders of magnitude higher thanthose inhibiting vascular smooth muscle contraction in vitroand in vivo They also exceed values that are commonlyused in clinical practice The daily dose of lacidipine forhypertensive patients is 007mgkg asymp4- to 14-fold lower thanthe 2 doses used in SPSHR The maximum daily dose ofnifedipine given to hypertensive patients is 20mgkg asymp40-fold lower thanwhatwere used [131]These discrepanciesmaybe related to differences in bioavailability of CA between ratsand humans [131]
Accordingly in routine clinical use 14-DHPCCBs donotreach the concentrations required for antioxidant activity invitro [131]
Another data concerning the effect of CA DHPs on OSrelated to LDL is presented under Section 35
(b) Effect of DHPs on Isolated Rat Liver and Heart Mitochon-dria As a major cellular source of oxygen radicals (Cadenas[4 5]) mitochondria are promising targets for pharmaco-logical and toxicological actions of various membrane-activecompounds including several 14-DHP derivatives Zernig etal [132] have discovered CA binding sites associated with aninner mitochondrial membrane anion channel
More than 40-year long research onmitochondrial effectsof the DHPs (on their bioenergetics chemiosmotic proper-ties and ion fluxes) clearly points them out as mitochondri-otropic compounds
The activity of the first 35 synthesized compounds(derivatives of 14-DHP their heteroaromatic analogues
12 Oxidative Medicine and Cellular Longevity
NAD-H+ and butylated hydroxytoluene (BHT BOT)) orig-inally was examined in rat liver mitochondrial LP system inthe presence of Fe2+ ions and using the ultraweak chemilu-minescence method (Dubur et al [89])
Several 14-DHP derivatives Hantzsch ester diludine andits analogues were found to be effective antioxidants in thisexperimental system changing the kinetics of LP lengtheningthe time of the appearance of the maximum of the slowburst of the chemiluminescence (latency latent period) anddiminishing the reaction rate (the tangent of the slope angleduring the time in which the amplitude of the slow burstcharacterizing LP rate increases) and its peak value Theirpresence has influenced the reaction constant 119870
6 in relation
to a very significant reduction of lipid hydroperoxides andorinactivation of free radicals as follows
ROO∙ + ROO∙ 997888rarr P + h]lowast termination (1)
(P = molecular products) or
ROO∙ + ROO∙ +H2O 997888rarr ROH + RO∙ + 1O
2
lowast (2)
In this study diludine was one of themost active compoundsDHPs had activity similar to the standard synthetic AO-BHT(ionol) However when plotted against applied concentrationand time window diludinersquos activity profile differed from thatof BHT
There were also similar studies (using different LP rateexperimental detection system and method Hunter et al[133]) based on exploring a group of 26 26-dimethyl-35-disubstituted- and 26-dimethyl-345-trisubstituted-14-dihydropyridines (14-H
2Py=14-DHPs) and five related pyri-
dines as inhibitors of rat liver Mit swelling (Δ119860520119905) and O
2
uptake by ascorbic acid- (AsA-) dependent lipid peroxidationand as modulators of Mit swelling induced by Na+-linoleateor Na+-pyrophosphate (Velena et al [112])
Some of tested 4-DHPs (4-unsubstituted 35-dialkoxy-carbonyl-26-dimethyl-14-DHPs and 35-diamido-26-dim-ethyl-14-DHPs both 4-unsubstituted or those possessinglipophilic 4-aryl- groups) have shown significant AO andmembrane stabilizing activity These studies further revealedthat 14-DHPs preferably act as AO during the stages ofinitiation and prolongation of LP chain reactions at lowconcentrations The studied 14-DHPs had IC
50(when 119881
0119881
or 1205911205910= 2) 01 120583M to 100 120583M and the minimal activity was
scored for oxidized (heteroaromatized) derivativesAt the concentration of 100120583M 35-di-n-butyloxycarbo-
nyl-26-dimethyl-14-DHP entirely stops mitochondrialswelling in the presence of 08mM Na+-pyrophosphateAt the same concentration the following compoundsalter the mitochondrial swelling rate in the presence ofnatural protonophore Na+-linoleate 35-di-p-hydroxyphen-oxycarbonyl- and 35-di-p-tolyloxycarbonyl-26-dimethyl-14-DHPs 35-diethoxycarbonyl-26-dimethyl-pyridine (oxi-dized form of Hantzsch ester) and more lipophilic 35-diamyloxycarbonyl-26-dimethyl-pyridine The alteration ofswelling may be scored as prolonged promoted acceleratedor inhibited The type of alteration depends on the structureand concentration of 14-DHPs the type of initiators of theswelling process and the medium composition
In accord with previously published Janerorsquos results (lackof AO for Ca2+ antagonists nifedipine and nicardipine evenat 500120583M concentration in LP tests performed on heartmembrane [134]) no antioxidative activity for 4-phenyl sub-stituted derivatives of 35-dialkoxycarbonyl 14-DHP (closeanalogues of Ca2+ antagonists) was found contrary to various4-nitrophenyl 14-DHP derivatives calcium antagonists forwhich the significant antioxidant activity was reported [3146ndash53]
Studies made on phosphatidylcholine liposomes (ourunpublished data) suggest approximately three and twotimes more antioxidative activity for 100 120583M 4-unsubstitutedDHP compound diludine when compared to 4-substitutedDHPs riodipinenifedipine and nicardipine respectively atmethemoglobin-induced LP (oxygraphy)
Inhibition of mitochondrial AsA-dependent LP and sta-bilization ofmitochondriawere shown to be characteristic fora large group of 14-DHP compounds [112] showing to pos-sess the AOA in simplest in vitro systems (Tirzit andDuburs [39] Zilber et al [44] and Dubur et al [45])based on reactions with the stable free radical 11-diphenyl-2-picrylhydrazyl (DPPH) LP of fatty acid ester (linethole andmethyloleate) emulsions and phospholipid (phosphatidyl-choline) liposomes Generally these properties did not coin-cide with Ca2+ antagonism Depending on DHP structure itseems that AOA properties are less specific than Ca2+ antago-nist properties Both properties may be interrelated but notinterdependent
These data show that the presence and the nature ofa substituent in position 4 as well as 35-substituentsare important factors for 14-DHP antioxidant effects invarious systems that is AsA-dependent nonenzymatic aswell as enzymatic NADPH-dependent lipid peroxidationSometimes the efficacy of inhibition of nonenzymatic LPby 14-DHPs is higher than the inhibition of the enzymaticLP However the action may be opposite stimulation of theLP Hantzsch ester (HEH diludine) and its close analoguesexhibited significant AOA and membrane stabilizing prop-erties in both AsA-dependent nonenzymatic peroxidationof mitochondria and NADPH-dependent enzymatic LP ofmicrosomes usually at similar 10 to 100120583M concentrations[112]
The order of AOpotency (IC50
values) in vitro depends ondrug structure as well as on the experimental conditions andspecificity of the biological system Eachmethod for determi-nation of AOA and ARA has advantages and disadvantages(Karadag et al [135])
Accordingly as reported by Gubskiı et al [136] IC50
forthe AsA-dependent LP was 025 120583M and 20 120583M for 14-DHPCa2+ antagonists nitrepine (nitrendipine) and nifedipinerespectively Takei et alrsquos [137 138] studies on mitochondrialswelling induced by LP or arachidonic acid in the rat braindetermined the IC
50values of 127 105 1568 and 384 120583Mfor
efonidipine nicardipine nifedipine and nimodipine respec-tively For LDL in the copper-induced oxidation system theorder of potencywas vitamin Egt felodipinegt 2-chlorophenylanalogue of nifedipine gt nifedipine gt amlodipine nitrendip-ine verapamil and diltiazem (Rojstaczer and Triggle [119])
Oxidative Medicine and Cellular Longevity 13
It was interesting to compare the AOAofDHPswith theirsusceptibility to oxidation that is electron and hydrogendonating properties
It has been estimated that electron donor substituentsin positions 2 and 6 of 14-DHP cycle usually promoteoxidation while electron acceptor substituents promotequench oxidation Stronger electron acceptors in positions 3and 5 also significantly quench oxidation These estimationsare based on studies including chemical enzymatic andelectrochemical oxidation of 14-DHPderivatives (Dubur andUldrikis [70] Duburs et al [71] and Stradin et al [139])
On the other hand diminished AOA of 14-DHP relatesto presence of substituents in position 4 (both electron donorand electron acceptor) (Velena et al [112])
35-Dicarbamoyl substituents possess minimal quench-ing feature and are followed by benzoyl- acetyl- andalkoxycarbonyl- groups Maximal decrease was obtainedwith condensed substituents (ie oxoindeno- or oxocyclo-hexeno- groups) and a CN-group 4-Unsubstituted 35-dicar-bamoyl derivatives can be easily oxidized and consequen-tially inactivated whereas 4-substituted 35-dicarbamoyl-14-DHPs possess an oxidation potential analogous to the 4-unsubstituted 35-COOR derivatives Therefore they haveadequate electron donor properties and are considerablystableThismay be the reason for significantmembrane stabi-lization upon exposure to 4-substituted derivatives Ofimportance their AOA was usually more pronounced incomparison to 4-unsubstituted derivatives
Among them 26-dimethyl-35-difurfuryloxycarbonyl-14-DHP showed the highest antioxidative activity In thegroup of 35-dialkoxycarbonyl derivatives the strongestactivity was attributed to compounds with medium lengthalkyl chains (i-butyl- t-butyl- and i-amyl- substituents) highlevel of lipophilicity minimal electron acceptor propertiesand moderate steric hindrance as contrasted to short or longalkyl chain ester derivatives (35-dimethoxycarbonyl- 35-diethoxycarbonyl derivatives and 35-didodecyloxycarbonylderivative) These data demonstrate the bell-shaped depen-dence of AOA on alkyl chain length [112] and are in accordwith results obtained in liposomes However these datadiffer from those obtained in emulsions where diludine wasthe most active compound Finally oxidized heteroaromaticderivatives showed only minimal activity
In both LP systems studied (AsA-dependent in mito-chondria and NADPH-dependent in microsomes) some of14-DHPs showed activity similar to classical antioxidantbutylated hydroxytoluene (ionol BHT) (Velena et al [112])However there was a significant difference related to con-centration and incubation time It allowed us to postu-late that 14-dihydropyridines (InH) acting as antioxidants-reductants and scavengers of reactive oxygen species and lipidfree radicals preferably influence initiation and propagation(prolongation) of lipid peroxidation chain reactions (1)ndash(5) according to Scheme 2 The phenomenon is particularlyprominent in the presence of Fe2+ and other ions of variablevalency
Chain break and termination reactions (6)ndash(10) of theLP reaction cascade [89] were influenced by 14-DHPs in alesser degree than were initiation and propagation steps This
may be important for their therapeutic effects even in theadvanced stages of LP
Scheme 2 (stages of initiation propagation and terminationof lipid peroxidation chain reactions (1ndash10)) Initiation andpropagation reactions are as follows
(8) RO∙ + In∙minus rarr Y (Y = molecular products)(9) ROO∙ + Fe2+ rarr Fe3+ + X (X = molecular products)(10) RO∙ + RO∙minus rarr Y (Y = molecular products)
In the reversible swelling of mitochondria accompanyingLP (initiated by mixture of 5mM GSSG1mM GSH) several14-DHPs showed low or no activity manifested only as adecrease of the swelling amplitude without a rate decreaseAn addition of GSH (4mM) or ATP to swollenmitochondriacaused their contraction in both control and tested systemIt may be suggested that 14-DHPs acting as antioxidantsin mitochondria preferably influence LP reactions initiatedby ions with variable valency or their complexes with hemetype compounds methemoglobin hemin hematin and soforth (Velena et al [112]) If the peroxidation process has amaximal velocity and 50 percent of initial O
2were consumed
14-DHPs cannot completely break the chain reactions andprevent subsequent membrane damage by addition of DHPsubstance at 10 120583M concentration at the moment of 50percent oxygen consumption the subsequent oxygen uptakeproceeded unchanged This observation is important for theapplication of DHPs as inhibitors of initiation and to a lesserdegree propagation stages of LP chain reactions
The influence of 14-DHPs on Mit swelling is not strictlyassociated with their own oxidation There is the possibilitythat the labilizing (or stabilizing) effect relates to surfaceactivity (connected with substituent lipophilicity) or may bethe consequence of complexation with some -OH (or -CH
3)
group sensitive receptors at the mitochondrial membraneNamely a bathochromic shift of the absorption band maxi-mum (about 10 nm) was observed in the visible region beforeswelling However after swelling in the presence of Na+linoleate the spectrum returns to its initial value [112]
Some 14-DHPs not only protect mitochondria againstswelling caused by AsA-dependent LP salts of fatty acids
14 Oxidative Medicine and Cellular Longevity
in vitro [112] but also have beneficial effects on repairingtheir integrity in vivo after exposure to irradiation hepato-toxins ischemia hypoxia or hypothermia Some of themwere shown to normalize the process of intracellular repara-tion and physiological regeneration of ultrastructures Theywere also shown to stimulate reparative processes If pre-treated with 14-DHPs irradiatedmitochondria will not swell(Ivanov et al [140 141])
Diludine ionol and some other AOs mitochondria pro-tectors act as anti-ischemic agents If applied prophylacticallyin vivo they may prevent ischemic and reperfusion lesionsin heart kidney and other organs (Bilenko et al [113]) Theeffect is dependent on applied dose timing and way ofapplicationWhen added onto the cryoconservationmediumfor mitochondria preservation 14-DHPs prevented decreaseof membrane potential normalized facilitated respirationand prevented loss of mitochondrial Na+ and Ca2+ ionsafter thawing ([112] see citation number 36 (Subbota et alKharkov 1984) therein) Diludine was stronger protectorwhen compared to ionol
CA drug foridone (riodipine) was shown to possesscardioprotective features primarily due to is protective effecton mitochondria exposed to OS [142 143]
Similarly the DHP water-soluble antiarrhythmic com-pound glutapyrone inhibits initiation of LP by free radicalsin erythrocytes and heart mitochondria Its cardioprotectiveeffect has been experimentally shown in heart mitochondrialmembranes especially during deep hypothermia (Utno et al[144])
Cerebrocrast was effective in several translation modelsmimicking pathological situations known to be associatedwith cellular OS The potential protective action of 14-DHP derivatives (4-substituted compounds cerebrocrastgammapyrone glutapyrone and 4-unsubstituted drug dieth-one) has been studied in rat liver in experimental modelsrelevant for oxidative stress and mitochondrial bioenergetics(Fernandes et al [145]) When succinate was used as therespiratory substrate higher concentrations (gt25 120583M) ofcerebrocrast depressed respiratory control ratio (RCR) ADPto oxygen ratio (ADPO) state 3 and uncoupled respirationrates transmembrane potential (deltapsi) and the phosphatecarrier rate At the same time state 4 respiration rate wasthree times increased At concentrations lower than 25120583Mcerebrocrast inhibited mitochondrial IMAC and partiallyprevented Ca2+-induced opening of the mitochondrial PTPGammapyrone glutapyrone and diethone did not inducethese phenomena When applied at concentrations up to100 120583M cerebrocrast gammapyrone and glutapyrone didnot affect ADPFe2+-induced LP of mitochondria in rat liver(as measured by oxygen consumption and TBARS forma-tion) On the other hand low diethone concentrations (upto 5 120583M) inhibited it in a dose-dependent manner Diethonealso prevented against deltapsi dissipation induced by LPinitiated by ADPFe2+ Based on these data it may bespeculated that cerebrocrast (inhibition of the IMAC) anddiethone (acting as an AO) may provide effective protectionof mitochondria during OS Cerebrocrast has shown sometherapeutic potential for treatment of several pathologicalconditions related to cellular OS [145]
5-Acetyl(carbamoyl)-6-methylsulfanyl-14-DHP-carbo-nitriles (Figure 3) with minor differences in their molecularstructure displaying antioxidant and antiradical activitiesin vitro show different biological activities Namely 4-p-chlorophenyl derivative OSI-1146 displays AO and anti-radical activities in cardiovascular OS models whereasOSI-3701 and OSI-3761 display hepatoprotective activityThus these compounds may be potentially useful for treat-ing several pathological processes including those associatedwith OS (Fernandes et al [146]) However besides mito-chondria the cellular targets for their pharmacologicalactions have not been fully investigated [146] All these com-pounds increase the susceptibility of Mit to MPT The mostpotent is OSI-3701 although it does not affect bioenergeticparameters
Although all these compounds protected mitochondriaagainst LP induced by the oxidant pair ADPFe2+ OSI-1146was shown to be the most potent Current data point outmitochondria as potential targets for protective and toxicactions of DHPs suggesting that the potential for their use astherapeutic agents should also take into consideration theirtoxic effects on mitochondria (Fernandes et al [146])
Several structurally different DHP derivatives (antioxi-dant diludine (diethone) as a 4-unsubstituted DHP 4-substi-tuted DHPs CA foridone (bicyclic compound) and the 4-phenyldiethone compound where phenyl group is joined tothe DHP in position 4) inhibited the 1-methyl-4-phenyl-pyridinium iodide (MPP+) induced ROS production incerebellar granule cells (CGC) with a distinct potency orderforidone (26-dimethyl-35-dimethoxycarbonyl-4-(o-difluo-romethoxyphenyl)-14-dihydropyridine) gt 26-dimethyl-35-diethoxycarbonyl-4-phenyl-14-dihydropyridine gt diludineThey also reversed the MPP+-induced decrease of the mito-chondrial membrane potential in the same order (Klimavi-ciusa et al [147]) Accordingly it was postulated that theclassical two-ring (bicyclic) structure of DHP derivativesrepresents an advantage in relation to neuroprotection andROS defense and is independent on compoundrsquos propertiesrelated to calcium ions
Novel adamantane-containing 14-DHP compounds (Kli-maviciusa et al [148]) were also found to improve mitochon-drial functions (MPP+ model) (Klimaviciusa et al [148])Klusa et al [149] have discovered antineurotoxic effects of14-DHP taurine derivative tauropyrone recorded as Mitfunction improvement
Many 14-DHPs including Ca2+ antagonists and AOmodify LP processes and influencemitochondrial function invarious organs (liver heart kidney and brain) in a differentway and degree Their beneficial action oxygen or lipidfree radical scavenging antioxidative effects binding withor intercalating into phospholipid bilayer regulation of iongating and regulation of mitochondrial permeability transi-tion pores (Tirzit and Duburs [39] Zilber et al [44] andDubur et al [45]) separately or in combination with eachother depends on two strong elements (1) their individ-ual structure including nature of substituents and theirpositions and (2) the nature of the biological system Forexample the direction of LP (inhibition of promotion) wasshown to depend on structure and concentration of applied
Oxidative Medicine and Cellular Longevity 15
14-DHPs as well as stages of chain reactions Accordinglymitochondrial swelling may be prolonged (retarded) accel-erated (promoted) or inhibited (Velena et al [112])
Therefore there is a ground for 14-dihydropyridineseither Ca2+ antagonists or antioxidants to be nominated asuseful tools in development of ldquomitochondrial drugsrdquo relatedto the control of OS
(c) DHPs as AOs in Endoplasmic Reticulum (Inhibition ofNADPH-Dependent LP System) Inhibition of NADPH Oxi-dase by DHPs Elevated level of NADPH oxidase 4- (NOX4-)derived hydrogen peroxide (H
2O2) joined with concomitant
decrease of nitric oxide (NO) mediated signaling and reac-tive oxygen species scavengers are considered to be centralfactor in molecular pathogenesis of fibrosis (Sampson etal [150]) Inhibition of microsomal NADPH-dependent LPwith particular focus on NADPH oxidases (NOX1ndash5 andDUOX1) may be very important for neuro- cardio- andhepatoprotection (Velena et al [112] Leto and Geiszt [151]Griendling et al [152] and Chen et al [153]) Endoplasmicreticulum may be an important target as this is where 14-DHPs could display their antioxidative properties (Velena etal [112] Leto and Geiszt [151] Griendling et al [152] andChen et al [153])
However the initiation of LP in the NADPH-dependentmicrosomal system does not appear to involve either super-oxide or hydrogen peroxide since neither SOD nor cata-lase can inhibit it On the other hand reduced iron playsan important role in both the initiation and propaga-tion of NADPH-dependent microsomal lipid peroxidation(Hochstein and Ernster [154] and Repetto et al [111])
Many DHPs possess inhibitory activity not only towardsAsA-dependent LP in mitochondria but also towardsNADPH-dependent LP as shown in isolated rat liver micro-somes (Velena et al [112]) This means that these compoundsinteract with the shared parts (nonenzymatic and enzymatic)of LP pathways
Microcalorimetry and fluorescent probes procedureswere used for studying the interaction of alpha-tocopheroland 14-DHPs with endoplasmic reticulum membranes andmodel systems human serum albumin and phospholipidbilayers [155] Modification of microviscosity of the endo-plasmatic reticular membranes depends on localization ofantioxidants within the protein structures or phospholipidphase Increase of membrane structuralization under theinfluence of 14-DHPs blocked their antioxidant action inspontaneous and induced lipid peroxidation
Inhibition of rat heart and liver microsomal lipid perox-idation by nifedipine was observed [156] while Goncalves etal [157] found antioxidant effect of calcium antagonists onmicrosomal membranes isolated from different brain areas
Nitroaryl-14-DHPs are both calcium channel antagonistsand antioxidant agents (Letelier et al [158 159]) commonlyused for treatment of cardiovascular diseases These drugsmust be metabolized through cytochrome P450 oxidativesystem (NADPH-cytochrome P450 reductase) mainly local-ized in the hepatic endoplasmic reticulum Several lipophilicdrugs generate OS while being metabolized by this cellularsystem Thus DHP antioxidant properties may prevent the
OS associated with hepatic biotransformation of drugs Var-ious commercial and new nitro-phenyl-DHPs were studiedagainst LP using rat liver microsomes under oxidative stress[159]
Incubation of rat liver microsomes with the 41015840-nitro-4-phenyl-14-DHP compounds (26-dimethyl-4-(41015840-nitro-phenyl)-14-dihydropyridin-35-diethyl-dicarboxylate andN-ethyl-26-dimethyl-4-(41015840-nitrophenyl)-14-dihydropyri-din-35-dimethyl-dicarboxylate) results in an inhibitionof LP the UDPGT (UDP-glucuronyltransferase) oxidativeactivation and the microsomal thiol oxidation induced byFe3+ascorbate a generator system of ROS This effect wasalso produced by nitrofurantoin and naphthalene in thepresence of NADPH
Interestingly IC50
ofDHPs obtained frommicrosomal LPassays decreased to the same extent as the microsomal thiolsoxidation provoked by Fe3+ascorbate [159] Neverthelessthe AO effects of a nitrophenyl-DHP compound in whichhydrogen at position one of the DHP ring was replaced bythe ethyl groupwere significantlyweaker Authors speculatedthat DHPs can resemble NADH transferring one hydrogenatom of 4-position (Hminus) to anion superoxide and another ofthe 1-position (H+) by way of a cationic radical intermediateto generate pyridine derivatives and water [159]
The AO effects of various tested DHP derivatives (m- andp-NO
2phenyl as well as methyl or ethyl and isopropyl-DHP
35-dicarboxylate derivatives) were not significantly differentThe authors assumed that the -NH- group of the dihydropy-ridine ring could contribute both to the development ofthe calcium channel antagonism and to the antioxidativeproperties of DHPs [159]
Prevention of the membrane LP seemingly depends onthe concentration of potential antioxidants such as vitaminE or even 14-DHP in lipids However only the differencesin synthetic DHPs lipophilicity cannot explain significantvariations of DHPs concentration in microsomal membraneand cannot clarify the strength of their antioxidative activityThis work [159] has further demonstrated that 14-DHPsmay prevent the OS induced by biotransformation of somedrugs for example antibiotic nitrofurantoin Simultaneousadministration of DHPs and nitrofurantoinmay be beneficialin reducing nitrofurantoin side effects
While most of Ca antagonist 14-DHPs are metabolizedby CYP3A4 (Guengerich et al [160]) not all of them are goodinhibitors of its activity Thus nicardipine but not nifedipineand nitrendipine inhibits CYP3A4 in vitro [53] Interactionof different DHPs with various types of cytochrome P450 wasdescribed by Carosati et al [53] It was also reported thatDHP class calcium channel blockers reduce the antiplateleteffect of clopidogrel (Park et al [161])This implies themutualinteractions of both drugs with CYP3A4
(3) In Vivo Evaluation of nifedipine effects on Saccharomycescerevisiaewas recently published (Asma andReda [162]) Sur-prisingly nifedipine exercised a toxic effect on Saccharomycescerevisiae shown through measuring cellular proliferationrespiratory activity and the level of some biomarkers (CATand MDA)
16 Oxidative Medicine and Cellular Longevity
However majority of data obtained on various animalcells and tissues by other authors show the protective role ofDHPs against both LP and oxidative stress [113 163 164]
The AOA attributed to many 14-DHPs Ca2+ antag-onists and other compounds reflecting on catalytic LDLperoxidation (see Section 331 (2) and Section 35) shouldencourage their testing for treating cardiovascular diseasesandor alterations of lipid metabolism
The possibility that 14-DHP-based calcium antagonistsexert an antiatherosclerotic action (via inhibition of LDLoxidation and other mechanisms) has been proved by manyexperimental data [165] and several clinical trials Besidesantihypertensive effect nicardipine was shown to possessantioxidative and antielastase activity [165 166] These prop-erties may be useful for prevention of inflammatory reactionwhich is relevant for hypertension pathogenesis
14-DHPs administration inhibits LDL oxidation medi-ated by oxygen radicals leading to decreased carotid inti-mal media thickness and reduced progression of coronaryatherosclerosis [130] It additionally preserves Apo B-100integrity against ROS Of importance antiatherogenic mech-anisms differ between animals and humans (primarily inthe stage of conversion of aldehydes to carboxylic acids)(Parthasarathy et al [167])
For example furyl-DHP compound (FDP-1 diethyl 26-dimethyl-4-(furyl)-14-dihydropyridine-35-dicarboxylate)was shown to act as an antioxidant (decreasing MDA GOTand FFA release of ischemic myocardium and inhibiting Ca-ATPase of erythrocyte membranes) preventing against heartmyocardium ischemia-reperfusion injury and arrhythmiawhen applied (in rats) at 10mgkg (Liu et al [168])
Similarly antioxidative effects of azelnidipine andamlodipine prevented neuronal damage by CCBs aftertransient focal ischemia in rats (Lukic-Panin et al [169])
Allanore et al [170] found that both nifedipine andnicardipine significantly decrease the mean level of plasmamarkers for oxidative stress in patients suffering from sys-temic sclerosis
Antioxidants may be considered as promising neuropro-tective compounds Still while experimental data demon-strate neuroprotective effect in vitro and in animal mod-els clinical evidence is still unsatisfactory and insufficient[171]
(a) Role of Metabolism of DHPs in Their AOA Metabolicpathways and ldquobioavailabilityrdquo of the probable AOA com-pound determine antioxidant activity in vivo Antioxidantmetabolites may vary in stability and activity leading to twoopposite scenarios lack or presence of activity substantiallycontributing to the overall AOA [172] Metabolic biotransfor-mation of DHPs includes oxidation (heteroaromatization)side chain ester group cleavage (deesterification) and 4-substituent abstraction ao [160] None of the DHPs metabo-lites was shown to be more toxic than original reduced formof the compound The commonly detected metabolites ofthe DHPs do not seem to possess the AO activity (withsome exceptions as in the case of metabolites of nifedipineand its analogues including nitrosonifedipine [173 174]) (seefurther in Section 35) Due to DHPs intrinsic instability
achieving andmaintaining an adequate concentrationmay beproblematic both in vitro and in vivo
(b) Role of Concentration and Lipophilicity (MembraneWateror LipidWater Partition Coefficients) of DHPs inTheir Actionas AOs and Antiradical Compounds Antioxidative effects ofany antioxidant depend on its concentration at the site ofaction This parameter is hardly measurable especially intwo-phase systems representing one of obstacles in com-parison to AOA upon applying various compounds [172]It is often incorrectly assumed that the concentrations inthe aqueous solution and at the site of action are the sameHowever even when the concentration in the aqueous phasemay be well controlled the concentration at the site ofaction in the lipid matrix of the membranes might fluctuatebetween different test compounds depending on a differencein lipophilicity [175] The prevention of the membrane LPalso seems to be dependent on the DHP concentration in thelipidmatrix (Mason andTrumbore [46]) and its amphiphilic-ity For example AOA of diludine is associated with itslipophilicity and consequential ability to be incorporatedinto liposomes (Panasenko et al [176]) It was also foundthat diludine easily incorporates into the outer monolayer oferythrocyte membranes [176]
Membranebuffer partition coefficients (lambda) weredirectly measured in the sarcolemma and sarcoplasmicreticulum membranes for three CA DHPs The obtainedvalues were in a broad range between 5000 and 150000(Herbette et al [177])These drugs interact primarily with themembrane bilayer component but may also bind to proteinsboth nonreceptors and receptors The intrinsic forward rateconstants for DHP binding to sarcolemmal calcium channelreceptors were apparently not strongly dependent on theirmembrane partition coefficients For example nimodipine(lambda = 6300) had a forward rate constant of 68 plusmn 06 times106Ms whereas the forward rate constant for Bay P 8857
(lambda = 149000) was 14plusmn08times107Ms Since these DHPsare highly liposoluble model calculations for this bindingreaction demonstrated that these rates on lipid solubilitywould probably not be reflected in the experimental forwardrate constants In addition the intrinsic forward rate constantfor nimodipine binding to sarcolemmal calcium channelreceptors was found not to be linearly dependent on theviscosity of the buffer medium over a fivefold range The rateof drug nonspecific binding to nonreceptor protein present inhighly purified sarcoplasmic reticulum membranes appearsto be extremely fast at least 103 times faster than specificdrug binding to the receptor in the sarcolemma Authorsconcluded that partitioning into the lipid bilayer matrix ofthe sarcolemma could be a general property of CA DHPsand may be a prerequisite for their binding to sarcolemmalmembrane receptors (Herbette et al [177])
The binding of DHP calcium channel agonists and antag-onists (including those with AO properties) to receptors incardiac sarcolemmal membranes is a complex reaction thatmay involve an interaction with the lipid bilayer matrix ofthe sarcolemma (Herbette et al [178]) Belevitch et al [179]studied the binding of DHP CCBs (riodipine and nifedip-ine) and verapamil to model and biological membranes by
Oxidative Medicine and Cellular Longevity 17
fluorescence analysis The consistent location of Ca agonistBay K 8644 was determined to be within the region ofthe first few methylene segments of the fatty acyl chains ofthe membranes (Mason et al [180]) This position is nearto that observed for the DHP calcium channel antagonistsnimodipine and Bay P 8857
Themajority of studies onOSwere performedwithDHPswith various lipophilicity but only a few studies reportedamphiphilicity ofDHPderivatives AmphiphilicDHPderiva-tive K-2-11 reduced the cellular generation of ROS It alsorevealed complete reversal of multidrug resistance (MDR) ofthe resistant cells K-2-11 was more efficient than well-knownMDR inhibitor verapamil Cytotoxic effects of anticancerdrug doxorubicin were enhanced by K-2-11 in bothMDR andparental nonresistant cell line (Cindric et al [181]) K-2-11suppresses increase of ROS and consequentially prevents NF-120581B activation leading to decreased expression of MDR1 andincreased expression of antiapoptotic genes This signalingswitch is necessary for restoring the chemosensitivity ofcancer cells This phenomenon is characteristic both for14-DHPs [182] (18 novel asymmetrical DHPs bearing 3-pyridyl methyl carboxylate and alkyl carboxylate moietiesat C3 and C5 positions resp as well as nitrophenyl orheteroaromatic rings at C4) and for their oxidized formspyridine compounds (Zhou et al [183])
34 Dependence of AOA of DHPs on the Experimental SystemAO effect of DHPs depends on their structure and theexperimental system used (in vitromodel system subcellularorganelle and cells ex vivo and in vivo) Ideally for theevaluation of the profile and value of DHPs AO propertieseach compound should be tested in as many systems aspossible (Dubur et al [45])
Lipidomics studies have been traditionally explored forstudying AOA of DHPs Proteomics methods are less rep-resented and are mostly focused on the properties of DHPsrelated to scavenging of protein free radicals So far there areno studies on the role of DHPs in scavenging nitrosoperoxy-carbonate the reactive species formed out of peroxynitrite inthe presence of carbon dioxide Although it was shown thatalbumin binds diludine no studies revealed the relevance ofthis effect for the AOA of diludine
There are findings showing that dihydropyridine calciumantagonists (DHPs CA) could indirectly play a beneficialprotective role during development of atherosclerosisNamely Berkels et al [184] have studied antioxidativeproperties of four substances the DHP prototype CAnifedipine the long-acting CA lacidipine the DHP calciumchannel agonist BayK8644 and the bulkyDHPderivate BayO 5572 in three different models (1) in an in vitro superoxideanion generating system (hypoxanthinexanthine oxidase)for testing the ldquopurerdquo antioxidative effect (2) in an artificialmembrane preparation (dimyristoylphosphatidylcholine) formimicking a more physiological environment and (3) underconditions of stimulated ROS release (hyperglycemia) fromnative endothelial cells derived from porcine coronary arter-ies
The study also revealed the potential correlation betweenlipophilic and AO properties of DHPs In the first model
Bay K 8644 was significantly more effective in scavengingsuperoxide anions than lacidipine Bay O 5572 or nifedipine(micro- to millimolar concentration range) Addition of anartificial membrane preparation resulted in an enhancedAO effect with lacidipine being the most effective DHP inquenching radicals (low micromolar concentration range)In the third model mimicking hyperglycemia (30mmolL)nifedipine was significantly more potent antioxidant (ther-apeutical nanomolar concentration range) than the otherDHPs Calculated lipophilicity of these four substances(lacidipine gt Bay O 5572 gt Bay K 8644 gt nifedipine) waspositively correlated with antioxidative potential only in thesecond experimental model It has been concluded that AOproperties of DHP substances need to be tested in variousmodels for demonstrating that nifedipine exhibits ROS-quenching properties in a therapeutic concentration range[184]
341 AOA of DHPs in Isolated Cells and Cell Cultures(Comparison with Other Simplest Systems) Although DHPspossess neuromodulatory andor antimutagenic propertiesthe mechanisms of action related to these phenomena arenot entirely elucidated Borovic et al [185] have studied 14-dihydroisonicotinic acid (14-DHINA) derivatives of 14-DHP water-soluble analogues of a well-known AO diludine(diethone) 26-dimethyl-35-diethoxycarbonyl-14-dihydro-isonicotinic acid sodium 2-(26-dimethyl-35-diethoxycar-bonyl-14-dihydropyridine-4-carboxamido)glutamate gluta-pyrone and sodium 2-(26-dimethyl-35-diethoxycarbonyl-14-dihydropyridine-4-carboxamido)ethane-sulphate tauro-pyrone as AO and bioprotectors (Figure 4)
14-DHINArsquos activities were studied in comparison toTrolox by NN-diphenyl-N1015840-picrylhydrazyl (DPPH∙) deoxy-ribose degradation ABTS∙ radical scavenging and AOA(antioxidative capacity method) assays copper-induced LPof cultured rat liver cells (MDA determination by HPLCand 4-hydroxynonenal-protein conjugates by dot-blot) 3H-thymidine incorporation and trypan blue assay for liver cellsgrowth and viability Ic decreased the amount of 4-HNE-protein adducts In all assays Ia was the most potent AOable to completely abolish copper induced LP of liver cellswhile Ic only slightly decreased it Thus AOA is importantactivity principle of Ia which was even superior to Trolox intreated cell cultures Ia (and its analogues) are easily oxidizedin the Fenton system (Rubene et al [186]) exerting ARA too
35 Peculiarities Related to Antioxidative and AntiradicalActivity of Some 14-DHPs Ca Antagonists Nine commer-cialized structurally and functionally different DHPs CAwill be discussed further Their common feature is ability toprevent OS This also counts for some of their metabolitesas already discussed The comparative effects of some DHPsCA on oxidative stress-induced modification of LDL werealready reviewed in Section 331 (2)-(a) AOA of CA DHPswas discussed in Sections 331 (2)-(b) and 331 (2)-(c)
351 Nifedipine and Its Close Analogues Nifedipine vera-pamil and antiarrhythmic-antihypoxic drug stobadin wereshown to depress lipid peroxidation of phosphatidylcholine
18 Oxidative Medicine and Cellular Longevity
NH
COOH
NH
COONa
Glutapyrone
NH
Gammapyrone
NH
C 2H5OOC COOC2H5
Tauropyrone
14-DHINA
H3C H3C
H3C
H3CCH3 CH3
CH3
CH3
COOC2H5COOC2H5
COOC2H5 C2H5OOCC2H5OOCC2H5OOC
CONHCH(CH2)2COONa CONH(CH2)3COONa
CONH(CH2)2SO3Na
Figure 4 Derivatives of 14-dihydroisonicotinic acid (14-DHINA)
liposomes (Ondrias et al [187]) However data obtained insome other experimental systems are conflicting
In an in vitromodel of sarcolemmal membrane lipid per-oxidation three calcium blockers (nifedipine verapamil anddiltiazem) exhibited concentration-dependent (10ndash400 120583M)inhibitory effects [188 189] Nifedipine the most effectivecalcium blocker was more than two-fold potent compared topropranolol achieving significant effect at 10 120583M Nifedipineprotective role on LP using reduced glutathione as modelmarker was recently described (Ray et al [190]) Antiper-oxidative properties of CA nifedipine and its analogueswere explored in different systemspathogenic processesatherogenesis (Henry [165]) brain focal ischemia (Yamatoet al [191]) nephroprotection related to cyclosporine intake(Chander and Chopra [192]) and hepatoprotection relatedto intake of diethyldithiocarbamate (Gaafa et al [193])Recent data suggest that nifedipine action as protector forendothelial cells proceeds independently from its CA proper-ties
The absence of antioxidant effects of nifedipine anddiltiazemonmyocardialmembrane lipid peroxidation oppo-site to nisoldipine and propranolol was also described[194] Nisoldipine and propranolol were shown to havea concentration-dependent antiperoxidant effect with IC
50
values of 282 and 501 120583M respectively Finally nisol-dipine appeared to possess dual antiperoxidant mecha-nisms involving both preventive and chain-breaking proper-ties
These findings were confirmed in some other studiesincluding reports on the lack of antioxidative activity ofnifedipine and nicardipine even at 500120583M concentrationin heart membrane lipid peroxidation tests [134] SimilarlyROS formation in bovine aorta smooth muscle cells was notaffected by addition of amlodipine nimodipine and nife-dipine [123]
(1) Metabolites of Nifedipine and Its Analogues as Antioxidantsand Regulators of OS Antioxidant activity of nifedipine35-dimethoxycarbonyl-26-dimethyl-4-(2-nitrophenyl)-14-dihydropyridine was originally studied in vitro by Kirule etal [195] and Tirzit et al [196] According to the kinetic dataof peroxide accumulation and the ESR spectra (inhibition ofthe autoxidation of methyl oleate in presence of nifedipine)AO action was exerted by the formation of nitroso analogueof the oxidized nifedipine nitroso nifedipine 26-dimethyl-4-(2-nitrosophenyl)-35-pyridine dicarboxylate (NO-NIF)This nitroso aromatic derivative can form nitroxyl radicalsexhibiting remarkable AOA in the presence of unsaturatedfatty acids and lipids [196]
The primary species of free radicals that have beenobtained and identified were ion radicals of the nitrophenyltype (Ogle et al [76]) Such a mechanism coincides withmechanisms proposed afterwards by Nunez-Vergara et al[96] Lopez-Alarcon et al [103] Valenzuela et al [104]Fukuhara et al [174] and Yanez et al [197]
There are also data showing that nitroso compounds mayinhibit LP by direct radical trapping and subsequent forma-tion of stable nitroxide radicals It was further found that thereactivity between the synthesized 14-DHP derivatives withalkylperoxyl radicals involves electron transfer reactionsThisis documented by the presence of pyridine as a final productof the reaction and complete oxidation of the nitroso groupin the case of the nitrosoaryl 14-dihydropyridine derivatives(Valenzuela et al [104]) Tested compounds reacted fastertoward alkylperoxyl radicals and ABTS radical cation thanalkyl ones (Lopez-Alarcon et al [103])
Nitrosonifedipine a photodegradation product of nifedi-pine significantly recovers cellular damage induced by tumornecrosis factor-alpha It also prevents toxic effects of cumeneperoxide which hampers integrity of cell membranes throughoxidative stress Its positive effects are equal to Trolox-C
Oxidative Medicine and Cellular Longevity 19
As a result nitrosonifedipine was already a long time agoclaimed as a candidate for a new class of antioxidative drugs(Kirule et al [195]) cellular protectors against oxidative stressin glomerular endothelial cells [174]
Moreover Misik et al [198] Ondrias et al [199] andStasko et al [200] studied AOA of nifedipine and its oxidizednitroso analogue NO-NIF prevents the progression of type2 diabetic nephropathy associated with endothelial dysfunc-tion through selective AO effects (Ishizawa et al [201]) NO-NIF administration reduces albuminuria and proteinuriaas well as glomerular expansion without affecting glucosemetabolism or systolic blood pressure NO-NIF also sup-presses renal and systemic OS and decreases the expressionof intercellular adhesion molecule-1 (ICAM-1) a marker ofendothelial cell injury in the glomeruli of the KKAy miceSimilar effects were achieved in endothelial nitric oxide syn-thase (eNOS) knockout mice Moreover NO-NIF suppressesurinary angiotensinogen (AGT) excretion and intrarenalAGT protein expression in proximal tubular cells in theKKAy mice On the other hand hyperglycemia-inducedmitochondrial superoxide production was not attenuated byNO-NIF in cultured endothelial cells
Fujii and Berliner found EPR evidence for free radicaladducts of nifedipine in vivo [202] The nature of these rad-icals was surmised by comparing the reaction of illuminatednitrosonifedipine with polyunsaturated fatty acids Surpris-ingly identical radical spectra were detected from excisedliver doped with nonilluminated nifedipine suggesting thatthis drug can be enzymatically converted in vivo to its nitrosoanalogue without the requirement for illumination This isone of the first reports of in vivo EPR evidence for a class ofunsaturated fatty acid radical conjugates resulting from thenormal metabolism of a common drug
Dıaz-Araya et al [173] studied some 4-nitrophenyl-DHPson Fe3+ initiated LP in rat brain slices LP as measuredby MDA formation was inhibited by all the tested nitro-aryl derivatives of 14-DHP over a wide range of concen-trations On the basis of both time course and IC
50experi-
ments the tentative order of AOA on rat brain slices wasnicardipine gt nisoldipine gt (RSSR)-furnidipine gt (RRSS)-furnidipine gt nitrendipine gt nimodipine gt nifedipine14-DHP derivatives that lack a nitro group in the mole-cule (isradipine and amlodipine) also inhibited LP in ratbrain slices but at higher concentrations than that of nitro-substituted derivatives All tested compounds reduced andoxidized nitrosoaryl derivatives (26-dimethyl-4-(2-nitro-sophenyl)-35-pyridinedicarboxylic acid dimethyl ester (pho-tooxidation product of nifedipine ndash NTP) ao) and weremore potent inhibitors of LP than their parent molecules(Valenzuela et al [104])
The electrooxidation process of 4-nitrosoaromatic DHPsis a strongly pH-dependent (two-electron two-proton mech-anism) ECEC type of mechanism that is the sequenceeminusH+eminusH+ at pH gt 85 ECCE mechanism (eminusH+H+eminus)at pH lt 85 dominates Reduction reaction of nitroso groupis as follows R-NO + 2eminus + 2H+ rarr RNHOH (Bollo et al[203])
352 Lacidipine It is a generic DHP type antihypertensiveCA 35-diethyl 4-2-[(1E)-3-(tert-butoxy)-3-oxoprop-1-en-1-yl]phenyl-26-dimethyl-14-dihydropyridine-35-dicarboxy-late
Ursini [204] described redox behaviour of lacidipine andshowed its tissue protective features Cristofori et al studiedantiatherosclerotic activity in addition to lacidipinersquos CAand AO properties [205] Lacidipine reduced the extent ofatherosclerotic area in hypercholesterolemic apoE-deficientmice (these mice show widespread vascular lesions whichclosely resemble the inflammatory fibrous plaques seen inhumans in atherosclerosis) The reduction may be associatedwith the capacity of the drug to maintain endothelial NOlevels at concentrations useful to protect against vasculardamage This work suggested that DHPs modulate vascularrelaxation via increased release of NO
Herbette et al [178] remarked optimal hydrophobicity oflacidipine due to cinnamic acid substituent so membraneinteractions and facilitation of the treatment of atherosclero-sis could proceed (see also Section 331 (2)-(a))
353 Amlodipine Amlodipine (Norvasc) (RS)-3-ethyl5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-14-dihydropyridine-35-dicarboxylate (AML) hasan antioxidant effect on vessels in vitro and is a 3rd genera-tion of charged dihydropyridine CCB that is widely used forthe treatment of hypertensive patients
Amlodipine was shown to have the highest affinity(amlodipine gt verapamil ≫ diltiazem) for the membranebilayer (119870
119901= 104) It produced the significant changes in
membrane thermodynamic properties including a reductionin the thermal phase transition temperature (minus11) enthalpy(minus14) and cooperative unit size (minus59) relative to thecontrol phosphatidylcholine liposomes (Mason et al [49])
Amlodipine AOA is related to its reductant nature orhydrogen donor properties respectively Its ability for donat-ing protons and electrons to the lipid peroxide moleculesblocks the LP process
Amlodipine and even its enantiomers (Zhang et al [206])act as ROS andNOS effectors in several model systems of OSAntioxidant properties of amlodipine were recently reviewedby Vitolina et al [32] Both in vitro and in vivo studiesof amlodipine AO properties revealed inhibition of lipidsoxidative damage primarily those associated with cellularmembranes and lipoprotein particles (LDL) (Mason et al[50])
Under controlled experimental conditions in vitro amlo-dipine showed AOA and ARA by inhibition of lipid peroxideformation and trapping ROS Its scavenging activity forhydroxyl and peroxyl radicals at concentrations as low as100 nmolL (which is remarkably less compared to the classi-cal antioxidants GSH uric acid and Trolox) was shown to beindependent of the calcium channel modulation (Franzoni etal [207])
AML showed efficiency as scavenger of peroxyl radicals(TOSC assay 5945 plusmn 544 unitsmg) significantly stronger(gt50 119875 lt 0001) than GSH (2733plusmn 636 unitsmg) and 70weaker (119875 lt 00001) than uric acid (18144 plusmn 696 unitsmg)and Trolox (17522 plusmn 734 unitsmg)
20 Oxidative Medicine and Cellular Longevity
Of interest the scavenging capacity of AML towardshydroxyl radicals (1455 plusmn 154 unitsmg) was 320 higher(119875 lt 000001) than that of GSH (358 plusmn 112 unitsmg) 20higher than that of uric acid (1198plusmn121 unitsmg) and 100higher than that of Trolox (759 plusmn 143 unitsmg)
Amlodipine was shown to increase enzyme activity ofparaoxonase (PON) and glutathione peroxidase (GSH-Px)However it also decreases glutathione reductase (GSSG-R)activity and diminishes the concentration of the endogenousantioxidant 120572-tocopherol (vitamin E) Moreover AML in aconcentration of 2 ngmL decreased the content of malonicdialdehyde and activity of superoxide dismutase in the blood(Gatsura [208])
Verapamil and amlodipine produced a potent anti-ischemic effect and reduced area of myocardial infarction inrats The observed changes were accompanied by inhibitionof LP In contrast to verapamil in vitro application of AML ina dose of 50 ngmL decreased hemoglobin affinity for oxygenWhen present in a concentration of 2 ngmLAMDdecreasedthe content of MDA and activity of SOD in the blood
On the other hand amlodipine shows no activity relatedto inhibition of macrophage superoxide release and cellmigration which occurs as a consequence of decreasedTNF120572induced O
2
∙ releaseAmlodipine-induced reduction of OS in the brain is
associated with sympathoinhibitory effects in stroke-pronespontaneously hypertensive rats (SHRSP) (Hirooka et al[209]) Antihypertensive treatment with amlodipine reducedOS in all examined areas of the brain and decreased bloodpressure without a reflex increase in sympathetic nerveactivity Nicardipine another CA DHP surprisingly wassignificantly less active than amlodipine
354 Lercanidipine Tomlinson and Benzie reported AOeffect of lercanidipine [210] which is well known as anti-hypertensive drug Zanidip 2[(33-diphenylpropyl)(methyl)-amino]-11-dimethylethyl methyl 26-dimethyl-4-(3-nitro-phenyl)-14-dihydropyridine-35-dicarboxylate Compara-tive data about this drug AOA were presented in parts of thispaper about other individual CA DHPs and in the part aboutthe ex vivo DHPs effects on LDL
355 Nimodipine Nimodipine (ND) commercially knownas Nimotop is 3-(2-methoxyethyl) 5-propan-2-yl 26-dim-ethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxy-late It is centrally active CA
Treatment with glutathione blocked andwith nimodipineattenuated neuronal cell death caused by prolonged exposureof cell culture to 4-HNE (Faraqui [211])
Nascimento et al [212] found AO effect of nimodipine inyoung rats after pilocarpine- (PIL-) induced (in 400mgkg)seizures The PIL administration increased the striatal cata-lase (CAT) activity The administration of ND 30mgkg30min before PIL preserved normal value of CAT activityOn the other hand no difference was detected in the animalstreated with lower dose 10mgkg These results confirmthe neuroprotectiveantiepileptic effect of ND in young ratssuggesting that this drug acts positively on lipid peroxidation
(in both doses) Nimodipine cannot induce these effects viablockade of Ca2+ channel
Ismailoglu et al [213] studied the therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjury These beneficial effects in rats after cerebral corticalinjury seemed to be related to AOA of nimodipine
356 Benidipine Licensed in Japan and South Asia as CA(CCB) benidipine possesses AO properties Chemically it is5-methyl 3-[(3R)-1-(phenylmethyl)piperidin-3-yl] 26-dim-ethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxy-late (or its hydrochloride (4R)-rel-35-pyridinedicarboxylicacid 14-dihydro-26-dimethyl-4-(3-nitrophenyl)- 3-methyl5-[(3R)-1-(phenylmethyl)-3-piperidinyl] ester hydrochloride(1 1))
Benidipine influences processes connected with OS inseveral ways It prevents lysophosphatidylcholine- (lysoPC)-induced injury and ROS production in human aorticendothelial cells (HAECs) (Matsubara and Hasegawa [214])Matsubara et al [215] explained this effect based on stimula-tion of nitric oxide release
LysoPC is a component of oxidized low-density lipopro-teins (oxLDLs) which plays an important role in the patho-genesis of atherosclerosis Pretreatmentwith benidipine (03ndash3 120583molL) for 24 h protected against lysoPC-induced cyto-toxicity in the HAECs through inhibition of both lysoPC-stimulated ROS production and caspase-37-like activationwith a similar potency Since caspase-37 is involved inexecuting the apoptotic process the reduction of the activityof this enzyme by benidipine may explain the antiapoptoticeffect of the drug However benidipine did not suppresslysoPC-induced phosphorylation of mitogen-activated pro-tein kinases and Ca2+ influx in HAECs These results suggestthat the antioxidant properties of benidipine may be respon-sible for its ability to inhibit ROS production a possiblereason for reduced activation of caspase-37 In conclusionbenidipine suppresses lysoPC-induced endothelial dysfunc-tion through inhibition of ROS production which is due atleast in part to its antioxidant effect and not through theinhibition of L-type voltage-dependent calcium channels
Matsubara and Hasegawa [216] examined the effectsof benidipine on cytokine-induced expression of adhesionmolecules and chemokines (chemoattractants) which areimportant for the adhesion of monocytes to endotheliumPretreatment of HAECs with benidipine (03ndash10 120583molL)for 24 h significantly suppressed cytokine-induced vascularcell adhesion molecule-1 (VCAM-1) and intracellular celladhesion molecule-1 (ICAM-1) mRNA and protein expres-sion resulting in reduced adhesion of THP-1 monocytesBenidipine also suppressed induction of monocyte chemoat-tractant protein-1 (MCP-1) and interleukin-8 Benidipinealso inhibited redox-sensitive transcriptional nuclear factor-120581B (NF-120581B) pathway as determined by Western blotting ofinhibitory 120581B (I120581B) phosphorylation and luciferase reporterassay Results of analysis using optical isomers of benidip-ine and antioxidants suggest that these inhibitory effectswere dependent on pharmacological effects other than Ca2+antagonism Benidipine may thus have anti-inflammatoryproperties and benefits for the treatment of atherosclerosis
Oxidative Medicine and Cellular Longevity 21
Benidipine was also shown to inhibit ROS production inpolymorphonuclear leukocytes and oxidative stress in salt-loaded stroke-prone spontaneously hypertensive rats (Mat-subara et al [217])
It should be mentioned that other DHPs also haveendothelial AO actions [218]
357 Azelnidipine (AZL) Azelnidipine 3-[1-[di(phen-yl)methyl]azetidin-3-yl] 5-propan-2-yl 2-amino-6-methyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate(AZL) CAS number 123524-52-7 is commercially available4-nitroaryl-DHP type calcium antagonist with long-actingantihypertensive action (long-acting CA (CCB)) and a lowreported incidence of tachycardia It additionally possessesbeneficial effects in OS and diabetic conditions
Azelnidipine prevents cardiac dysfunction in strepto-zotocin-diabetic rats by reducing intracellular calcium accu-mulation (altering intracellular Ca2+ handling proteins) OSand apoptosis (Kain et al [219]) AZL can reduce the superox-ide production It exerts its protective effects by targeting theNADPH oxidase and mitochondrial redox enzymes AZL-treated diabetic rats express enhanced level of bcl-2 in thelysates of heart muscle indicating that AZL plays protectiverole in cardiac apoptosis
It has been previously observed that azelnidipine inhibitstumor necrosis factor-alpha-induced endothelial cell (EC)oxidative stress through its AO properties (Nakamura etal [220]) Azelnidipine but not nitrendipine completelyinhibits the Ang II-induced ROS generation in ECs (Matsuiet al [221])
Furthermore azelnidipine but not nitrendipine wasfound to partially restore decreased pigment epithelium-derived factor (PEDF) mRNA levels in Ang II-exposed ECsThis study suggests that AZL influence depends on its antiox-idative properties Authors concluded that upregulation ofPEDF by azelnidipine may become a therapeutic targetfor the treatment of diabetic retinopathy associated withhypertension
Antihypertensive agents with AO effects are potentiallyuseful for diabetic patients with hypertension While DHPtypeCAare among themost frequently used antihypertensivedrugs azelnidipine has been reported to have a unique AOeffect in vitro and in vivo in experimental animals (Ohmuraet al [222]) In hypertensive diabetic patients azelnidipinetreatment for 12 weeks induced a more significant decreasein erythrocyte LOOH level than amlodipine although thevalues related to blood pressure during each treatmentremained comparable These data confirm the usefulness ofLOOH level in erythrocyte membrane as a marker of OS invivo and indicate that azelnidipine has a unique antioxidativeproperty in humans
Daikuhara et al [223] reported the results of the OLCAstudy based on combination of (1) olmesartan and a calciumchannel blocker (azelnidipine) or (2) candesartan and a CCBamlodipine in two groups of diabetic hypertensive patientsPatients treated with the first combination presented highlypersistent early morning antihypertensive effect and strongerdecrease in heart rate fasting blood glucose andHbA1c levels
and microalbuminuria when compared to patients treatedwith the combination (2) Because diabetes is associated withsevere chronic OS the observed results might be at least in apart due to the AOA of azelnidipine
In favor of this are findings of Abe et al [224] who foundadditive antioxidative effects of azelnidipine on angiotensinreceptor blocker olmesartan treatment for type 2 diabeticpatients with albuminuria
Similarly the AOA of thiazolidinediones (insulin sensi-tizer) and their effect on cardiovascular function in type 2diabetic model rats and also those of some DHPs (nifedipineamlodipine or AZL commonly used antianginal and anti-hypertensive agents) in cultured human endothelial cells LPwere examined (Mizushige [225]) The AOA was evaluatedby measuring 8-iso-prostaglandine F
2120572concentration and
azelnidipine exhibited potent AOAInsulin (INS) resistance combined with hyperinsuline-
mia is involved in the generation of OS A relation-ship exists between increased production of ROS and thediverse pathogenic mechanisms involved in diabetic vascularcomplications including nephropathy Manabe et al [226]revealed that high doses of INS augmented mesangial cellproliferation through generation of intracellular ROS andactivation of redox signaling pathways Cell proliferation wasincreased in a dose-dependent manner by high doses of INS(01ndash10 120583M) but was inhibited by 01120583M AZL Namely theINS-increased phosphorylation of mitogen activated proteinkinaseextracellular signal-regulated kinase 12 (MAPKERK12) was inhibited by 01 120583MAZL The same AZL concen-tration blocked intracellular ROS production more effec-tively than 01 120583M nifedipine The NADPH oxidase inhibitorapocynin (001ndash01120583M) prevented INS-induced mesangialcell proliferation So azelnidipine inhibits insulin-inducedmesangial cell proliferation by inhibiting the productionof ROS Therefore azelnidipine may have the potential toprotect against the onset of diabetic nephropathy and slowits progression
Azelnidipine inhibited H2O2-induced cell death in
neonatal rat cardiomyocytes (Koyama et al [227]) Azelnidip-ine and nifedipine did not affect theH
2O2-induced activation
of extracellular signal-regulated protein kinases (ERK) andp38 MAPK (mitogen-activated protein kinase) In contrastazelnidipine but not nifedipine inhibited H
2O2-induced c-
Jun NH2-terminal kinases (JNK) activation Authors con-
cluded that azelnidipine has inhibited theH2O2-induced JNK
activation and cardiac cell death Therefore azelnidipine mayhave cardioprotective effects against OS
A specific atheroprotection activity of azelnidipine relatesto inhibition of TNF-120572-induced activator protein-1 activa-tion and interleukin-8 expression in human umbilical veinendothelial cells (HUVEC) through suppression of NADPHoxidase-mediated reactive oxygen species generation (Naka-mura et al [220]) TNF-120572 could play a central role in patho-genesis of insulin resistance and accelerated atherosclerosis inthe metabolic syndrome The concentration of AZL found tobe effective in these in vitro experiments is within therapeuticrange As EC do not possess voltage-operated L-type calciumchannels it is suggested that the beneficial effects of azelni-dipine are not likely due to CA property but to its unique AO
22 Oxidative Medicine and Cellular Longevity
ability Furthermore it has been recently found that serumlevels of monocyte chemoattractant protein-1 a biomarkerfor subclinical atherosclerosis were significantly decreased bythe AZL treatment in patients with essential hypertension Inthis paper [220] authors hypothesize that due to its uniqueTNF-120572 signalmodulatory activity and antioxidative propertyazelnidipine may be a promising DHP for targeting diabetesand cardiovascular diseases in hypertensive patients withmetabolic syndrome
Shinomiya et al [228] evaluated its AOA in culturedhuman arterial EC under OS Azelnidipine has shown apotent antioxidative effect that could be of significant clinicalbenefit when combined with its long-lasting antihypertensiveaction and low incidence of tachycardia
Azelnidipine inhibited TGF-1205731 and angiotensin II- (AngII-) activated 1205721(I) collagen mRNA expression in hepaticstellate cells (HSCs) (Ohyama et al [229]) FurthermoreTGF-1205731- and Ang II-induced OS and TGF-1205731-induced p38and JNK phosphorylation were reduced inHSCs treated withAZL Azelnidipine significantly decreased inflammatory cellinfiltration profibrotic genes expression HSC activation LPoxidative DNA damage and fibrosis in liver of CCl
4- or
TAA-treated mice Finally AZL prevented decrease of theexpression of some AO enzymes and accelerated regressionof liver fibrosis in CCl
4-treated mice Hence the antifibrotic
mechanism of AZL against CCl4-induced liver fibrosis in
mice may have been due to an increased level of AO defenseAs azelnidipine is widely used in clinical practice withoutserious adverse effects it may provide an effective newstrategy for antifibrotic therapy
358 Manidipine Manidipine (2-[4-(diphenylmethyl)pip-erazin-1-yl]ethyl methyl 26-dimethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate) is a DHP CCB withreported nephroprotective properties Calo et al [230] stud-ied effect of manidipine on gene expression and proteinlevel of OS related proteins p22(phox) (human neutrophilcytochrome b light chain (CYBA)) and heme oxygenase-1HO-1 Relevance for antihypertensive effects was revealedThe study assessed the effect of manidipine on normalsubjectsrsquo monocyte gene and protein expression of OS relatedproteins such as p22phox a NADPH oxidase system subunitcritical in generating O
2
∙minus and HO-1 induced by and pro-tective against OS Manidipine was compared with the ACEinhibitor captopril and the CCB nifedipine in the presenceand in the absence of sodiumarsenite (NaAsO
2) as an inducer
of OS Monocyte p22phox (CYBA) mRNA production wasreduced by both manidipine and captopril while no changeswere induced by nifedipine Manidipine increased monocyteHO-1 mRNA production while nifedipine and captoprilshowed no effect The effects of manidipine on p22phoxand HO-1 gene expression in the presence of OS were alsoconfirmed at the protein level Thus manidipine seems tosuppress p22phox and to increase the HO-1 mRNA produc-tion and protein level The manidipine-induced increase ofHO-1 gene and protein expression seems to be a peculiareffect of this drug since it is not observed with captopriland nifedipine This effect together with the reduction of
p22phoxmRNAproduction could play a role in its protectivemechanism against OS
359 Mebudipine The protective effect of mebudipine (14-dihydro-26-dimethyl-4-(3-nitrophenyl)-35-pyridinedicar-boxylic acid 3-methyl-5-tert-butyl ester BAY-n-6391) wasrevealed on OS and LP (MDA decrease SOD GPX andcatalase increase) in myocardial ischemic-reperfusion injuryin male rats (Ghyasi et al [231])
There are articles about other commercial and experi-mental DHPs on OS but we have reviewed only the mostcommonly studied compounds Effects of other commercialCA DHPs on OS are also mentioned in several parts of thisreview
36 14-DHPs Ca Agonists andTheir AOA and ARA For themost popular calcium agonist DHP Bay K 8644 no reactionwith peroxyl radicals was registered (Toniolo et al [114])However interactionwith other compounds possessing AOAand ARA (quercetin) was found
Opposite to that AON-acetylcysteine (NAC) diminishedincrease in Ca2+ transient amplitude and cell shorteninginduced by ISO and forskolin whereas NAC had no effecton the (S)-(minus)-methyl-14-dihydro-26-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylatemdash(minus)-BayK 8644-induced increases (Andersson et al [232])
Increased vasoconstriction responses to Bay K 8644 (3 times10minus7ndash3times 10minus5M)were significantly decreased by pyridoindoleantioxidant stobadine treatment in diabetes (Ceylan-Isik etal [233])
The functional interaction between two L-type Ca2+channel activators quercetin and Bay K 8644 has beeninvestigated in vascular smooth muscle cells Biological ARAcompound quercetin at nutritionally meaningful concen-trations limited the responsiveness of vascular L-type Ca2+channels to the pharmacological stimulation operated by BayK 8644 These data contribute to a better understanding ofquercetin effects on experimental in vivo cardioprotection(Saponara et al [234]) Thus these findings indicated thatalthough Bay K 8644 does not exert potent and direct AOAyet acting as calcium agonist it may affect efficiency of AOsubstances and vice versa
Interaction of grapefruit juice (containing quercetin andits analogues) with DHPs CA diminished effectiveness of CAaction of DHPs (Sica [235])
37 Interpretations of the Mechanism(s) of RadicalScavenging and AOA by DHPs
371 Molecular Mechanism(s) of Radical Scavenging andAOA of DHPs in the Model Systems 35-Dicarbonyl-14-di-hydropyridine derivatives possess powerful bis-120573-carbony-lvinyl-amino conjugation and for that reason cannot be con-sidered as ordinary amino antioxidants The electron andorH donation from DHPs ensures their reductant role andresults in AOA and ARA Oxidation reaction from DHPsresults in production of corresponding heteroaromatic pyri-dine derivatives
Oxidative Medicine and Cellular Longevity 23
Detailed studies were made about substituent in DHPring positions 14- namely 4-unsubstituted- 4-substituted4-alkyl- 4-aryl- 4-alkylaryl- ao 26- 35- (diacetyl ordialkoxycarbonyl chain ao) electronic and steric effects onAOA and ARA of DHPs [44 45 51] see Sections 331and 35 The bell-shaped dependence of DHPs AOA onthe 35-dialkoxycarbonyl- chain length was observed [4445 107 109 112] with the maximum activity at C
2H5ndash
C4H9 Decrease of AOA and incorporation into liposomes for
DHPs with alkyl chains longer than R gt C4H9further were
clarified as probable tendency to self-aggregation of thesecompounds ([51] and citation number 245 therein) Electronacceptorelectron donor properties are relevant for expres-sion of AOA or ARA of 35-disubstituted DHPs 35-Diacyl-substituted and 35-dicarbanilido- and 35-dipyridylamido-substituted DHPs are more active as AOs as their 35-dicyano-substituted analogues which have electron acceptorproperties [186]
Dubur et al [89] observed overwhelming steric influenceof substituents in position 4 of the DHP ring Gaviraghiet al [163 164] proposed that AO activity of DHPs ispartly dependent on capacity of the 14-DHP ring to donateelectrons to the propagating radical (ROO∙ or RO∙) and toreduce it to a less reactive form The abstraction (donation)of electron andor H in the oxidation and LP reactionstakes place from all 35-dicarbonyl-14-DHP systems andresults in the formation of corresponding pyridine derivatives(Augustyniak et al [51]) The physicochemical mechanism ofARA and AOA of 14-DHP has been extensively studied anddiscussed (Mulder et al [236]) but precise mechanisms oftheir activity need further clarification
The reactivity of C-4 substituted 14-DHPs possessingeither secondary or tertiary nitrogen atom in the DHP ringtoward alkyl alkylperoxyl radicals and ABTS radical cationwas determined in aqueous media at pH 74 [103] Thesecompounds reacted faster toward alkylperoxyl radicals andABTS radical cation than alkyl ones N-Ethyl-substitutedDHPs showed the lowest reactivity
The 4-methyl substituted DHP was the most reac-tive compound in previously mentioned reactions (Lopez-Alarcon et al [103]) However it was less active (068versus 10) than Trolox-C DHPs having electron-donatingsubstituents (4-Me-DHP and p-MeO-Phe-DHP) showed thehighest kinetic rate constants toward ABTS radical cation p-nitro-Phe-DHP a compound with an electron-withdrawingsubstituent showed a lower kinetic rate constant and N-alkyl-DHP compounds show kinetic rate constants lowerthan the -NH-DHP
Hydrogen at the 1-position of the DHP ring was revealedaccording to the deuteriumkinetic isotope effect studies to beinvolved in the proposedARAmechanismThis fact ismostlynoticeable in the case of alkyl radicals N-Ethyl-substitutedDHPs show the lowest reactivity when compared to Troloxor nisoldipine In all cases the respective pyridine derivativewas detected as the main product of the reaction (Lopez-Alarcon et al [103]) Authors indicate that the kinetic rateconstants toward alkyl alkylperoxyl andABTS radical cationdepend on the nature of the substituents in the C-4 positionof DHP and the presence of the secondary amine group in the
dihydropyridine ring that is the presence of the hydrogen in1-position
Yanez et al [197] have studied the reactivity of 11derivatives of 14-DHPs (including commercial CA) withalkylperoxyl radicals and ABTS radical cation The tested14-DHPs were 83-fold more reactive towards alkylperoxylradicals than to the ABTS cation radical All commercial14-DHP type CCBs were weaker than Trolox-C The par-ticipation of the hydrogen atom in the 1-position appearsto be very relevant for exhibited reactivity Hantzsch ester(diludine)was again found to be themost active compound inthe reaction with alkylperoxyl radicals 23-fold more activethan Trolox The photodegradation product of nifedipine(nitrosophenyl derivative of pyridine) also showed a highactivity Kinetic rate constants for the reaction between 14-DHP compounds and alkylperoxyl radicals exhibited a fairlygood linear correlation with the oxidation peak potentialof DHP derivatives However the activity of tested 14-DHPs towards ABTS radical cation showed an independencebetween kinetic rate constants and oxidation peak potentials
Kirule et al [195] andTirzit et al [196] studiedmechanismof AOA of 4-nitrophenyl-14-DHPs nifedipine and its ana-logues involving formation of 4-(21015840-nitrosophenyl)-pyridinederivative (as active principle) as a result of intramolecularredox reaction using chemical electrochemical and bio-chemical approaches (see Sections 331 and 351)
Nunez-Vergara et al [237] reported the electrochemicaloxidation of C4-hydroxyphenyl-substituted 14-DHP deriva-tives The oxidation proceeds via formation of the unstabledihydropyridyl radical as confirmed by controlled-potentialelectrolysis (CPE) and ESR experiments This type of 14-DHPs has significant activity towards the radicals even whencompared with commercial 14-DHP drugs with well-knownantioxidant ability
It was observed that nicardipine preferentially targets RO∙radicals and is inactive against ROO∙ Lacidipine on theother hand is equally active towards both types of radicals(Gaviraghi et al [164]) The cytoprotective effect againstexposure to H
2O2was more significant for lacidipine (ID
50=
14 nM its log119875 = 54 membrane partition = 136000 assumesposition located 7 A near to the membrane center otherless lipophilic DHPs located 12ndash16 A far from the center)as compared to amlodipine nifedipine and nicardipine insmooth muscle cell culture (Gaviraghi et al [164]) Oxidativeeffect of H
2O2shifts the Ca channel toward an open state
Thus the redox property of CCBs DHPs may augment theirCCB properties
Oxidation of pharmacologically active Hantzsch 14-dihydropyridines was found by electrogenerated superoxideusing a voltammetric approach in DMSO solutions (Ortiz etal [238] and Ortiz et al [239]) Raghuvanshi and Singh [240]have also reported oxidative aromatization of these DHPsinduced by superoxide
Chemiluminescence (CL) was used in the studies ana-lyzing the antioxidant activity of 12 various 4-flavonil-14-dihydropyridine derivatives (Kruk et al [241]) on a chemicalsystem involving a superoxide radical anion These deriva-tives showed structural similarity to flavonoids with respectto the presence of rings A B and C The results obtained in
24 Oxidative Medicine and Cellular Longevity
this study indicate that the tested derivatives may catalyzeconversion of superoxide radicals through mimicking theactivity of superoxide dismutase by delivering H+ for reac-tion
O2
minus∙+O2
minus∙+ 2H+ 997888rarr H
2O2+1O2
(3)
The enhanced emission of the light in the presence oftested compounds was significant and related to stimulatedproduction ofH
2O2and 1O
2fromO
2
∙The latter specieswereremoved from the reactionmixture by the following sequenceof reactions
H+
O2
minus∙997888rarr HO
2
∙
HO2
∙+O2
∙minus997888rarr HO
2
minus+1O2
2HO2
∙997888rarr H
2O2+1O2
2 (1O2) 997888rarr (O
2)2+ h]lowast
(4)
or to take part in spontaneous dismutation of H2O2
2H2O2997888rarr 2H
2O + 1O
2(5)
The authors have offered an original concept of action for 4-flavonil-14-dihydropyridine derivatives unrelated to that ofO2
∙ radical-trapping chain-breaking antioxidants Insteadthey showed that these compounds act similar to superoxidedismutases converting O
2
∙ to H2O2 Hydrogen peroxide
is less toxic for cells than O2
∙ because it is predominantlyremoved by peroxidases and catalases Finally AO effect ofthese DHPs differed from those mediated by flavonoids witha catechol structure of ring B which are well-known 1O
2
quenchersMulder and collaborators came to similar conclusions
especially related to molecular mechanisms of antioxidativeactivity of DHPs [236]TheAOproperties of Hantzsch 14-di-hydropyridine esters and two dibenzo-14-dihydropyridines910-dihydroacridine (DHAC) and N-methyl-910-dihydro-acridine (N-Me-DHAC) have been explored by determin-ing the autoxidation of styrene or cumene at 30∘C Theseexperiments showed that Hantzsch esters are virtually inac-tive as chain-breaking antioxidants (CB-AOs) contrary tothe findings observed by Lopez-Alarcon et al [103] whoused CB-AOA in aqueous media at pH 74 Their reactivitytoward peroxyl radicals was shown to be some 5 orders ofmagnitude lower than that of the excellent CB-AO 22578-pentamethyl-6-hydroxy-chroman (PMHC)
DHAC was found to be sim10 times less reactive thanPMHC kinetic measurements using DHAC N-deuterio-DHAC and N-Me-DHAC pointing out the abstraction ofN-H hydrogen in DHAC by peroxyl radicals despite the factthat the calculated C-H bond dissociation enthalpy (BDE) inDHAC is about 11 kcalmol lower than the N-H BDE Therates of hydrogen atom abstraction by the 22-diphenyl-1-picrylhydrazyl radical (DPPH∙) have also been determined
for the same series of compounds The trends in the peroxyl∙and DPPH∙ rate constants were found to be similar [236]
Tirzit et al [242] have observed quenching of singletoxygen by DHPs This observation paved the ground forfurther research related to reactions of DHPs with hydroxylradicals (Tirzit et al [243]) singlet oxygen (Kazush etal [94]) and mechanisms of action A series of 14-DHPderivatives in NAD-H-Cu2+-H
2O2system inhibited forming
of the hydroxyl radical (HO∙) while 14-DHP derivativeswith electron donor substituents in the molecule were shownto be capable themselves of generating HO∙ in the presenceof Cu2+ and H
2O2 Rubene et al [186] also described
interaction of 14-DHP derivatives with Fentonrsquos reagentwhich produces hydroxyl radical (HO∙) Rate constants ofthe DHPs reaction (1st order) with HO∙ radical were highin the range 109 L times mol times secminus1 close to that of NADHcysteine and thiourea 35-Diacetyl- derivatives reacted fastercompared to 35-dialkoxycarbonyl- ones The reaction ratedecrease was observed in the case of substitution at position4 as compared to 4-unsubstituted DHPs Some DHPs havingelectron donor -COOminus groups in the 35- or 26- positionsof DHP ring reacted immediately (having rate constantshigher as 109 L times mol times secminus1) Rate constants with HO
2
∙
and O2
∙minus radicals were of lower degree Thus DHPs actingas oxygen radical scavengers could effectively inhibit ROSrelated reactions of LP initiation stage
Nifedipine and nitrendipine reactivity toward singletoxygen was also studied [244] Nifedipine was shown tobe a good scavenger of excited oxygen mainly via physicaldeactivation with values of the total rate constant rangingfrom 208 times 105Mminus1 sminus1 (in dioxane) to 930 times 105Mminus1 sminus1(in propylene carbonate)The less reactive pathway generateda photooxidation product For that reason a mechanisminvolving a perepoxide-like encounter complex in the firststep of the reaction path was proposed (see [244] Figures8 and 9 therein) The dependence was observed on solventmicroscopic parameters of the total rate constant for the reac-tion between singlet oxygen and 14-DHPs These findingsshow that nifedipine possesses stronger protective activity inbiological systems than nitrendipine
Density-functional-theory (DFT) calculations made byWang et al [245] confirmed the former experimental obser-vations that Hantzsch ester diludine is potent antioxi-dant with high H atom-donating ability and relatively lowprooxidant activity Possible reaction pathways for radicalsderived from 14-dihydropyridine and the resonance modesfor radical species were given [245]
Moreover two ethoxycarbonyl (EtOCO) substituentsat C(2) and C(6) should further enhance Hantzsch esterdiludine H-atom-donating ability due to resonance effectsHowever DHPs should be used in nonpolar rather than inpolar solvents since in the latter not H-atom but electrontransfer is preferred in the radical scavenging process [245]
Mulder et al [246] proposed that quantum-thermochem-ical calculations must be used with caution to indicate ldquoapromising lead antioxidantrdquo as they criticized the density-functional-theory (DFT) calculations made by Wang et al[245]
Oxidative Medicine and Cellular Longevity 25
372 Possible Mechanisms of DHPs ARA and AOA in the Bio-logical Systems Interaction with Other OSModifiers Some ofthese mechanisms were already described (Sections 331 (2)-(b) 331 (2)-(c) 331 (3)-(b) 35)
Enzymatic sources of ROSwith confirmed functional rolein hypertension are NADPH oxidase NO synthase (NOS)xanthine oxidase and cyclooxygenase Godfraind [3] hasreviewed AO effects and protective action of calcium channelblockers (CCBs) Yao et al [247] observed antioxidant effects(as inhibition of LP) for cardio- and neuroprotective CCBs(3ndash300 120583molL) including 7 DHPs in homogenates of ratbrain IC
50values (120583M) were as follows nifedipine (515) gt
barnidipine (586) gt benidipine (712) gt nicardipine (1293)gt amlodipine (1355) gt nilvadipine (1673) gt nitrendipine(2521) gt diltiazem (gt300) = verapamil (gt300) There arealso research articles describing the AO properties of CCBsthrough direct scavenging effect or through preservationof the endogenous SOD activity These findings indicatethat CCBs may also act by reducing the production ofvasoconstrictors angiotensin and endothelin
When present in concentrations that can be achievedin plasma CCBs may inhibit LP formation [3] This AOactivity seems to be typical for high lipophilic CCBs becausetheir chemical structure facilitates proton-donating andresonance-stabilization mechanisms that quench the freeradical reaction Their insertion in the membrane nearpolyunsaturated fatty acids at relatively high concentrationspotentiates proton donation (or atomary H) to lipid peroxidemolecules thereby blocking the peroxidation process Theremaining unpaired free electron associated with the CCBmolecule can be stabilized in well-defined resonance struc-tures associated with the DHP ring (Mason et al [48])
The radical reaction (according to Godfraind [3]) thatdescribes the AO effects of a DHP CCBs is LOOlowast + DHPrarr LOOH + DHPlowast (where LOOlowast is lipid peroxide radical)which in general is reaction (7) of the LP reaction cascadeconsisting of sim10 reactions (Scheme 2) [89]
As the rate constants of in vitro interaction of 4-substituted DHPs with peroxyl radicals are three ordersof magnitude lower than that of the vitamin E derivativethese DHPs must be considered as weak AO (Ursini [204])However due to partition coefficient of DHPs in membranesand in case of specific binding high local concentration ofDHPs may be obtained
DHPs without CCB properties for instance Bay w 9798although structurally related to nifedipine inhibit TNF-120572-induced vascular cell adhesion molecule-1 expression inendothelial cells by suppressing reactive oxygen speciesgeneration [248]
Mitrega et al [249] have discovered that antiarrhythmicand hemodynamic effects of oxidized heteroaromatic DHPsoxy nifedipine oxy nimodipine oxy nitrendipine and oxynisoldipine suggest that CCB DHPs and their metabolitescould act at least in two ways targeting OS related eventsas reductants (see Section 351 (1)) andor bypassing OSrelatedmetabolic routes Authors postulated that contrary tocurrent belief NIF metabolites are pharmacologically activeATP sensitive potassium channels were mentioned as a tar-get
38 DHPs Anti- or Prooxidants Several substances (ascorbicacid being the most commonly studied) can serve either asantioxidants or as prooxidants depending on given condi-tions (Herbert [250]) Therefore Halliwell [251] has reporteddilemma related to polyphenols as possible antioxidantsand prooxidants causing experimental artifacts (about 25)by oxidation of antioxidant compounds in the cell culturemedia Nevertheless it is generally accepted opinion thatpolyphenols act as antioxidants in vivo Studies on DHPs alsoface such a dilemmaThe exact roles (anti- or prooxidative) ofany specific DHP depend on its structure appliedachievedconcentration and specificity of the targetexperimentaltesting system
This situation resembles the case of antioxidative effectsof tocopherol which depends on the fate of the secondaryradical as proposed by Winterbourn [252] The question wasldquoVitamin E - Pro- or Antioxidantrdquo
997888rarr chain termination of lipid peroxidation
(6)
Prooxidant
Toc∙ + Lipid-H 997888rarr Lipid∙ (in LDL particles) (7)
This example shows that generally speaking any AO mustfulfil several criteria to be considered as an effective com-pound physiologically
(i) It must be able to functionally interact with endoge-nous scavengers even at low concentrations
(ii) It must affect endogenous pathways of OS(iii) It should not have undesirable adverse effect(iv) It should manifest the antioxidant efficacy dependent
on the oxidant(v) It must discriminate among different strategies
needed for 1-electron and 2-electron processes(vi) Radical scavengers can be prooxidant unless linked to
a radical sink (Winterbourn [252])
According to these statements DHPs could be effective asAO under physiological conditions in vivo (Godfraind [3]and others [30 31 38]) and in vitro in various experimentalsystems (cell and tissue) (see Sections 33 34 35)
Hence calcium antagonists appeared to disrupt thefine balance between the production and scavenging ofROS Nifedipine verapamil and diltiazem were shown toinduce significant oxidative stress in the epididymal sperm(increased MDA and decreased catalase and superoxidedismutase activity) This may be the reason for the inductionof male infertility [253]
The dualism of 14-DHP effects has been recorded asinhibition or promotion of LP as quenching or initiating
26 Oxidative Medicine and Cellular Longevity
oxygen and nitrogen free radical chain reactions radiopro-tecting or radiosensitizing antagonizing or synergizing Ca2+in electromechanical coupling as well as in the membranestabilization or labilization
39 Could DHPs Be Involved in Antioxidative Stress Beforebeing applied in vivo the optimal dose and optimal timeintervals forDHPs applicationmust be knownNamely whileROS have been traditionally considered as toxic byproductsof aerobic metabolism we know nowadays that ROS may actas essential signaling molecules needed for the control ofmany different physiological processes Whether the role ofROS will be damaging protective or signaling depends onthe delicate equilibrium between time- and location-specificROS production and scavenging Accordingly the imbalanceof the increased AO potential so-called antioxidative stresscould be dangerous similar to chronic OS in particular incase of extended exposure Inappropriate interventions inthe oxidative homeostasis by excessive antioxidants especiallyin case of chronic exposure to antioxidants might havevery negative effects as was published in the ATBC studyshowing an increased cancer incidence in smokers treatedby excessive beta-carotene [254] Therefore overconsump-tion of any natural or synthetic AO including DHPs asdietary supplements or drugs must be avoided in order tosuppress oxidative damage and must not disrupt the well-integrated antioxidant defense network (Poljsak [255] andPoljsak and Milisav [256]) This is especially important whenadministrating lipid-soluble antioxidants that can be storedin biomembranes thus not only attenuating or preventing LPbut also affecting physiological effects of the natural antiox-idants in particular tocopherol The interrelationship withthe status of endogenous antioxidantsprooxidants should befollowed
DHPs primarily suppress the initiation stages of LPprocessThey do not entirely stop the LP propagation Actingsynergistically with tocopherol diludine may prevent patho-logical excess of ROS production within the lipid moiety ofthe cellular membranes and LDL However due to its lowsolubility and fast metabolism its concentration in the cellsis low For that reason it cannot cause antioxidative stresseven if used for an extended period of time Thus diludine(diethone) could be only a mild antioxidant it has potentialfor restoring the pool of natural antioxidants (as synergist of120572-tocopherol and polyphenols) in the cells
Moreover DHPs CA used for cardioprotection andvasodilatation as commercial drugs in low concentrationsare fast metabolized via CYP3A4 and for that reason theirapplication does not induce cellular AO stress [53 160]However Godfraind and Salomone [257] have postulated noevidence that allows recommending dietary supplementationwith antioxidants for the primary or secondary prevention ofcardiovascular disease
So far there are no reports on antioxidative stress causedby some DHPs diludine and its analogues Diludine andits analogues therefore could act as adaptogens supportinghormetic effects of mild oxidative stress These compoundsmay act as potential multisided modulators of Yin-Yang
cycles of redox and cell functions (the electroplasmic cycle)(Wagner et al [258])
4 Conclusions
14-Dihydropyridines (14-DHPs) have broad spectrum ofOS modulating activities DHPs have reducing and lipidperoxidation inhibitor properties act as reductants in simplechemical systems and stabilize various biological systems(LDL mitochondria microsomes cells and tissues) againstOS Examples and peculiarities and mechanisms of antiox-idant activity (AOA) and antiradical activity (ARA) as wellas stress-protective effect of DHPs including commercialcalcium antagonists (CA) were highlighted These activitiesdepend on various structural parameters related to DHPs(presence and character of substituents) lipophilicity anddepth of the incorporation in the biologicalmembranesTheyalso depend on the experimental model system for exploringthe lipid peroxidation or oxidative stress Stress-protectiveeffect of some metabolites of CA (nifedipine) is reviewedAlthough some DHPs including CA have prooxidant prop-erties (on epididymal sperm cells) they can generally beconsidered as potent antioxidants Therefore comparisonof the AOA and ARA of different DHPs (mutually andwith other AOs) was described in detail According to thedata presented the DHPs might be considered as bellwetheramong synthetic compounds targeting OS and as a kind ofpharmacological measure for respective field of organic andmedicinal chemistry
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
Authors from Latvian IOS acknowledge ESF 201300021DP1112013APIAVIAA011 and National Research Pro-gramme PUBLIC HEALTHBiomedicine of the Republicof Latvia for financial support administration of the Insti-tute for technical support and Rufus Smits PhD for con-sultations in English The support of Cooperation in Euro-pean System of Science and Technology (COST) Domain ofChemistry Molecular Sciences and Technologies (CMST)was of highest importance for preparation of this paper
[2] D J Triggle ldquo14-Dihydropyridines as calcium channel ligandsand privileged structuresrdquoCellular andMolecular Neurobiologyvol 23 no 3 pp 293ndash303 2003
[3] T Godfraind ldquoAntioxidant effects and the therapeutic modeof action of calcium channel blockers in hypertension andatherosclerosisrdquo Philosophical Transactions of the Royal SocietyB Biological Sciences vol 360 no 1464 pp 2259ndash2272 2005
[4] E Cadenas ldquoMitochondrial free radical production and cellsignalingrdquoMolecular Aspects of Medicine vol 25 no 1-2 pp 17ndash26 2004
[5] E Cadenas ldquoFree radicals oxidative stress and diseasesrdquo inLecture PSC 616 p 38 Missouri University of Science andTechnology Rolla Mo USA httpwwwcarnicominstituteorgarticlesenrique cadenaspdf
[6] K Rahman ldquoStudies on free radicals antioxidants and co-fac-torsrdquo Clinical Interventions in Aging vol 2 no 2 pp 219ndash2362007
[7] V Bocci and G Valacchi ldquoFree radicals and antioxidants howto reestablish redox homeostasis in chronic diseasesrdquo CurrentMedicinal Chemistry vol 20 no 27 pp 3397ndash3415 2013
[8] M Valko C J Rhodes J Moncol M Izakovic and M MazurldquoFree radicals metals and antioxidants in oxidative stress-induced cancerrdquo Chemico-Biological Interactions vol 160 no 1pp 1ndash40 2006
[9] G Bartosz ldquoReactive oxygen species destroyers or messen-gersrdquo Biochemical Pharmacology vol 77 no 8 pp 1303ndash13152009
[10] R Visconti and D Grieco ldquoNew insights on oxidative stress incancerrdquo Current Opinion in Drug Discovery and Developmentvol 12 no 2 pp 240ndash245 2009
[11] R N Kujundzic N Zarkovic and K G Troselj ldquoPyridinenucleotides in regulation of cell death and survival by redoxand non-redox reactionsrdquo Critical Reviews in Eukaryotic GeneExpression vol 24 no 4 pp 287ndash309 2014
[12] B Halliwell and J M C Gutteridge ldquoThe definition and mea-surement of antioxidants in biological systemsrdquo Free RadicalBiology and Medicine vol 18 no 1 pp 125ndash126 1995
[13] V D Kancheva and O T Kasaikina ldquoBio-antioxidantsmdashachemical base of their antioxidant activity and beneficial effect
on human healthrdquo Current Medicinal Chemistry vol 20 no 37pp 4784ndash4805 2013
[14] H V Panglossi Ed Frontiers in Antioxidants Research NovaScience Publishers New York NY USA 2006
[15] E B Burlakova E M Molochkina and G A NikiforovldquoHybrid antioxidantsrdquo Oxidation Communications vol 31 no4 pp 739ndash757 2008 httpmembraneustceducnpaperpdfHybrid20Antioxidantspdf
[16] A Bast and G R M M Haenen ldquoTen misconceptions aboutantioxidantsrdquo Trends in Pharmacological Sciences vol 34 no 8pp 430ndash436 2013
[17] E B Burlakova A V 0lesenko E M Molochkina N PPalmina and N G Khrapova Bioantioxidants for RadiationDamage and Malignant Growth Nauka Moscow Russia 1975(Russian)
[18] J Fang T Seki and H Maeda ldquoTherapeutic strategies by mod-ulating oxygen stress in cancer and inflammationrdquo AdvancedDrug Delivery Reviews vol 61 no 4 pp 290ndash302 2009
[19] M Valko D Leibfritz J Moncol M T D Cronin M Mazurand J Telser ldquoFree radicals and antioxidants in normal physi-ological functions and human diseaserdquo International Journal ofBiochemistry and Cell Biology vol 39 no 1 pp 44ndash84 2007
[20] M Jimenez-Del-Rio and C Velez-Pardo ldquoThe bad the goodand the ugly about oxidative stressrdquo Oxidative Medicine andCellular Longevity vol 2012 Article ID 163913 13 pages 2012
[21] C D Kamat S Gadal M Mhatre K S Williamson Q N Pyeand K Hensley ldquoAntioxidants in central nervous system dis-eases preclinical promise and translational challengesrdquo Journalof Alzheimerrsquos Disease vol 15 no 3 pp 473ndash493 2008
[22] A Pompella H Sies R Wacker et al ldquoThe use of totalantioxidant capacity as surrogate marker for food quality andits effect on health is to be discouragedrdquo Nutrition vol 30 no7-8 pp 791ndash793 2014
[23] Z Ye and H Song ldquoAntioxidant vitamins intake and the risk ofcoronary heart disease meta-analysis of cohort studiesrdquo Euro-pean Journal of Cardiovascular Prevention and Rehabilitationvol 15 no 1 pp 26ndash34 2008
[24] P Knekt J Ritz M A Pereira et al ldquoAntioxidant vitamins andcoronary heart disease risk a pooled analysis of 9 cohortsrdquoTheAmerican Journal of Clinical Nutrition vol 80 no 6 pp 1508ndash1520 2004
[25] A C Carr and M C M Vissers ldquoSynthetic or food-derivedvitamin Cmdashare they equally bioavailablerdquo Nutrients vol 5 no11 pp 4284ndash4304 2013
[26] R Tabrizchi ldquoEdaravoneMitsubishi-TokyordquoCurrentOpinion inInvestigational Drugs vol 1 no 3 pp 347ndash354 2000
[27] K Kikuchi S Tancharoen N Takeshige et al ldquoThe efficacy ofedaravone (radicut) a free radical scavenger for cardiovasculardiseaserdquo International Journal of Molecular Sciences vol 14 no7 pp 13909ndash13930 2013
[28] D Mauzerall and F H Westheimer ldquo1-Benzyldihydronicoti-namidemdasha model for reduced DPNrdquo Journal of the AmericanChemical Society vol 77 no 8 pp 2261ndash2264 1955 ChemicalAbstracts vol 50 Article ID 2588i 1956
[29] F Bossert and W Vater ldquo14-Dihydropyridinesmdasha basis fordeveloping new drugsrdquo Medicinal Research Reviews vol 9 no3 pp 291ndash324 1989
[30] G Swarnalatha G Prasanthi N Sirisha and CMadhusudhanaChetty ldquo14-Dihydropyridines a multtifunctional moleculemdash areviewrdquo International Journal of ChemTech Research vol 3 no1 pp 75ndash89 2011
28 Oxidative Medicine and Cellular Longevity
[31] M Cataldi and F Bruno ldquo14-Dihydropyridines the multiplepersonalities of a blockbuster drug familyrdquo Translational Medi-cine UniSa vol 4 no 2 pp 12ndash26 2012 httpwwwncbinlmnihgovpmcarticlesPMC3728803
[32] R Vitolina A Krauze G Duburs and A Velena ldquoAspects ofthe amlodipine pleiotropy in biochemistry pharmacology andclinicsrdquo International Journal of Pharmaceutical Sciences andResearch vol 3 no 5 pp 1215ndash1232 2012
[33] D Grover S N Mokale and M T Shete ldquoDihydropyridinea novel pharmacophorerdquo International Journal of Pharmaceu-tical Erudition vol 1 no 2 pp 16ndash29 2011 httppharmaeru-ditionorgContentPaper20111-RV-320Final2016-29pdf
[34] A M Vijesh A M Isloor S K Peethambar K N ShivanandaT Arulmoli and N A Isloor ldquoHantzsch reaction synthesis andcharacterization of somenew 14-dihydropyridine derivatives aspotent antimicrobial and antioxidant agentsrdquo European Journalof Medicinal Chemistry vol 46 no 11 pp 5591ndash5597 2011
[35] P Mehta and P Verma ldquoAntimicrobial activity of some deriva-tives of 14-dihydropyridinesrdquo Journal of Chemistry vol 2013Article ID 865128 4 pages 2013
[36] P Olejnıkova L Svorc D Olsovska et al ldquoAntimicrobialactivity of novel C2-substituted 14-dihydropyridine analoguesrdquoScientia Pharmaceutica vol 82 no 2 pp 221ndash232 2014
[37] S Sepehri H Perez Sanchez and A Fassihi ldquoHantzsch-typedihydropyridines and biginelli-type tetra-hydropyrimidinesa review of their chemotherapeutic activitiesrdquo Journal of Phar-macy amp Pharmaceutical Sciences vol 18 no 1 pp 1ndash52 2015httpsejournalslibraryualbertacaindexphpJPPSarticleview2383617863
[38] S A Khedkar and P B Auti ldquo14-Dihydropyridines a classof pharmacologically important moleculesrdquo Mini-Reviews inMedicinal Chemistry vol 14 no 3 pp 282ndash290 2014
[39] G D Tirzit and G Ya Duburs ldquo14-dihydropyridines as inhi-bitors of free-radical reactionsrdquo Chemistry of Heterocyclic Com-pounds vol 8 no 1 pp 126ndash127 1972 Translated from KhimiyaGeterotsiklicheskikh Soedinenii no1 pp 133ndash134 1972 (Rus-sian)
[40] I Bogeski R Kappl C Kummerow R Gulaboski M Hothand B A Niemeyer ldquoRedox regulation of calcium ion channelschemical and physiological aspectsrdquoCell Calcium vol 50 no 5pp 407ndash423 2011
[41] S A Giller G Y Dubur Y R Uldrikis et al ldquoDiludine [Themethod to obtain 35-dicarbonylderivatives of 26-dimethyl-14-dihydropyridines]rdquo Authors certificate of USSR no 3004651971 [Byull Izobret no13 p 95 1971] and following patentsPatent of England no 1294650 1973 Patent of France no2055458 1971 Patent of Japan no 702883 1973 Patent ofHolland no 149787 1976 Patent of Italy no 969022 1974 Patentof FRG no 2036403 1978 US Patent no 3883673 1975 USPatent no 3948924 1976
[42] S A Giller G Y Dubur Y R Uldrikis et al ldquoImprovementsin or relating to the stabilization of carotenerdquo GB Patent no1294650 1972
[43] S A Giller G Y Dubur Y R Uldrikis et al ldquoStabilization ofcarotenerdquo US Patent no 3883673 1975 Chemical Abstracts vol83 Article ID 95193 1975
[44] Yu A Zilber G Ya Dubur K K Kumsar and A Kh VelenaldquoThe effect of antioxidants on the peroxidation of bimole-cular phospholipid membranesrdquo Latvijas PSR ZA Vestis Izves-tia Akademii Nauk Latviyskoy SSR vol 6 pp 80ndash82 1971(Russian) translated from the original Russian Doc Accesion
No AD0771751 distributed by NTIS US Department of Com-merce httpwwwdticmildtictrfulltextu2771751pdf
[45] G Ya Dubur Yu A Zilbers A Kh Velena A O Kumerovaand G D Tirzitis ldquoMultistage study of regulation of peroxida-tion processes in biological membranes by antioxidants of 14-dihydropyridine grouprdquo Izvestiya Akademii Nauk LatviyskoySSR vol 336 no 7 pp 65ndash68 1975 (Russian)
[46] R P Mason and M W Trumbore ldquoDifferential membraneinteractions of calcium channel blockers Implications forantioxidant activityrdquo Biochemical Pharmacology vol 51 no 5pp 653ndash660 1996
[47] R P Mason M F Walter M W Trumbore E G Olmstead Jrand P E Mason ldquoMembrane antioxidant effects of the chargeddihydropyridine calcium antagonist amlodipinerdquo Journal ofMolecular and Cellular Cardiology vol 31 no 1 pp 275ndash2811999
[48] R PMason I T MakMW Trumbore and P EMason ldquoAnti-oxidant properties of calcium antagonists related to membranebiophysical interactionsrdquo American Journal of Cardiology vol84 no 4 pp 16ndash22 1999
[49] R PMasonMW Trumbore and P EMason ldquoMembrane bio-physical interaction of amlodipine and antioxidant propertiesrdquoDrugs vol 59 no 2 pp 9ndash16 2000 (French)
[50] R P Mason P Marche and T H Hintze ldquoNovel vascularbiology of third-generation L-type calcium channel antagonistsAncillary actions of amlodipinerdquo Arteriosclerosis Thrombosisand Vascular Biology vol 23 no 12 pp 2155ndash2163 2003
[51] A Augustyniak G Bartosz A Cipak et al ldquoNatural andsynthetic antioxidants an updated overviewrdquo Free RadicalResearch vol 44 no 10 pp 1216ndash1262 2010
[52] T Grune N Zarkovic and K Kostelidou ldquoLipid peroxidationresearch in Europe and the COST B35 action lsquoLipid Peroxida-tion Associated Disordersrsquordquo Free Radical Research vol 44 no10 pp 1095ndash1097 2010
[53] E Carosati P Ioan M Micucci et al ldquo14-Dihydropyridinescaffold in medicinal chemistry the story so far and perspec-tives (part 2) action in other targets and antitargetsrdquo CurrentMedicinal Chemistry vol 19 no 25 pp 4306ndash4323 2012
[54] U Eisner and J Kuthan ldquoThe chemistry of dihydropyridinesrdquoChemical Reviews vol 72 no 1 pp 1ndash42 1972 httpwwwsci-encemadnessorgtalkfilesphppid=138742ampaid=6475
[55] J Kuthan and A Kurfurst ldquoDevelopment in dihydropyri-dine chemistryrdquo Industrial amp Engineering Chemistry ProductResearch and Development vol 21 no 2 pp 191ndash261 1982
[56] A Sausins and G Duburs ldquoSynthesis of 14-dihydropyridinesby cyclocondensation reactionsrdquo Heterocycles vol 27 no 1 pp269ndash289 1988
[57] A E Sausins and G Y Duburs ldquoSynthesis of 14-dihydro-pyridines in cyclocondensation reactions (review)rdquo Chemistryof Heterocyclic Compounds vol 28 no 4 pp 363ndash391 1992Translated from Khimiya Geterotsiklicheskikh Soedinenii no 4pp 435ndash467 1992 (Russian)
[58] S Kazda ldquoTwenty years of dihydropyridinesrdquo in Dihydropy-ridines Progress in Pharmacology and Therapy W-D Busse BGarthoff and F Seuter Eds pp 1ndash12 Springer Verlag BerlinGermany 1993
[59] J-P Wan and Y Liu ldquoRecent advances in new multicomponentsynthesis of structurally diversified 14-dihydropyridinesrdquo RSCAdvances vol 2 no 26 pp 9763ndash9777 2012
[61] Reaxys Database[62] J Tuttle ldquoStructure mechanism and reactivity of hantzsch
estersrdquo in MacMillan Lab Group Meeting (082504) p 332004 httpwwwprincetoneduchemistrymacmillangroup-meetingsJBT20Hantzschpdf
[63] A Saini S Kumar and J S Sandhu ldquoHantzsch reaction recentadvances in Hantzsch 14-dihydropyridinesrdquo Journal of Sci-entific amp Industrial Research vol 67 pp 95ndash111 2008
[64] L LW Cheung S A Styler and A P Dicks ldquoRapid and conve-nient synthesis of the 14-dihydropyridine privileged structurerdquoJournal of Chemical Education vol 87 no 6 pp 628ndash630 2010
[65] A Kumar R A Maurya S Sharma M Kumar and G BhatialdquoSynthesis and biological evaluation of N-aryl-14-dihydro-pyridines as novel antidyslipidemic and antioxidant agentsrdquoEuropean Journal of Medicinal Chemistry vol 45 no 2 pp 501ndash509 2010
[66] R S Kumar A Idhayadhulla A J Abdul Nasser and J SelvinldquoSynthesis and anticoagulant activity of a new series of 14-dihydropyridine derivativesrdquo European Journal of MedicinalChemistry vol 46 no 2 pp 804ndash810 2011
[67] H A Stefani C B Oliveira R B Almeida et al ldquoDihydro-pyrimidin-(2H)-ones obtained by ultrasound irradiation anew class of potential antioxidant agentsrdquo European Journal ofMedicinal Chemistry vol 41 no 4 pp 513ndash518 2006
[68] H Sun C Shang L Jin and J Zhang ldquoSynthesis and antiox-idant activity of a series of novel 3-chalcone-substituted 14-dihydropyridine derivativesrdquoHeterocyclic Communications vol18 no 5-6 pp 239ndash243 2012
[69] D B Tikhonov and B S Zhorov ldquoStructural model for dihy-dropyridine binding to L-type calcium channelsrdquo The Journalof Biological Chemistry vol 284 no 28 pp 19006ndash19017 2009
[70] G Y Dubur and Y R Uldrikis ldquoThe oxidation of 14-dihydro-pyridinesrdquo Chemistry of Heterocyclic Compounds vol 6 no 1pp 80ndash84 1970 Translated from Khimiya GeterotsiklicheskikhSoedinenii no 1 pp 83ndash88 1970 (Russian)
[71] G Ya Duburs A O Kumerova and Ya R Uldrikis ldquoEnzymicoxidation of hydrogenated pyridines with peroxidase-hydrogenperoxide systemrdquoLatvijas PSRZAVestis vol 73 no 7 pp 73ndash771970 (Russian) Chemical Abstracts vol 73 Article ID 94913g1970
[72] K Xie Y-C Liu Y Cui J-GWang Y Fu andT CWMak ldquoN-methyl-(R)-3-(tert-butyl)-sulfinyl-14-dihydropyridine a novelNADHmodel compoundrdquoMolecules vol 12 no 3 pp 415ndash4222007
[73] S Tamagaki T Mimura and W Tagaki ldquoMetal-ion-facilitatedoxidations of dihydropyridines with molecular oxygen andhydrogen peroxiderdquo Journal of the Chemical Society PerkinTransactions 2 no 10 pp 1645ndash1650 1990
[74] D Tirzite G Tirzitis andD Antipova ldquoReductive ability of 14-dihydropyridine derivatives in relation to ions of trivalent ironrdquoChemistry of Heterocyclic Compounds vol 35 no 5 pp 592ndash594 1999
[76] J Ogle J Stradins and L Baumane ldquoFormation and decay offree cation-radicals in the course of electro-oxidation of 12- and14-dihydropyridines (Hantzsch esters)rdquo Electrochimica Actavol 39 no 1 pp 73ndash79 1994
[77] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for the
synthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts C Wittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Berlin Germany 2010
[78] WDu and Zh Yu ldquoBiomimetic in situ regeneration of cofactorsNAD(P)+ and NAD(P)H models hantzsch esters and dihy-drophenanthridinerdquo Synlett vol 23 no 9 pp 1300ndash1304 2012
[79] H K Chenault and G M Whitesides ldquoRegeneration ofnicotinamide cofactors for use in organic synthesisrdquo AppliedBiochemistry and Biotechnology vol 14 no 2 pp 147ndash197 1987
[80] Y R Uldrikis A A Zidermane E A Biseniex I E Preisa GY Dubur and G D Tirzit ldquoEsters of 26-dimethyl-14-dihydro-pyridine-35-dicarboxylic acid and method of obtainingthereofrdquo WO 8000345 A1 1978 httpworldwideespacenetcompublicationDetailsbiblioDB=EPODOCampII=1ampND=3ampadjacent=trueamplocale=en EPampFT=Dampdate=19800306ampCC=WOampNR=8000345A1ampKC=A1
[81] Y Sambongi H Nitta K Ichihashi M Futai and I Ueda ldquoAnovel water-soluble Hantzsch 14-dihydropyridine compoundthat functions in biological processes through NADH regener-ationrdquo Journal of Organic Chemistry vol 67 no 10 pp 3499ndash3501 2002
[82] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for thesynthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts ChWittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Verlag Berlin Germany 2010
[83] T Okamura T Kikuchi A Nagamine et al ldquoAn approach formeasuring in vivo cerebral redox states using the oxidative con-version of dihydropyridine to pyridinium ion and themetabolictrapping principlerdquo Free Radical Biology and Medicine vol 38no 9 pp 1197ndash1205 2005
[84] K A Schellenberg and F H Westheimer ldquoA free-radicaloxidation of a dihydropyridine1ardquo The Journal of OrganicChemistry vol 30 no 6 pp 1859ndash1862 1965
[85] K A Schellenberg ldquoReaction of hydroxyl radical with thymi-dine Scavenging by a dihydropyridinerdquo Federation Proceedingsvol 38 no 3 I p 1433 1979
[86] E S Huyser J A K Harmony and F L McMillian ldquoPeroxideoxidations of dihydropyridine derivativesrdquo Journal of the Amer-ican Chemical Society vol 94 no 9 pp 3176ndash3180 1972
[87] A Sakamoto S T Ohnishi and R Ogawa ldquoInhibition of lipidperoxidation by some dihydropyridine derivativesrdquo Journal ofAnesthesia vol 7 no 2 pp 193ndash197 1993
[88] R Hardeland ldquoReview Neuroprotection by radical avoidancesearch for suitable agentsrdquo Molecules vol 14 no 12 pp 5054ndash5102 2009
[89] G Ya Dubur A Kh Velena V M Gukasov and Yu AVladimirov ldquoRegulation of peroxidation of mitochondrialmembrane lipids initiated by Fe2+ ions by antoxidants of the14-dihydropyridine series in experiments in vitrordquo Biomed-itsinskaya Khimiya vol 22 no 5 pp 665ndash673 1976 (Russian)Chemical Abstracts vol 88 Article ID 2640 1977
[90] G RMMHaenenM J T J Arts A Bast andMD ColemanldquoStructure and activity in assessing antioxidant activity in vitroand in vivo a critical appraisal illustrated with the flavonoidsrdquoEnvironmental Toxicology and Pharmacology vol 21 no 2 pp191ndash198 2006
[91] G Tirzitis and G Bartosz ldquoDetermination of antiradical andantioxidant activity basic principles and new insightsrdquo ActaBiochimica Polonica vol 57 no 2 pp 139ndash142 2010
30 Oxidative Medicine and Cellular Longevity
[92] G R Buettner and R P Mason ldquoSpin-trapping methods fordetecting superoxide and hydroxyl free radicals in vitro and invivordquo inCritical Reviews of Oxidative Stress and Aging Advancesin Basic Science Diagnostics and Intervention R G Cutler andH Rodriguez Eds vol 1 chapter 2 pp 27ndash38World ScientificLondon UK 2003
[93] M M Tarpey and I Fridovich ldquoMethods of detection ofvascular reactive species Nitric oxide superoxide hydrogenperoxide and peroxynitriterdquo Circulation Research vol 89 no3 pp 224ndash236 2001
[94] E Y Kazush E I Sagun G D Tirzit and G Y DaburldquoQuenching of singlet oxygen by electron donating derivativesof 14-dihydropyridinerdquo Chemistry of Heterocyclic Compoundsvol 30 no 5 pp 562ndash563 1994
[95] G Tirzitis E Kazush and G Duburs ldquoReaction of 14-dihydropyridine derivatives with peroxynitrite anionrdquo Chem-istry of Heterocyclic Compounds vol 34 no 3 pp 321ndash3231998 (Russian) Translated from Khimiya GeterotsiklicheskikhSoedinenii no 3 pp 355ndash357 1998
[96] L J Nunez-Vergara C Lopez-Alarcon P A Navarrete-EncinaA M Atria C Camargo and J A Squella ldquoElectrochemicaland EPR characterization of 14-dihydropyridines Reactivitytowards alkyl radicalsrdquo Free Radical Research vol 37 no 1 pp109ndash120 2003
[97] D Tirzite A Krauze A Zubareva G Tirzitis and G DubursldquoSynthesis and antiradical activity of 5-acetyl-2-alkylthio-4-aryl-6-methyl-14-dihydropyridine-3-carboxylic acid nitrilesrdquoChemistry of Heterocyclic Compounds vol 38 no 7 pp 795ndash800 2002
[98] H Ohkawa N Ohishi and K Yagi ldquoAssay for lipid peroxidesin animal tissues by thiobarbituric acid reactionrdquo AnalyticalBiochemistry vol 95 no 2 pp 351ndash358 1979
[99] N Zarkovic ldquo4-Hydroxynonenal as a bioactive marker ofpathophysiological processesrdquo Molecular Aspects of Medicinevol 24 no 4-5 pp 281ndash291 2003
[100] M Parola G Bellomo G Robino G Barrera and M UDianzani ldquo4-Hydroxynonenal as a biological signal molecularbasis and pathophysiological implicationsrdquo Antioxidants andRedox Signaling vol 1 no 3 pp 255ndash284 1999
[101] T Lovakovic M Poljak-Blazi G Duburs et al ldquoGrowthmodulation of human cells in vitro by mild oxidative stressand 14-dihydropyridine derivative antioxidantsrdquo CollegiumAntropologicum vol 35 no 1 pp 137ndash141 2011
[102] R van den Berg G R M M Haenen H van den Bergand A Bast ldquoApplicability of an improved Trolox equivalentantioxidant capacity (TEAC) assay for evaluation of antioxidantcapacity measurements of mixturesrdquo Food Chemistry vol 66no 4 pp 511ndash517 1999
[103] C Lopez-Alarcon P Navarrete C Camargo J A Squella andL J Nunez-Vergara ldquoReactivity of 14-dihydropyridines towardalkyl alkylperoxyl radicals and ABTS radical cationrdquo ChemicalResearch in Toxicology vol 16 no 2 pp 208ndash215 2003
[104] V Valenzuela P Santander C Camargo J A Squella C Lopez-Alarcon and L J Nunez-Vergara ldquo14-Dihydropyridines reac-tivity of nitrosoaryl and nitroaryl derivatives with alkylperoxylradicals andABTS radical cationrdquo Free Radical Research vol 38no 7 pp 715ndash727 2004
[105] L G Tsetlin N A Chebotareva B I Kurganov A K VelenaG Y Dubur and V Z Lankin ldquoStudy of 14-dihydropyridinesas lipoxygenase inhibitors with the use of hydrated reversedmicellesrdquo Pharmaceutical Chemistry Journal vol 22 no 6 pp425ndash428 1988 (Russian)
[106] J Panek Z Reblova L Kocirkova et al ldquoAntioxidant activityof dihydropyridine derivativesrdquo Czech Journal of Food Sciencesvol 18 pp 144ndash145 2000
[107] G Tirzitis I Kirule and G Duburs ldquoAntioxidationsaktivitatder 35-dicarbonylderivate des 26-demethyl-14-dihydropyri-dinsrdquo Fett Wissenschaft TechnologieFat Science Technology vol90 no 10 pp 411ndash413 1988
[108] M Plotniece G Tirzitis Y Uldrikis et al ldquoSynthesis of 14-dihydropyridine derivatives having an oxy- alkoxy- or dimeth-ylaminophenyl substituent in the 4 position their antioxidantactivity and their binding to phospholipid membranesrdquo Chem-istry of Heterocyclic Compounds vol 32 no 10 pp 1166ndash11721996 Translated from Khimiya Geterotsiklicheskikh Soedineniino 10(352) pp 1358ndash1365 1996 (Russian)
[109] D Y Rubene V S Sharov V I Olenev G D Tirzit G Y Duburand Y A Vladimirov ldquoUse of chemiluminescent method forthe evaluation of antioxidant activity of some derivatives of 14-dihydropyridinerdquo Russian Journal of Physical Chemistry A vol55 no 2 pp 511ndash512 1981 (Russian)
[110] M C R Symons and JM C Gutteridge Free Radicals and IronChemistry Biology and Medicine Oxford Science PublicationsOxford University Press Oxford UK 1998
[111] M Repetto J Semprine and A Boveris ldquoLipid peroxidationchemical mechanism biological implications and analyticaldeterminationrdquo in Lipid Peroxidation A Catala Ed Section ILipid Peroxidation Chemical Mechanisms Antioxidants Bio-logical Implications of Biochemistry Genetics and MolecularBiology chapter 1 pp 3ndash30 InTech Rijeka Croatia 2012
[112] A Velena J Zilbers and G Duburs ldquoDerivatives of 14-dihydropyridines asmodulators of ascorbate-induced lipid per-oxidation and high-amplitude swelling ofmitochondria causedby ascorbate sodium linoleate and sodiumpyrophosphaterdquoCellBiochemistry and Function vol 17 no 4 pp 237ndash252 1999
[113] M V Bilenko L N Shelenkova G Y Dubur and A K VelenaldquoUse of antioxidants to prevent renal damage during acuteischemia and reperfusionrdquo Bulletin of Experimental Biology andMedicine vol 96 no 3 pp 1195ndash1198 1983 Translated fromByulletenrsquo Eksperimentalrsquonoi Biologii i Meditsiny vol 96 no 9pp 8ndash11 1983 (Russian)
[114] R Toniolo F Tubaro F Ursini and G Bontempelli ldquoAn elec-troanalytical investigation on the redox properties of calciumantagonist dihydropyridinesrdquo Electroanalysis vol 15 no 10 pp855ndash861 2003
[115] L Kourimska J Pokorny and G Tirzitis ldquoThe antioxidant aci-tivity of 26-dimethyl-35-diethoxycarbonyl-14-dihydropyri-dine in edible oilsrdquo Nahrung vol 37 no 1 pp 91ndash93 1993
[116] C Lopez-Alarcon H Speisky J A Squella C Olea-Azar CCamargo and L J Nunez-Vergara ldquoReactivity of 14-dihydro-pyridines toward SIN-1-derived peroxynitriterdquo PharmaceuticalResearch vol 21 no 10 pp 1750ndash1757 2004
[117] R A Olek W Ziolkowski J J Kaczor L Greci J Popinigisand J Antosiewicz ldquoAntioxidant activity of NADH and its ana-loguemdashan in vitro studyrdquo Journal of Biochemistry andMolecularBiology vol 37 no 4 pp 416ndash421 2004
[118] E Niki N Noguchi and N Gotoh ldquoInhibition of oxidativemodification of low density lipoprotein by antioxidantsrdquo Jour-nal of Nutritional Science andVitaminology vol 39 supplementpp S1ndashS8 1993
[119] N Rojstaczer and D J Triggle ldquoStructure-function relation-ships of calcium antagonists effect on oxidative modificationof low density lipoproteinrdquo Biochemical Pharmacology vol 51no 2 pp 141ndash150 1996
Oxidative Medicine and Cellular Longevity 31
[120] A Sevanian L Shen and FUrsini ldquoInhibition of LDLoxidationand oxidized LDL-induced cytotoxicity by dihydropyridinecalcium antagonistsrdquo Pharmaceutical Research vol 17 no 8 pp999ndash1006 2000
[121] A Negre-Salvayre and R Salvayre ldquoProtection by Ca2+ channelblockers (nifedipine diltiazem and verapamil) against the tox-icity of oxidized low density lipoprotein to cultured lymphoidcellsrdquo British Journal of Pharmacology vol 107 no 3 pp 738ndash744 1992
[122] A Negre-Salvayre G FitoussiM Troly and R Salvayre ldquoCom-parative cytoprotective effect of dihydropyridine calcium chan-nel blockers against the toxicity of oxidized low density lipopro-tein for cultured lymphoid cellsrdquo Biochemical Pharmacologyvol 44 no 12 pp 2379ndash2386 1992
[123] L Cominacini A F Pasini U Garbin et al ldquoAntioxidant activ-ity of different dihydropyridinesrdquo Biochemical and BiophysicalResearch Communications vol 302 no 4 pp 679ndash684 2003
[124] L Cominacini U Garbin A Fratta Pasini et al ldquoOxidized low-density lipoprotein increases the production of intracellularreactive oxygen species in endothelial cells inhibitory effect oflacidipinerdquo Journal of Hypertension vol 16 no 12 part 2 pp1913ndash1919 1998
[125] H M Lander ldquoAn essential role for free radicals and derivedspecies in signal transductionrdquo The FASEB Journal vol 11 no2 pp 118ndash124 1997
[126] M L L Martinez E Rizzi M M Castro et al ldquoLercanidipinedecreases vascular matrix metalloproteinase-2 activity andprotects against vascular dysfunction in diabetic ratsrdquo EuropeanJournal of Pharmacology vol 599 no 1ndash3 pp 110ndash116 2008
[127] P Lesnik C Dachet L Petit et al ldquoImpact of a combinationof a calcium antagonist and a 120573-blocker on cell- and copper-mediated oxidation of LDL and on the accumulation and effluxof cholesterol in human macrophages and murine J774 cellsrdquoArteriosclerosis Thrombosis and Vascular Biology vol 17 no 5pp 979ndash988 1997
[128] G Sobal E J Menzel and H Sinzinger ldquoCalcium antagonistsas inhibitors of in vitro low density lipoprotein oxidation andglycationrdquoBiochemical Pharmacology vol 61 no 3 pp 373ndash3792001
[129] E Lupo R Locher B Weisser and W Vetter ldquoIn vitro antiox-idant activity of calcium antagonists against LDL oxidationcompared with 120572-tocopherolrdquo Biochemical and BiophysicalResearch Communications vol 203 no 3 pp 1803ndash1808 1994
[130] J Zou Y Li H-Q Fan and J-G Wang ldquoEffects of dihydropy-ridine calcium channel blockers on oxidized low-density lipo-protein induced proliferation and oxidative stress of vascularsmooth muscle cellsrdquo BMC Research Notes vol 5 article 1682012
[131] C Napoli S Salomone T Godfraind et al ldquo14-Dihydro-pyridine calcium channel blockers inhibit plasma and LDL oxi-dation and formation of oxidation-specific epitopes in the arte-rial wall and prolong survival in stroke-prone spontaneouslyhypertensive ratsrdquo Stroke vol 30 no 9 pp 1907ndash1915 1999
[132] G Zernig I Graziadei T Moshammer C Zech N Reider andH Glossmann ldquoMitochondrial Ca2+ antagonist binding sitesare associated with an inner mitochondrial membrane anionchannelrdquo Molecular Pharmacology vol 38 no 3 pp 362ndash3691990
[133] F E Hunter Jr A Scott P E Hochstein et al ldquoStudies of themechanism of ascorbate-induced swelling and lysis of isolatedliver mitochondriardquo The Journal of Biological Chemistry vol239 pp 604ndash613 1964
[134] D R Janero B Burghardt and R Lopez ldquoProtection of cardiacmembrane phospholipid against oxidative injury by calciumantagonistsrdquoBiochemical Pharmacology vol 37 no 21 pp 4197ndash4203 1988
[135] A Karadag B Ozcelik and S S Saner ldquoReview of methods todetermine antioxidant capacitiesrdquo FoodAnalyticalMethods vol2 no 1 pp 41ndash60 2009
[136] Y I Gubskiı N V Litvinova and E V Shnurko-TabakovaldquoAntioxidant and antiradical activity of various classes of antiox-idantsrdquo Ukrainskiı Biokhimicheskiı Zhurnal vol 66 no 4 pp114ndash116 1994 (Russian)
[137] M Takei M Hiramatsu and A Mori ldquoInhibitory effects ofcalcium antagonists onmitochondrial swelling induced by lipidperoxidation or arachidonic acid in the rat brain in vitrordquoNeurochemical Research vol 19 no 9 pp 1199ndash1206 1994
[138] M Takei M Hiramatsu R Edamatsu and A Mori ldquoFreeradical scavenging by calcium antagonistsrdquo Neurosciences vol20 no 2 pp 75ndash82 1994
[139] Ya P Stradin G Ya Dubur Yu A Beilis Ya R Uldrikis andA F Korotkova ldquoVoltammetry of 14-dihydropyridine deriva-tives I Potentials of electrochemical oxidation of 35-diacyl-and 35-di(alkoxycarbonyl)-14-dihydropyridines in acetoni-trilerdquo Chemistry of Heterocyclic Compounds no 1 pp 84ndash871972 (Russian)
[140] E V Ivanov T V Ponomarjova G N Merkusev et al ldquoEinneuer Haut-Radioprotektor Diethon (experimentelle Unter-suchung)rdquo Radiobiologia Radiotherapia vol 31 no 1 pp 69ndash78 1990
[141] E V Ivanov T V Ponomareva G N Merkushev et al ldquoRadia-tion modulating properties of derivates of 14-dihydropyridineand 12345678910-decahydroacridine-18 dionerdquo Radiat-sionnaia Biologiia Radioecologiia vol 44 no 5 pp 550ndash5592004 (Russian)
[142] R O Vitolinia D A Berzinia A K Velena I A Vutsina A AKimenis and G Y Duburs ldquoThe protective effects of the cal-cium antagonist foridon in acute myocardial ischaemiardquo Kardi-ologiya vol 27 no 3 pp 90ndash93 1987 (Russian)
[143] A H Velena G Ya Duburs R O Vitolina et al ldquoEffect ofryodipine on electromechanical parameters of heart and vesselscAMP phosphodiesterase activity and swelling-contractioncycle of mitochondriardquo Arzneimittelforschung vol 35 no 6 pp907ndash914 1985
[144] L I Utno Z E Lipsberga A A Silova M I Girgensone EA Bisenieks and G I Ia ldquoCardioprotective properties of a 14-dihydropyridine derivative glutapyrone in deep hypothermiardquoBiulletenrsquo Eksperimentalrsquonoı Biologii i Meditsiny vol 108 no 11pp 558ndash561 1989 (Russian)
[145] M A S FernandesM S Santos J A F Vicente et al ldquoEffects of14-dihydropyridine derivatives (cerebrocrast gammapyroneglutapyrone and diethone) onmitochondrial bioenergetics andoxidative stress a comparative studyrdquoMitochondrion vol 3 no1 pp 47ndash59 2003
[146] M A S Fernandes M S Santos A J M Moreno et al ldquoEffectsof 5-acetyl(carbamoyl)-6-methylsulfanyl-14-dihydropyridine-5-carbonitriles on rat liver mitochondrial functionrdquo Toxicologyin Vitro vol 23 no 7 pp 1333ndash1341 2009
[147] L Klimaviciusa A Kalda A Kaasik et al ldquoNeuroprotectiveactivity of 14-dihydropyridine derivatives structure determi-nantsrdquo Proceedings of the Latvian Academy of Sciences BNatural Exact and Applied Sciences vol 61 no 1-2 pp 33ndash372007
32 Oxidative Medicine and Cellular Longevity
[148] L Klimaviciusa M A S Fernandes N Lencberga et alldquoTargeting the mitochondria by novel adamantane-containing14-dihydropyridine compoundsrdquo in Bioenergetics K B ClarkEd pp 257ndash272 InTech 2012
[149] V Klusa L Klimaviciusa G Duburs J Poikans and AZharkovsky ldquoAnti-neurotoxic effects of tauropyrone a taurineanaloguerdquo Advances in Experimental Medicine and Biology vol583 pp 499ndash508 2006
[150] N Sampson P Berger and Ch Zenzmaier ldquoRedox signalingas a therapeutic target to inhibit myofibroblast activation indegenerative fibrotic diseaserdquo BioMed Research Internationalvol 2014 Article ID 131737 14 pages 2014
[151] T L Leto and M Geiszt ldquoRole of Nox family NADPH oxidasesin host defenserdquoAntioxidantsampRedox Signaling vol 8 no 9-10pp 1549ndash1561 2006
[152] K K Griendling D Sorescu and M Ushio-Fukai ldquoNAD(P)Hoxidase role in cardiovascular biology and diseaserdquo CirculationResearch vol 86 no 5 pp 494ndash501 2000
[153] H Chen Y S Song and P H Chan ldquoInhibition of NADPHoxi-dase is neuroprotective after ischemia-reperfusionrdquo Journal ofCerebral Blood Flow and Metabolism vol 29 no 7 pp 1262ndash1272 2009
[154] P Hochstein and L Ernster ldquoADP-activated lipid peroxidationcoupled to the TPNH oxidase system of microsomesrdquo Biochem-ical and Biophysical Research Communications vol 12 no 5 pp388ndash394 1963
[155] I I Gubskiı AGGoriushkoNV Litvinova et al ldquoAntioxidantproperties and membranotropic effect of certain derivatives of14-dihydropyridinerdquo Ukrainskiı Biokhimicheskiı Zhurnal vol71 no 4 pp 35ndash39 1999 (Russian)
[156] F Engineer and R Sridhar ldquoInhibition of rat heart andliver microsomal lipid peroxidation by nifedipinerdquo BiochemicalPharmacology vol 38 no 8 pp 1279ndash1285 1989
[157] T Goncalves A P Carvalho and C R Oliveira ldquoAntioxidanteffect of calcium antagonists on microsomai membranes iso-lated from different brain areasrdquo European Journal of Pharma-cology vol 204 no 3 pp 315ndash322 1991
[158] M E Letelier P Izquierdo L Godoy A M Lepe and MFaundez ldquoLiver microsomal biotransformation of nitro-aryldrugs mechanism for potential oxidative stress inductionrdquoJournal of Applied Toxicology vol 24 no 6 pp 519ndash525 2004
[159] M E Letelier P Entrala C Lopez-Alarcon et al ldquoNitroaryl-14-dihydropyridines as antioxidants against rat liver microsomesoxidation induced by ironascorbate Nitrofurantoin and naph-thalenerdquo Toxicology in Vitro vol 21 no 8 pp 1610ndash1618 2007
[160] F P Guengerich W R Brian M Iwasaki M-A Sari CBaarnhielm and P Berntsson ldquoOxidation of dihydropyridinecalcium channel blockers and analogues by human liver cyto-chrome P-450 IIIA4rdquo Journal of Medicinal Chemistry vol 34no 6 pp 1838ndash1844 1991
[161] S H Park S-W RhaW-Y Shin et al ldquoAS-160 Calcium channelblockers of dihydropyridine class reduce the antiplatelet effectof Clopidogrel what is clinical impactrdquo The American Journalof Cardiology vol 107 no 8 supplement p 47A 2011
[162] C Asma and D M Reda ldquoEvaluation of dihydropyridinecalcium antagonist effects on the stress bioindicator orga-nism Saccharomyces cerevisiaerdquo Annals of Biological Researchvol 4 no 10 pp 40ndash46 2013 httpscholarsresearchlibrarycomABR-vol4-iss10ABR-2013-4-10-40-46pdf
[163] G Gaviraghi A M Pastorino E Ratti and D G TristldquoCalcium channel blockers with antioxidant activityrdquo in Free
Radicals Lipoprotein Oxidation andAtherosclerosis G BellomoG Finardi E Maggi and E Rice-Evans Eds pp 431ndash456Richelieu Press London UK 1995
[164] G Gaviraghi AM Pastorino E Ratti and D G Trist ldquoAntiox-idant dihydropyridines a new and comprehensive therapy forfree radical-induced cardiovascular diseasesrdquo in Free Radicalsin Biology and Environment F Minisci Ed vol 27 of NATOASI Series pp 193ndash221 Springer Dordrecht The Netherlands1997
[165] P D Henry ldquoAntiperoxidative actions of calcium antagonistsand atherogenesisrdquo Journal of Cardiovascular Pharmacologyvol 18 supplement 1 pp S6ndashS10 1991
[166] F Kouoh B Gressier T Dine et al ldquoAntioxidant effects andanti-elastase activity of the calcium antagonist nicardipine onactivated human and rabbit neutrophilsmdasha potential antiath-erosclerotic property of calcium antagonistsrdquo CardiovascularDrugs andTherapy vol 16 no 6 pp 515ndash520 2002
[167] S Parthasarathy D Litvinov K Selvarajan and M GarelnabildquoLipid peroxidation and decompositionmdashconflicting roles inplaque vulnerability and stabilityrdquo Biochimica et BiophysicaActa vol 1781 no 5 pp 221ndash231 2008
[168] D-Q Liu Z-Q Pang D-H Zhao and B-H Sheng ldquoEffects offuryl-dihydropyridines I on lipid peroxides of ischemic myo-cardium and ATPases activity of erythrocyte membranes inratsrdquo Acta Pharmacologica Sinica vol 12 no 3 pp 253ndash2561991
[169] V Lukic-Panin T Kamiya H Zhang et al ldquoPrevention of neu-ronal damage by calcium channel blockers with antioxidativeeffects after transient focal ischemia in ratsrdquo Brain Research vol1176 no 1 pp 143ndash150 2007
[170] Y Allanore D Borderie H Lemarechal O G Ekindjian andA Kahan ldquoAcute and sustained effects of dihydropyridine-typecalcium channel antagonists on oxidative stress in systemicsclerosisrdquo American Journal of Medicine vol 116 no 9 pp 595ndash600 2004
[171] I Casetta V Govoni and E Granieri ldquoOxidative stress antioxi-dants and neurodegenerative diseasesrdquo Current PharmaceuticalDesign vol 11 no 16 pp 2033ndash2052 2005
[172] M J T J Arts Assessing antioxidant activity [PhD the-sis] Maastricht University Maastricht The Netherlands 2007httparnounimaasnlshowcgifid=8676
[173] G Dıaz-Araya L Godoy L Naranjo A Squella M E Letelierand L J Nunez-Vergara ldquoAntioxidant effects of 14-dihydro-pyridine and nitroso aryl derivatives on the Fe+3ascorbate-stimulated lipid peroxidation in rat brain slicesrdquo General Phar-macology The Vascular System vol 31 no 3 pp 385ndash391 1998
[174] Y Fukuhara K Tsuchiya Y Horinouchi et al ldquoProtectiveeffect of photodegradation product of nifedipine against tumornecrosis factor 120572-induced oxidative stress in human glomerularendothelial cellsrdquo Journal of Medical Investigation vol 58 no1-2 pp 118ndash126 2011
[175] W Stengel M Jainz and K Andreas ldquoDifferent potencies ofdihydropyridine derivatives in blocking T-type but not L-typeCa2+ channels in neuroblastoma-glioma hybrid cellsrdquo EuropeanJournal of Pharmacology vol 342 no 2-3 pp 339ndash345 1998
[176] O M Panasenko D J Tirzite G D Tirzitis and G J DubursldquoEffect of some 14-dihydropyridine derivatives on structuralorganization of erythrocyte membranesrdquo Biologicheskie Mem-brany (Biochemistry (Moscow) Series A Membrane and CellBiology) vol 1 pp 919ndash925 1984 (Russian)
[177] L G Herbette Y M H Vant Erve and D G Rhodes ldquoInter-action of 14 dihydropyridine calcium channel antagonists with
Oxidative Medicine and Cellular Longevity 33
biological membranes lipid bilayer partitioning could occurbefore drug binding to receptorsrdquo Journal of Molecular andCellular Cardiology vol 21 no 2 pp 187ndash201 1989
[178] L G Herbette P E Mason G Gaviraghi T N Tulenko andR P Mason ldquoThe molecular basis for lacidipinersquos unique phar-macokinetics optimal hydrophobicity results in membraneinteractions that may facilitate the treatment of atherosclerosisrdquoJournal of Cardiovascular Pharmacology vol 23 supplement 5pp S16ndashS25 1994
[179] G V Belevitch G Y Dubur G E Dobretsov N K Kurek andM M Spirin ldquoCalcium antagonists riodipine nifedipine andverapamil binding to model and biological membranes fluore-scence analysisrdquo Biologicheskie Membrany (Biochemistry(Moscow) Series A Membrane and Cell Biology) vol 5 pp768ndash776 1988 (Russian)
[180] R P Mason G E Gonye D W Chester and L G HerbetteldquoPartitioning and location of Bay K 8644 14-dihydropyridinecalcium channel agonist in model and biological membranesrdquoBiophysical Journal vol 55 no 4 pp 769ndash778 1989
[181] M Cindric A Cipak J Serly et al ldquoReversal of multidrugresistance inmurine lymphoma cells by amphiphilic dihydropy-ridine antioxidant derivativerdquo Anticancer Research vol 30 no10 pp 4063ndash4070 2010
[182] F Shekari H Sadeghpour K Javidnia et al ldquoCytotoxic andmultidrug resistance reversal activities of novel 14-dihydro-pyridines against human cancer cellsrdquo European Journal ofPharmacology vol 746 no 1 pp 233ndash244 2015
[183] X-F Zhou Q Shao R A Coburn and M E Morris ldquoQuanti-tative structure-activity relationship and quantitative structure-pharmacokinetics relationship of 14-dihydropyridines andpyridines as multidrug resistance modulatorsrdquo PharmaceuticalResearch vol 22 no 12 pp 1989ndash1996 2005
[184] R Berkels T Breitenbach H Bartels et al ldquoDifferent antioxida-tive potencies of dihydropyridine calcium channel modulatorsin various modelsrdquo Vascular Pharmacology vol 42 no 4 pp145ndash152 2005
[185] S Borovic G Tirzitis D Tirzite et al ldquoBioactive 14-dihydro-isonicotinic acid derivatives prevent oxidative damage of livercellsrdquo European Journal of Pharmacology vol 537 no 1ndash3 pp12ndash19 2006
[186] D Ya Rubene G D Tirzitis and G Ya Duburs ldquoInteractionof some 14-dihydropyridine derivatives with Fentonrsquos reagentrdquoLatvijas PSRZinatnuAkademijas Vestis Kimijas Serija Proceed-ings of the Latvian SSR Academy of Sciences Chemistry Seriespp 212ndash216 1982 (Russian)
[187] K Ondrias V Misık D Gergel and A Stasko ldquoLipid per-oxidation of phosphatidylcholine liposomes depressed by thecalcium channel blockers nifedipine and verapamil and bythe antiarrhythmic-antihypoxic drug stobadinerdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1003 no 3pp 238ndash245 1989
[188] I T Mak and W B Weglicki ldquoComparative antioxidant acti-vities of propranolol nifedipine verapamil and diltiazemagainst sarcolemmal membrane lipid peroxidationrdquoCirculationResearch vol 66 no 5 pp 1449ndash1452 1990
[189] I T Mak P Boehme and W B Weglicki ldquoProtective effects ofcalcium channel blockers against free radical-impaired endo-thelial cell proliferationrdquo Biochemical Pharmacology vol 50 no9 pp 1531ndash1534 1995
[190] S Ray S Mondal and N Dana ldquoEvaluation of protective roleof nifedipine on lipid peroxidation using reduced glutathione as
model markerrdquo Oxidants and Antioxidants in Medical Sciencevol 1 no 2 pp 97ndash100 2012
[191] M Yamato T Shiba T Ide Y Honda K-I Yamada andH Tsutsui ldquoNifedipine treatment reduces brain damage aftertransient focal ischemia possibly through its antioxidativeeffectsrdquoHypertension Research vol 34 no 7 pp 840ndash845 2011
[192] V Chander and K Chopra ldquoNifedipine attenuates changes innitric oxide levels renal oxidative stress and nephrotoxicityinduced by cyclosporinerdquo Renal Failure vol 27 no 4 pp 441ndash450 2005
[193] K M Gaafa M M Badawy and A A Hamza ldquoThe protectiveeffects of ascorbic acid cimetidine and nifedipine on diethyl-dithiocarbamate-induced hepatic toxicity in albino ratsrdquo Drugand Chemical Toxicology vol 34 no 4 pp 405ndash419 2011
[194] H Sugawara K Tobise and S Onodera ldquoAbsence of antiox-idant effects of nifedipine and diltiazem on myocardial mem-brane lipid peroxidation in contrast with those of nisoldipineand propranololrdquo Biochemical Pharmacology vol 47 no 5 pp887ndash892 1994
[195] I E Kirule D Y Rubene E A Bisenieks G D Tirzit and GY Dubur ldquo4-Nitrophenyl-14-dihydropyridinesmdasha new groupof inhibitors of peroxide oxidationrdquo Chemistry of HeterocyclicCompounds vol 18 no 3 p 316 1982
[196] G D Tirzit I E Kirule L K Baumane R A Gavar Y PStradynrsquo andG YDubur ldquoMechanism of the antioxidant actionof 26-dimethyl-35-dimethoxy-carbonyl-4-(2-nitrophenyl)14-dihydropyridinerdquoChemistry ofHeterocyclic Compounds vol 20no 8 pp 915ndash918 1984
[197] C Yanez C Lopez-Alarcon C Camargo V Valenzuela J ASquella and L J Nunez-Vergara ldquoStructural effects on thereactivity 14-dihydropyridines with alkylperoxyl radicals andABTS radical cationrdquo Bioorganic and Medicinal Chemistry vol12 no 9 pp 2459ndash2468 2004
[198] VMisik A J Stasko D Gergel and K Ondrias ldquoSpin-trappingand antioxidant properties of illuminated and nonilluminatednifedipine and nimodipine in heart homogenate and modelsystemrdquo Molecular Pharmacology vol 40 no 3 pp 435ndash4391991
[199] K Ondrias V Misık A Stasko D Gergelrsquo and M HromadovaldquoComparison of antioxidant properties of nifedipine and illu-minated nifedipine with nitroso spin traps in low densitylipoproteins and phosphatidylcholine liposomesrdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1211 no 1pp 114ndash119 1994
[200] A Stasko V Brezova S Biskupic K Ondrias and V MisıkldquoReactive radical intermediates formed from illuminated nife-dipinerdquoFree Radical Biology andMedicine vol 17 no 6 pp 545ndash556 1994
[201] K Ishizawa Y Izawa-Ishizawa N Yamano et al ldquoNitrosoni-fedipine ameliorates the progression of type 2 diabetic nephro-pathy by exerting antioxidative effectsrdquo PLoS ONE vol 9 no 1Article ID e86335 2014
[202] H Fujii and L J Berliner ldquoIn vivo EPR evidence for free radicaladducts of nifedipinerdquoMagnetic Resonance in Medicine vol 42no 4 pp 691ndash694 1999
[203] S Bollo S Finger J C Sturm L J Nunez-Vergara and JA Squella ldquoCyclic voltammetry and scanning electrochemicalmicroscopy studies of the heterogeneous electron transferreaction of some nitrosoaromatic compoundsrdquo ElectrochimicaActa vol 52 no 15 pp 4892ndash4898 2007
34 Oxidative Medicine and Cellular Longevity
[204] F Ursini ldquoTissue protection by lacidipine insight from redoxbehaviorrdquo Journal of Cardiovascular Pharmacology vol 30supplement 2 pp S28ndashS30 1997
[205] P G Cristofori F A Crivellente I Faustinelli et al ldquoInvolve-ment of the nitric oxide system in the anti-atheroscleroticpotential of lacidipine in the apoE-deficient mouse a mor-phological functional and electrochemical studyrdquo ToxicologicPathology vol 32 no 4 pp 493ndash499 2004
[206] X-P Zhang E L Kit S Mital S Chahwala and T HHintze ldquoParadoxical release of nitric oxide by an L-type calciumchannel antagonist the R+ enantiomer of amlodipinerdquo Journalof Cardiovascular Pharmacology vol 39 no 2 pp 208ndash2142002
[207] F Franzoni G Santoro F Regoli et al ldquoAn in vitro study of theperoxyl and hydroxyl radical scavenging capacity of the calciumantagonist amlodipinerdquo Biomedicine and Pharmacotherapy vol58 no 8 pp 423ndash426 2004
[208] S V Gatsura ldquoOxygen-dependent mechanisms underlying theantiischemic effect of verapamil and amlodipinerdquo Bulletin ofExperimental Biology and Medicine vol 137 no 1 pp 40ndash422004
[209] Y Hirooka Y Kimura M Nozoe Y Sagara K Ito and KSunagawa ldquoAmlodipine-induced reduction of oxidative stressin the brain is associated with sympatho-inhibitory effects instroke-prone spontaneously hypertensive ratsrdquo HypertensionResearch vol 29 no 1 pp 49ndash56 2006
[210] B Tomlinson and I F F Benzie ldquoAntioxidant effect of lercani-dipine (note)rdquo Hypertension vol 42 no 4 pp e10ndashe11 2003
[211] A A Faraqui ldquoNeurochemical aspects of 4-hydroxynonenalrdquoin Lipid Mediators and Their Metabolism in the Brain A AFaraqui Ed chapter 6 pp 159ndash191 Springer New York NYUSA 2011
[212] V S NascimentoM S DrsquoAlva A AOliveira et al ldquoAntioxidanteffect of nimodipine in young rats after pilocarpine-inducedseizuresrdquo Pharmacology Biochemistry and Behavior vol 82 no1 pp 11ndash16 2005
[213] O Ismailoglu P Atilla S Palaoglu et al ldquoThe therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjuryrdquo Turkish Neurosurgery vol 22 no 6 pp 740ndash746 2012
[214] M Matsubara and K Hasegawa ldquoBenidipine a dihydropy-ridine-calcium channel blocker prevents lysophosphatidyl-choline-induced injury and reactive oxygen species productionin human aortic endothelial cellsrdquo Atherosclerosis vol 178 no1 pp 57ndash66 2005
[215] M Matsubara K Yao and K Hasegawa ldquoBenidipine adihydropyridine-calcium channel blocker inhibits lysophos-phatidylcholine-induced endothelial injury via stimulation ofnitric oxide releaserdquo Pharmacological Research vol 53 no 1 pp35ndash43 2006
[216] MMatsubara and K Hasegawa ldquoEffects of benidipine a dihyd-ropyridine-Ca2+ channel blocker on expression of cytokine-induced adhesion molecules and chemoattractants in humanaortic endothelial cellsrdquo European Journal of Pharmacology vol498 no 1ndash3 pp 303ndash314 2004
[217] M Matsubara O Akizuki J-I Ikeda K Saeki K Yao and KSasaki ldquoBenidipine an anti-hypertensive drug inhibits reactiveoxygen species production in polymorphonuclear leukocytesand oxidative stress in salt-loaded stroke-prone spontaneouslyhypertensive ratsrdquo European Journal of Pharmacology vol 580no 1-2 pp 201ndash213 2008
[218] A C Rosenkranz H Lob T Breitenbach R Berkels and RRoesen ldquoEndothelial antioxidant actions of dihydropyridines
and angiotensin converting enzyme inhibitorsrdquo European Jour-nal of Pharmacology vol 529 no 1ndash3 pp 55ndash62 2006
[219] V Kain S Kumar and S L Sitasawad ldquoAzelnidipine preventscardiac dysfunction in streptozotocin-diabetic rats by reducingintracellular calcium accumulation oxidative stress and apop-tosisrdquo Cardiovascular Diabetology vol 10 article 97 2011
[220] K Nakamura S Yamagishi and H Inoue ldquoUnique atheropro-tective property of azelnidipine a dihydropyridine-based cal-cium antagonistrdquoMedical Hypotheses vol 65 no 1 pp 155ndash1572005
[221] TMatsui S Yamagishi K Nakamura S Kikuchi andH InoueldquoAzelnidipine a dihydropyridine-based calcium antagonistinhibits angiotensin II-induced oxidative stress generation anddownregulation of pigment epithelium-derived factor mRNAlevels in microvascular endothelial cellsrdquo Drugs under Experi-mental and Clinical Research vol 31 no 5-6 pp 215ndash219 2005
[222] C Ohmura H Watada T Shimizu et al ldquoCalcium channelblocker azelnidipine reduces lipid hydroperoxides in patientswith type 2 diabetes independent of blood pressurerdquo EndocrineJournal vol 54 no 5 pp 805ndash811 2007
[223] H Daikuhara F Kikuchi and T Ishida ldquoThe combination ofOLmesartan and a CAlcium channel blocker (azelnidipine) orcandesartan and a calcium channel blocker (amlodipine) intype 2 diabetic hypertensive patients theOLCA studyrdquoDiabetesand Vascular Disease Research vol 9 no 4 pp 280ndash286 2012
[224] MAbe NMaruyama KOkada SMatsumoto KMatsumotoand M Soma ldquoAdditive antioxidative effects of azelnidipine onangiotensin receptor blocker olmesartan treatment for type 2diabetic patients with albuminuriardquoHypertension Research vol34 no 8 pp 935ndash941 2011
[225] K Mizushige ldquoAntioxidative activities of thiazolidinedionesand dihydropyridine-type calcium antagonistsrdquo IRYOmdashJapa-nese Journal of National Medical Services vol 59 no 11 pp 581ndash592 2005
[226] S Manabe T Okura T Fukuoka and J Higaki ldquoAntioxidativeeffects of azelnidipine on mesangial cell proliferation inducedby highly concentrated insulinrdquo European Journal of Pharma-cology vol 567 no 3 pp 252ndash257 2007
[227] Y Koyama Y Takeishi H Takahashi et al ldquoAzelnidipine inhi-bits H
2O2-induced cell death in neonatal rat cardiomyocytesrdquo
CardiovascularDrugs andTherapy vol 21 no 1 pp 69ndash72 2007[228] K Shinomiya K Mizushige M Fukunaga et al ldquoAntioxidant
effect of a new calcium antagonist azelnipidine in culturedhuman arterial endothelial cellsrdquo Journal of International Med-ical Research vol 32 no 2 pp 170ndash175 2004
[229] T Ohyama K Sato K Kishimoto et al ldquoAzelnidipine is acalcium blocker that attenuates liver fibrosis and may increaseantioxidant defencerdquo British Journal of Pharmacology vol 165no 4 pp 1173ndash1187 2012
[230] L A Calo F Zaghetto E Pagnin P A Davis A Sempliciniand A C Pessina ldquoEffect of manidipine on gene expressionand protein level of oxidative stress-related proteins p22phoxand HO-1 Relevance for antihypertensive and anti-remodelingeffectsrdquo Journal of Cardiovascular Pharmacology vol 43 no 4pp 531ndash538 2004
[231] R Ghyasi G Sepehri M Mohammadi R Badalzadeh and AGhyasi ldquoEffect of mebudipine on oxidative stress and lipid per-oxidation in myocardial ischemic-reperfusion injury in maleratrdquo Journal of Research in Medical Sciences vol 17 no 12 pp1150ndash1155 2012
Oxidative Medicine and Cellular Longevity 35
[232] DCAndersson J Fauconnier T Yamada et al ldquoMitochondrialproduction of reactive oxygen species contributes to the 120573-adrenergic stimulation of mouse cardiomycytesrdquoThe Journal ofPhysiology vol 589 no 7 pp 1791ndash1801 2011
[233] A F Ceylan-Isik N Ari M Stefek et al ldquoEffects of a long-term treatment with an antioxidant pyridoindole on vascularresponsiveness in diabetes-induced aging ratsrdquo Current AgingScience vol 4 no 2 pp 150ndash157 2011
[234] S Saponara G Sgaragli and F Fusi ldquoQuercetin antagonismof Bay K 8644 effects on rat tail artery L-type Ca2+ channelsrdquoEuropean Journal of Pharmacology vol 598 no 1ndash3 pp 75ndash802008
[235] D A Sica ldquoInteraction of grapefruit juice and calcium channelblockersrdquo American Journal of Hypertension vol 19 no 7 pp768ndash773 2006
[236] P Mulder G Litwinienko S Lin P D MacLean L R CBarclay and K U Ingold ldquoThe L-type calcium channel block-ers Hantzsch 14-dihydropyridines are not peroxyl radical-trapping chain-breaking antioxidantsrdquo Chemical Research inToxicology vol 19 no 1 pp 79ndash85 2006
[237] L J Nunez-Vergara R Salazar C Camargo et al ldquoOxidation ofC4-hydroxyphenyl 14-dihydropyridines in dimethylsulfoxideand its reactivity towards alkylperoxyl radicals in aqueousmediumrdquo Bioorganic and Medicinal Chemistry vol 15 no 12pp 4318ndash4326 2007
[238] M E Ortiz L J Nunez-Vergara and J A Squella ldquoRelativereactivity of dihydropyridine derivatives to electrogeneratedsuperoxide ion in DMSO solutions a voltammetric approachrdquoPharmaceutical Research vol 20 no 2 pp 292ndash296 2003
[239] M E Ortiz L J Nunez-Vergara C Camargo and J A SquellaldquoOxidation of Hantzsch 14-dihydropyridines of pharmacolog-ical significance by electrogenerated superoxiderdquo Pharmaceuti-cal Research vol 21 no 3 pp 428ndash435 2004
[240] R S Raghuvanshi and K N Singh ldquoSuperoxide induced oxida-tive aromatization of Hantzsch 14-dihydropyridinesrdquo IndianJournal of Chemistry Section B Organic and Medicinal Chem-istry vol 47 no 11 pp 1735ndash1738 2008
[241] I Kruk A Kladna K Lichszteld et al ldquoAntioxidant activityof 4-flavonil-14-dihydropyridine derivativesrdquo Biopolymers vol62 no 3 pp 163ndash167 2001
[242] G D Tirzit I M Byteva K I Salokhiddinov G P Gurinovichand G Y Dubur ldquo14-Dihydropyridine derivatives as deactiva-tors of singlet oxygenrdquo Chemistry of Heterocyclic Compoundsvol 17 no 7 pp 682ndash684 1981
[243] G D Tirzit E Y Kazush and G Y Dubur ldquoInfluence of14-dihydropyridine derivatives on the generation of hydroxylradicalsrdquo Chemistry of Heterocyclic Compounds vol 28 no 4pp 435ndash437 1992
[244] N A Pizarro-Urzua and L J Nunez-Vergara ldquoNifedipine andnitrendipine reactivity toward singlet oxygenrdquo Journal of Photo-chemistry and Photobiology A Chemistry vol 175 no 2-3 pp129ndash137 2005
[245] L-F Wang H-Y Zhang L Konga Z-W Chena and J-G ShildquoDFT calculations indicate that 14-dihydropyridine is a promis-ing lead antioxidantrdquo Helvetica Chimica Acta vol 87 no 6 pp1515ndash1521 2004
[246] P Mulder H-G Korth and K U Ingold ldquoWhy quantum-thermochemical calculations must be used with caution toindicate lsquoa promising lead antioxidantrsquordquoHelvetica Chimica Actavol 88 no 2 pp 370ndash374 2005
[247] K Yao Y Ina K Nagashima K Ohmori and T Ohno ldquoAntiox-idant effects of calcium antagonists in rat brain homogenatesrdquo
Biological and Pharmaceutical Bulletin vol 23 no 6 pp 766ndash769 2000
[248] T Matsui S-I Yamagishi K Nakamura and H Inoue ldquoBayw 9798 a dihydropyridine structurally related to nifedipinewith no calcium channel-blocking properties inhibits tumournecrosis factor-120572-induced vascular cell adhesion molecule-1expression in endothelial cells by suppressing reactive oxygenspecies generationrdquo Journal of International Medical Researchvol 35 no 6 pp 886ndash891 2007
[249] K AMitrega B VargheseM Porc and T F Krzeminski ldquoAnti-arrhythmic and hemodynamic effects of oxy nifedipine oxynimodipine oxy nitrendipine and oxy nisoldipinerdquo Pharmaco-logical Research vol 66 no 4 pp 300ndash308 2012
[250] V Herbert ldquoSymposium prooxidant effects of antioxidantvitamins Introductionrdquo The Journal of Nutrition vol 126 no4 supplement pp 1197Sndash1200S 1996 httpjnnutritionorgcontent1264 Suppl1197Sfullpdf
[251] B Halliwell ldquoAre polyphenols antioxidants or pro-oxidantsWhat do we learn from cell culture and in vivo studiesrdquoArchives of Biochemistry and Biophysics vol 476 no 2 pp 107ndash112 2008
[252] C Winterbourn Pro-Oxidants or Antioxidants ChristchurchSchool of Medicine Depatment of Pathology Free RadicalSchool SFRBMUniversity of Otago San Francisco Calif USA2009 httpwwwsfrbmorgfrsWinterbournpdf
[253] A Morakinyo B Iranloye and O Adegoke ldquoCalcium antag-onists modulate oxidative stress and acrosomal reaction in ratspermatozoardquo Archives of Medical Science vol 7 no 4 pp 613ndash618 2011
[254] The Alpha-Tocopherol Beta Carotene Cancer Prevention StudyGroup ldquoThe effect of vitamin E and beta carotene on theincidence of lung cancer and other cancers in male smokersrdquoTheNew England Journal of Medicine vol 330 no 15 pp 1029ndash1035 1994
[255] B Poljsak ldquoStrategies for reducing or preventing the generationof oxidative stressrdquo Oxidative Medicine and Cellular Longevityvol 2011 Article ID 194586 15 pages 2011
[256] B Poljsak and I Milisav ldquoThe neglected significance of lsquoanti-oxidative stressrsquordquoOxidativeMedicine and Cellular Longevity vol2012 Article ID 480895 12 pages 2012
[257] T Godfraind and S Salomone ldquoAmbiguities in dietary antiox-idant supplementation compared to calcium channel blockerstherapyrdquo Frontiers in Pharmacology vol 6 article 10 2015
[258] H Wagner H Norr and H Winterhoff ldquoDrugs with adap-togenic effects for strengthening the powers of resistancerdquoZeitschrift fur Phytotherapie vol 13 no 2 pp 42ndash54 1992
8 Oxidative Medicine and Cellular Longevity
fact in the interaction with the target proteins (it should bementioned that there are no studies on LP with other Ca2+agonists)
The decreased oxidation potential correlates with AOcapacity and increased basic characterThese findings suggestthe relevance of the electron density on the DHP ring
For all the DHP compounds investigated the overalloxidation process proceeds through two consecutive one-electron releases a primary one-electron step accompaniedby a fast proton release and the formation of a neutral radical(PyH∙) undergoing a second much easier one-electron step[114]
The final product is the protonated form of the parentpyridine derivative This pattern is relevant for the antioxida-tive activity since the radical intermediate is far less prone tobe reduced than oxidized
In the case of CA DHPs the release of protons compli-cates the overall oxidation process by introducing a ldquopara-siticrdquo side reaction where a coupling between protons and thestarting species takes place
This DHP self-protonation subtracts part of the originalspecies from the electrode process because the parent cationicspecies are no longer electroactive
Conversely the calcium agonist DHP which is less proneto be oxidized turned out to be so weak base to be evenunable to undergo the self-protonation reaction
Thus the combined effect of oxidation potentials andproton binding capacity of DHPs is a key element for theredox transition relevant for their AO activity Yet opposingeffects (antagonistic versus agonistic) on protein targets ascalcium ion channels connected with protein thiol oxidationto disulfide should be also considered [114]
Kourimska et al [115] found AO effect of diludine (HEH)in edible oil Reactivity of 14-DHPs toward SIN-1-derivedperoxynitrite was shown by Lopez-Alarcon et al [116] Oleket al [117] discovered antioxidative activity of NADH and itsanalogue in vitro
Further see as referred in several subparts below Sections34 35 and 37
(2) Ex Vivo (on Lipid Peroxidation in LDL MitochondriaMicrosomes and Cells) Main chemical structures of DHPsexamined in numerous studies and reviewed in this paper arepresented in Figures 1 and 2
(a) Various DHPs Calcium Antagonists as Inhibitors of LDLPeroxidation Free radicals induce peroxidation of LDLThis process proceeds by a chain mechanism which revealsphosphatidylcholine hydroperoxides and cholesteryl esterhydroperoxides as themajor primary products [118] Calciumantagonist DHPs could act as antioxidants on LDL at leastin three ways (1) as inhibitors of isolated LDL peroxi-dation caused by various inducers (Cu2+ ions UV lightand xanthinexanthine oxidase system) (2) if preincubatedwith cells preventing against intracellular LDL oxidation (3)preventing against the harmful effect of oxidized LDL on cellsand decreasing cytotoxicity [119ndash131]
Combined application of ascorbic acid and CA DHPs(amlodipine and felodipine) has an additive (cytoprotective
and LDL antioxidant activity) effect [120] It includes acombination of peroxide-degrading and peroxyl radical scav-enging reactions thus demonstrating the importance of LPduring LDL oxidation and cytotoxicity induced by oxidizedLDL Cytoprotection is associated with inhibition of oxidant-induced increases in intracellular free calcium
Similar to the othermodel systems the recorded values ofthe tested DHPs related to AO activity on LDL LP and relatedevents [119ndash131] depend on the prooxidant model system andmethods used for activity measuring (see Tables 1ndash5)
Commercial Ca2+ antagonists (including 14-DHP deri-vatives) as well as some other 14-DHPs with less CA activitywere shown to decrease the rate of oxidation (detected asTBARS) of low-density lipoprotein (LDL) induced by Cu2+ions (CuSO
4) in two different cell lines U937 human mono-
cyte-like and J774A1 murine monocyte-macrophage cellline (Rojstaczer and Triggle [119]) The strongest effect wasrecorded for vitamin E followed by felodipine 2-Cl analogueof nifedipine nifedipine amlodipine nitrendipine vera-pamil and diltiazem
Rojstaczer and Triggle [119] found that CA from differentchemical groups had a concentration-dependent effect asantioxidants against LDL oxidation (see Table 1) Howeverthe order of potency (activity rank order ARO) of the drug(s)again depends on the oxidation system and the antioxidantassay Both CA and antioxidative effects relate to the 2- (or o-orto-) substituent of the 4-phenyl ring in the same potencyorder 119900 gt 119898 ≫ 119901 [119] On the other hand the require-ment for the 14-DHP ring is essential for both AOA andCa2+channel antagonism A charged substituent at the position C-2 of the 14-DHP ring influences the AO activity (analogousto [46ndash53]) However some other factors should not beneglected for example although amlodipine has a positivelycharged amine at this position this modificationmakes it lesslipophilic and indirectly less potent antioxidant
Similar results were obtained when testing antioxidanteffect of CA on LDL peroxidation in bovine aortic endothelialcells (BAECs) (Cominacini et al [123] see Tables 2 and 3) aswell as in HUVECs (Lupo et al [129]) (see Table 4)
Cominacini et al [123] observed antioxidant effect ofCCBs and 120572-tocopherol in BAECs The order of potency(see Tables 2 and 3) [123] was however different than inU937 human monocyte-like and J774A1 murine monocyte-macrophage cells (see Rojstaczer and Triggle [119] Table 1)The tested DHPs were lacidipine amlodipine lercanidipinenimodipine and nifedipine (in two different intracellularconcentrations 2 and 4 fmol) ROS production was signif-icantly lowered only by lacidipine (which is the compoundwith the highest lipophilicity) and lercanidipine the effectof lacidipine was much more evident than lercanidipineSurprisingly amlodipine nimodipine and nifedipine had noeffect on ROS formation suggesting that the positive effectson the earliest events of atherosclerosis are a peculiarity oflacidipine molecule through its antioxidant activity
The strong AO action of lacidipine may be related tothe lipophilic cinnamic acid side chain which favors a drugpartitioning in the membrane due to favorable physicochem-ical (hydrophobic) interactions of drug hydrophobic residues
Oxidative Medicine and Cellular Longevity 9
Table 1 Relative structure-function relationships of calcium antagonists (DHPs verapamil and diltiazem) and vitamin E Effect on oxidativemodification of isolated ex vivo human low-density lipoprotein using two various oxidation systems (copper (II) ions induced and monocyteinduced) Compiled according to data presented by Rojstaczer and Triggle [119]
Compound
Systems of LDL oxidation
Copper (II) ions induced system (comparison of three methods) Monocyte induced celloxidation system
Methods
Reduction of TBARS level of LDL(relative efficacy)
Degradation of oxidized[125I] LDL by J774
macrophages
Relative electrophoreticmobility of LDL on
agarose gel
TBARS content of LDL(in )
Relative efficacy (activity rank order (ARO) ARO = I for the most effective) effective inhibitor concentration [IC] in120583M
with polyunsaturated groups of membrane phospholipidsHowever DHPs can also reduce the oxLDL-induced ROSconcentration by affecting some intracellular ROS producerssuch as NADPH oxidases xanthine oxidase and cyclooxyge-nase enzymes The activity of these enzymes contributes tointracellular ROS elevation [125]
Preincubation of HUVECs with lacidipine inhibited anincrease of intracellular ROS caused by oxidized LDL [124]
Lupo et al [129] have studied the dose-dependent (1 510 and 50 120583M) AOA of various CA (verapamil diltiazemand DHPs nifedipine amlodipine isradipine or lacidipine)
Table 3Modulation of ROS formation in BAECs by CA (DHPs andverapamil) and vitamin E Compiled according to data presented byCominacini et al [123]
Compound
Method of flow cytometry (reduced2101584071015840-dichlorofluorescein diacetate(DCFH-DA) oxidation by ROS)
Activity rank order(ARO = I for the highest activity ARO = III for
the mindest activity)(Effective [IC] 1 5 10 50 120583M)
Lacidipine + + + (ARO = I)Lercanidipine + + (ARO = II)Amlodipine No effectNifedipine No effectNimodipine No effectVerapamil + (ARO = III)120572-Tocopherol + + + (ARO = I)
against normolipidemic human blood LDL oxidation com-pared with 120572-tocopherol by measuring the content of TBARSand the diene formation (see Table 4)
10 Oxidative Medicine and Cellular Longevity
Table 4 Normolipidemic human blood LDL (025mgmL) in vitro oxidation in the presence of 5 120583M CuSO4and CA of 3 types (DHPs
verapamil and diltiazem) and vitamin E Compiled according to Lupo et al [129]
Compound
MethodsTBARS method (fluorimetry at 515 nm533 nm 4 hours
preincubation of LDL with compounds and copper (II)ions 320 TBARS increase in control during 4 h
period)
Inhibition of conjugated diene formation (at 234 nm)expressed as prolongation of induction period (in
of control) 119905contr = 368min
Effective [IC] (in 120583M)1 120583M 10120583M 50 120583M
Activity rank order (ARO= I for the highest activity
ARO = VII for themindest activity)
Effective [IC] (in 120583M)1 120583M 5 120583M 10120583M 50 120583M
Activity rank order (ARO= I for the highest activity
ARO = VII for themindest activity)
Nifedipine 10120583M50 120583M ARO = III
5 120583M10120583M 15050 120583M 213
ARO = III
Amlodipine 50 120583M ARO = IV5 120583M
10120583M 12250120583M 138
ARO = IVndashVI
Isradipine 50 120583M ARO = VI 10120583M 15050 120583M 183 ARO = IVndashVI
Lacidipine1 120583M10120583M50 120583M
ARO = II5 120583M
10120583M 19250 120583M 283
ARO = II
Verapamil 50 120583M ARO = V 10120583M 15050 120583M 178 ARO = IVndashVI
Diltiazem No effect No effect (ARO = VII) No effect No effect (ARO = VII)
Vitamin E1 120583M
10120583M (IC50)
50 120583M (20 of control)ARO = I
5 120583M10 120583M 23050 120583M 370
ARO = I
Table 5 Antiproliferative effect (oxLDL-induced HUVSMCs proliferation) of CA DHPs and simultaneous oxLDL-induced ROS productionscavenging Comparison with N-acetyl-L-cysteine NAC (intracellular ROS scavenger) Compiled according to data presented by Zou et al2012 [130]
DHP compound
MethodsAntiproliferative effect against proproliferative effectinduced by oxLDL (50 120583gmL) (UV detection of
formazan production from tetrazolium salt)
oxLDL-induced ROS production (fluorescent DCF(2101584071015840-dichlorofluorescein) production)
Effective [IC] in120583M and I in
Amlodipine 3 120583M I = 18 3 120583M 10 120583M No effectI = 20
S(minus)-Amlodipine No effect No effect
Lacidipine 10 120583M30 120583M
I = 21I = 27 10120583M Isim23 of control
N-Acetyl-L-cysteineNAC
mdash 5000 120583M(5mM) I = 28
As presented (Table 4 according to [129]) for diltiazem(poor lipid solubility) noAOwas detected whereas the otherCA and 120572-tocopherol have demonstrated AOA at least atconcentrations of 10 and 50120583M 120572-tocopherol gt lacidipinegt nifedipine gt isradipine verapamil and amlodipine Addi-tionally120572-tocopherol and lacidipinewere able to significantlyattenuate in vitro LDL oxidation at 1 and 5120583M Theseresults have confirmed the highest activity for the stronglylipophilic DHP type CA compound lacidipine This might be
a possible antiatherogenic mechanism of CA since oxidativemodification enhances the atherogenic potential of LDL
The lipid peroxidation of LDL promoted either by UVradiation or by copper ions was inhibited (antioxidant effect)by nisoldipine in a dose-dependentmanner (IC
50values were
evaluated at around 10 120583M) nimodipine was less potent (IC50
around 50ndash100 120583M) and nicardipine almost inactive In addi-tion to this indirect protective effect CA DHPs nisoldipineand nimodipine exerted direct protective effect on lymphoid
Oxidative Medicine and Cellular Longevity 11
cells against toxicity of previously oxidized LDL The IC50
values were 6 plusmn 2 and 80 plusmn 20 120583M respectively [122] Theinhibition of the cytotoxic effect of LDL oxidized in thepresence of DHP type Ca2+ channel blockers correlated wellwith protection from oxidation by these compounds Com-plete protection cannot be obtained because the DHPs arecytotoxic themselves The potential relevance to the preven-tion of atherogenesis is envisaged
DHP typeCCBnifedipinewas themost effective inhibitorof oxidation promoted either by UV radiation or by copperions in experiments with cultured lymphoid cells LDL (2mgapoBmL) CCBs from other two CCB classes diltiazem andverapamil were only poorly active or completely ineffective[121] The protective effect of nifedipine occurs at two levelsbesides its direct antioxidant effect by inhibition of LDLoxidation it also exhibits a direct cytoprotective effect againstcytotoxicity of oxidized LDL by yet unknown mechanismsThe protective effect of CCBs was not due to an inhibitionof LDL uptake This effect seems to be independent of theinhibition of LDL oxidation per se since LDL was oxidizedin the absence of the drug before the incubation withcells Moreover this direct protective effect was observedat lower concentrations (IC
50of 1 plusmn 02 120583M) compared to
the antioxidant effect (IC50
of TBARS inhibition is around10 plusmn 2 120583M at UV promoted and 4 plusmn 05 120583M by Cu2+ ionsinitiated) The AO effect of nifedipine is also correlated withthe protection of endogenous tocopherols (IC
50= 50 120583M)
It was suggested that the AO effect of CCBs protected cellsindirectly from the cytotoxic effect of oxidized LDL [121]
A recent study has reported that beneficial vascular effectsof lercanidipine in diabetic rats depend on its antioxidantactivity related to attenuating the increase in oxidativestress and in vascular matrix metalloproteinase-2 (MMP-2) (Martinez et al [126]) Lesnik et al [127] studied theimpact of a combination of this calcium antagonist and a120573-blocker atenolol on cell- and copper-mediated oxidationof LDL and on the accumulation and efflux of cholesterolin human macrophages and murine J774 cells They realizedthat lercanidipine reduced the oxidative modification of LDLrather than diminished cholesterol accumulation in humanfoam cells
Comparing the antioxidative action of CA (DHPs amlo-dipine lacidipine nifedipine and isradipine as well as diltia-zem and semotiadil) in the copper-catalyzed oxidation oflow-density lipoprotein (LDL) with that of glycated (g)gly-coxidated (go) LDL demonstrated that the strongest AOeffects during long-term LDL glycation are seen for isradip-ine lacidipine nifedipine and semotiadil [128] Inhibitoryeffects were in the range 10minus5ndash10minus3MAuthors suggested thatdue to the increased generation of ROS by glucose-modifiedLDL the chain-breaking capacity of CA may be overriddenThe AOA of CA depends on their lipophilicity and theirability to incorporate into the LDL particle that is to reachthe site of peroxidation CA like other AOs significantlyretards advanced glycation end products (AGE) formationwhereas initial glycation reactions such as Amadori productformation are only weakly inhibited The observation thatboth oxidative changes and at least long-termglycation effectsare indeed drastically reduced by CA is corroborated by
fluorescence analysis AGE-ELISA quantitation of lipid per-oxidation and TBARS measurement of long-term ggo LDL
The effects of lipophilic DHP calcium channel blockerson oxidized LDL-induced proliferation and oxidative stressof vascular smooth muscle cells were also studied [130] (seeTable 5)
Lacidipine and amlodipine reduced carotid intima-media thickness by decreasing proliferative effect of oxLDLwhereas (S-)-amlodipine had no antiproliferative effect ROS-MAPKs (mitogen-activated protein kinases) pathway mightbe involved in the mechanism
Both 14-DHP CCBs lacidipine and nifedipine reduceplasma and LDL oxidation and formation of oxidation-specific epitopes Their application may also relate to pro-longed survival of rats independently of blood pressuremod-ifications (in the SPSHR model 1mgkg per day lacidipineand 80mgkg per day nifedipine) These results suggestedthat the protective effect of these two 14-DHP drugs invivo as shown in cerebral ischemia and stroke may in partresult from inhibition of LDL oxidative process althoughthese two drugs possess different lipophilic properties [131]Both lacidipine (03 and 10mgkg) andnifedipine (80mgkg)prolonged lag time of the conjugated diene formation inLDL isolated from arterial wall and 119905max These drugssignificantly reduced electrophoreticmobility of oxLDL fromSPSHR subjected to XXO oxidation system 14-DHP CCBsalso protected apolipoprotein B which is important for thebinding with macrophage LDL receptor lysine residues Thedoses used (gt10minus6molL for SPSHR and normotensive WKYrats) however are 2 to 3 orders of magnitude higher thanthose inhibiting vascular smooth muscle contraction in vitroand in vivo They also exceed values that are commonlyused in clinical practice The daily dose of lacidipine forhypertensive patients is 007mgkg asymp4- to 14-fold lower thanthe 2 doses used in SPSHR The maximum daily dose ofnifedipine given to hypertensive patients is 20mgkg asymp40-fold lower thanwhatwere used [131]These discrepanciesmaybe related to differences in bioavailability of CA between ratsand humans [131]
Accordingly in routine clinical use 14-DHPCCBs donotreach the concentrations required for antioxidant activity invitro [131]
Another data concerning the effect of CA DHPs on OSrelated to LDL is presented under Section 35
(b) Effect of DHPs on Isolated Rat Liver and Heart Mitochon-dria As a major cellular source of oxygen radicals (Cadenas[4 5]) mitochondria are promising targets for pharmaco-logical and toxicological actions of various membrane-activecompounds including several 14-DHP derivatives Zernig etal [132] have discovered CA binding sites associated with aninner mitochondrial membrane anion channel
More than 40-year long research onmitochondrial effectsof the DHPs (on their bioenergetics chemiosmotic proper-ties and ion fluxes) clearly points them out as mitochondri-otropic compounds
The activity of the first 35 synthesized compounds(derivatives of 14-DHP their heteroaromatic analogues
12 Oxidative Medicine and Cellular Longevity
NAD-H+ and butylated hydroxytoluene (BHT BOT)) orig-inally was examined in rat liver mitochondrial LP system inthe presence of Fe2+ ions and using the ultraweak chemilu-minescence method (Dubur et al [89])
Several 14-DHP derivatives Hantzsch ester diludine andits analogues were found to be effective antioxidants in thisexperimental system changing the kinetics of LP lengtheningthe time of the appearance of the maximum of the slowburst of the chemiluminescence (latency latent period) anddiminishing the reaction rate (the tangent of the slope angleduring the time in which the amplitude of the slow burstcharacterizing LP rate increases) and its peak value Theirpresence has influenced the reaction constant 119870
6 in relation
to a very significant reduction of lipid hydroperoxides andorinactivation of free radicals as follows
ROO∙ + ROO∙ 997888rarr P + h]lowast termination (1)
(P = molecular products) or
ROO∙ + ROO∙ +H2O 997888rarr ROH + RO∙ + 1O
2
lowast (2)
In this study diludine was one of themost active compoundsDHPs had activity similar to the standard synthetic AO-BHT(ionol) However when plotted against applied concentrationand time window diludinersquos activity profile differed from thatof BHT
There were also similar studies (using different LP rateexperimental detection system and method Hunter et al[133]) based on exploring a group of 26 26-dimethyl-35-disubstituted- and 26-dimethyl-345-trisubstituted-14-dihydropyridines (14-H
2Py=14-DHPs) and five related pyri-
dines as inhibitors of rat liver Mit swelling (Δ119860520119905) and O
2
uptake by ascorbic acid- (AsA-) dependent lipid peroxidationand as modulators of Mit swelling induced by Na+-linoleateor Na+-pyrophosphate (Velena et al [112])
Some of tested 4-DHPs (4-unsubstituted 35-dialkoxy-carbonyl-26-dimethyl-14-DHPs and 35-diamido-26-dim-ethyl-14-DHPs both 4-unsubstituted or those possessinglipophilic 4-aryl- groups) have shown significant AO andmembrane stabilizing activity These studies further revealedthat 14-DHPs preferably act as AO during the stages ofinitiation and prolongation of LP chain reactions at lowconcentrations The studied 14-DHPs had IC
50(when 119881
0119881
or 1205911205910= 2) 01 120583M to 100 120583M and the minimal activity was
scored for oxidized (heteroaromatized) derivativesAt the concentration of 100120583M 35-di-n-butyloxycarbo-
nyl-26-dimethyl-14-DHP entirely stops mitochondrialswelling in the presence of 08mM Na+-pyrophosphateAt the same concentration the following compoundsalter the mitochondrial swelling rate in the presence ofnatural protonophore Na+-linoleate 35-di-p-hydroxyphen-oxycarbonyl- and 35-di-p-tolyloxycarbonyl-26-dimethyl-14-DHPs 35-diethoxycarbonyl-26-dimethyl-pyridine (oxi-dized form of Hantzsch ester) and more lipophilic 35-diamyloxycarbonyl-26-dimethyl-pyridine The alteration ofswelling may be scored as prolonged promoted acceleratedor inhibited The type of alteration depends on the structureand concentration of 14-DHPs the type of initiators of theswelling process and the medium composition
In accord with previously published Janerorsquos results (lackof AO for Ca2+ antagonists nifedipine and nicardipine evenat 500120583M concentration in LP tests performed on heartmembrane [134]) no antioxidative activity for 4-phenyl sub-stituted derivatives of 35-dialkoxycarbonyl 14-DHP (closeanalogues of Ca2+ antagonists) was found contrary to various4-nitrophenyl 14-DHP derivatives calcium antagonists forwhich the significant antioxidant activity was reported [3146ndash53]
Studies made on phosphatidylcholine liposomes (ourunpublished data) suggest approximately three and twotimes more antioxidative activity for 100 120583M 4-unsubstitutedDHP compound diludine when compared to 4-substitutedDHPs riodipinenifedipine and nicardipine respectively atmethemoglobin-induced LP (oxygraphy)
Inhibition of mitochondrial AsA-dependent LP and sta-bilization ofmitochondriawere shown to be characteristic fora large group of 14-DHP compounds [112] showing to pos-sess the AOA in simplest in vitro systems (Tirzit andDuburs [39] Zilber et al [44] and Dubur et al [45])based on reactions with the stable free radical 11-diphenyl-2-picrylhydrazyl (DPPH) LP of fatty acid ester (linethole andmethyloleate) emulsions and phospholipid (phosphatidyl-choline) liposomes Generally these properties did not coin-cide with Ca2+ antagonism Depending on DHP structure itseems that AOA properties are less specific than Ca2+ antago-nist properties Both properties may be interrelated but notinterdependent
These data show that the presence and the nature ofa substituent in position 4 as well as 35-substituentsare important factors for 14-DHP antioxidant effects invarious systems that is AsA-dependent nonenzymatic aswell as enzymatic NADPH-dependent lipid peroxidationSometimes the efficacy of inhibition of nonenzymatic LPby 14-DHPs is higher than the inhibition of the enzymaticLP However the action may be opposite stimulation of theLP Hantzsch ester (HEH diludine) and its close analoguesexhibited significant AOA and membrane stabilizing prop-erties in both AsA-dependent nonenzymatic peroxidationof mitochondria and NADPH-dependent enzymatic LP ofmicrosomes usually at similar 10 to 100120583M concentrations[112]
The order of AOpotency (IC50
values) in vitro depends ondrug structure as well as on the experimental conditions andspecificity of the biological system Eachmethod for determi-nation of AOA and ARA has advantages and disadvantages(Karadag et al [135])
Accordingly as reported by Gubskiı et al [136] IC50
forthe AsA-dependent LP was 025 120583M and 20 120583M for 14-DHPCa2+ antagonists nitrepine (nitrendipine) and nifedipinerespectively Takei et alrsquos [137 138] studies on mitochondrialswelling induced by LP or arachidonic acid in the rat braindetermined the IC
50values of 127 105 1568 and 384 120583Mfor
efonidipine nicardipine nifedipine and nimodipine respec-tively For LDL in the copper-induced oxidation system theorder of potencywas vitamin Egt felodipinegt 2-chlorophenylanalogue of nifedipine gt nifedipine gt amlodipine nitrendip-ine verapamil and diltiazem (Rojstaczer and Triggle [119])
Oxidative Medicine and Cellular Longevity 13
It was interesting to compare the AOAofDHPswith theirsusceptibility to oxidation that is electron and hydrogendonating properties
It has been estimated that electron donor substituentsin positions 2 and 6 of 14-DHP cycle usually promoteoxidation while electron acceptor substituents promotequench oxidation Stronger electron acceptors in positions 3and 5 also significantly quench oxidation These estimationsare based on studies including chemical enzymatic andelectrochemical oxidation of 14-DHPderivatives (Dubur andUldrikis [70] Duburs et al [71] and Stradin et al [139])
On the other hand diminished AOA of 14-DHP relatesto presence of substituents in position 4 (both electron donorand electron acceptor) (Velena et al [112])
35-Dicarbamoyl substituents possess minimal quench-ing feature and are followed by benzoyl- acetyl- andalkoxycarbonyl- groups Maximal decrease was obtainedwith condensed substituents (ie oxoindeno- or oxocyclo-hexeno- groups) and a CN-group 4-Unsubstituted 35-dicar-bamoyl derivatives can be easily oxidized and consequen-tially inactivated whereas 4-substituted 35-dicarbamoyl-14-DHPs possess an oxidation potential analogous to the 4-unsubstituted 35-COOR derivatives Therefore they haveadequate electron donor properties and are considerablystableThismay be the reason for significantmembrane stabi-lization upon exposure to 4-substituted derivatives Ofimportance their AOA was usually more pronounced incomparison to 4-unsubstituted derivatives
Among them 26-dimethyl-35-difurfuryloxycarbonyl-14-DHP showed the highest antioxidative activity In thegroup of 35-dialkoxycarbonyl derivatives the strongestactivity was attributed to compounds with medium lengthalkyl chains (i-butyl- t-butyl- and i-amyl- substituents) highlevel of lipophilicity minimal electron acceptor propertiesand moderate steric hindrance as contrasted to short or longalkyl chain ester derivatives (35-dimethoxycarbonyl- 35-diethoxycarbonyl derivatives and 35-didodecyloxycarbonylderivative) These data demonstrate the bell-shaped depen-dence of AOA on alkyl chain length [112] and are in accordwith results obtained in liposomes However these datadiffer from those obtained in emulsions where diludine wasthe most active compound Finally oxidized heteroaromaticderivatives showed only minimal activity
In both LP systems studied (AsA-dependent in mito-chondria and NADPH-dependent in microsomes) some of14-DHPs showed activity similar to classical antioxidantbutylated hydroxytoluene (ionol BHT) (Velena et al [112])However there was a significant difference related to con-centration and incubation time It allowed us to postu-late that 14-dihydropyridines (InH) acting as antioxidants-reductants and scavengers of reactive oxygen species and lipidfree radicals preferably influence initiation and propagation(prolongation) of lipid peroxidation chain reactions (1)ndash(5) according to Scheme 2 The phenomenon is particularlyprominent in the presence of Fe2+ and other ions of variablevalency
Chain break and termination reactions (6)ndash(10) of theLP reaction cascade [89] were influenced by 14-DHPs in alesser degree than were initiation and propagation steps This
may be important for their therapeutic effects even in theadvanced stages of LP
Scheme 2 (stages of initiation propagation and terminationof lipid peroxidation chain reactions (1ndash10)) Initiation andpropagation reactions are as follows
(8) RO∙ + In∙minus rarr Y (Y = molecular products)(9) ROO∙ + Fe2+ rarr Fe3+ + X (X = molecular products)(10) RO∙ + RO∙minus rarr Y (Y = molecular products)
In the reversible swelling of mitochondria accompanyingLP (initiated by mixture of 5mM GSSG1mM GSH) several14-DHPs showed low or no activity manifested only as adecrease of the swelling amplitude without a rate decreaseAn addition of GSH (4mM) or ATP to swollenmitochondriacaused their contraction in both control and tested systemIt may be suggested that 14-DHPs acting as antioxidantsin mitochondria preferably influence LP reactions initiatedby ions with variable valency or their complexes with hemetype compounds methemoglobin hemin hematin and soforth (Velena et al [112]) If the peroxidation process has amaximal velocity and 50 percent of initial O
2were consumed
14-DHPs cannot completely break the chain reactions andprevent subsequent membrane damage by addition of DHPsubstance at 10 120583M concentration at the moment of 50percent oxygen consumption the subsequent oxygen uptakeproceeded unchanged This observation is important for theapplication of DHPs as inhibitors of initiation and to a lesserdegree propagation stages of LP chain reactions
The influence of 14-DHPs on Mit swelling is not strictlyassociated with their own oxidation There is the possibilitythat the labilizing (or stabilizing) effect relates to surfaceactivity (connected with substituent lipophilicity) or may bethe consequence of complexation with some -OH (or -CH
3)
group sensitive receptors at the mitochondrial membraneNamely a bathochromic shift of the absorption band maxi-mum (about 10 nm) was observed in the visible region beforeswelling However after swelling in the presence of Na+linoleate the spectrum returns to its initial value [112]
Some 14-DHPs not only protect mitochondria againstswelling caused by AsA-dependent LP salts of fatty acids
14 Oxidative Medicine and Cellular Longevity
in vitro [112] but also have beneficial effects on repairingtheir integrity in vivo after exposure to irradiation hepato-toxins ischemia hypoxia or hypothermia Some of themwere shown to normalize the process of intracellular repara-tion and physiological regeneration of ultrastructures Theywere also shown to stimulate reparative processes If pre-treated with 14-DHPs irradiatedmitochondria will not swell(Ivanov et al [140 141])
Diludine ionol and some other AOs mitochondria pro-tectors act as anti-ischemic agents If applied prophylacticallyin vivo they may prevent ischemic and reperfusion lesionsin heart kidney and other organs (Bilenko et al [113]) Theeffect is dependent on applied dose timing and way ofapplicationWhen added onto the cryoconservationmediumfor mitochondria preservation 14-DHPs prevented decreaseof membrane potential normalized facilitated respirationand prevented loss of mitochondrial Na+ and Ca2+ ionsafter thawing ([112] see citation number 36 (Subbota et alKharkov 1984) therein) Diludine was stronger protectorwhen compared to ionol
CA drug foridone (riodipine) was shown to possesscardioprotective features primarily due to is protective effecton mitochondria exposed to OS [142 143]
Similarly the DHP water-soluble antiarrhythmic com-pound glutapyrone inhibits initiation of LP by free radicalsin erythrocytes and heart mitochondria Its cardioprotectiveeffect has been experimentally shown in heart mitochondrialmembranes especially during deep hypothermia (Utno et al[144])
Cerebrocrast was effective in several translation modelsmimicking pathological situations known to be associatedwith cellular OS The potential protective action of 14-DHP derivatives (4-substituted compounds cerebrocrastgammapyrone glutapyrone and 4-unsubstituted drug dieth-one) has been studied in rat liver in experimental modelsrelevant for oxidative stress and mitochondrial bioenergetics(Fernandes et al [145]) When succinate was used as therespiratory substrate higher concentrations (gt25 120583M) ofcerebrocrast depressed respiratory control ratio (RCR) ADPto oxygen ratio (ADPO) state 3 and uncoupled respirationrates transmembrane potential (deltapsi) and the phosphatecarrier rate At the same time state 4 respiration rate wasthree times increased At concentrations lower than 25120583Mcerebrocrast inhibited mitochondrial IMAC and partiallyprevented Ca2+-induced opening of the mitochondrial PTPGammapyrone glutapyrone and diethone did not inducethese phenomena When applied at concentrations up to100 120583M cerebrocrast gammapyrone and glutapyrone didnot affect ADPFe2+-induced LP of mitochondria in rat liver(as measured by oxygen consumption and TBARS forma-tion) On the other hand low diethone concentrations (upto 5 120583M) inhibited it in a dose-dependent manner Diethonealso prevented against deltapsi dissipation induced by LPinitiated by ADPFe2+ Based on these data it may bespeculated that cerebrocrast (inhibition of the IMAC) anddiethone (acting as an AO) may provide effective protectionof mitochondria during OS Cerebrocrast has shown sometherapeutic potential for treatment of several pathologicalconditions related to cellular OS [145]
5-Acetyl(carbamoyl)-6-methylsulfanyl-14-DHP-carbo-nitriles (Figure 3) with minor differences in their molecularstructure displaying antioxidant and antiradical activitiesin vitro show different biological activities Namely 4-p-chlorophenyl derivative OSI-1146 displays AO and anti-radical activities in cardiovascular OS models whereasOSI-3701 and OSI-3761 display hepatoprotective activityThus these compounds may be potentially useful for treat-ing several pathological processes including those associatedwith OS (Fernandes et al [146]) However besides mito-chondria the cellular targets for their pharmacologicalactions have not been fully investigated [146] All these com-pounds increase the susceptibility of Mit to MPT The mostpotent is OSI-3701 although it does not affect bioenergeticparameters
Although all these compounds protected mitochondriaagainst LP induced by the oxidant pair ADPFe2+ OSI-1146was shown to be the most potent Current data point outmitochondria as potential targets for protective and toxicactions of DHPs suggesting that the potential for their use astherapeutic agents should also take into consideration theirtoxic effects on mitochondria (Fernandes et al [146])
Several structurally different DHP derivatives (antioxi-dant diludine (diethone) as a 4-unsubstituted DHP 4-substi-tuted DHPs CA foridone (bicyclic compound) and the 4-phenyldiethone compound where phenyl group is joined tothe DHP in position 4) inhibited the 1-methyl-4-phenyl-pyridinium iodide (MPP+) induced ROS production incerebellar granule cells (CGC) with a distinct potency orderforidone (26-dimethyl-35-dimethoxycarbonyl-4-(o-difluo-romethoxyphenyl)-14-dihydropyridine) gt 26-dimethyl-35-diethoxycarbonyl-4-phenyl-14-dihydropyridine gt diludineThey also reversed the MPP+-induced decrease of the mito-chondrial membrane potential in the same order (Klimavi-ciusa et al [147]) Accordingly it was postulated that theclassical two-ring (bicyclic) structure of DHP derivativesrepresents an advantage in relation to neuroprotection andROS defense and is independent on compoundrsquos propertiesrelated to calcium ions
Novel adamantane-containing 14-DHP compounds (Kli-maviciusa et al [148]) were also found to improve mitochon-drial functions (MPP+ model) (Klimaviciusa et al [148])Klusa et al [149] have discovered antineurotoxic effects of14-DHP taurine derivative tauropyrone recorded as Mitfunction improvement
Many 14-DHPs including Ca2+ antagonists and AOmodify LP processes and influencemitochondrial function invarious organs (liver heart kidney and brain) in a differentway and degree Their beneficial action oxygen or lipidfree radical scavenging antioxidative effects binding withor intercalating into phospholipid bilayer regulation of iongating and regulation of mitochondrial permeability transi-tion pores (Tirzit and Duburs [39] Zilber et al [44] andDubur et al [45]) separately or in combination with eachother depends on two strong elements (1) their individ-ual structure including nature of substituents and theirpositions and (2) the nature of the biological system Forexample the direction of LP (inhibition of promotion) wasshown to depend on structure and concentration of applied
Oxidative Medicine and Cellular Longevity 15
14-DHPs as well as stages of chain reactions Accordinglymitochondrial swelling may be prolonged (retarded) accel-erated (promoted) or inhibited (Velena et al [112])
Therefore there is a ground for 14-dihydropyridineseither Ca2+ antagonists or antioxidants to be nominated asuseful tools in development of ldquomitochondrial drugsrdquo relatedto the control of OS
(c) DHPs as AOs in Endoplasmic Reticulum (Inhibition ofNADPH-Dependent LP System) Inhibition of NADPH Oxi-dase by DHPs Elevated level of NADPH oxidase 4- (NOX4-)derived hydrogen peroxide (H
2O2) joined with concomitant
decrease of nitric oxide (NO) mediated signaling and reac-tive oxygen species scavengers are considered to be centralfactor in molecular pathogenesis of fibrosis (Sampson etal [150]) Inhibition of microsomal NADPH-dependent LPwith particular focus on NADPH oxidases (NOX1ndash5 andDUOX1) may be very important for neuro- cardio- andhepatoprotection (Velena et al [112] Leto and Geiszt [151]Griendling et al [152] and Chen et al [153]) Endoplasmicreticulum may be an important target as this is where 14-DHPs could display their antioxidative properties (Velena etal [112] Leto and Geiszt [151] Griendling et al [152] andChen et al [153])
However the initiation of LP in the NADPH-dependentmicrosomal system does not appear to involve either super-oxide or hydrogen peroxide since neither SOD nor cata-lase can inhibit it On the other hand reduced iron playsan important role in both the initiation and propaga-tion of NADPH-dependent microsomal lipid peroxidation(Hochstein and Ernster [154] and Repetto et al [111])
Many DHPs possess inhibitory activity not only towardsAsA-dependent LP in mitochondria but also towardsNADPH-dependent LP as shown in isolated rat liver micro-somes (Velena et al [112]) This means that these compoundsinteract with the shared parts (nonenzymatic and enzymatic)of LP pathways
Microcalorimetry and fluorescent probes procedureswere used for studying the interaction of alpha-tocopheroland 14-DHPs with endoplasmic reticulum membranes andmodel systems human serum albumin and phospholipidbilayers [155] Modification of microviscosity of the endo-plasmatic reticular membranes depends on localization ofantioxidants within the protein structures or phospholipidphase Increase of membrane structuralization under theinfluence of 14-DHPs blocked their antioxidant action inspontaneous and induced lipid peroxidation
Inhibition of rat heart and liver microsomal lipid perox-idation by nifedipine was observed [156] while Goncalves etal [157] found antioxidant effect of calcium antagonists onmicrosomal membranes isolated from different brain areas
Nitroaryl-14-DHPs are both calcium channel antagonistsand antioxidant agents (Letelier et al [158 159]) commonlyused for treatment of cardiovascular diseases These drugsmust be metabolized through cytochrome P450 oxidativesystem (NADPH-cytochrome P450 reductase) mainly local-ized in the hepatic endoplasmic reticulum Several lipophilicdrugs generate OS while being metabolized by this cellularsystem Thus DHP antioxidant properties may prevent the
OS associated with hepatic biotransformation of drugs Var-ious commercial and new nitro-phenyl-DHPs were studiedagainst LP using rat liver microsomes under oxidative stress[159]
Incubation of rat liver microsomes with the 41015840-nitro-4-phenyl-14-DHP compounds (26-dimethyl-4-(41015840-nitro-phenyl)-14-dihydropyridin-35-diethyl-dicarboxylate andN-ethyl-26-dimethyl-4-(41015840-nitrophenyl)-14-dihydropyri-din-35-dimethyl-dicarboxylate) results in an inhibitionof LP the UDPGT (UDP-glucuronyltransferase) oxidativeactivation and the microsomal thiol oxidation induced byFe3+ascorbate a generator system of ROS This effect wasalso produced by nitrofurantoin and naphthalene in thepresence of NADPH
Interestingly IC50
ofDHPs obtained frommicrosomal LPassays decreased to the same extent as the microsomal thiolsoxidation provoked by Fe3+ascorbate [159] Neverthelessthe AO effects of a nitrophenyl-DHP compound in whichhydrogen at position one of the DHP ring was replaced bythe ethyl groupwere significantlyweaker Authors speculatedthat DHPs can resemble NADH transferring one hydrogenatom of 4-position (Hminus) to anion superoxide and another ofthe 1-position (H+) by way of a cationic radical intermediateto generate pyridine derivatives and water [159]
The AO effects of various tested DHP derivatives (m- andp-NO
2phenyl as well as methyl or ethyl and isopropyl-DHP
35-dicarboxylate derivatives) were not significantly differentThe authors assumed that the -NH- group of the dihydropy-ridine ring could contribute both to the development ofthe calcium channel antagonism and to the antioxidativeproperties of DHPs [159]
Prevention of the membrane LP seemingly depends onthe concentration of potential antioxidants such as vitaminE or even 14-DHP in lipids However only the differencesin synthetic DHPs lipophilicity cannot explain significantvariations of DHPs concentration in microsomal membraneand cannot clarify the strength of their antioxidative activityThis work [159] has further demonstrated that 14-DHPsmay prevent the OS induced by biotransformation of somedrugs for example antibiotic nitrofurantoin Simultaneousadministration of DHPs and nitrofurantoinmay be beneficialin reducing nitrofurantoin side effects
While most of Ca antagonist 14-DHPs are metabolizedby CYP3A4 (Guengerich et al [160]) not all of them are goodinhibitors of its activity Thus nicardipine but not nifedipineand nitrendipine inhibits CYP3A4 in vitro [53] Interactionof different DHPs with various types of cytochrome P450 wasdescribed by Carosati et al [53] It was also reported thatDHP class calcium channel blockers reduce the antiplateleteffect of clopidogrel (Park et al [161])This implies themutualinteractions of both drugs with CYP3A4
(3) In Vivo Evaluation of nifedipine effects on Saccharomycescerevisiaewas recently published (Asma andReda [162]) Sur-prisingly nifedipine exercised a toxic effect on Saccharomycescerevisiae shown through measuring cellular proliferationrespiratory activity and the level of some biomarkers (CATand MDA)
16 Oxidative Medicine and Cellular Longevity
However majority of data obtained on various animalcells and tissues by other authors show the protective role ofDHPs against both LP and oxidative stress [113 163 164]
The AOA attributed to many 14-DHPs Ca2+ antag-onists and other compounds reflecting on catalytic LDLperoxidation (see Section 331 (2) and Section 35) shouldencourage their testing for treating cardiovascular diseasesandor alterations of lipid metabolism
The possibility that 14-DHP-based calcium antagonistsexert an antiatherosclerotic action (via inhibition of LDLoxidation and other mechanisms) has been proved by manyexperimental data [165] and several clinical trials Besidesantihypertensive effect nicardipine was shown to possessantioxidative and antielastase activity [165 166] These prop-erties may be useful for prevention of inflammatory reactionwhich is relevant for hypertension pathogenesis
14-DHPs administration inhibits LDL oxidation medi-ated by oxygen radicals leading to decreased carotid inti-mal media thickness and reduced progression of coronaryatherosclerosis [130] It additionally preserves Apo B-100integrity against ROS Of importance antiatherogenic mech-anisms differ between animals and humans (primarily inthe stage of conversion of aldehydes to carboxylic acids)(Parthasarathy et al [167])
For example furyl-DHP compound (FDP-1 diethyl 26-dimethyl-4-(furyl)-14-dihydropyridine-35-dicarboxylate)was shown to act as an antioxidant (decreasing MDA GOTand FFA release of ischemic myocardium and inhibiting Ca-ATPase of erythrocyte membranes) preventing against heartmyocardium ischemia-reperfusion injury and arrhythmiawhen applied (in rats) at 10mgkg (Liu et al [168])
Similarly antioxidative effects of azelnidipine andamlodipine prevented neuronal damage by CCBs aftertransient focal ischemia in rats (Lukic-Panin et al [169])
Allanore et al [170] found that both nifedipine andnicardipine significantly decrease the mean level of plasmamarkers for oxidative stress in patients suffering from sys-temic sclerosis
Antioxidants may be considered as promising neuropro-tective compounds Still while experimental data demon-strate neuroprotective effect in vitro and in animal mod-els clinical evidence is still unsatisfactory and insufficient[171]
(a) Role of Metabolism of DHPs in Their AOA Metabolicpathways and ldquobioavailabilityrdquo of the probable AOA com-pound determine antioxidant activity in vivo Antioxidantmetabolites may vary in stability and activity leading to twoopposite scenarios lack or presence of activity substantiallycontributing to the overall AOA [172] Metabolic biotransfor-mation of DHPs includes oxidation (heteroaromatization)side chain ester group cleavage (deesterification) and 4-substituent abstraction ao [160] None of the DHPs metabo-lites was shown to be more toxic than original reduced formof the compound The commonly detected metabolites ofthe DHPs do not seem to possess the AO activity (withsome exceptions as in the case of metabolites of nifedipineand its analogues including nitrosonifedipine [173 174]) (seefurther in Section 35) Due to DHPs intrinsic instability
achieving andmaintaining an adequate concentrationmay beproblematic both in vitro and in vivo
(b) Role of Concentration and Lipophilicity (MembraneWateror LipidWater Partition Coefficients) of DHPs inTheir Actionas AOs and Antiradical Compounds Antioxidative effects ofany antioxidant depend on its concentration at the site ofaction This parameter is hardly measurable especially intwo-phase systems representing one of obstacles in com-parison to AOA upon applying various compounds [172]It is often incorrectly assumed that the concentrations inthe aqueous solution and at the site of action are the sameHowever even when the concentration in the aqueous phasemay be well controlled the concentration at the site ofaction in the lipid matrix of the membranes might fluctuatebetween different test compounds depending on a differencein lipophilicity [175] The prevention of the membrane LPalso seems to be dependent on the DHP concentration in thelipidmatrix (Mason andTrumbore [46]) and its amphiphilic-ity For example AOA of diludine is associated with itslipophilicity and consequential ability to be incorporatedinto liposomes (Panasenko et al [176]) It was also foundthat diludine easily incorporates into the outer monolayer oferythrocyte membranes [176]
Membranebuffer partition coefficients (lambda) weredirectly measured in the sarcolemma and sarcoplasmicreticulum membranes for three CA DHPs The obtainedvalues were in a broad range between 5000 and 150000(Herbette et al [177])These drugs interact primarily with themembrane bilayer component but may also bind to proteinsboth nonreceptors and receptors The intrinsic forward rateconstants for DHP binding to sarcolemmal calcium channelreceptors were apparently not strongly dependent on theirmembrane partition coefficients For example nimodipine(lambda = 6300) had a forward rate constant of 68 plusmn 06 times106Ms whereas the forward rate constant for Bay P 8857
(lambda = 149000) was 14plusmn08times107Ms Since these DHPsare highly liposoluble model calculations for this bindingreaction demonstrated that these rates on lipid solubilitywould probably not be reflected in the experimental forwardrate constants In addition the intrinsic forward rate constantfor nimodipine binding to sarcolemmal calcium channelreceptors was found not to be linearly dependent on theviscosity of the buffer medium over a fivefold range The rateof drug nonspecific binding to nonreceptor protein present inhighly purified sarcoplasmic reticulum membranes appearsto be extremely fast at least 103 times faster than specificdrug binding to the receptor in the sarcolemma Authorsconcluded that partitioning into the lipid bilayer matrix ofthe sarcolemma could be a general property of CA DHPsand may be a prerequisite for their binding to sarcolemmalmembrane receptors (Herbette et al [177])
The binding of DHP calcium channel agonists and antag-onists (including those with AO properties) to receptors incardiac sarcolemmal membranes is a complex reaction thatmay involve an interaction with the lipid bilayer matrix ofthe sarcolemma (Herbette et al [178]) Belevitch et al [179]studied the binding of DHP CCBs (riodipine and nifedip-ine) and verapamil to model and biological membranes by
Oxidative Medicine and Cellular Longevity 17
fluorescence analysis The consistent location of Ca agonistBay K 8644 was determined to be within the region ofthe first few methylene segments of the fatty acyl chains ofthe membranes (Mason et al [180]) This position is nearto that observed for the DHP calcium channel antagonistsnimodipine and Bay P 8857
Themajority of studies onOSwere performedwithDHPswith various lipophilicity but only a few studies reportedamphiphilicity ofDHPderivatives AmphiphilicDHPderiva-tive K-2-11 reduced the cellular generation of ROS It alsorevealed complete reversal of multidrug resistance (MDR) ofthe resistant cells K-2-11 was more efficient than well-knownMDR inhibitor verapamil Cytotoxic effects of anticancerdrug doxorubicin were enhanced by K-2-11 in bothMDR andparental nonresistant cell line (Cindric et al [181]) K-2-11suppresses increase of ROS and consequentially prevents NF-120581B activation leading to decreased expression of MDR1 andincreased expression of antiapoptotic genes This signalingswitch is necessary for restoring the chemosensitivity ofcancer cells This phenomenon is characteristic both for14-DHPs [182] (18 novel asymmetrical DHPs bearing 3-pyridyl methyl carboxylate and alkyl carboxylate moietiesat C3 and C5 positions resp as well as nitrophenyl orheteroaromatic rings at C4) and for their oxidized formspyridine compounds (Zhou et al [183])
34 Dependence of AOA of DHPs on the Experimental SystemAO effect of DHPs depends on their structure and theexperimental system used (in vitromodel system subcellularorganelle and cells ex vivo and in vivo) Ideally for theevaluation of the profile and value of DHPs AO propertieseach compound should be tested in as many systems aspossible (Dubur et al [45])
Lipidomics studies have been traditionally explored forstudying AOA of DHPs Proteomics methods are less rep-resented and are mostly focused on the properties of DHPsrelated to scavenging of protein free radicals So far there areno studies on the role of DHPs in scavenging nitrosoperoxy-carbonate the reactive species formed out of peroxynitrite inthe presence of carbon dioxide Although it was shown thatalbumin binds diludine no studies revealed the relevance ofthis effect for the AOA of diludine
There are findings showing that dihydropyridine calciumantagonists (DHPs CA) could indirectly play a beneficialprotective role during development of atherosclerosisNamely Berkels et al [184] have studied antioxidativeproperties of four substances the DHP prototype CAnifedipine the long-acting CA lacidipine the DHP calciumchannel agonist BayK8644 and the bulkyDHPderivate BayO 5572 in three different models (1) in an in vitro superoxideanion generating system (hypoxanthinexanthine oxidase)for testing the ldquopurerdquo antioxidative effect (2) in an artificialmembrane preparation (dimyristoylphosphatidylcholine) formimicking a more physiological environment and (3) underconditions of stimulated ROS release (hyperglycemia) fromnative endothelial cells derived from porcine coronary arter-ies
The study also revealed the potential correlation betweenlipophilic and AO properties of DHPs In the first model
Bay K 8644 was significantly more effective in scavengingsuperoxide anions than lacidipine Bay O 5572 or nifedipine(micro- to millimolar concentration range) Addition of anartificial membrane preparation resulted in an enhancedAO effect with lacidipine being the most effective DHP inquenching radicals (low micromolar concentration range)In the third model mimicking hyperglycemia (30mmolL)nifedipine was significantly more potent antioxidant (ther-apeutical nanomolar concentration range) than the otherDHPs Calculated lipophilicity of these four substances(lacidipine gt Bay O 5572 gt Bay K 8644 gt nifedipine) waspositively correlated with antioxidative potential only in thesecond experimental model It has been concluded that AOproperties of DHP substances need to be tested in variousmodels for demonstrating that nifedipine exhibits ROS-quenching properties in a therapeutic concentration range[184]
341 AOA of DHPs in Isolated Cells and Cell Cultures(Comparison with Other Simplest Systems) Although DHPspossess neuromodulatory andor antimutagenic propertiesthe mechanisms of action related to these phenomena arenot entirely elucidated Borovic et al [185] have studied 14-dihydroisonicotinic acid (14-DHINA) derivatives of 14-DHP water-soluble analogues of a well-known AO diludine(diethone) 26-dimethyl-35-diethoxycarbonyl-14-dihydro-isonicotinic acid sodium 2-(26-dimethyl-35-diethoxycar-bonyl-14-dihydropyridine-4-carboxamido)glutamate gluta-pyrone and sodium 2-(26-dimethyl-35-diethoxycarbonyl-14-dihydropyridine-4-carboxamido)ethane-sulphate tauro-pyrone as AO and bioprotectors (Figure 4)
14-DHINArsquos activities were studied in comparison toTrolox by NN-diphenyl-N1015840-picrylhydrazyl (DPPH∙) deoxy-ribose degradation ABTS∙ radical scavenging and AOA(antioxidative capacity method) assays copper-induced LPof cultured rat liver cells (MDA determination by HPLCand 4-hydroxynonenal-protein conjugates by dot-blot) 3H-thymidine incorporation and trypan blue assay for liver cellsgrowth and viability Ic decreased the amount of 4-HNE-protein adducts In all assays Ia was the most potent AOable to completely abolish copper induced LP of liver cellswhile Ic only slightly decreased it Thus AOA is importantactivity principle of Ia which was even superior to Trolox intreated cell cultures Ia (and its analogues) are easily oxidizedin the Fenton system (Rubene et al [186]) exerting ARA too
35 Peculiarities Related to Antioxidative and AntiradicalActivity of Some 14-DHPs Ca Antagonists Nine commer-cialized structurally and functionally different DHPs CAwill be discussed further Their common feature is ability toprevent OS This also counts for some of their metabolitesas already discussed The comparative effects of some DHPsCA on oxidative stress-induced modification of LDL werealready reviewed in Section 331 (2)-(a) AOA of CA DHPswas discussed in Sections 331 (2)-(b) and 331 (2)-(c)
351 Nifedipine and Its Close Analogues Nifedipine vera-pamil and antiarrhythmic-antihypoxic drug stobadin wereshown to depress lipid peroxidation of phosphatidylcholine
18 Oxidative Medicine and Cellular Longevity
NH
COOH
NH
COONa
Glutapyrone
NH
Gammapyrone
NH
C 2H5OOC COOC2H5
Tauropyrone
14-DHINA
H3C H3C
H3C
H3CCH3 CH3
CH3
CH3
COOC2H5COOC2H5
COOC2H5 C2H5OOCC2H5OOCC2H5OOC
CONHCH(CH2)2COONa CONH(CH2)3COONa
CONH(CH2)2SO3Na
Figure 4 Derivatives of 14-dihydroisonicotinic acid (14-DHINA)
liposomes (Ondrias et al [187]) However data obtained insome other experimental systems are conflicting
In an in vitromodel of sarcolemmal membrane lipid per-oxidation three calcium blockers (nifedipine verapamil anddiltiazem) exhibited concentration-dependent (10ndash400 120583M)inhibitory effects [188 189] Nifedipine the most effectivecalcium blocker was more than two-fold potent compared topropranolol achieving significant effect at 10 120583M Nifedipineprotective role on LP using reduced glutathione as modelmarker was recently described (Ray et al [190]) Antiper-oxidative properties of CA nifedipine and its analogueswere explored in different systemspathogenic processesatherogenesis (Henry [165]) brain focal ischemia (Yamatoet al [191]) nephroprotection related to cyclosporine intake(Chander and Chopra [192]) and hepatoprotection relatedto intake of diethyldithiocarbamate (Gaafa et al [193])Recent data suggest that nifedipine action as protector forendothelial cells proceeds independently from its CA proper-ties
The absence of antioxidant effects of nifedipine anddiltiazemonmyocardialmembrane lipid peroxidation oppo-site to nisoldipine and propranolol was also described[194] Nisoldipine and propranolol were shown to havea concentration-dependent antiperoxidant effect with IC
50
values of 282 and 501 120583M respectively Finally nisol-dipine appeared to possess dual antiperoxidant mecha-nisms involving both preventive and chain-breaking proper-ties
These findings were confirmed in some other studiesincluding reports on the lack of antioxidative activity ofnifedipine and nicardipine even at 500120583M concentrationin heart membrane lipid peroxidation tests [134] SimilarlyROS formation in bovine aorta smooth muscle cells was notaffected by addition of amlodipine nimodipine and nife-dipine [123]
(1) Metabolites of Nifedipine and Its Analogues as Antioxidantsand Regulators of OS Antioxidant activity of nifedipine35-dimethoxycarbonyl-26-dimethyl-4-(2-nitrophenyl)-14-dihydropyridine was originally studied in vitro by Kirule etal [195] and Tirzit et al [196] According to the kinetic dataof peroxide accumulation and the ESR spectra (inhibition ofthe autoxidation of methyl oleate in presence of nifedipine)AO action was exerted by the formation of nitroso analogueof the oxidized nifedipine nitroso nifedipine 26-dimethyl-4-(2-nitrosophenyl)-35-pyridine dicarboxylate (NO-NIF)This nitroso aromatic derivative can form nitroxyl radicalsexhibiting remarkable AOA in the presence of unsaturatedfatty acids and lipids [196]
The primary species of free radicals that have beenobtained and identified were ion radicals of the nitrophenyltype (Ogle et al [76]) Such a mechanism coincides withmechanisms proposed afterwards by Nunez-Vergara et al[96] Lopez-Alarcon et al [103] Valenzuela et al [104]Fukuhara et al [174] and Yanez et al [197]
There are also data showing that nitroso compounds mayinhibit LP by direct radical trapping and subsequent forma-tion of stable nitroxide radicals It was further found that thereactivity between the synthesized 14-DHP derivatives withalkylperoxyl radicals involves electron transfer reactionsThisis documented by the presence of pyridine as a final productof the reaction and complete oxidation of the nitroso groupin the case of the nitrosoaryl 14-dihydropyridine derivatives(Valenzuela et al [104]) Tested compounds reacted fastertoward alkylperoxyl radicals and ABTS radical cation thanalkyl ones (Lopez-Alarcon et al [103])
Nitrosonifedipine a photodegradation product of nifedi-pine significantly recovers cellular damage induced by tumornecrosis factor-alpha It also prevents toxic effects of cumeneperoxide which hampers integrity of cell membranes throughoxidative stress Its positive effects are equal to Trolox-C
Oxidative Medicine and Cellular Longevity 19
As a result nitrosonifedipine was already a long time agoclaimed as a candidate for a new class of antioxidative drugs(Kirule et al [195]) cellular protectors against oxidative stressin glomerular endothelial cells [174]
Moreover Misik et al [198] Ondrias et al [199] andStasko et al [200] studied AOA of nifedipine and its oxidizednitroso analogue NO-NIF prevents the progression of type2 diabetic nephropathy associated with endothelial dysfunc-tion through selective AO effects (Ishizawa et al [201]) NO-NIF administration reduces albuminuria and proteinuriaas well as glomerular expansion without affecting glucosemetabolism or systolic blood pressure NO-NIF also sup-presses renal and systemic OS and decreases the expressionof intercellular adhesion molecule-1 (ICAM-1) a marker ofendothelial cell injury in the glomeruli of the KKAy miceSimilar effects were achieved in endothelial nitric oxide syn-thase (eNOS) knockout mice Moreover NO-NIF suppressesurinary angiotensinogen (AGT) excretion and intrarenalAGT protein expression in proximal tubular cells in theKKAy mice On the other hand hyperglycemia-inducedmitochondrial superoxide production was not attenuated byNO-NIF in cultured endothelial cells
Fujii and Berliner found EPR evidence for free radicaladducts of nifedipine in vivo [202] The nature of these rad-icals was surmised by comparing the reaction of illuminatednitrosonifedipine with polyunsaturated fatty acids Surpris-ingly identical radical spectra were detected from excisedliver doped with nonilluminated nifedipine suggesting thatthis drug can be enzymatically converted in vivo to its nitrosoanalogue without the requirement for illumination This isone of the first reports of in vivo EPR evidence for a class ofunsaturated fatty acid radical conjugates resulting from thenormal metabolism of a common drug
Dıaz-Araya et al [173] studied some 4-nitrophenyl-DHPson Fe3+ initiated LP in rat brain slices LP as measuredby MDA formation was inhibited by all the tested nitro-aryl derivatives of 14-DHP over a wide range of concen-trations On the basis of both time course and IC
50experi-
ments the tentative order of AOA on rat brain slices wasnicardipine gt nisoldipine gt (RSSR)-furnidipine gt (RRSS)-furnidipine gt nitrendipine gt nimodipine gt nifedipine14-DHP derivatives that lack a nitro group in the mole-cule (isradipine and amlodipine) also inhibited LP in ratbrain slices but at higher concentrations than that of nitro-substituted derivatives All tested compounds reduced andoxidized nitrosoaryl derivatives (26-dimethyl-4-(2-nitro-sophenyl)-35-pyridinedicarboxylic acid dimethyl ester (pho-tooxidation product of nifedipine ndash NTP) ao) and weremore potent inhibitors of LP than their parent molecules(Valenzuela et al [104])
The electrooxidation process of 4-nitrosoaromatic DHPsis a strongly pH-dependent (two-electron two-proton mech-anism) ECEC type of mechanism that is the sequenceeminusH+eminusH+ at pH gt 85 ECCE mechanism (eminusH+H+eminus)at pH lt 85 dominates Reduction reaction of nitroso groupis as follows R-NO + 2eminus + 2H+ rarr RNHOH (Bollo et al[203])
352 Lacidipine It is a generic DHP type antihypertensiveCA 35-diethyl 4-2-[(1E)-3-(tert-butoxy)-3-oxoprop-1-en-1-yl]phenyl-26-dimethyl-14-dihydropyridine-35-dicarboxy-late
Ursini [204] described redox behaviour of lacidipine andshowed its tissue protective features Cristofori et al studiedantiatherosclerotic activity in addition to lacidipinersquos CAand AO properties [205] Lacidipine reduced the extent ofatherosclerotic area in hypercholesterolemic apoE-deficientmice (these mice show widespread vascular lesions whichclosely resemble the inflammatory fibrous plaques seen inhumans in atherosclerosis) The reduction may be associatedwith the capacity of the drug to maintain endothelial NOlevels at concentrations useful to protect against vasculardamage This work suggested that DHPs modulate vascularrelaxation via increased release of NO
Herbette et al [178] remarked optimal hydrophobicity oflacidipine due to cinnamic acid substituent so membraneinteractions and facilitation of the treatment of atherosclero-sis could proceed (see also Section 331 (2)-(a))
353 Amlodipine Amlodipine (Norvasc) (RS)-3-ethyl5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-14-dihydropyridine-35-dicarboxylate (AML) hasan antioxidant effect on vessels in vitro and is a 3rd genera-tion of charged dihydropyridine CCB that is widely used forthe treatment of hypertensive patients
Amlodipine was shown to have the highest affinity(amlodipine gt verapamil ≫ diltiazem) for the membranebilayer (119870
119901= 104) It produced the significant changes in
membrane thermodynamic properties including a reductionin the thermal phase transition temperature (minus11) enthalpy(minus14) and cooperative unit size (minus59) relative to thecontrol phosphatidylcholine liposomes (Mason et al [49])
Amlodipine AOA is related to its reductant nature orhydrogen donor properties respectively Its ability for donat-ing protons and electrons to the lipid peroxide moleculesblocks the LP process
Amlodipine and even its enantiomers (Zhang et al [206])act as ROS andNOS effectors in several model systems of OSAntioxidant properties of amlodipine were recently reviewedby Vitolina et al [32] Both in vitro and in vivo studiesof amlodipine AO properties revealed inhibition of lipidsoxidative damage primarily those associated with cellularmembranes and lipoprotein particles (LDL) (Mason et al[50])
Under controlled experimental conditions in vitro amlo-dipine showed AOA and ARA by inhibition of lipid peroxideformation and trapping ROS Its scavenging activity forhydroxyl and peroxyl radicals at concentrations as low as100 nmolL (which is remarkably less compared to the classi-cal antioxidants GSH uric acid and Trolox) was shown to beindependent of the calcium channel modulation (Franzoni etal [207])
AML showed efficiency as scavenger of peroxyl radicals(TOSC assay 5945 plusmn 544 unitsmg) significantly stronger(gt50 119875 lt 0001) than GSH (2733plusmn 636 unitsmg) and 70weaker (119875 lt 00001) than uric acid (18144 plusmn 696 unitsmg)and Trolox (17522 plusmn 734 unitsmg)
20 Oxidative Medicine and Cellular Longevity
Of interest the scavenging capacity of AML towardshydroxyl radicals (1455 plusmn 154 unitsmg) was 320 higher(119875 lt 000001) than that of GSH (358 plusmn 112 unitsmg) 20higher than that of uric acid (1198plusmn121 unitsmg) and 100higher than that of Trolox (759 plusmn 143 unitsmg)
Amlodipine was shown to increase enzyme activity ofparaoxonase (PON) and glutathione peroxidase (GSH-Px)However it also decreases glutathione reductase (GSSG-R)activity and diminishes the concentration of the endogenousantioxidant 120572-tocopherol (vitamin E) Moreover AML in aconcentration of 2 ngmL decreased the content of malonicdialdehyde and activity of superoxide dismutase in the blood(Gatsura [208])
Verapamil and amlodipine produced a potent anti-ischemic effect and reduced area of myocardial infarction inrats The observed changes were accompanied by inhibitionof LP In contrast to verapamil in vitro application of AML ina dose of 50 ngmL decreased hemoglobin affinity for oxygenWhen present in a concentration of 2 ngmLAMDdecreasedthe content of MDA and activity of SOD in the blood
On the other hand amlodipine shows no activity relatedto inhibition of macrophage superoxide release and cellmigration which occurs as a consequence of decreasedTNF120572induced O
2
∙ releaseAmlodipine-induced reduction of OS in the brain is
associated with sympathoinhibitory effects in stroke-pronespontaneously hypertensive rats (SHRSP) (Hirooka et al[209]) Antihypertensive treatment with amlodipine reducedOS in all examined areas of the brain and decreased bloodpressure without a reflex increase in sympathetic nerveactivity Nicardipine another CA DHP surprisingly wassignificantly less active than amlodipine
354 Lercanidipine Tomlinson and Benzie reported AOeffect of lercanidipine [210] which is well known as anti-hypertensive drug Zanidip 2[(33-diphenylpropyl)(methyl)-amino]-11-dimethylethyl methyl 26-dimethyl-4-(3-nitro-phenyl)-14-dihydropyridine-35-dicarboxylate Compara-tive data about this drug AOA were presented in parts of thispaper about other individual CA DHPs and in the part aboutthe ex vivo DHPs effects on LDL
355 Nimodipine Nimodipine (ND) commercially knownas Nimotop is 3-(2-methoxyethyl) 5-propan-2-yl 26-dim-ethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxy-late It is centrally active CA
Treatment with glutathione blocked andwith nimodipineattenuated neuronal cell death caused by prolonged exposureof cell culture to 4-HNE (Faraqui [211])
Nascimento et al [212] found AO effect of nimodipine inyoung rats after pilocarpine- (PIL-) induced (in 400mgkg)seizures The PIL administration increased the striatal cata-lase (CAT) activity The administration of ND 30mgkg30min before PIL preserved normal value of CAT activityOn the other hand no difference was detected in the animalstreated with lower dose 10mgkg These results confirmthe neuroprotectiveantiepileptic effect of ND in young ratssuggesting that this drug acts positively on lipid peroxidation
(in both doses) Nimodipine cannot induce these effects viablockade of Ca2+ channel
Ismailoglu et al [213] studied the therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjury These beneficial effects in rats after cerebral corticalinjury seemed to be related to AOA of nimodipine
356 Benidipine Licensed in Japan and South Asia as CA(CCB) benidipine possesses AO properties Chemically it is5-methyl 3-[(3R)-1-(phenylmethyl)piperidin-3-yl] 26-dim-ethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxy-late (or its hydrochloride (4R)-rel-35-pyridinedicarboxylicacid 14-dihydro-26-dimethyl-4-(3-nitrophenyl)- 3-methyl5-[(3R)-1-(phenylmethyl)-3-piperidinyl] ester hydrochloride(1 1))
Benidipine influences processes connected with OS inseveral ways It prevents lysophosphatidylcholine- (lysoPC)-induced injury and ROS production in human aorticendothelial cells (HAECs) (Matsubara and Hasegawa [214])Matsubara et al [215] explained this effect based on stimula-tion of nitric oxide release
LysoPC is a component of oxidized low-density lipopro-teins (oxLDLs) which plays an important role in the patho-genesis of atherosclerosis Pretreatmentwith benidipine (03ndash3 120583molL) for 24 h protected against lysoPC-induced cyto-toxicity in the HAECs through inhibition of both lysoPC-stimulated ROS production and caspase-37-like activationwith a similar potency Since caspase-37 is involved inexecuting the apoptotic process the reduction of the activityof this enzyme by benidipine may explain the antiapoptoticeffect of the drug However benidipine did not suppresslysoPC-induced phosphorylation of mitogen-activated pro-tein kinases and Ca2+ influx in HAECs These results suggestthat the antioxidant properties of benidipine may be respon-sible for its ability to inhibit ROS production a possiblereason for reduced activation of caspase-37 In conclusionbenidipine suppresses lysoPC-induced endothelial dysfunc-tion through inhibition of ROS production which is due atleast in part to its antioxidant effect and not through theinhibition of L-type voltage-dependent calcium channels
Matsubara and Hasegawa [216] examined the effectsof benidipine on cytokine-induced expression of adhesionmolecules and chemokines (chemoattractants) which areimportant for the adhesion of monocytes to endotheliumPretreatment of HAECs with benidipine (03ndash10 120583molL)for 24 h significantly suppressed cytokine-induced vascularcell adhesion molecule-1 (VCAM-1) and intracellular celladhesion molecule-1 (ICAM-1) mRNA and protein expres-sion resulting in reduced adhesion of THP-1 monocytesBenidipine also suppressed induction of monocyte chemoat-tractant protein-1 (MCP-1) and interleukin-8 Benidipinealso inhibited redox-sensitive transcriptional nuclear factor-120581B (NF-120581B) pathway as determined by Western blotting ofinhibitory 120581B (I120581B) phosphorylation and luciferase reporterassay Results of analysis using optical isomers of benidip-ine and antioxidants suggest that these inhibitory effectswere dependent on pharmacological effects other than Ca2+antagonism Benidipine may thus have anti-inflammatoryproperties and benefits for the treatment of atherosclerosis
Oxidative Medicine and Cellular Longevity 21
Benidipine was also shown to inhibit ROS production inpolymorphonuclear leukocytes and oxidative stress in salt-loaded stroke-prone spontaneously hypertensive rats (Mat-subara et al [217])
It should be mentioned that other DHPs also haveendothelial AO actions [218]
357 Azelnidipine (AZL) Azelnidipine 3-[1-[di(phen-yl)methyl]azetidin-3-yl] 5-propan-2-yl 2-amino-6-methyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate(AZL) CAS number 123524-52-7 is commercially available4-nitroaryl-DHP type calcium antagonist with long-actingantihypertensive action (long-acting CA (CCB)) and a lowreported incidence of tachycardia It additionally possessesbeneficial effects in OS and diabetic conditions
Azelnidipine prevents cardiac dysfunction in strepto-zotocin-diabetic rats by reducing intracellular calcium accu-mulation (altering intracellular Ca2+ handling proteins) OSand apoptosis (Kain et al [219]) AZL can reduce the superox-ide production It exerts its protective effects by targeting theNADPH oxidase and mitochondrial redox enzymes AZL-treated diabetic rats express enhanced level of bcl-2 in thelysates of heart muscle indicating that AZL plays protectiverole in cardiac apoptosis
It has been previously observed that azelnidipine inhibitstumor necrosis factor-alpha-induced endothelial cell (EC)oxidative stress through its AO properties (Nakamura etal [220]) Azelnidipine but not nitrendipine completelyinhibits the Ang II-induced ROS generation in ECs (Matsuiet al [221])
Furthermore azelnidipine but not nitrendipine wasfound to partially restore decreased pigment epithelium-derived factor (PEDF) mRNA levels in Ang II-exposed ECsThis study suggests that AZL influence depends on its antiox-idative properties Authors concluded that upregulation ofPEDF by azelnidipine may become a therapeutic targetfor the treatment of diabetic retinopathy associated withhypertension
Antihypertensive agents with AO effects are potentiallyuseful for diabetic patients with hypertension While DHPtypeCAare among themost frequently used antihypertensivedrugs azelnidipine has been reported to have a unique AOeffect in vitro and in vivo in experimental animals (Ohmuraet al [222]) In hypertensive diabetic patients azelnidipinetreatment for 12 weeks induced a more significant decreasein erythrocyte LOOH level than amlodipine although thevalues related to blood pressure during each treatmentremained comparable These data confirm the usefulness ofLOOH level in erythrocyte membrane as a marker of OS invivo and indicate that azelnidipine has a unique antioxidativeproperty in humans
Daikuhara et al [223] reported the results of the OLCAstudy based on combination of (1) olmesartan and a calciumchannel blocker (azelnidipine) or (2) candesartan and a CCBamlodipine in two groups of diabetic hypertensive patientsPatients treated with the first combination presented highlypersistent early morning antihypertensive effect and strongerdecrease in heart rate fasting blood glucose andHbA1c levels
and microalbuminuria when compared to patients treatedwith the combination (2) Because diabetes is associated withsevere chronic OS the observed results might be at least in apart due to the AOA of azelnidipine
In favor of this are findings of Abe et al [224] who foundadditive antioxidative effects of azelnidipine on angiotensinreceptor blocker olmesartan treatment for type 2 diabeticpatients with albuminuria
Similarly the AOA of thiazolidinediones (insulin sensi-tizer) and their effect on cardiovascular function in type 2diabetic model rats and also those of some DHPs (nifedipineamlodipine or AZL commonly used antianginal and anti-hypertensive agents) in cultured human endothelial cells LPwere examined (Mizushige [225]) The AOA was evaluatedby measuring 8-iso-prostaglandine F
2120572concentration and
azelnidipine exhibited potent AOAInsulin (INS) resistance combined with hyperinsuline-
mia is involved in the generation of OS A relation-ship exists between increased production of ROS and thediverse pathogenic mechanisms involved in diabetic vascularcomplications including nephropathy Manabe et al [226]revealed that high doses of INS augmented mesangial cellproliferation through generation of intracellular ROS andactivation of redox signaling pathways Cell proliferation wasincreased in a dose-dependent manner by high doses of INS(01ndash10 120583M) but was inhibited by 01120583M AZL Namely theINS-increased phosphorylation of mitogen activated proteinkinaseextracellular signal-regulated kinase 12 (MAPKERK12) was inhibited by 01 120583MAZL The same AZL concen-tration blocked intracellular ROS production more effec-tively than 01 120583M nifedipine The NADPH oxidase inhibitorapocynin (001ndash01120583M) prevented INS-induced mesangialcell proliferation So azelnidipine inhibits insulin-inducedmesangial cell proliferation by inhibiting the productionof ROS Therefore azelnidipine may have the potential toprotect against the onset of diabetic nephropathy and slowits progression
Azelnidipine inhibited H2O2-induced cell death in
neonatal rat cardiomyocytes (Koyama et al [227]) Azelnidip-ine and nifedipine did not affect theH
2O2-induced activation
of extracellular signal-regulated protein kinases (ERK) andp38 MAPK (mitogen-activated protein kinase) In contrastazelnidipine but not nifedipine inhibited H
2O2-induced c-
Jun NH2-terminal kinases (JNK) activation Authors con-
cluded that azelnidipine has inhibited theH2O2-induced JNK
activation and cardiac cell death Therefore azelnidipine mayhave cardioprotective effects against OS
A specific atheroprotection activity of azelnidipine relatesto inhibition of TNF-120572-induced activator protein-1 activa-tion and interleukin-8 expression in human umbilical veinendothelial cells (HUVEC) through suppression of NADPHoxidase-mediated reactive oxygen species generation (Naka-mura et al [220]) TNF-120572 could play a central role in patho-genesis of insulin resistance and accelerated atherosclerosis inthe metabolic syndrome The concentration of AZL found tobe effective in these in vitro experiments is within therapeuticrange As EC do not possess voltage-operated L-type calciumchannels it is suggested that the beneficial effects of azelni-dipine are not likely due to CA property but to its unique AO
22 Oxidative Medicine and Cellular Longevity
ability Furthermore it has been recently found that serumlevels of monocyte chemoattractant protein-1 a biomarkerfor subclinical atherosclerosis were significantly decreased bythe AZL treatment in patients with essential hypertension Inthis paper [220] authors hypothesize that due to its uniqueTNF-120572 signalmodulatory activity and antioxidative propertyazelnidipine may be a promising DHP for targeting diabetesand cardiovascular diseases in hypertensive patients withmetabolic syndrome
Shinomiya et al [228] evaluated its AOA in culturedhuman arterial EC under OS Azelnidipine has shown apotent antioxidative effect that could be of significant clinicalbenefit when combined with its long-lasting antihypertensiveaction and low incidence of tachycardia
Azelnidipine inhibited TGF-1205731 and angiotensin II- (AngII-) activated 1205721(I) collagen mRNA expression in hepaticstellate cells (HSCs) (Ohyama et al [229]) FurthermoreTGF-1205731- and Ang II-induced OS and TGF-1205731-induced p38and JNK phosphorylation were reduced inHSCs treated withAZL Azelnidipine significantly decreased inflammatory cellinfiltration profibrotic genes expression HSC activation LPoxidative DNA damage and fibrosis in liver of CCl
4- or
TAA-treated mice Finally AZL prevented decrease of theexpression of some AO enzymes and accelerated regressionof liver fibrosis in CCl
4-treated mice Hence the antifibrotic
mechanism of AZL against CCl4-induced liver fibrosis in
mice may have been due to an increased level of AO defenseAs azelnidipine is widely used in clinical practice withoutserious adverse effects it may provide an effective newstrategy for antifibrotic therapy
358 Manidipine Manidipine (2-[4-(diphenylmethyl)pip-erazin-1-yl]ethyl methyl 26-dimethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate) is a DHP CCB withreported nephroprotective properties Calo et al [230] stud-ied effect of manidipine on gene expression and proteinlevel of OS related proteins p22(phox) (human neutrophilcytochrome b light chain (CYBA)) and heme oxygenase-1HO-1 Relevance for antihypertensive effects was revealedThe study assessed the effect of manidipine on normalsubjectsrsquo monocyte gene and protein expression of OS relatedproteins such as p22phox a NADPH oxidase system subunitcritical in generating O
2
∙minus and HO-1 induced by and pro-tective against OS Manidipine was compared with the ACEinhibitor captopril and the CCB nifedipine in the presenceand in the absence of sodiumarsenite (NaAsO
2) as an inducer
of OS Monocyte p22phox (CYBA) mRNA production wasreduced by both manidipine and captopril while no changeswere induced by nifedipine Manidipine increased monocyteHO-1 mRNA production while nifedipine and captoprilshowed no effect The effects of manidipine on p22phoxand HO-1 gene expression in the presence of OS were alsoconfirmed at the protein level Thus manidipine seems tosuppress p22phox and to increase the HO-1 mRNA produc-tion and protein level The manidipine-induced increase ofHO-1 gene and protein expression seems to be a peculiareffect of this drug since it is not observed with captopriland nifedipine This effect together with the reduction of
p22phoxmRNAproduction could play a role in its protectivemechanism against OS
359 Mebudipine The protective effect of mebudipine (14-dihydro-26-dimethyl-4-(3-nitrophenyl)-35-pyridinedicar-boxylic acid 3-methyl-5-tert-butyl ester BAY-n-6391) wasrevealed on OS and LP (MDA decrease SOD GPX andcatalase increase) in myocardial ischemic-reperfusion injuryin male rats (Ghyasi et al [231])
There are articles about other commercial and experi-mental DHPs on OS but we have reviewed only the mostcommonly studied compounds Effects of other commercialCA DHPs on OS are also mentioned in several parts of thisreview
36 14-DHPs Ca Agonists andTheir AOA and ARA For themost popular calcium agonist DHP Bay K 8644 no reactionwith peroxyl radicals was registered (Toniolo et al [114])However interactionwith other compounds possessing AOAand ARA (quercetin) was found
Opposite to that AON-acetylcysteine (NAC) diminishedincrease in Ca2+ transient amplitude and cell shorteninginduced by ISO and forskolin whereas NAC had no effecton the (S)-(minus)-methyl-14-dihydro-26-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylatemdash(minus)-BayK 8644-induced increases (Andersson et al [232])
Increased vasoconstriction responses to Bay K 8644 (3 times10minus7ndash3times 10minus5M)were significantly decreased by pyridoindoleantioxidant stobadine treatment in diabetes (Ceylan-Isik etal [233])
The functional interaction between two L-type Ca2+channel activators quercetin and Bay K 8644 has beeninvestigated in vascular smooth muscle cells Biological ARAcompound quercetin at nutritionally meaningful concen-trations limited the responsiveness of vascular L-type Ca2+channels to the pharmacological stimulation operated by BayK 8644 These data contribute to a better understanding ofquercetin effects on experimental in vivo cardioprotection(Saponara et al [234]) Thus these findings indicated thatalthough Bay K 8644 does not exert potent and direct AOAyet acting as calcium agonist it may affect efficiency of AOsubstances and vice versa
Interaction of grapefruit juice (containing quercetin andits analogues) with DHPs CA diminished effectiveness of CAaction of DHPs (Sica [235])
37 Interpretations of the Mechanism(s) of RadicalScavenging and AOA by DHPs
371 Molecular Mechanism(s) of Radical Scavenging andAOA of DHPs in the Model Systems 35-Dicarbonyl-14-di-hydropyridine derivatives possess powerful bis-120573-carbony-lvinyl-amino conjugation and for that reason cannot be con-sidered as ordinary amino antioxidants The electron andorH donation from DHPs ensures their reductant role andresults in AOA and ARA Oxidation reaction from DHPsresults in production of corresponding heteroaromatic pyri-dine derivatives
Oxidative Medicine and Cellular Longevity 23
Detailed studies were made about substituent in DHPring positions 14- namely 4-unsubstituted- 4-substituted4-alkyl- 4-aryl- 4-alkylaryl- ao 26- 35- (diacetyl ordialkoxycarbonyl chain ao) electronic and steric effects onAOA and ARA of DHPs [44 45 51] see Sections 331and 35 The bell-shaped dependence of DHPs AOA onthe 35-dialkoxycarbonyl- chain length was observed [4445 107 109 112] with the maximum activity at C
2H5ndash
C4H9 Decrease of AOA and incorporation into liposomes for
DHPs with alkyl chains longer than R gt C4H9further were
clarified as probable tendency to self-aggregation of thesecompounds ([51] and citation number 245 therein) Electronacceptorelectron donor properties are relevant for expres-sion of AOA or ARA of 35-disubstituted DHPs 35-Diacyl-substituted and 35-dicarbanilido- and 35-dipyridylamido-substituted DHPs are more active as AOs as their 35-dicyano-substituted analogues which have electron acceptorproperties [186]
Dubur et al [89] observed overwhelming steric influenceof substituents in position 4 of the DHP ring Gaviraghiet al [163 164] proposed that AO activity of DHPs ispartly dependent on capacity of the 14-DHP ring to donateelectrons to the propagating radical (ROO∙ or RO∙) and toreduce it to a less reactive form The abstraction (donation)of electron andor H in the oxidation and LP reactionstakes place from all 35-dicarbonyl-14-DHP systems andresults in the formation of corresponding pyridine derivatives(Augustyniak et al [51]) The physicochemical mechanism ofARA and AOA of 14-DHP has been extensively studied anddiscussed (Mulder et al [236]) but precise mechanisms oftheir activity need further clarification
The reactivity of C-4 substituted 14-DHPs possessingeither secondary or tertiary nitrogen atom in the DHP ringtoward alkyl alkylperoxyl radicals and ABTS radical cationwas determined in aqueous media at pH 74 [103] Thesecompounds reacted faster toward alkylperoxyl radicals andABTS radical cation than alkyl ones N-Ethyl-substitutedDHPs showed the lowest reactivity
The 4-methyl substituted DHP was the most reac-tive compound in previously mentioned reactions (Lopez-Alarcon et al [103]) However it was less active (068versus 10) than Trolox-C DHPs having electron-donatingsubstituents (4-Me-DHP and p-MeO-Phe-DHP) showed thehighest kinetic rate constants toward ABTS radical cation p-nitro-Phe-DHP a compound with an electron-withdrawingsubstituent showed a lower kinetic rate constant and N-alkyl-DHP compounds show kinetic rate constants lowerthan the -NH-DHP
Hydrogen at the 1-position of the DHP ring was revealedaccording to the deuteriumkinetic isotope effect studies to beinvolved in the proposedARAmechanismThis fact ismostlynoticeable in the case of alkyl radicals N-Ethyl-substitutedDHPs show the lowest reactivity when compared to Troloxor nisoldipine In all cases the respective pyridine derivativewas detected as the main product of the reaction (Lopez-Alarcon et al [103]) Authors indicate that the kinetic rateconstants toward alkyl alkylperoxyl andABTS radical cationdepend on the nature of the substituents in the C-4 positionof DHP and the presence of the secondary amine group in the
dihydropyridine ring that is the presence of the hydrogen in1-position
Yanez et al [197] have studied the reactivity of 11derivatives of 14-DHPs (including commercial CA) withalkylperoxyl radicals and ABTS radical cation The tested14-DHPs were 83-fold more reactive towards alkylperoxylradicals than to the ABTS cation radical All commercial14-DHP type CCBs were weaker than Trolox-C The par-ticipation of the hydrogen atom in the 1-position appearsto be very relevant for exhibited reactivity Hantzsch ester(diludine)was again found to be themost active compound inthe reaction with alkylperoxyl radicals 23-fold more activethan Trolox The photodegradation product of nifedipine(nitrosophenyl derivative of pyridine) also showed a highactivity Kinetic rate constants for the reaction between 14-DHP compounds and alkylperoxyl radicals exhibited a fairlygood linear correlation with the oxidation peak potentialof DHP derivatives However the activity of tested 14-DHPs towards ABTS radical cation showed an independencebetween kinetic rate constants and oxidation peak potentials
Kirule et al [195] andTirzit et al [196] studiedmechanismof AOA of 4-nitrophenyl-14-DHPs nifedipine and its ana-logues involving formation of 4-(21015840-nitrosophenyl)-pyridinederivative (as active principle) as a result of intramolecularredox reaction using chemical electrochemical and bio-chemical approaches (see Sections 331 and 351)
Nunez-Vergara et al [237] reported the electrochemicaloxidation of C4-hydroxyphenyl-substituted 14-DHP deriva-tives The oxidation proceeds via formation of the unstabledihydropyridyl radical as confirmed by controlled-potentialelectrolysis (CPE) and ESR experiments This type of 14-DHPs has significant activity towards the radicals even whencompared with commercial 14-DHP drugs with well-knownantioxidant ability
It was observed that nicardipine preferentially targets RO∙radicals and is inactive against ROO∙ Lacidipine on theother hand is equally active towards both types of radicals(Gaviraghi et al [164]) The cytoprotective effect againstexposure to H
2O2was more significant for lacidipine (ID
50=
14 nM its log119875 = 54 membrane partition = 136000 assumesposition located 7 A near to the membrane center otherless lipophilic DHPs located 12ndash16 A far from the center)as compared to amlodipine nifedipine and nicardipine insmooth muscle cell culture (Gaviraghi et al [164]) Oxidativeeffect of H
2O2shifts the Ca channel toward an open state
Thus the redox property of CCBs DHPs may augment theirCCB properties
Oxidation of pharmacologically active Hantzsch 14-dihydropyridines was found by electrogenerated superoxideusing a voltammetric approach in DMSO solutions (Ortiz etal [238] and Ortiz et al [239]) Raghuvanshi and Singh [240]have also reported oxidative aromatization of these DHPsinduced by superoxide
Chemiluminescence (CL) was used in the studies ana-lyzing the antioxidant activity of 12 various 4-flavonil-14-dihydropyridine derivatives (Kruk et al [241]) on a chemicalsystem involving a superoxide radical anion These deriva-tives showed structural similarity to flavonoids with respectto the presence of rings A B and C The results obtained in
24 Oxidative Medicine and Cellular Longevity
this study indicate that the tested derivatives may catalyzeconversion of superoxide radicals through mimicking theactivity of superoxide dismutase by delivering H+ for reac-tion
O2
minus∙+O2
minus∙+ 2H+ 997888rarr H
2O2+1O2
(3)
The enhanced emission of the light in the presence oftested compounds was significant and related to stimulatedproduction ofH
2O2and 1O
2fromO
2
∙The latter specieswereremoved from the reactionmixture by the following sequenceof reactions
H+
O2
minus∙997888rarr HO
2
∙
HO2
∙+O2
∙minus997888rarr HO
2
minus+1O2
2HO2
∙997888rarr H
2O2+1O2
2 (1O2) 997888rarr (O
2)2+ h]lowast
(4)
or to take part in spontaneous dismutation of H2O2
2H2O2997888rarr 2H
2O + 1O
2(5)
The authors have offered an original concept of action for 4-flavonil-14-dihydropyridine derivatives unrelated to that ofO2
∙ radical-trapping chain-breaking antioxidants Insteadthey showed that these compounds act similar to superoxidedismutases converting O
2
∙ to H2O2 Hydrogen peroxide
is less toxic for cells than O2
∙ because it is predominantlyremoved by peroxidases and catalases Finally AO effect ofthese DHPs differed from those mediated by flavonoids witha catechol structure of ring B which are well-known 1O
2
quenchersMulder and collaborators came to similar conclusions
especially related to molecular mechanisms of antioxidativeactivity of DHPs [236]TheAOproperties of Hantzsch 14-di-hydropyridine esters and two dibenzo-14-dihydropyridines910-dihydroacridine (DHAC) and N-methyl-910-dihydro-acridine (N-Me-DHAC) have been explored by determin-ing the autoxidation of styrene or cumene at 30∘C Theseexperiments showed that Hantzsch esters are virtually inac-tive as chain-breaking antioxidants (CB-AOs) contrary tothe findings observed by Lopez-Alarcon et al [103] whoused CB-AOA in aqueous media at pH 74 Their reactivitytoward peroxyl radicals was shown to be some 5 orders ofmagnitude lower than that of the excellent CB-AO 22578-pentamethyl-6-hydroxy-chroman (PMHC)
DHAC was found to be sim10 times less reactive thanPMHC kinetic measurements using DHAC N-deuterio-DHAC and N-Me-DHAC pointing out the abstraction ofN-H hydrogen in DHAC by peroxyl radicals despite the factthat the calculated C-H bond dissociation enthalpy (BDE) inDHAC is about 11 kcalmol lower than the N-H BDE Therates of hydrogen atom abstraction by the 22-diphenyl-1-picrylhydrazyl radical (DPPH∙) have also been determined
for the same series of compounds The trends in the peroxyl∙and DPPH∙ rate constants were found to be similar [236]
Tirzit et al [242] have observed quenching of singletoxygen by DHPs This observation paved the ground forfurther research related to reactions of DHPs with hydroxylradicals (Tirzit et al [243]) singlet oxygen (Kazush etal [94]) and mechanisms of action A series of 14-DHPderivatives in NAD-H-Cu2+-H
2O2system inhibited forming
of the hydroxyl radical (HO∙) while 14-DHP derivativeswith electron donor substituents in the molecule were shownto be capable themselves of generating HO∙ in the presenceof Cu2+ and H
2O2 Rubene et al [186] also described
interaction of 14-DHP derivatives with Fentonrsquos reagentwhich produces hydroxyl radical (HO∙) Rate constants ofthe DHPs reaction (1st order) with HO∙ radical were highin the range 109 L times mol times secminus1 close to that of NADHcysteine and thiourea 35-Diacetyl- derivatives reacted fastercompared to 35-dialkoxycarbonyl- ones The reaction ratedecrease was observed in the case of substitution at position4 as compared to 4-unsubstituted DHPs Some DHPs havingelectron donor -COOminus groups in the 35- or 26- positionsof DHP ring reacted immediately (having rate constantshigher as 109 L times mol times secminus1) Rate constants with HO
2
∙
and O2
∙minus radicals were of lower degree Thus DHPs actingas oxygen radical scavengers could effectively inhibit ROSrelated reactions of LP initiation stage
Nifedipine and nitrendipine reactivity toward singletoxygen was also studied [244] Nifedipine was shown tobe a good scavenger of excited oxygen mainly via physicaldeactivation with values of the total rate constant rangingfrom 208 times 105Mminus1 sminus1 (in dioxane) to 930 times 105Mminus1 sminus1(in propylene carbonate)The less reactive pathway generateda photooxidation product For that reason a mechanisminvolving a perepoxide-like encounter complex in the firststep of the reaction path was proposed (see [244] Figures8 and 9 therein) The dependence was observed on solventmicroscopic parameters of the total rate constant for the reac-tion between singlet oxygen and 14-DHPs These findingsshow that nifedipine possesses stronger protective activity inbiological systems than nitrendipine
Density-functional-theory (DFT) calculations made byWang et al [245] confirmed the former experimental obser-vations that Hantzsch ester diludine is potent antioxi-dant with high H atom-donating ability and relatively lowprooxidant activity Possible reaction pathways for radicalsderived from 14-dihydropyridine and the resonance modesfor radical species were given [245]
Moreover two ethoxycarbonyl (EtOCO) substituentsat C(2) and C(6) should further enhance Hantzsch esterdiludine H-atom-donating ability due to resonance effectsHowever DHPs should be used in nonpolar rather than inpolar solvents since in the latter not H-atom but electrontransfer is preferred in the radical scavenging process [245]
Mulder et al [246] proposed that quantum-thermochem-ical calculations must be used with caution to indicate ldquoapromising lead antioxidantrdquo as they criticized the density-functional-theory (DFT) calculations made by Wang et al[245]
Oxidative Medicine and Cellular Longevity 25
372 Possible Mechanisms of DHPs ARA and AOA in the Bio-logical Systems Interaction with Other OSModifiers Some ofthese mechanisms were already described (Sections 331 (2)-(b) 331 (2)-(c) 331 (3)-(b) 35)
Enzymatic sources of ROSwith confirmed functional rolein hypertension are NADPH oxidase NO synthase (NOS)xanthine oxidase and cyclooxygenase Godfraind [3] hasreviewed AO effects and protective action of calcium channelblockers (CCBs) Yao et al [247] observed antioxidant effects(as inhibition of LP) for cardio- and neuroprotective CCBs(3ndash300 120583molL) including 7 DHPs in homogenates of ratbrain IC
50values (120583M) were as follows nifedipine (515) gt
barnidipine (586) gt benidipine (712) gt nicardipine (1293)gt amlodipine (1355) gt nilvadipine (1673) gt nitrendipine(2521) gt diltiazem (gt300) = verapamil (gt300) There arealso research articles describing the AO properties of CCBsthrough direct scavenging effect or through preservationof the endogenous SOD activity These findings indicatethat CCBs may also act by reducing the production ofvasoconstrictors angiotensin and endothelin
When present in concentrations that can be achievedin plasma CCBs may inhibit LP formation [3] This AOactivity seems to be typical for high lipophilic CCBs becausetheir chemical structure facilitates proton-donating andresonance-stabilization mechanisms that quench the freeradical reaction Their insertion in the membrane nearpolyunsaturated fatty acids at relatively high concentrationspotentiates proton donation (or atomary H) to lipid peroxidemolecules thereby blocking the peroxidation process Theremaining unpaired free electron associated with the CCBmolecule can be stabilized in well-defined resonance struc-tures associated with the DHP ring (Mason et al [48])
The radical reaction (according to Godfraind [3]) thatdescribes the AO effects of a DHP CCBs is LOOlowast + DHPrarr LOOH + DHPlowast (where LOOlowast is lipid peroxide radical)which in general is reaction (7) of the LP reaction cascadeconsisting of sim10 reactions (Scheme 2) [89]
As the rate constants of in vitro interaction of 4-substituted DHPs with peroxyl radicals are three ordersof magnitude lower than that of the vitamin E derivativethese DHPs must be considered as weak AO (Ursini [204])However due to partition coefficient of DHPs in membranesand in case of specific binding high local concentration ofDHPs may be obtained
DHPs without CCB properties for instance Bay w 9798although structurally related to nifedipine inhibit TNF-120572-induced vascular cell adhesion molecule-1 expression inendothelial cells by suppressing reactive oxygen speciesgeneration [248]
Mitrega et al [249] have discovered that antiarrhythmicand hemodynamic effects of oxidized heteroaromatic DHPsoxy nifedipine oxy nimodipine oxy nitrendipine and oxynisoldipine suggest that CCB DHPs and their metabolitescould act at least in two ways targeting OS related eventsas reductants (see Section 351 (1)) andor bypassing OSrelatedmetabolic routes Authors postulated that contrary tocurrent belief NIF metabolites are pharmacologically activeATP sensitive potassium channels were mentioned as a tar-get
38 DHPs Anti- or Prooxidants Several substances (ascorbicacid being the most commonly studied) can serve either asantioxidants or as prooxidants depending on given condi-tions (Herbert [250]) Therefore Halliwell [251] has reporteddilemma related to polyphenols as possible antioxidantsand prooxidants causing experimental artifacts (about 25)by oxidation of antioxidant compounds in the cell culturemedia Nevertheless it is generally accepted opinion thatpolyphenols act as antioxidants in vivo Studies on DHPs alsoface such a dilemmaThe exact roles (anti- or prooxidative) ofany specific DHP depend on its structure appliedachievedconcentration and specificity of the targetexperimentaltesting system
This situation resembles the case of antioxidative effectsof tocopherol which depends on the fate of the secondaryradical as proposed by Winterbourn [252] The question wasldquoVitamin E - Pro- or Antioxidantrdquo
997888rarr chain termination of lipid peroxidation
(6)
Prooxidant
Toc∙ + Lipid-H 997888rarr Lipid∙ (in LDL particles) (7)
This example shows that generally speaking any AO mustfulfil several criteria to be considered as an effective com-pound physiologically
(i) It must be able to functionally interact with endoge-nous scavengers even at low concentrations
(ii) It must affect endogenous pathways of OS(iii) It should not have undesirable adverse effect(iv) It should manifest the antioxidant efficacy dependent
on the oxidant(v) It must discriminate among different strategies
needed for 1-electron and 2-electron processes(vi) Radical scavengers can be prooxidant unless linked to
a radical sink (Winterbourn [252])
According to these statements DHPs could be effective asAO under physiological conditions in vivo (Godfraind [3]and others [30 31 38]) and in vitro in various experimentalsystems (cell and tissue) (see Sections 33 34 35)
Hence calcium antagonists appeared to disrupt thefine balance between the production and scavenging ofROS Nifedipine verapamil and diltiazem were shown toinduce significant oxidative stress in the epididymal sperm(increased MDA and decreased catalase and superoxidedismutase activity) This may be the reason for the inductionof male infertility [253]
The dualism of 14-DHP effects has been recorded asinhibition or promotion of LP as quenching or initiating
26 Oxidative Medicine and Cellular Longevity
oxygen and nitrogen free radical chain reactions radiopro-tecting or radiosensitizing antagonizing or synergizing Ca2+in electromechanical coupling as well as in the membranestabilization or labilization
39 Could DHPs Be Involved in Antioxidative Stress Beforebeing applied in vivo the optimal dose and optimal timeintervals forDHPs applicationmust be knownNamely whileROS have been traditionally considered as toxic byproductsof aerobic metabolism we know nowadays that ROS may actas essential signaling molecules needed for the control ofmany different physiological processes Whether the role ofROS will be damaging protective or signaling depends onthe delicate equilibrium between time- and location-specificROS production and scavenging Accordingly the imbalanceof the increased AO potential so-called antioxidative stresscould be dangerous similar to chronic OS in particular incase of extended exposure Inappropriate interventions inthe oxidative homeostasis by excessive antioxidants especiallyin case of chronic exposure to antioxidants might havevery negative effects as was published in the ATBC studyshowing an increased cancer incidence in smokers treatedby excessive beta-carotene [254] Therefore overconsump-tion of any natural or synthetic AO including DHPs asdietary supplements or drugs must be avoided in order tosuppress oxidative damage and must not disrupt the well-integrated antioxidant defense network (Poljsak [255] andPoljsak and Milisav [256]) This is especially important whenadministrating lipid-soluble antioxidants that can be storedin biomembranes thus not only attenuating or preventing LPbut also affecting physiological effects of the natural antiox-idants in particular tocopherol The interrelationship withthe status of endogenous antioxidantsprooxidants should befollowed
DHPs primarily suppress the initiation stages of LPprocessThey do not entirely stop the LP propagation Actingsynergistically with tocopherol diludine may prevent patho-logical excess of ROS production within the lipid moiety ofthe cellular membranes and LDL However due to its lowsolubility and fast metabolism its concentration in the cellsis low For that reason it cannot cause antioxidative stresseven if used for an extended period of time Thus diludine(diethone) could be only a mild antioxidant it has potentialfor restoring the pool of natural antioxidants (as synergist of120572-tocopherol and polyphenols) in the cells
Moreover DHPs CA used for cardioprotection andvasodilatation as commercial drugs in low concentrationsare fast metabolized via CYP3A4 and for that reason theirapplication does not induce cellular AO stress [53 160]However Godfraind and Salomone [257] have postulated noevidence that allows recommending dietary supplementationwith antioxidants for the primary or secondary prevention ofcardiovascular disease
So far there are no reports on antioxidative stress causedby some DHPs diludine and its analogues Diludine andits analogues therefore could act as adaptogens supportinghormetic effects of mild oxidative stress These compoundsmay act as potential multisided modulators of Yin-Yang
cycles of redox and cell functions (the electroplasmic cycle)(Wagner et al [258])
4 Conclusions
14-Dihydropyridines (14-DHPs) have broad spectrum ofOS modulating activities DHPs have reducing and lipidperoxidation inhibitor properties act as reductants in simplechemical systems and stabilize various biological systems(LDL mitochondria microsomes cells and tissues) againstOS Examples and peculiarities and mechanisms of antiox-idant activity (AOA) and antiradical activity (ARA) as wellas stress-protective effect of DHPs including commercialcalcium antagonists (CA) were highlighted These activitiesdepend on various structural parameters related to DHPs(presence and character of substituents) lipophilicity anddepth of the incorporation in the biologicalmembranesTheyalso depend on the experimental model system for exploringthe lipid peroxidation or oxidative stress Stress-protectiveeffect of some metabolites of CA (nifedipine) is reviewedAlthough some DHPs including CA have prooxidant prop-erties (on epididymal sperm cells) they can generally beconsidered as potent antioxidants Therefore comparisonof the AOA and ARA of different DHPs (mutually andwith other AOs) was described in detail According to thedata presented the DHPs might be considered as bellwetheramong synthetic compounds targeting OS and as a kind ofpharmacological measure for respective field of organic andmedicinal chemistry
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
Authors from Latvian IOS acknowledge ESF 201300021DP1112013APIAVIAA011 and National Research Pro-gramme PUBLIC HEALTHBiomedicine of the Republicof Latvia for financial support administration of the Insti-tute for technical support and Rufus Smits PhD for con-sultations in English The support of Cooperation in Euro-pean System of Science and Technology (COST) Domain ofChemistry Molecular Sciences and Technologies (CMST)was of highest importance for preparation of this paper
[2] D J Triggle ldquo14-Dihydropyridines as calcium channel ligandsand privileged structuresrdquoCellular andMolecular Neurobiologyvol 23 no 3 pp 293ndash303 2003
[3] T Godfraind ldquoAntioxidant effects and the therapeutic modeof action of calcium channel blockers in hypertension andatherosclerosisrdquo Philosophical Transactions of the Royal SocietyB Biological Sciences vol 360 no 1464 pp 2259ndash2272 2005
[4] E Cadenas ldquoMitochondrial free radical production and cellsignalingrdquoMolecular Aspects of Medicine vol 25 no 1-2 pp 17ndash26 2004
[5] E Cadenas ldquoFree radicals oxidative stress and diseasesrdquo inLecture PSC 616 p 38 Missouri University of Science andTechnology Rolla Mo USA httpwwwcarnicominstituteorgarticlesenrique cadenaspdf
[6] K Rahman ldquoStudies on free radicals antioxidants and co-fac-torsrdquo Clinical Interventions in Aging vol 2 no 2 pp 219ndash2362007
[7] V Bocci and G Valacchi ldquoFree radicals and antioxidants howto reestablish redox homeostasis in chronic diseasesrdquo CurrentMedicinal Chemistry vol 20 no 27 pp 3397ndash3415 2013
[8] M Valko C J Rhodes J Moncol M Izakovic and M MazurldquoFree radicals metals and antioxidants in oxidative stress-induced cancerrdquo Chemico-Biological Interactions vol 160 no 1pp 1ndash40 2006
[9] G Bartosz ldquoReactive oxygen species destroyers or messen-gersrdquo Biochemical Pharmacology vol 77 no 8 pp 1303ndash13152009
[10] R Visconti and D Grieco ldquoNew insights on oxidative stress incancerrdquo Current Opinion in Drug Discovery and Developmentvol 12 no 2 pp 240ndash245 2009
[11] R N Kujundzic N Zarkovic and K G Troselj ldquoPyridinenucleotides in regulation of cell death and survival by redoxand non-redox reactionsrdquo Critical Reviews in Eukaryotic GeneExpression vol 24 no 4 pp 287ndash309 2014
[12] B Halliwell and J M C Gutteridge ldquoThe definition and mea-surement of antioxidants in biological systemsrdquo Free RadicalBiology and Medicine vol 18 no 1 pp 125ndash126 1995
[13] V D Kancheva and O T Kasaikina ldquoBio-antioxidantsmdashachemical base of their antioxidant activity and beneficial effect
on human healthrdquo Current Medicinal Chemistry vol 20 no 37pp 4784ndash4805 2013
[14] H V Panglossi Ed Frontiers in Antioxidants Research NovaScience Publishers New York NY USA 2006
[15] E B Burlakova E M Molochkina and G A NikiforovldquoHybrid antioxidantsrdquo Oxidation Communications vol 31 no4 pp 739ndash757 2008 httpmembraneustceducnpaperpdfHybrid20Antioxidantspdf
[16] A Bast and G R M M Haenen ldquoTen misconceptions aboutantioxidantsrdquo Trends in Pharmacological Sciences vol 34 no 8pp 430ndash436 2013
[17] E B Burlakova A V 0lesenko E M Molochkina N PPalmina and N G Khrapova Bioantioxidants for RadiationDamage and Malignant Growth Nauka Moscow Russia 1975(Russian)
[18] J Fang T Seki and H Maeda ldquoTherapeutic strategies by mod-ulating oxygen stress in cancer and inflammationrdquo AdvancedDrug Delivery Reviews vol 61 no 4 pp 290ndash302 2009
[19] M Valko D Leibfritz J Moncol M T D Cronin M Mazurand J Telser ldquoFree radicals and antioxidants in normal physi-ological functions and human diseaserdquo International Journal ofBiochemistry and Cell Biology vol 39 no 1 pp 44ndash84 2007
[20] M Jimenez-Del-Rio and C Velez-Pardo ldquoThe bad the goodand the ugly about oxidative stressrdquo Oxidative Medicine andCellular Longevity vol 2012 Article ID 163913 13 pages 2012
[21] C D Kamat S Gadal M Mhatre K S Williamson Q N Pyeand K Hensley ldquoAntioxidants in central nervous system dis-eases preclinical promise and translational challengesrdquo Journalof Alzheimerrsquos Disease vol 15 no 3 pp 473ndash493 2008
[22] A Pompella H Sies R Wacker et al ldquoThe use of totalantioxidant capacity as surrogate marker for food quality andits effect on health is to be discouragedrdquo Nutrition vol 30 no7-8 pp 791ndash793 2014
[23] Z Ye and H Song ldquoAntioxidant vitamins intake and the risk ofcoronary heart disease meta-analysis of cohort studiesrdquo Euro-pean Journal of Cardiovascular Prevention and Rehabilitationvol 15 no 1 pp 26ndash34 2008
[24] P Knekt J Ritz M A Pereira et al ldquoAntioxidant vitamins andcoronary heart disease risk a pooled analysis of 9 cohortsrdquoTheAmerican Journal of Clinical Nutrition vol 80 no 6 pp 1508ndash1520 2004
[25] A C Carr and M C M Vissers ldquoSynthetic or food-derivedvitamin Cmdashare they equally bioavailablerdquo Nutrients vol 5 no11 pp 4284ndash4304 2013
[26] R Tabrizchi ldquoEdaravoneMitsubishi-TokyordquoCurrentOpinion inInvestigational Drugs vol 1 no 3 pp 347ndash354 2000
[27] K Kikuchi S Tancharoen N Takeshige et al ldquoThe efficacy ofedaravone (radicut) a free radical scavenger for cardiovasculardiseaserdquo International Journal of Molecular Sciences vol 14 no7 pp 13909ndash13930 2013
[28] D Mauzerall and F H Westheimer ldquo1-Benzyldihydronicoti-namidemdasha model for reduced DPNrdquo Journal of the AmericanChemical Society vol 77 no 8 pp 2261ndash2264 1955 ChemicalAbstracts vol 50 Article ID 2588i 1956
[29] F Bossert and W Vater ldquo14-Dihydropyridinesmdasha basis fordeveloping new drugsrdquo Medicinal Research Reviews vol 9 no3 pp 291ndash324 1989
[30] G Swarnalatha G Prasanthi N Sirisha and CMadhusudhanaChetty ldquo14-Dihydropyridines a multtifunctional moleculemdash areviewrdquo International Journal of ChemTech Research vol 3 no1 pp 75ndash89 2011
28 Oxidative Medicine and Cellular Longevity
[31] M Cataldi and F Bruno ldquo14-Dihydropyridines the multiplepersonalities of a blockbuster drug familyrdquo Translational Medi-cine UniSa vol 4 no 2 pp 12ndash26 2012 httpwwwncbinlmnihgovpmcarticlesPMC3728803
[32] R Vitolina A Krauze G Duburs and A Velena ldquoAspects ofthe amlodipine pleiotropy in biochemistry pharmacology andclinicsrdquo International Journal of Pharmaceutical Sciences andResearch vol 3 no 5 pp 1215ndash1232 2012
[33] D Grover S N Mokale and M T Shete ldquoDihydropyridinea novel pharmacophorerdquo International Journal of Pharmaceu-tical Erudition vol 1 no 2 pp 16ndash29 2011 httppharmaeru-ditionorgContentPaper20111-RV-320Final2016-29pdf
[34] A M Vijesh A M Isloor S K Peethambar K N ShivanandaT Arulmoli and N A Isloor ldquoHantzsch reaction synthesis andcharacterization of somenew 14-dihydropyridine derivatives aspotent antimicrobial and antioxidant agentsrdquo European Journalof Medicinal Chemistry vol 46 no 11 pp 5591ndash5597 2011
[35] P Mehta and P Verma ldquoAntimicrobial activity of some deriva-tives of 14-dihydropyridinesrdquo Journal of Chemistry vol 2013Article ID 865128 4 pages 2013
[36] P Olejnıkova L Svorc D Olsovska et al ldquoAntimicrobialactivity of novel C2-substituted 14-dihydropyridine analoguesrdquoScientia Pharmaceutica vol 82 no 2 pp 221ndash232 2014
[37] S Sepehri H Perez Sanchez and A Fassihi ldquoHantzsch-typedihydropyridines and biginelli-type tetra-hydropyrimidinesa review of their chemotherapeutic activitiesrdquo Journal of Phar-macy amp Pharmaceutical Sciences vol 18 no 1 pp 1ndash52 2015httpsejournalslibraryualbertacaindexphpJPPSarticleview2383617863
[38] S A Khedkar and P B Auti ldquo14-Dihydropyridines a classof pharmacologically important moleculesrdquo Mini-Reviews inMedicinal Chemistry vol 14 no 3 pp 282ndash290 2014
[39] G D Tirzit and G Ya Duburs ldquo14-dihydropyridines as inhi-bitors of free-radical reactionsrdquo Chemistry of Heterocyclic Com-pounds vol 8 no 1 pp 126ndash127 1972 Translated from KhimiyaGeterotsiklicheskikh Soedinenii no1 pp 133ndash134 1972 (Rus-sian)
[40] I Bogeski R Kappl C Kummerow R Gulaboski M Hothand B A Niemeyer ldquoRedox regulation of calcium ion channelschemical and physiological aspectsrdquoCell Calcium vol 50 no 5pp 407ndash423 2011
[41] S A Giller G Y Dubur Y R Uldrikis et al ldquoDiludine [Themethod to obtain 35-dicarbonylderivatives of 26-dimethyl-14-dihydropyridines]rdquo Authors certificate of USSR no 3004651971 [Byull Izobret no13 p 95 1971] and following patentsPatent of England no 1294650 1973 Patent of France no2055458 1971 Patent of Japan no 702883 1973 Patent ofHolland no 149787 1976 Patent of Italy no 969022 1974 Patentof FRG no 2036403 1978 US Patent no 3883673 1975 USPatent no 3948924 1976
[42] S A Giller G Y Dubur Y R Uldrikis et al ldquoImprovementsin or relating to the stabilization of carotenerdquo GB Patent no1294650 1972
[43] S A Giller G Y Dubur Y R Uldrikis et al ldquoStabilization ofcarotenerdquo US Patent no 3883673 1975 Chemical Abstracts vol83 Article ID 95193 1975
[44] Yu A Zilber G Ya Dubur K K Kumsar and A Kh VelenaldquoThe effect of antioxidants on the peroxidation of bimole-cular phospholipid membranesrdquo Latvijas PSR ZA Vestis Izves-tia Akademii Nauk Latviyskoy SSR vol 6 pp 80ndash82 1971(Russian) translated from the original Russian Doc Accesion
No AD0771751 distributed by NTIS US Department of Com-merce httpwwwdticmildtictrfulltextu2771751pdf
[45] G Ya Dubur Yu A Zilbers A Kh Velena A O Kumerovaand G D Tirzitis ldquoMultistage study of regulation of peroxida-tion processes in biological membranes by antioxidants of 14-dihydropyridine grouprdquo Izvestiya Akademii Nauk LatviyskoySSR vol 336 no 7 pp 65ndash68 1975 (Russian)
[46] R P Mason and M W Trumbore ldquoDifferential membraneinteractions of calcium channel blockers Implications forantioxidant activityrdquo Biochemical Pharmacology vol 51 no 5pp 653ndash660 1996
[47] R P Mason M F Walter M W Trumbore E G Olmstead Jrand P E Mason ldquoMembrane antioxidant effects of the chargeddihydropyridine calcium antagonist amlodipinerdquo Journal ofMolecular and Cellular Cardiology vol 31 no 1 pp 275ndash2811999
[48] R PMason I T MakMW Trumbore and P EMason ldquoAnti-oxidant properties of calcium antagonists related to membranebiophysical interactionsrdquo American Journal of Cardiology vol84 no 4 pp 16ndash22 1999
[49] R PMasonMW Trumbore and P EMason ldquoMembrane bio-physical interaction of amlodipine and antioxidant propertiesrdquoDrugs vol 59 no 2 pp 9ndash16 2000 (French)
[50] R P Mason P Marche and T H Hintze ldquoNovel vascularbiology of third-generation L-type calcium channel antagonistsAncillary actions of amlodipinerdquo Arteriosclerosis Thrombosisand Vascular Biology vol 23 no 12 pp 2155ndash2163 2003
[51] A Augustyniak G Bartosz A Cipak et al ldquoNatural andsynthetic antioxidants an updated overviewrdquo Free RadicalResearch vol 44 no 10 pp 1216ndash1262 2010
[52] T Grune N Zarkovic and K Kostelidou ldquoLipid peroxidationresearch in Europe and the COST B35 action lsquoLipid Peroxida-tion Associated Disordersrsquordquo Free Radical Research vol 44 no10 pp 1095ndash1097 2010
[53] E Carosati P Ioan M Micucci et al ldquo14-Dihydropyridinescaffold in medicinal chemistry the story so far and perspec-tives (part 2) action in other targets and antitargetsrdquo CurrentMedicinal Chemistry vol 19 no 25 pp 4306ndash4323 2012
[54] U Eisner and J Kuthan ldquoThe chemistry of dihydropyridinesrdquoChemical Reviews vol 72 no 1 pp 1ndash42 1972 httpwwwsci-encemadnessorgtalkfilesphppid=138742ampaid=6475
[55] J Kuthan and A Kurfurst ldquoDevelopment in dihydropyri-dine chemistryrdquo Industrial amp Engineering Chemistry ProductResearch and Development vol 21 no 2 pp 191ndash261 1982
[56] A Sausins and G Duburs ldquoSynthesis of 14-dihydropyridinesby cyclocondensation reactionsrdquo Heterocycles vol 27 no 1 pp269ndash289 1988
[57] A E Sausins and G Y Duburs ldquoSynthesis of 14-dihydro-pyridines in cyclocondensation reactions (review)rdquo Chemistryof Heterocyclic Compounds vol 28 no 4 pp 363ndash391 1992Translated from Khimiya Geterotsiklicheskikh Soedinenii no 4pp 435ndash467 1992 (Russian)
[58] S Kazda ldquoTwenty years of dihydropyridinesrdquo in Dihydropy-ridines Progress in Pharmacology and Therapy W-D Busse BGarthoff and F Seuter Eds pp 1ndash12 Springer Verlag BerlinGermany 1993
[59] J-P Wan and Y Liu ldquoRecent advances in new multicomponentsynthesis of structurally diversified 14-dihydropyridinesrdquo RSCAdvances vol 2 no 26 pp 9763ndash9777 2012
[61] Reaxys Database[62] J Tuttle ldquoStructure mechanism and reactivity of hantzsch
estersrdquo in MacMillan Lab Group Meeting (082504) p 332004 httpwwwprincetoneduchemistrymacmillangroup-meetingsJBT20Hantzschpdf
[63] A Saini S Kumar and J S Sandhu ldquoHantzsch reaction recentadvances in Hantzsch 14-dihydropyridinesrdquo Journal of Sci-entific amp Industrial Research vol 67 pp 95ndash111 2008
[64] L LW Cheung S A Styler and A P Dicks ldquoRapid and conve-nient synthesis of the 14-dihydropyridine privileged structurerdquoJournal of Chemical Education vol 87 no 6 pp 628ndash630 2010
[65] A Kumar R A Maurya S Sharma M Kumar and G BhatialdquoSynthesis and biological evaluation of N-aryl-14-dihydro-pyridines as novel antidyslipidemic and antioxidant agentsrdquoEuropean Journal of Medicinal Chemistry vol 45 no 2 pp 501ndash509 2010
[66] R S Kumar A Idhayadhulla A J Abdul Nasser and J SelvinldquoSynthesis and anticoagulant activity of a new series of 14-dihydropyridine derivativesrdquo European Journal of MedicinalChemistry vol 46 no 2 pp 804ndash810 2011
[67] H A Stefani C B Oliveira R B Almeida et al ldquoDihydro-pyrimidin-(2H)-ones obtained by ultrasound irradiation anew class of potential antioxidant agentsrdquo European Journal ofMedicinal Chemistry vol 41 no 4 pp 513ndash518 2006
[68] H Sun C Shang L Jin and J Zhang ldquoSynthesis and antiox-idant activity of a series of novel 3-chalcone-substituted 14-dihydropyridine derivativesrdquoHeterocyclic Communications vol18 no 5-6 pp 239ndash243 2012
[69] D B Tikhonov and B S Zhorov ldquoStructural model for dihy-dropyridine binding to L-type calcium channelsrdquo The Journalof Biological Chemistry vol 284 no 28 pp 19006ndash19017 2009
[70] G Y Dubur and Y R Uldrikis ldquoThe oxidation of 14-dihydro-pyridinesrdquo Chemistry of Heterocyclic Compounds vol 6 no 1pp 80ndash84 1970 Translated from Khimiya GeterotsiklicheskikhSoedinenii no 1 pp 83ndash88 1970 (Russian)
[71] G Ya Duburs A O Kumerova and Ya R Uldrikis ldquoEnzymicoxidation of hydrogenated pyridines with peroxidase-hydrogenperoxide systemrdquoLatvijas PSRZAVestis vol 73 no 7 pp 73ndash771970 (Russian) Chemical Abstracts vol 73 Article ID 94913g1970
[72] K Xie Y-C Liu Y Cui J-GWang Y Fu andT CWMak ldquoN-methyl-(R)-3-(tert-butyl)-sulfinyl-14-dihydropyridine a novelNADHmodel compoundrdquoMolecules vol 12 no 3 pp 415ndash4222007
[73] S Tamagaki T Mimura and W Tagaki ldquoMetal-ion-facilitatedoxidations of dihydropyridines with molecular oxygen andhydrogen peroxiderdquo Journal of the Chemical Society PerkinTransactions 2 no 10 pp 1645ndash1650 1990
[74] D Tirzite G Tirzitis andD Antipova ldquoReductive ability of 14-dihydropyridine derivatives in relation to ions of trivalent ironrdquoChemistry of Heterocyclic Compounds vol 35 no 5 pp 592ndash594 1999
[76] J Ogle J Stradins and L Baumane ldquoFormation and decay offree cation-radicals in the course of electro-oxidation of 12- and14-dihydropyridines (Hantzsch esters)rdquo Electrochimica Actavol 39 no 1 pp 73ndash79 1994
[77] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for the
synthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts C Wittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Berlin Germany 2010
[78] WDu and Zh Yu ldquoBiomimetic in situ regeneration of cofactorsNAD(P)+ and NAD(P)H models hantzsch esters and dihy-drophenanthridinerdquo Synlett vol 23 no 9 pp 1300ndash1304 2012
[79] H K Chenault and G M Whitesides ldquoRegeneration ofnicotinamide cofactors for use in organic synthesisrdquo AppliedBiochemistry and Biotechnology vol 14 no 2 pp 147ndash197 1987
[80] Y R Uldrikis A A Zidermane E A Biseniex I E Preisa GY Dubur and G D Tirzit ldquoEsters of 26-dimethyl-14-dihydro-pyridine-35-dicarboxylic acid and method of obtainingthereofrdquo WO 8000345 A1 1978 httpworldwideespacenetcompublicationDetailsbiblioDB=EPODOCampII=1ampND=3ampadjacent=trueamplocale=en EPampFT=Dampdate=19800306ampCC=WOampNR=8000345A1ampKC=A1
[81] Y Sambongi H Nitta K Ichihashi M Futai and I Ueda ldquoAnovel water-soluble Hantzsch 14-dihydropyridine compoundthat functions in biological processes through NADH regener-ationrdquo Journal of Organic Chemistry vol 67 no 10 pp 3499ndash3501 2002
[82] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for thesynthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts ChWittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Verlag Berlin Germany 2010
[83] T Okamura T Kikuchi A Nagamine et al ldquoAn approach formeasuring in vivo cerebral redox states using the oxidative con-version of dihydropyridine to pyridinium ion and themetabolictrapping principlerdquo Free Radical Biology and Medicine vol 38no 9 pp 1197ndash1205 2005
[84] K A Schellenberg and F H Westheimer ldquoA free-radicaloxidation of a dihydropyridine1ardquo The Journal of OrganicChemistry vol 30 no 6 pp 1859ndash1862 1965
[85] K A Schellenberg ldquoReaction of hydroxyl radical with thymi-dine Scavenging by a dihydropyridinerdquo Federation Proceedingsvol 38 no 3 I p 1433 1979
[86] E S Huyser J A K Harmony and F L McMillian ldquoPeroxideoxidations of dihydropyridine derivativesrdquo Journal of the Amer-ican Chemical Society vol 94 no 9 pp 3176ndash3180 1972
[87] A Sakamoto S T Ohnishi and R Ogawa ldquoInhibition of lipidperoxidation by some dihydropyridine derivativesrdquo Journal ofAnesthesia vol 7 no 2 pp 193ndash197 1993
[88] R Hardeland ldquoReview Neuroprotection by radical avoidancesearch for suitable agentsrdquo Molecules vol 14 no 12 pp 5054ndash5102 2009
[89] G Ya Dubur A Kh Velena V M Gukasov and Yu AVladimirov ldquoRegulation of peroxidation of mitochondrialmembrane lipids initiated by Fe2+ ions by antoxidants of the14-dihydropyridine series in experiments in vitrordquo Biomed-itsinskaya Khimiya vol 22 no 5 pp 665ndash673 1976 (Russian)Chemical Abstracts vol 88 Article ID 2640 1977
[90] G RMMHaenenM J T J Arts A Bast andMD ColemanldquoStructure and activity in assessing antioxidant activity in vitroand in vivo a critical appraisal illustrated with the flavonoidsrdquoEnvironmental Toxicology and Pharmacology vol 21 no 2 pp191ndash198 2006
[91] G Tirzitis and G Bartosz ldquoDetermination of antiradical andantioxidant activity basic principles and new insightsrdquo ActaBiochimica Polonica vol 57 no 2 pp 139ndash142 2010
30 Oxidative Medicine and Cellular Longevity
[92] G R Buettner and R P Mason ldquoSpin-trapping methods fordetecting superoxide and hydroxyl free radicals in vitro and invivordquo inCritical Reviews of Oxidative Stress and Aging Advancesin Basic Science Diagnostics and Intervention R G Cutler andH Rodriguez Eds vol 1 chapter 2 pp 27ndash38World ScientificLondon UK 2003
[93] M M Tarpey and I Fridovich ldquoMethods of detection ofvascular reactive species Nitric oxide superoxide hydrogenperoxide and peroxynitriterdquo Circulation Research vol 89 no3 pp 224ndash236 2001
[94] E Y Kazush E I Sagun G D Tirzit and G Y DaburldquoQuenching of singlet oxygen by electron donating derivativesof 14-dihydropyridinerdquo Chemistry of Heterocyclic Compoundsvol 30 no 5 pp 562ndash563 1994
[95] G Tirzitis E Kazush and G Duburs ldquoReaction of 14-dihydropyridine derivatives with peroxynitrite anionrdquo Chem-istry of Heterocyclic Compounds vol 34 no 3 pp 321ndash3231998 (Russian) Translated from Khimiya GeterotsiklicheskikhSoedinenii no 3 pp 355ndash357 1998
[96] L J Nunez-Vergara C Lopez-Alarcon P A Navarrete-EncinaA M Atria C Camargo and J A Squella ldquoElectrochemicaland EPR characterization of 14-dihydropyridines Reactivitytowards alkyl radicalsrdquo Free Radical Research vol 37 no 1 pp109ndash120 2003
[97] D Tirzite A Krauze A Zubareva G Tirzitis and G DubursldquoSynthesis and antiradical activity of 5-acetyl-2-alkylthio-4-aryl-6-methyl-14-dihydropyridine-3-carboxylic acid nitrilesrdquoChemistry of Heterocyclic Compounds vol 38 no 7 pp 795ndash800 2002
[98] H Ohkawa N Ohishi and K Yagi ldquoAssay for lipid peroxidesin animal tissues by thiobarbituric acid reactionrdquo AnalyticalBiochemistry vol 95 no 2 pp 351ndash358 1979
[99] N Zarkovic ldquo4-Hydroxynonenal as a bioactive marker ofpathophysiological processesrdquo Molecular Aspects of Medicinevol 24 no 4-5 pp 281ndash291 2003
[100] M Parola G Bellomo G Robino G Barrera and M UDianzani ldquo4-Hydroxynonenal as a biological signal molecularbasis and pathophysiological implicationsrdquo Antioxidants andRedox Signaling vol 1 no 3 pp 255ndash284 1999
[101] T Lovakovic M Poljak-Blazi G Duburs et al ldquoGrowthmodulation of human cells in vitro by mild oxidative stressand 14-dihydropyridine derivative antioxidantsrdquo CollegiumAntropologicum vol 35 no 1 pp 137ndash141 2011
[102] R van den Berg G R M M Haenen H van den Bergand A Bast ldquoApplicability of an improved Trolox equivalentantioxidant capacity (TEAC) assay for evaluation of antioxidantcapacity measurements of mixturesrdquo Food Chemistry vol 66no 4 pp 511ndash517 1999
[103] C Lopez-Alarcon P Navarrete C Camargo J A Squella andL J Nunez-Vergara ldquoReactivity of 14-dihydropyridines towardalkyl alkylperoxyl radicals and ABTS radical cationrdquo ChemicalResearch in Toxicology vol 16 no 2 pp 208ndash215 2003
[104] V Valenzuela P Santander C Camargo J A Squella C Lopez-Alarcon and L J Nunez-Vergara ldquo14-Dihydropyridines reac-tivity of nitrosoaryl and nitroaryl derivatives with alkylperoxylradicals andABTS radical cationrdquo Free Radical Research vol 38no 7 pp 715ndash727 2004
[105] L G Tsetlin N A Chebotareva B I Kurganov A K VelenaG Y Dubur and V Z Lankin ldquoStudy of 14-dihydropyridinesas lipoxygenase inhibitors with the use of hydrated reversedmicellesrdquo Pharmaceutical Chemistry Journal vol 22 no 6 pp425ndash428 1988 (Russian)
[106] J Panek Z Reblova L Kocirkova et al ldquoAntioxidant activityof dihydropyridine derivativesrdquo Czech Journal of Food Sciencesvol 18 pp 144ndash145 2000
[107] G Tirzitis I Kirule and G Duburs ldquoAntioxidationsaktivitatder 35-dicarbonylderivate des 26-demethyl-14-dihydropyri-dinsrdquo Fett Wissenschaft TechnologieFat Science Technology vol90 no 10 pp 411ndash413 1988
[108] M Plotniece G Tirzitis Y Uldrikis et al ldquoSynthesis of 14-dihydropyridine derivatives having an oxy- alkoxy- or dimeth-ylaminophenyl substituent in the 4 position their antioxidantactivity and their binding to phospholipid membranesrdquo Chem-istry of Heterocyclic Compounds vol 32 no 10 pp 1166ndash11721996 Translated from Khimiya Geterotsiklicheskikh Soedineniino 10(352) pp 1358ndash1365 1996 (Russian)
[109] D Y Rubene V S Sharov V I Olenev G D Tirzit G Y Duburand Y A Vladimirov ldquoUse of chemiluminescent method forthe evaluation of antioxidant activity of some derivatives of 14-dihydropyridinerdquo Russian Journal of Physical Chemistry A vol55 no 2 pp 511ndash512 1981 (Russian)
[110] M C R Symons and JM C Gutteridge Free Radicals and IronChemistry Biology and Medicine Oxford Science PublicationsOxford University Press Oxford UK 1998
[111] M Repetto J Semprine and A Boveris ldquoLipid peroxidationchemical mechanism biological implications and analyticaldeterminationrdquo in Lipid Peroxidation A Catala Ed Section ILipid Peroxidation Chemical Mechanisms Antioxidants Bio-logical Implications of Biochemistry Genetics and MolecularBiology chapter 1 pp 3ndash30 InTech Rijeka Croatia 2012
[112] A Velena J Zilbers and G Duburs ldquoDerivatives of 14-dihydropyridines asmodulators of ascorbate-induced lipid per-oxidation and high-amplitude swelling ofmitochondria causedby ascorbate sodium linoleate and sodiumpyrophosphaterdquoCellBiochemistry and Function vol 17 no 4 pp 237ndash252 1999
[113] M V Bilenko L N Shelenkova G Y Dubur and A K VelenaldquoUse of antioxidants to prevent renal damage during acuteischemia and reperfusionrdquo Bulletin of Experimental Biology andMedicine vol 96 no 3 pp 1195ndash1198 1983 Translated fromByulletenrsquo Eksperimentalrsquonoi Biologii i Meditsiny vol 96 no 9pp 8ndash11 1983 (Russian)
[114] R Toniolo F Tubaro F Ursini and G Bontempelli ldquoAn elec-troanalytical investigation on the redox properties of calciumantagonist dihydropyridinesrdquo Electroanalysis vol 15 no 10 pp855ndash861 2003
[115] L Kourimska J Pokorny and G Tirzitis ldquoThe antioxidant aci-tivity of 26-dimethyl-35-diethoxycarbonyl-14-dihydropyri-dine in edible oilsrdquo Nahrung vol 37 no 1 pp 91ndash93 1993
[116] C Lopez-Alarcon H Speisky J A Squella C Olea-Azar CCamargo and L J Nunez-Vergara ldquoReactivity of 14-dihydro-pyridines toward SIN-1-derived peroxynitriterdquo PharmaceuticalResearch vol 21 no 10 pp 1750ndash1757 2004
[117] R A Olek W Ziolkowski J J Kaczor L Greci J Popinigisand J Antosiewicz ldquoAntioxidant activity of NADH and its ana-loguemdashan in vitro studyrdquo Journal of Biochemistry andMolecularBiology vol 37 no 4 pp 416ndash421 2004
[118] E Niki N Noguchi and N Gotoh ldquoInhibition of oxidativemodification of low density lipoprotein by antioxidantsrdquo Jour-nal of Nutritional Science andVitaminology vol 39 supplementpp S1ndashS8 1993
[119] N Rojstaczer and D J Triggle ldquoStructure-function relation-ships of calcium antagonists effect on oxidative modificationof low density lipoproteinrdquo Biochemical Pharmacology vol 51no 2 pp 141ndash150 1996
Oxidative Medicine and Cellular Longevity 31
[120] A Sevanian L Shen and FUrsini ldquoInhibition of LDLoxidationand oxidized LDL-induced cytotoxicity by dihydropyridinecalcium antagonistsrdquo Pharmaceutical Research vol 17 no 8 pp999ndash1006 2000
[121] A Negre-Salvayre and R Salvayre ldquoProtection by Ca2+ channelblockers (nifedipine diltiazem and verapamil) against the tox-icity of oxidized low density lipoprotein to cultured lymphoidcellsrdquo British Journal of Pharmacology vol 107 no 3 pp 738ndash744 1992
[122] A Negre-Salvayre G FitoussiM Troly and R Salvayre ldquoCom-parative cytoprotective effect of dihydropyridine calcium chan-nel blockers against the toxicity of oxidized low density lipopro-tein for cultured lymphoid cellsrdquo Biochemical Pharmacologyvol 44 no 12 pp 2379ndash2386 1992
[123] L Cominacini A F Pasini U Garbin et al ldquoAntioxidant activ-ity of different dihydropyridinesrdquo Biochemical and BiophysicalResearch Communications vol 302 no 4 pp 679ndash684 2003
[124] L Cominacini U Garbin A Fratta Pasini et al ldquoOxidized low-density lipoprotein increases the production of intracellularreactive oxygen species in endothelial cells inhibitory effect oflacidipinerdquo Journal of Hypertension vol 16 no 12 part 2 pp1913ndash1919 1998
[125] H M Lander ldquoAn essential role for free radicals and derivedspecies in signal transductionrdquo The FASEB Journal vol 11 no2 pp 118ndash124 1997
[126] M L L Martinez E Rizzi M M Castro et al ldquoLercanidipinedecreases vascular matrix metalloproteinase-2 activity andprotects against vascular dysfunction in diabetic ratsrdquo EuropeanJournal of Pharmacology vol 599 no 1ndash3 pp 110ndash116 2008
[127] P Lesnik C Dachet L Petit et al ldquoImpact of a combinationof a calcium antagonist and a 120573-blocker on cell- and copper-mediated oxidation of LDL and on the accumulation and effluxof cholesterol in human macrophages and murine J774 cellsrdquoArteriosclerosis Thrombosis and Vascular Biology vol 17 no 5pp 979ndash988 1997
[128] G Sobal E J Menzel and H Sinzinger ldquoCalcium antagonistsas inhibitors of in vitro low density lipoprotein oxidation andglycationrdquoBiochemical Pharmacology vol 61 no 3 pp 373ndash3792001
[129] E Lupo R Locher B Weisser and W Vetter ldquoIn vitro antiox-idant activity of calcium antagonists against LDL oxidationcompared with 120572-tocopherolrdquo Biochemical and BiophysicalResearch Communications vol 203 no 3 pp 1803ndash1808 1994
[130] J Zou Y Li H-Q Fan and J-G Wang ldquoEffects of dihydropy-ridine calcium channel blockers on oxidized low-density lipo-protein induced proliferation and oxidative stress of vascularsmooth muscle cellsrdquo BMC Research Notes vol 5 article 1682012
[131] C Napoli S Salomone T Godfraind et al ldquo14-Dihydro-pyridine calcium channel blockers inhibit plasma and LDL oxi-dation and formation of oxidation-specific epitopes in the arte-rial wall and prolong survival in stroke-prone spontaneouslyhypertensive ratsrdquo Stroke vol 30 no 9 pp 1907ndash1915 1999
[132] G Zernig I Graziadei T Moshammer C Zech N Reider andH Glossmann ldquoMitochondrial Ca2+ antagonist binding sitesare associated with an inner mitochondrial membrane anionchannelrdquo Molecular Pharmacology vol 38 no 3 pp 362ndash3691990
[133] F E Hunter Jr A Scott P E Hochstein et al ldquoStudies of themechanism of ascorbate-induced swelling and lysis of isolatedliver mitochondriardquo The Journal of Biological Chemistry vol239 pp 604ndash613 1964
[134] D R Janero B Burghardt and R Lopez ldquoProtection of cardiacmembrane phospholipid against oxidative injury by calciumantagonistsrdquoBiochemical Pharmacology vol 37 no 21 pp 4197ndash4203 1988
[135] A Karadag B Ozcelik and S S Saner ldquoReview of methods todetermine antioxidant capacitiesrdquo FoodAnalyticalMethods vol2 no 1 pp 41ndash60 2009
[136] Y I Gubskiı N V Litvinova and E V Shnurko-TabakovaldquoAntioxidant and antiradical activity of various classes of antiox-idantsrdquo Ukrainskiı Biokhimicheskiı Zhurnal vol 66 no 4 pp114ndash116 1994 (Russian)
[137] M Takei M Hiramatsu and A Mori ldquoInhibitory effects ofcalcium antagonists onmitochondrial swelling induced by lipidperoxidation or arachidonic acid in the rat brain in vitrordquoNeurochemical Research vol 19 no 9 pp 1199ndash1206 1994
[138] M Takei M Hiramatsu R Edamatsu and A Mori ldquoFreeradical scavenging by calcium antagonistsrdquo Neurosciences vol20 no 2 pp 75ndash82 1994
[139] Ya P Stradin G Ya Dubur Yu A Beilis Ya R Uldrikis andA F Korotkova ldquoVoltammetry of 14-dihydropyridine deriva-tives I Potentials of electrochemical oxidation of 35-diacyl-and 35-di(alkoxycarbonyl)-14-dihydropyridines in acetoni-trilerdquo Chemistry of Heterocyclic Compounds no 1 pp 84ndash871972 (Russian)
[140] E V Ivanov T V Ponomarjova G N Merkusev et al ldquoEinneuer Haut-Radioprotektor Diethon (experimentelle Unter-suchung)rdquo Radiobiologia Radiotherapia vol 31 no 1 pp 69ndash78 1990
[141] E V Ivanov T V Ponomareva G N Merkushev et al ldquoRadia-tion modulating properties of derivates of 14-dihydropyridineand 12345678910-decahydroacridine-18 dionerdquo Radiat-sionnaia Biologiia Radioecologiia vol 44 no 5 pp 550ndash5592004 (Russian)
[142] R O Vitolinia D A Berzinia A K Velena I A Vutsina A AKimenis and G Y Duburs ldquoThe protective effects of the cal-cium antagonist foridon in acute myocardial ischaemiardquo Kardi-ologiya vol 27 no 3 pp 90ndash93 1987 (Russian)
[143] A H Velena G Ya Duburs R O Vitolina et al ldquoEffect ofryodipine on electromechanical parameters of heart and vesselscAMP phosphodiesterase activity and swelling-contractioncycle of mitochondriardquo Arzneimittelforschung vol 35 no 6 pp907ndash914 1985
[144] L I Utno Z E Lipsberga A A Silova M I Girgensone EA Bisenieks and G I Ia ldquoCardioprotective properties of a 14-dihydropyridine derivative glutapyrone in deep hypothermiardquoBiulletenrsquo Eksperimentalrsquonoı Biologii i Meditsiny vol 108 no 11pp 558ndash561 1989 (Russian)
[145] M A S FernandesM S Santos J A F Vicente et al ldquoEffects of14-dihydropyridine derivatives (cerebrocrast gammapyroneglutapyrone and diethone) onmitochondrial bioenergetics andoxidative stress a comparative studyrdquoMitochondrion vol 3 no1 pp 47ndash59 2003
[146] M A S Fernandes M S Santos A J M Moreno et al ldquoEffectsof 5-acetyl(carbamoyl)-6-methylsulfanyl-14-dihydropyridine-5-carbonitriles on rat liver mitochondrial functionrdquo Toxicologyin Vitro vol 23 no 7 pp 1333ndash1341 2009
[147] L Klimaviciusa A Kalda A Kaasik et al ldquoNeuroprotectiveactivity of 14-dihydropyridine derivatives structure determi-nantsrdquo Proceedings of the Latvian Academy of Sciences BNatural Exact and Applied Sciences vol 61 no 1-2 pp 33ndash372007
32 Oxidative Medicine and Cellular Longevity
[148] L Klimaviciusa M A S Fernandes N Lencberga et alldquoTargeting the mitochondria by novel adamantane-containing14-dihydropyridine compoundsrdquo in Bioenergetics K B ClarkEd pp 257ndash272 InTech 2012
[149] V Klusa L Klimaviciusa G Duburs J Poikans and AZharkovsky ldquoAnti-neurotoxic effects of tauropyrone a taurineanaloguerdquo Advances in Experimental Medicine and Biology vol583 pp 499ndash508 2006
[150] N Sampson P Berger and Ch Zenzmaier ldquoRedox signalingas a therapeutic target to inhibit myofibroblast activation indegenerative fibrotic diseaserdquo BioMed Research Internationalvol 2014 Article ID 131737 14 pages 2014
[151] T L Leto and M Geiszt ldquoRole of Nox family NADPH oxidasesin host defenserdquoAntioxidantsampRedox Signaling vol 8 no 9-10pp 1549ndash1561 2006
[152] K K Griendling D Sorescu and M Ushio-Fukai ldquoNAD(P)Hoxidase role in cardiovascular biology and diseaserdquo CirculationResearch vol 86 no 5 pp 494ndash501 2000
[153] H Chen Y S Song and P H Chan ldquoInhibition of NADPHoxi-dase is neuroprotective after ischemia-reperfusionrdquo Journal ofCerebral Blood Flow and Metabolism vol 29 no 7 pp 1262ndash1272 2009
[154] P Hochstein and L Ernster ldquoADP-activated lipid peroxidationcoupled to the TPNH oxidase system of microsomesrdquo Biochem-ical and Biophysical Research Communications vol 12 no 5 pp388ndash394 1963
[155] I I Gubskiı AGGoriushkoNV Litvinova et al ldquoAntioxidantproperties and membranotropic effect of certain derivatives of14-dihydropyridinerdquo Ukrainskiı Biokhimicheskiı Zhurnal vol71 no 4 pp 35ndash39 1999 (Russian)
[156] F Engineer and R Sridhar ldquoInhibition of rat heart andliver microsomal lipid peroxidation by nifedipinerdquo BiochemicalPharmacology vol 38 no 8 pp 1279ndash1285 1989
[157] T Goncalves A P Carvalho and C R Oliveira ldquoAntioxidanteffect of calcium antagonists on microsomai membranes iso-lated from different brain areasrdquo European Journal of Pharma-cology vol 204 no 3 pp 315ndash322 1991
[158] M E Letelier P Izquierdo L Godoy A M Lepe and MFaundez ldquoLiver microsomal biotransformation of nitro-aryldrugs mechanism for potential oxidative stress inductionrdquoJournal of Applied Toxicology vol 24 no 6 pp 519ndash525 2004
[159] M E Letelier P Entrala C Lopez-Alarcon et al ldquoNitroaryl-14-dihydropyridines as antioxidants against rat liver microsomesoxidation induced by ironascorbate Nitrofurantoin and naph-thalenerdquo Toxicology in Vitro vol 21 no 8 pp 1610ndash1618 2007
[160] F P Guengerich W R Brian M Iwasaki M-A Sari CBaarnhielm and P Berntsson ldquoOxidation of dihydropyridinecalcium channel blockers and analogues by human liver cyto-chrome P-450 IIIA4rdquo Journal of Medicinal Chemistry vol 34no 6 pp 1838ndash1844 1991
[161] S H Park S-W RhaW-Y Shin et al ldquoAS-160 Calcium channelblockers of dihydropyridine class reduce the antiplatelet effectof Clopidogrel what is clinical impactrdquo The American Journalof Cardiology vol 107 no 8 supplement p 47A 2011
[162] C Asma and D M Reda ldquoEvaluation of dihydropyridinecalcium antagonist effects on the stress bioindicator orga-nism Saccharomyces cerevisiaerdquo Annals of Biological Researchvol 4 no 10 pp 40ndash46 2013 httpscholarsresearchlibrarycomABR-vol4-iss10ABR-2013-4-10-40-46pdf
[163] G Gaviraghi A M Pastorino E Ratti and D G TristldquoCalcium channel blockers with antioxidant activityrdquo in Free
Radicals Lipoprotein Oxidation andAtherosclerosis G BellomoG Finardi E Maggi and E Rice-Evans Eds pp 431ndash456Richelieu Press London UK 1995
[164] G Gaviraghi AM Pastorino E Ratti and D G Trist ldquoAntiox-idant dihydropyridines a new and comprehensive therapy forfree radical-induced cardiovascular diseasesrdquo in Free Radicalsin Biology and Environment F Minisci Ed vol 27 of NATOASI Series pp 193ndash221 Springer Dordrecht The Netherlands1997
[165] P D Henry ldquoAntiperoxidative actions of calcium antagonistsand atherogenesisrdquo Journal of Cardiovascular Pharmacologyvol 18 supplement 1 pp S6ndashS10 1991
[166] F Kouoh B Gressier T Dine et al ldquoAntioxidant effects andanti-elastase activity of the calcium antagonist nicardipine onactivated human and rabbit neutrophilsmdasha potential antiath-erosclerotic property of calcium antagonistsrdquo CardiovascularDrugs andTherapy vol 16 no 6 pp 515ndash520 2002
[167] S Parthasarathy D Litvinov K Selvarajan and M GarelnabildquoLipid peroxidation and decompositionmdashconflicting roles inplaque vulnerability and stabilityrdquo Biochimica et BiophysicaActa vol 1781 no 5 pp 221ndash231 2008
[168] D-Q Liu Z-Q Pang D-H Zhao and B-H Sheng ldquoEffects offuryl-dihydropyridines I on lipid peroxides of ischemic myo-cardium and ATPases activity of erythrocyte membranes inratsrdquo Acta Pharmacologica Sinica vol 12 no 3 pp 253ndash2561991
[169] V Lukic-Panin T Kamiya H Zhang et al ldquoPrevention of neu-ronal damage by calcium channel blockers with antioxidativeeffects after transient focal ischemia in ratsrdquo Brain Research vol1176 no 1 pp 143ndash150 2007
[170] Y Allanore D Borderie H Lemarechal O G Ekindjian andA Kahan ldquoAcute and sustained effects of dihydropyridine-typecalcium channel antagonists on oxidative stress in systemicsclerosisrdquo American Journal of Medicine vol 116 no 9 pp 595ndash600 2004
[171] I Casetta V Govoni and E Granieri ldquoOxidative stress antioxi-dants and neurodegenerative diseasesrdquo Current PharmaceuticalDesign vol 11 no 16 pp 2033ndash2052 2005
[172] M J T J Arts Assessing antioxidant activity [PhD the-sis] Maastricht University Maastricht The Netherlands 2007httparnounimaasnlshowcgifid=8676
[173] G Dıaz-Araya L Godoy L Naranjo A Squella M E Letelierand L J Nunez-Vergara ldquoAntioxidant effects of 14-dihydro-pyridine and nitroso aryl derivatives on the Fe+3ascorbate-stimulated lipid peroxidation in rat brain slicesrdquo General Phar-macology The Vascular System vol 31 no 3 pp 385ndash391 1998
[174] Y Fukuhara K Tsuchiya Y Horinouchi et al ldquoProtectiveeffect of photodegradation product of nifedipine against tumornecrosis factor 120572-induced oxidative stress in human glomerularendothelial cellsrdquo Journal of Medical Investigation vol 58 no1-2 pp 118ndash126 2011
[175] W Stengel M Jainz and K Andreas ldquoDifferent potencies ofdihydropyridine derivatives in blocking T-type but not L-typeCa2+ channels in neuroblastoma-glioma hybrid cellsrdquo EuropeanJournal of Pharmacology vol 342 no 2-3 pp 339ndash345 1998
[176] O M Panasenko D J Tirzite G D Tirzitis and G J DubursldquoEffect of some 14-dihydropyridine derivatives on structuralorganization of erythrocyte membranesrdquo Biologicheskie Mem-brany (Biochemistry (Moscow) Series A Membrane and CellBiology) vol 1 pp 919ndash925 1984 (Russian)
[177] L G Herbette Y M H Vant Erve and D G Rhodes ldquoInter-action of 14 dihydropyridine calcium channel antagonists with
Oxidative Medicine and Cellular Longevity 33
biological membranes lipid bilayer partitioning could occurbefore drug binding to receptorsrdquo Journal of Molecular andCellular Cardiology vol 21 no 2 pp 187ndash201 1989
[178] L G Herbette P E Mason G Gaviraghi T N Tulenko andR P Mason ldquoThe molecular basis for lacidipinersquos unique phar-macokinetics optimal hydrophobicity results in membraneinteractions that may facilitate the treatment of atherosclerosisrdquoJournal of Cardiovascular Pharmacology vol 23 supplement 5pp S16ndashS25 1994
[179] G V Belevitch G Y Dubur G E Dobretsov N K Kurek andM M Spirin ldquoCalcium antagonists riodipine nifedipine andverapamil binding to model and biological membranes fluore-scence analysisrdquo Biologicheskie Membrany (Biochemistry(Moscow) Series A Membrane and Cell Biology) vol 5 pp768ndash776 1988 (Russian)
[180] R P Mason G E Gonye D W Chester and L G HerbetteldquoPartitioning and location of Bay K 8644 14-dihydropyridinecalcium channel agonist in model and biological membranesrdquoBiophysical Journal vol 55 no 4 pp 769ndash778 1989
[181] M Cindric A Cipak J Serly et al ldquoReversal of multidrugresistance inmurine lymphoma cells by amphiphilic dihydropy-ridine antioxidant derivativerdquo Anticancer Research vol 30 no10 pp 4063ndash4070 2010
[182] F Shekari H Sadeghpour K Javidnia et al ldquoCytotoxic andmultidrug resistance reversal activities of novel 14-dihydro-pyridines against human cancer cellsrdquo European Journal ofPharmacology vol 746 no 1 pp 233ndash244 2015
[183] X-F Zhou Q Shao R A Coburn and M E Morris ldquoQuanti-tative structure-activity relationship and quantitative structure-pharmacokinetics relationship of 14-dihydropyridines andpyridines as multidrug resistance modulatorsrdquo PharmaceuticalResearch vol 22 no 12 pp 1989ndash1996 2005
[184] R Berkels T Breitenbach H Bartels et al ldquoDifferent antioxida-tive potencies of dihydropyridine calcium channel modulatorsin various modelsrdquo Vascular Pharmacology vol 42 no 4 pp145ndash152 2005
[185] S Borovic G Tirzitis D Tirzite et al ldquoBioactive 14-dihydro-isonicotinic acid derivatives prevent oxidative damage of livercellsrdquo European Journal of Pharmacology vol 537 no 1ndash3 pp12ndash19 2006
[186] D Ya Rubene G D Tirzitis and G Ya Duburs ldquoInteractionof some 14-dihydropyridine derivatives with Fentonrsquos reagentrdquoLatvijas PSRZinatnuAkademijas Vestis Kimijas Serija Proceed-ings of the Latvian SSR Academy of Sciences Chemistry Seriespp 212ndash216 1982 (Russian)
[187] K Ondrias V Misık D Gergel and A Stasko ldquoLipid per-oxidation of phosphatidylcholine liposomes depressed by thecalcium channel blockers nifedipine and verapamil and bythe antiarrhythmic-antihypoxic drug stobadinerdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1003 no 3pp 238ndash245 1989
[188] I T Mak and W B Weglicki ldquoComparative antioxidant acti-vities of propranolol nifedipine verapamil and diltiazemagainst sarcolemmal membrane lipid peroxidationrdquoCirculationResearch vol 66 no 5 pp 1449ndash1452 1990
[189] I T Mak P Boehme and W B Weglicki ldquoProtective effects ofcalcium channel blockers against free radical-impaired endo-thelial cell proliferationrdquo Biochemical Pharmacology vol 50 no9 pp 1531ndash1534 1995
[190] S Ray S Mondal and N Dana ldquoEvaluation of protective roleof nifedipine on lipid peroxidation using reduced glutathione as
model markerrdquo Oxidants and Antioxidants in Medical Sciencevol 1 no 2 pp 97ndash100 2012
[191] M Yamato T Shiba T Ide Y Honda K-I Yamada andH Tsutsui ldquoNifedipine treatment reduces brain damage aftertransient focal ischemia possibly through its antioxidativeeffectsrdquoHypertension Research vol 34 no 7 pp 840ndash845 2011
[192] V Chander and K Chopra ldquoNifedipine attenuates changes innitric oxide levels renal oxidative stress and nephrotoxicityinduced by cyclosporinerdquo Renal Failure vol 27 no 4 pp 441ndash450 2005
[193] K M Gaafa M M Badawy and A A Hamza ldquoThe protectiveeffects of ascorbic acid cimetidine and nifedipine on diethyl-dithiocarbamate-induced hepatic toxicity in albino ratsrdquo Drugand Chemical Toxicology vol 34 no 4 pp 405ndash419 2011
[194] H Sugawara K Tobise and S Onodera ldquoAbsence of antiox-idant effects of nifedipine and diltiazem on myocardial mem-brane lipid peroxidation in contrast with those of nisoldipineand propranololrdquo Biochemical Pharmacology vol 47 no 5 pp887ndash892 1994
[195] I E Kirule D Y Rubene E A Bisenieks G D Tirzit and GY Dubur ldquo4-Nitrophenyl-14-dihydropyridinesmdasha new groupof inhibitors of peroxide oxidationrdquo Chemistry of HeterocyclicCompounds vol 18 no 3 p 316 1982
[196] G D Tirzit I E Kirule L K Baumane R A Gavar Y PStradynrsquo andG YDubur ldquoMechanism of the antioxidant actionof 26-dimethyl-35-dimethoxy-carbonyl-4-(2-nitrophenyl)14-dihydropyridinerdquoChemistry ofHeterocyclic Compounds vol 20no 8 pp 915ndash918 1984
[197] C Yanez C Lopez-Alarcon C Camargo V Valenzuela J ASquella and L J Nunez-Vergara ldquoStructural effects on thereactivity 14-dihydropyridines with alkylperoxyl radicals andABTS radical cationrdquo Bioorganic and Medicinal Chemistry vol12 no 9 pp 2459ndash2468 2004
[198] VMisik A J Stasko D Gergel and K Ondrias ldquoSpin-trappingand antioxidant properties of illuminated and nonilluminatednifedipine and nimodipine in heart homogenate and modelsystemrdquo Molecular Pharmacology vol 40 no 3 pp 435ndash4391991
[199] K Ondrias V Misık A Stasko D Gergelrsquo and M HromadovaldquoComparison of antioxidant properties of nifedipine and illu-minated nifedipine with nitroso spin traps in low densitylipoproteins and phosphatidylcholine liposomesrdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1211 no 1pp 114ndash119 1994
[200] A Stasko V Brezova S Biskupic K Ondrias and V MisıkldquoReactive radical intermediates formed from illuminated nife-dipinerdquoFree Radical Biology andMedicine vol 17 no 6 pp 545ndash556 1994
[201] K Ishizawa Y Izawa-Ishizawa N Yamano et al ldquoNitrosoni-fedipine ameliorates the progression of type 2 diabetic nephro-pathy by exerting antioxidative effectsrdquo PLoS ONE vol 9 no 1Article ID e86335 2014
[202] H Fujii and L J Berliner ldquoIn vivo EPR evidence for free radicaladducts of nifedipinerdquoMagnetic Resonance in Medicine vol 42no 4 pp 691ndash694 1999
[203] S Bollo S Finger J C Sturm L J Nunez-Vergara and JA Squella ldquoCyclic voltammetry and scanning electrochemicalmicroscopy studies of the heterogeneous electron transferreaction of some nitrosoaromatic compoundsrdquo ElectrochimicaActa vol 52 no 15 pp 4892ndash4898 2007
34 Oxidative Medicine and Cellular Longevity
[204] F Ursini ldquoTissue protection by lacidipine insight from redoxbehaviorrdquo Journal of Cardiovascular Pharmacology vol 30supplement 2 pp S28ndashS30 1997
[205] P G Cristofori F A Crivellente I Faustinelli et al ldquoInvolve-ment of the nitric oxide system in the anti-atheroscleroticpotential of lacidipine in the apoE-deficient mouse a mor-phological functional and electrochemical studyrdquo ToxicologicPathology vol 32 no 4 pp 493ndash499 2004
[206] X-P Zhang E L Kit S Mital S Chahwala and T HHintze ldquoParadoxical release of nitric oxide by an L-type calciumchannel antagonist the R+ enantiomer of amlodipinerdquo Journalof Cardiovascular Pharmacology vol 39 no 2 pp 208ndash2142002
[207] F Franzoni G Santoro F Regoli et al ldquoAn in vitro study of theperoxyl and hydroxyl radical scavenging capacity of the calciumantagonist amlodipinerdquo Biomedicine and Pharmacotherapy vol58 no 8 pp 423ndash426 2004
[208] S V Gatsura ldquoOxygen-dependent mechanisms underlying theantiischemic effect of verapamil and amlodipinerdquo Bulletin ofExperimental Biology and Medicine vol 137 no 1 pp 40ndash422004
[209] Y Hirooka Y Kimura M Nozoe Y Sagara K Ito and KSunagawa ldquoAmlodipine-induced reduction of oxidative stressin the brain is associated with sympatho-inhibitory effects instroke-prone spontaneously hypertensive ratsrdquo HypertensionResearch vol 29 no 1 pp 49ndash56 2006
[210] B Tomlinson and I F F Benzie ldquoAntioxidant effect of lercani-dipine (note)rdquo Hypertension vol 42 no 4 pp e10ndashe11 2003
[211] A A Faraqui ldquoNeurochemical aspects of 4-hydroxynonenalrdquoin Lipid Mediators and Their Metabolism in the Brain A AFaraqui Ed chapter 6 pp 159ndash191 Springer New York NYUSA 2011
[212] V S NascimentoM S DrsquoAlva A AOliveira et al ldquoAntioxidanteffect of nimodipine in young rats after pilocarpine-inducedseizuresrdquo Pharmacology Biochemistry and Behavior vol 82 no1 pp 11ndash16 2005
[213] O Ismailoglu P Atilla S Palaoglu et al ldquoThe therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjuryrdquo Turkish Neurosurgery vol 22 no 6 pp 740ndash746 2012
[214] M Matsubara and K Hasegawa ldquoBenidipine a dihydropy-ridine-calcium channel blocker prevents lysophosphatidyl-choline-induced injury and reactive oxygen species productionin human aortic endothelial cellsrdquo Atherosclerosis vol 178 no1 pp 57ndash66 2005
[215] M Matsubara K Yao and K Hasegawa ldquoBenidipine adihydropyridine-calcium channel blocker inhibits lysophos-phatidylcholine-induced endothelial injury via stimulation ofnitric oxide releaserdquo Pharmacological Research vol 53 no 1 pp35ndash43 2006
[216] MMatsubara and K Hasegawa ldquoEffects of benidipine a dihyd-ropyridine-Ca2+ channel blocker on expression of cytokine-induced adhesion molecules and chemoattractants in humanaortic endothelial cellsrdquo European Journal of Pharmacology vol498 no 1ndash3 pp 303ndash314 2004
[217] M Matsubara O Akizuki J-I Ikeda K Saeki K Yao and KSasaki ldquoBenidipine an anti-hypertensive drug inhibits reactiveoxygen species production in polymorphonuclear leukocytesand oxidative stress in salt-loaded stroke-prone spontaneouslyhypertensive ratsrdquo European Journal of Pharmacology vol 580no 1-2 pp 201ndash213 2008
[218] A C Rosenkranz H Lob T Breitenbach R Berkels and RRoesen ldquoEndothelial antioxidant actions of dihydropyridines
and angiotensin converting enzyme inhibitorsrdquo European Jour-nal of Pharmacology vol 529 no 1ndash3 pp 55ndash62 2006
[219] V Kain S Kumar and S L Sitasawad ldquoAzelnidipine preventscardiac dysfunction in streptozotocin-diabetic rats by reducingintracellular calcium accumulation oxidative stress and apop-tosisrdquo Cardiovascular Diabetology vol 10 article 97 2011
[220] K Nakamura S Yamagishi and H Inoue ldquoUnique atheropro-tective property of azelnidipine a dihydropyridine-based cal-cium antagonistrdquoMedical Hypotheses vol 65 no 1 pp 155ndash1572005
[221] TMatsui S Yamagishi K Nakamura S Kikuchi andH InoueldquoAzelnidipine a dihydropyridine-based calcium antagonistinhibits angiotensin II-induced oxidative stress generation anddownregulation of pigment epithelium-derived factor mRNAlevels in microvascular endothelial cellsrdquo Drugs under Experi-mental and Clinical Research vol 31 no 5-6 pp 215ndash219 2005
[222] C Ohmura H Watada T Shimizu et al ldquoCalcium channelblocker azelnidipine reduces lipid hydroperoxides in patientswith type 2 diabetes independent of blood pressurerdquo EndocrineJournal vol 54 no 5 pp 805ndash811 2007
[223] H Daikuhara F Kikuchi and T Ishida ldquoThe combination ofOLmesartan and a CAlcium channel blocker (azelnidipine) orcandesartan and a calcium channel blocker (amlodipine) intype 2 diabetic hypertensive patients theOLCA studyrdquoDiabetesand Vascular Disease Research vol 9 no 4 pp 280ndash286 2012
[224] MAbe NMaruyama KOkada SMatsumoto KMatsumotoand M Soma ldquoAdditive antioxidative effects of azelnidipine onangiotensin receptor blocker olmesartan treatment for type 2diabetic patients with albuminuriardquoHypertension Research vol34 no 8 pp 935ndash941 2011
[225] K Mizushige ldquoAntioxidative activities of thiazolidinedionesand dihydropyridine-type calcium antagonistsrdquo IRYOmdashJapa-nese Journal of National Medical Services vol 59 no 11 pp 581ndash592 2005
[226] S Manabe T Okura T Fukuoka and J Higaki ldquoAntioxidativeeffects of azelnidipine on mesangial cell proliferation inducedby highly concentrated insulinrdquo European Journal of Pharma-cology vol 567 no 3 pp 252ndash257 2007
[227] Y Koyama Y Takeishi H Takahashi et al ldquoAzelnidipine inhi-bits H
2O2-induced cell death in neonatal rat cardiomyocytesrdquo
CardiovascularDrugs andTherapy vol 21 no 1 pp 69ndash72 2007[228] K Shinomiya K Mizushige M Fukunaga et al ldquoAntioxidant
effect of a new calcium antagonist azelnipidine in culturedhuman arterial endothelial cellsrdquo Journal of International Med-ical Research vol 32 no 2 pp 170ndash175 2004
[229] T Ohyama K Sato K Kishimoto et al ldquoAzelnidipine is acalcium blocker that attenuates liver fibrosis and may increaseantioxidant defencerdquo British Journal of Pharmacology vol 165no 4 pp 1173ndash1187 2012
[230] L A Calo F Zaghetto E Pagnin P A Davis A Sempliciniand A C Pessina ldquoEffect of manidipine on gene expressionand protein level of oxidative stress-related proteins p22phoxand HO-1 Relevance for antihypertensive and anti-remodelingeffectsrdquo Journal of Cardiovascular Pharmacology vol 43 no 4pp 531ndash538 2004
[231] R Ghyasi G Sepehri M Mohammadi R Badalzadeh and AGhyasi ldquoEffect of mebudipine on oxidative stress and lipid per-oxidation in myocardial ischemic-reperfusion injury in maleratrdquo Journal of Research in Medical Sciences vol 17 no 12 pp1150ndash1155 2012
Oxidative Medicine and Cellular Longevity 35
[232] DCAndersson J Fauconnier T Yamada et al ldquoMitochondrialproduction of reactive oxygen species contributes to the 120573-adrenergic stimulation of mouse cardiomycytesrdquoThe Journal ofPhysiology vol 589 no 7 pp 1791ndash1801 2011
[233] A F Ceylan-Isik N Ari M Stefek et al ldquoEffects of a long-term treatment with an antioxidant pyridoindole on vascularresponsiveness in diabetes-induced aging ratsrdquo Current AgingScience vol 4 no 2 pp 150ndash157 2011
[234] S Saponara G Sgaragli and F Fusi ldquoQuercetin antagonismof Bay K 8644 effects on rat tail artery L-type Ca2+ channelsrdquoEuropean Journal of Pharmacology vol 598 no 1ndash3 pp 75ndash802008
[235] D A Sica ldquoInteraction of grapefruit juice and calcium channelblockersrdquo American Journal of Hypertension vol 19 no 7 pp768ndash773 2006
[236] P Mulder G Litwinienko S Lin P D MacLean L R CBarclay and K U Ingold ldquoThe L-type calcium channel block-ers Hantzsch 14-dihydropyridines are not peroxyl radical-trapping chain-breaking antioxidantsrdquo Chemical Research inToxicology vol 19 no 1 pp 79ndash85 2006
[237] L J Nunez-Vergara R Salazar C Camargo et al ldquoOxidation ofC4-hydroxyphenyl 14-dihydropyridines in dimethylsulfoxideand its reactivity towards alkylperoxyl radicals in aqueousmediumrdquo Bioorganic and Medicinal Chemistry vol 15 no 12pp 4318ndash4326 2007
[238] M E Ortiz L J Nunez-Vergara and J A Squella ldquoRelativereactivity of dihydropyridine derivatives to electrogeneratedsuperoxide ion in DMSO solutions a voltammetric approachrdquoPharmaceutical Research vol 20 no 2 pp 292ndash296 2003
[239] M E Ortiz L J Nunez-Vergara C Camargo and J A SquellaldquoOxidation of Hantzsch 14-dihydropyridines of pharmacolog-ical significance by electrogenerated superoxiderdquo Pharmaceuti-cal Research vol 21 no 3 pp 428ndash435 2004
[240] R S Raghuvanshi and K N Singh ldquoSuperoxide induced oxida-tive aromatization of Hantzsch 14-dihydropyridinesrdquo IndianJournal of Chemistry Section B Organic and Medicinal Chem-istry vol 47 no 11 pp 1735ndash1738 2008
[241] I Kruk A Kladna K Lichszteld et al ldquoAntioxidant activityof 4-flavonil-14-dihydropyridine derivativesrdquo Biopolymers vol62 no 3 pp 163ndash167 2001
[242] G D Tirzit I M Byteva K I Salokhiddinov G P Gurinovichand G Y Dubur ldquo14-Dihydropyridine derivatives as deactiva-tors of singlet oxygenrdquo Chemistry of Heterocyclic Compoundsvol 17 no 7 pp 682ndash684 1981
[243] G D Tirzit E Y Kazush and G Y Dubur ldquoInfluence of14-dihydropyridine derivatives on the generation of hydroxylradicalsrdquo Chemistry of Heterocyclic Compounds vol 28 no 4pp 435ndash437 1992
[244] N A Pizarro-Urzua and L J Nunez-Vergara ldquoNifedipine andnitrendipine reactivity toward singlet oxygenrdquo Journal of Photo-chemistry and Photobiology A Chemistry vol 175 no 2-3 pp129ndash137 2005
[245] L-F Wang H-Y Zhang L Konga Z-W Chena and J-G ShildquoDFT calculations indicate that 14-dihydropyridine is a promis-ing lead antioxidantrdquo Helvetica Chimica Acta vol 87 no 6 pp1515ndash1521 2004
[246] P Mulder H-G Korth and K U Ingold ldquoWhy quantum-thermochemical calculations must be used with caution toindicate lsquoa promising lead antioxidantrsquordquoHelvetica Chimica Actavol 88 no 2 pp 370ndash374 2005
[247] K Yao Y Ina K Nagashima K Ohmori and T Ohno ldquoAntiox-idant effects of calcium antagonists in rat brain homogenatesrdquo
Biological and Pharmaceutical Bulletin vol 23 no 6 pp 766ndash769 2000
[248] T Matsui S-I Yamagishi K Nakamura and H Inoue ldquoBayw 9798 a dihydropyridine structurally related to nifedipinewith no calcium channel-blocking properties inhibits tumournecrosis factor-120572-induced vascular cell adhesion molecule-1expression in endothelial cells by suppressing reactive oxygenspecies generationrdquo Journal of International Medical Researchvol 35 no 6 pp 886ndash891 2007
[249] K AMitrega B VargheseM Porc and T F Krzeminski ldquoAnti-arrhythmic and hemodynamic effects of oxy nifedipine oxynimodipine oxy nitrendipine and oxy nisoldipinerdquo Pharmaco-logical Research vol 66 no 4 pp 300ndash308 2012
[250] V Herbert ldquoSymposium prooxidant effects of antioxidantvitamins Introductionrdquo The Journal of Nutrition vol 126 no4 supplement pp 1197Sndash1200S 1996 httpjnnutritionorgcontent1264 Suppl1197Sfullpdf
[251] B Halliwell ldquoAre polyphenols antioxidants or pro-oxidantsWhat do we learn from cell culture and in vivo studiesrdquoArchives of Biochemistry and Biophysics vol 476 no 2 pp 107ndash112 2008
[252] C Winterbourn Pro-Oxidants or Antioxidants ChristchurchSchool of Medicine Depatment of Pathology Free RadicalSchool SFRBMUniversity of Otago San Francisco Calif USA2009 httpwwwsfrbmorgfrsWinterbournpdf
[253] A Morakinyo B Iranloye and O Adegoke ldquoCalcium antag-onists modulate oxidative stress and acrosomal reaction in ratspermatozoardquo Archives of Medical Science vol 7 no 4 pp 613ndash618 2011
[254] The Alpha-Tocopherol Beta Carotene Cancer Prevention StudyGroup ldquoThe effect of vitamin E and beta carotene on theincidence of lung cancer and other cancers in male smokersrdquoTheNew England Journal of Medicine vol 330 no 15 pp 1029ndash1035 1994
[255] B Poljsak ldquoStrategies for reducing or preventing the generationof oxidative stressrdquo Oxidative Medicine and Cellular Longevityvol 2011 Article ID 194586 15 pages 2011
[256] B Poljsak and I Milisav ldquoThe neglected significance of lsquoanti-oxidative stressrsquordquoOxidativeMedicine and Cellular Longevity vol2012 Article ID 480895 12 pages 2012
[257] T Godfraind and S Salomone ldquoAmbiguities in dietary antiox-idant supplementation compared to calcium channel blockerstherapyrdquo Frontiers in Pharmacology vol 6 article 10 2015
[258] H Wagner H Norr and H Winterhoff ldquoDrugs with adap-togenic effects for strengthening the powers of resistancerdquoZeitschrift fur Phytotherapie vol 13 no 2 pp 42ndash54 1992
Oxidative Medicine and Cellular Longevity 9
Table 1 Relative structure-function relationships of calcium antagonists (DHPs verapamil and diltiazem) and vitamin E Effect on oxidativemodification of isolated ex vivo human low-density lipoprotein using two various oxidation systems (copper (II) ions induced and monocyteinduced) Compiled according to data presented by Rojstaczer and Triggle [119]
Compound
Systems of LDL oxidation
Copper (II) ions induced system (comparison of three methods) Monocyte induced celloxidation system
Methods
Reduction of TBARS level of LDL(relative efficacy)
Degradation of oxidized[125I] LDL by J774
macrophages
Relative electrophoreticmobility of LDL on
agarose gel
TBARS content of LDL(in )
Relative efficacy (activity rank order (ARO) ARO = I for the most effective) effective inhibitor concentration [IC] in120583M
with polyunsaturated groups of membrane phospholipidsHowever DHPs can also reduce the oxLDL-induced ROSconcentration by affecting some intracellular ROS producerssuch as NADPH oxidases xanthine oxidase and cyclooxyge-nase enzymes The activity of these enzymes contributes tointracellular ROS elevation [125]
Preincubation of HUVECs with lacidipine inhibited anincrease of intracellular ROS caused by oxidized LDL [124]
Lupo et al [129] have studied the dose-dependent (1 510 and 50 120583M) AOA of various CA (verapamil diltiazemand DHPs nifedipine amlodipine isradipine or lacidipine)
Table 3Modulation of ROS formation in BAECs by CA (DHPs andverapamil) and vitamin E Compiled according to data presented byCominacini et al [123]
Compound
Method of flow cytometry (reduced2101584071015840-dichlorofluorescein diacetate(DCFH-DA) oxidation by ROS)
Activity rank order(ARO = I for the highest activity ARO = III for
the mindest activity)(Effective [IC] 1 5 10 50 120583M)
Lacidipine + + + (ARO = I)Lercanidipine + + (ARO = II)Amlodipine No effectNifedipine No effectNimodipine No effectVerapamil + (ARO = III)120572-Tocopherol + + + (ARO = I)
against normolipidemic human blood LDL oxidation com-pared with 120572-tocopherol by measuring the content of TBARSand the diene formation (see Table 4)
10 Oxidative Medicine and Cellular Longevity
Table 4 Normolipidemic human blood LDL (025mgmL) in vitro oxidation in the presence of 5 120583M CuSO4and CA of 3 types (DHPs
verapamil and diltiazem) and vitamin E Compiled according to Lupo et al [129]
Compound
MethodsTBARS method (fluorimetry at 515 nm533 nm 4 hours
preincubation of LDL with compounds and copper (II)ions 320 TBARS increase in control during 4 h
period)
Inhibition of conjugated diene formation (at 234 nm)expressed as prolongation of induction period (in
of control) 119905contr = 368min
Effective [IC] (in 120583M)1 120583M 10120583M 50 120583M
Activity rank order (ARO= I for the highest activity
ARO = VII for themindest activity)
Effective [IC] (in 120583M)1 120583M 5 120583M 10120583M 50 120583M
Activity rank order (ARO= I for the highest activity
ARO = VII for themindest activity)
Nifedipine 10120583M50 120583M ARO = III
5 120583M10120583M 15050 120583M 213
ARO = III
Amlodipine 50 120583M ARO = IV5 120583M
10120583M 12250120583M 138
ARO = IVndashVI
Isradipine 50 120583M ARO = VI 10120583M 15050 120583M 183 ARO = IVndashVI
Lacidipine1 120583M10120583M50 120583M
ARO = II5 120583M
10120583M 19250 120583M 283
ARO = II
Verapamil 50 120583M ARO = V 10120583M 15050 120583M 178 ARO = IVndashVI
Diltiazem No effect No effect (ARO = VII) No effect No effect (ARO = VII)
Vitamin E1 120583M
10120583M (IC50)
50 120583M (20 of control)ARO = I
5 120583M10 120583M 23050 120583M 370
ARO = I
Table 5 Antiproliferative effect (oxLDL-induced HUVSMCs proliferation) of CA DHPs and simultaneous oxLDL-induced ROS productionscavenging Comparison with N-acetyl-L-cysteine NAC (intracellular ROS scavenger) Compiled according to data presented by Zou et al2012 [130]
DHP compound
MethodsAntiproliferative effect against proproliferative effectinduced by oxLDL (50 120583gmL) (UV detection of
formazan production from tetrazolium salt)
oxLDL-induced ROS production (fluorescent DCF(2101584071015840-dichlorofluorescein) production)
Effective [IC] in120583M and I in
Amlodipine 3 120583M I = 18 3 120583M 10 120583M No effectI = 20
S(minus)-Amlodipine No effect No effect
Lacidipine 10 120583M30 120583M
I = 21I = 27 10120583M Isim23 of control
N-Acetyl-L-cysteineNAC
mdash 5000 120583M(5mM) I = 28
As presented (Table 4 according to [129]) for diltiazem(poor lipid solubility) noAOwas detected whereas the otherCA and 120572-tocopherol have demonstrated AOA at least atconcentrations of 10 and 50120583M 120572-tocopherol gt lacidipinegt nifedipine gt isradipine verapamil and amlodipine Addi-tionally120572-tocopherol and lacidipinewere able to significantlyattenuate in vitro LDL oxidation at 1 and 5120583M Theseresults have confirmed the highest activity for the stronglylipophilic DHP type CA compound lacidipine This might be
a possible antiatherogenic mechanism of CA since oxidativemodification enhances the atherogenic potential of LDL
The lipid peroxidation of LDL promoted either by UVradiation or by copper ions was inhibited (antioxidant effect)by nisoldipine in a dose-dependentmanner (IC
50values were
evaluated at around 10 120583M) nimodipine was less potent (IC50
around 50ndash100 120583M) and nicardipine almost inactive In addi-tion to this indirect protective effect CA DHPs nisoldipineand nimodipine exerted direct protective effect on lymphoid
Oxidative Medicine and Cellular Longevity 11
cells against toxicity of previously oxidized LDL The IC50
values were 6 plusmn 2 and 80 plusmn 20 120583M respectively [122] Theinhibition of the cytotoxic effect of LDL oxidized in thepresence of DHP type Ca2+ channel blockers correlated wellwith protection from oxidation by these compounds Com-plete protection cannot be obtained because the DHPs arecytotoxic themselves The potential relevance to the preven-tion of atherogenesis is envisaged
DHP typeCCBnifedipinewas themost effective inhibitorof oxidation promoted either by UV radiation or by copperions in experiments with cultured lymphoid cells LDL (2mgapoBmL) CCBs from other two CCB classes diltiazem andverapamil were only poorly active or completely ineffective[121] The protective effect of nifedipine occurs at two levelsbesides its direct antioxidant effect by inhibition of LDLoxidation it also exhibits a direct cytoprotective effect againstcytotoxicity of oxidized LDL by yet unknown mechanismsThe protective effect of CCBs was not due to an inhibitionof LDL uptake This effect seems to be independent of theinhibition of LDL oxidation per se since LDL was oxidizedin the absence of the drug before the incubation withcells Moreover this direct protective effect was observedat lower concentrations (IC
50of 1 plusmn 02 120583M) compared to
the antioxidant effect (IC50
of TBARS inhibition is around10 plusmn 2 120583M at UV promoted and 4 plusmn 05 120583M by Cu2+ ionsinitiated) The AO effect of nifedipine is also correlated withthe protection of endogenous tocopherols (IC
50= 50 120583M)
It was suggested that the AO effect of CCBs protected cellsindirectly from the cytotoxic effect of oxidized LDL [121]
A recent study has reported that beneficial vascular effectsof lercanidipine in diabetic rats depend on its antioxidantactivity related to attenuating the increase in oxidativestress and in vascular matrix metalloproteinase-2 (MMP-2) (Martinez et al [126]) Lesnik et al [127] studied theimpact of a combination of this calcium antagonist and a120573-blocker atenolol on cell- and copper-mediated oxidationof LDL and on the accumulation and efflux of cholesterolin human macrophages and murine J774 cells They realizedthat lercanidipine reduced the oxidative modification of LDLrather than diminished cholesterol accumulation in humanfoam cells
Comparing the antioxidative action of CA (DHPs amlo-dipine lacidipine nifedipine and isradipine as well as diltia-zem and semotiadil) in the copper-catalyzed oxidation oflow-density lipoprotein (LDL) with that of glycated (g)gly-coxidated (go) LDL demonstrated that the strongest AOeffects during long-term LDL glycation are seen for isradip-ine lacidipine nifedipine and semotiadil [128] Inhibitoryeffects were in the range 10minus5ndash10minus3MAuthors suggested thatdue to the increased generation of ROS by glucose-modifiedLDL the chain-breaking capacity of CA may be overriddenThe AOA of CA depends on their lipophilicity and theirability to incorporate into the LDL particle that is to reachthe site of peroxidation CA like other AOs significantlyretards advanced glycation end products (AGE) formationwhereas initial glycation reactions such as Amadori productformation are only weakly inhibited The observation thatboth oxidative changes and at least long-termglycation effectsare indeed drastically reduced by CA is corroborated by
fluorescence analysis AGE-ELISA quantitation of lipid per-oxidation and TBARS measurement of long-term ggo LDL
The effects of lipophilic DHP calcium channel blockerson oxidized LDL-induced proliferation and oxidative stressof vascular smooth muscle cells were also studied [130] (seeTable 5)
Lacidipine and amlodipine reduced carotid intima-media thickness by decreasing proliferative effect of oxLDLwhereas (S-)-amlodipine had no antiproliferative effect ROS-MAPKs (mitogen-activated protein kinases) pathway mightbe involved in the mechanism
Both 14-DHP CCBs lacidipine and nifedipine reduceplasma and LDL oxidation and formation of oxidation-specific epitopes Their application may also relate to pro-longed survival of rats independently of blood pressuremod-ifications (in the SPSHR model 1mgkg per day lacidipineand 80mgkg per day nifedipine) These results suggestedthat the protective effect of these two 14-DHP drugs invivo as shown in cerebral ischemia and stroke may in partresult from inhibition of LDL oxidative process althoughthese two drugs possess different lipophilic properties [131]Both lacidipine (03 and 10mgkg) andnifedipine (80mgkg)prolonged lag time of the conjugated diene formation inLDL isolated from arterial wall and 119905max These drugssignificantly reduced electrophoreticmobility of oxLDL fromSPSHR subjected to XXO oxidation system 14-DHP CCBsalso protected apolipoprotein B which is important for thebinding with macrophage LDL receptor lysine residues Thedoses used (gt10minus6molL for SPSHR and normotensive WKYrats) however are 2 to 3 orders of magnitude higher thanthose inhibiting vascular smooth muscle contraction in vitroand in vivo They also exceed values that are commonlyused in clinical practice The daily dose of lacidipine forhypertensive patients is 007mgkg asymp4- to 14-fold lower thanthe 2 doses used in SPSHR The maximum daily dose ofnifedipine given to hypertensive patients is 20mgkg asymp40-fold lower thanwhatwere used [131]These discrepanciesmaybe related to differences in bioavailability of CA between ratsand humans [131]
Accordingly in routine clinical use 14-DHPCCBs donotreach the concentrations required for antioxidant activity invitro [131]
Another data concerning the effect of CA DHPs on OSrelated to LDL is presented under Section 35
(b) Effect of DHPs on Isolated Rat Liver and Heart Mitochon-dria As a major cellular source of oxygen radicals (Cadenas[4 5]) mitochondria are promising targets for pharmaco-logical and toxicological actions of various membrane-activecompounds including several 14-DHP derivatives Zernig etal [132] have discovered CA binding sites associated with aninner mitochondrial membrane anion channel
More than 40-year long research onmitochondrial effectsof the DHPs (on their bioenergetics chemiosmotic proper-ties and ion fluxes) clearly points them out as mitochondri-otropic compounds
The activity of the first 35 synthesized compounds(derivatives of 14-DHP their heteroaromatic analogues
12 Oxidative Medicine and Cellular Longevity
NAD-H+ and butylated hydroxytoluene (BHT BOT)) orig-inally was examined in rat liver mitochondrial LP system inthe presence of Fe2+ ions and using the ultraweak chemilu-minescence method (Dubur et al [89])
Several 14-DHP derivatives Hantzsch ester diludine andits analogues were found to be effective antioxidants in thisexperimental system changing the kinetics of LP lengtheningthe time of the appearance of the maximum of the slowburst of the chemiluminescence (latency latent period) anddiminishing the reaction rate (the tangent of the slope angleduring the time in which the amplitude of the slow burstcharacterizing LP rate increases) and its peak value Theirpresence has influenced the reaction constant 119870
6 in relation
to a very significant reduction of lipid hydroperoxides andorinactivation of free radicals as follows
ROO∙ + ROO∙ 997888rarr P + h]lowast termination (1)
(P = molecular products) or
ROO∙ + ROO∙ +H2O 997888rarr ROH + RO∙ + 1O
2
lowast (2)
In this study diludine was one of themost active compoundsDHPs had activity similar to the standard synthetic AO-BHT(ionol) However when plotted against applied concentrationand time window diludinersquos activity profile differed from thatof BHT
There were also similar studies (using different LP rateexperimental detection system and method Hunter et al[133]) based on exploring a group of 26 26-dimethyl-35-disubstituted- and 26-dimethyl-345-trisubstituted-14-dihydropyridines (14-H
2Py=14-DHPs) and five related pyri-
dines as inhibitors of rat liver Mit swelling (Δ119860520119905) and O
2
uptake by ascorbic acid- (AsA-) dependent lipid peroxidationand as modulators of Mit swelling induced by Na+-linoleateor Na+-pyrophosphate (Velena et al [112])
Some of tested 4-DHPs (4-unsubstituted 35-dialkoxy-carbonyl-26-dimethyl-14-DHPs and 35-diamido-26-dim-ethyl-14-DHPs both 4-unsubstituted or those possessinglipophilic 4-aryl- groups) have shown significant AO andmembrane stabilizing activity These studies further revealedthat 14-DHPs preferably act as AO during the stages ofinitiation and prolongation of LP chain reactions at lowconcentrations The studied 14-DHPs had IC
50(when 119881
0119881
or 1205911205910= 2) 01 120583M to 100 120583M and the minimal activity was
scored for oxidized (heteroaromatized) derivativesAt the concentration of 100120583M 35-di-n-butyloxycarbo-
nyl-26-dimethyl-14-DHP entirely stops mitochondrialswelling in the presence of 08mM Na+-pyrophosphateAt the same concentration the following compoundsalter the mitochondrial swelling rate in the presence ofnatural protonophore Na+-linoleate 35-di-p-hydroxyphen-oxycarbonyl- and 35-di-p-tolyloxycarbonyl-26-dimethyl-14-DHPs 35-diethoxycarbonyl-26-dimethyl-pyridine (oxi-dized form of Hantzsch ester) and more lipophilic 35-diamyloxycarbonyl-26-dimethyl-pyridine The alteration ofswelling may be scored as prolonged promoted acceleratedor inhibited The type of alteration depends on the structureand concentration of 14-DHPs the type of initiators of theswelling process and the medium composition
In accord with previously published Janerorsquos results (lackof AO for Ca2+ antagonists nifedipine and nicardipine evenat 500120583M concentration in LP tests performed on heartmembrane [134]) no antioxidative activity for 4-phenyl sub-stituted derivatives of 35-dialkoxycarbonyl 14-DHP (closeanalogues of Ca2+ antagonists) was found contrary to various4-nitrophenyl 14-DHP derivatives calcium antagonists forwhich the significant antioxidant activity was reported [3146ndash53]
Studies made on phosphatidylcholine liposomes (ourunpublished data) suggest approximately three and twotimes more antioxidative activity for 100 120583M 4-unsubstitutedDHP compound diludine when compared to 4-substitutedDHPs riodipinenifedipine and nicardipine respectively atmethemoglobin-induced LP (oxygraphy)
Inhibition of mitochondrial AsA-dependent LP and sta-bilization ofmitochondriawere shown to be characteristic fora large group of 14-DHP compounds [112] showing to pos-sess the AOA in simplest in vitro systems (Tirzit andDuburs [39] Zilber et al [44] and Dubur et al [45])based on reactions with the stable free radical 11-diphenyl-2-picrylhydrazyl (DPPH) LP of fatty acid ester (linethole andmethyloleate) emulsions and phospholipid (phosphatidyl-choline) liposomes Generally these properties did not coin-cide with Ca2+ antagonism Depending on DHP structure itseems that AOA properties are less specific than Ca2+ antago-nist properties Both properties may be interrelated but notinterdependent
These data show that the presence and the nature ofa substituent in position 4 as well as 35-substituentsare important factors for 14-DHP antioxidant effects invarious systems that is AsA-dependent nonenzymatic aswell as enzymatic NADPH-dependent lipid peroxidationSometimes the efficacy of inhibition of nonenzymatic LPby 14-DHPs is higher than the inhibition of the enzymaticLP However the action may be opposite stimulation of theLP Hantzsch ester (HEH diludine) and its close analoguesexhibited significant AOA and membrane stabilizing prop-erties in both AsA-dependent nonenzymatic peroxidationof mitochondria and NADPH-dependent enzymatic LP ofmicrosomes usually at similar 10 to 100120583M concentrations[112]
The order of AOpotency (IC50
values) in vitro depends ondrug structure as well as on the experimental conditions andspecificity of the biological system Eachmethod for determi-nation of AOA and ARA has advantages and disadvantages(Karadag et al [135])
Accordingly as reported by Gubskiı et al [136] IC50
forthe AsA-dependent LP was 025 120583M and 20 120583M for 14-DHPCa2+ antagonists nitrepine (nitrendipine) and nifedipinerespectively Takei et alrsquos [137 138] studies on mitochondrialswelling induced by LP or arachidonic acid in the rat braindetermined the IC
50values of 127 105 1568 and 384 120583Mfor
efonidipine nicardipine nifedipine and nimodipine respec-tively For LDL in the copper-induced oxidation system theorder of potencywas vitamin Egt felodipinegt 2-chlorophenylanalogue of nifedipine gt nifedipine gt amlodipine nitrendip-ine verapamil and diltiazem (Rojstaczer and Triggle [119])
Oxidative Medicine and Cellular Longevity 13
It was interesting to compare the AOAofDHPswith theirsusceptibility to oxidation that is electron and hydrogendonating properties
It has been estimated that electron donor substituentsin positions 2 and 6 of 14-DHP cycle usually promoteoxidation while electron acceptor substituents promotequench oxidation Stronger electron acceptors in positions 3and 5 also significantly quench oxidation These estimationsare based on studies including chemical enzymatic andelectrochemical oxidation of 14-DHPderivatives (Dubur andUldrikis [70] Duburs et al [71] and Stradin et al [139])
On the other hand diminished AOA of 14-DHP relatesto presence of substituents in position 4 (both electron donorand electron acceptor) (Velena et al [112])
35-Dicarbamoyl substituents possess minimal quench-ing feature and are followed by benzoyl- acetyl- andalkoxycarbonyl- groups Maximal decrease was obtainedwith condensed substituents (ie oxoindeno- or oxocyclo-hexeno- groups) and a CN-group 4-Unsubstituted 35-dicar-bamoyl derivatives can be easily oxidized and consequen-tially inactivated whereas 4-substituted 35-dicarbamoyl-14-DHPs possess an oxidation potential analogous to the 4-unsubstituted 35-COOR derivatives Therefore they haveadequate electron donor properties and are considerablystableThismay be the reason for significantmembrane stabi-lization upon exposure to 4-substituted derivatives Ofimportance their AOA was usually more pronounced incomparison to 4-unsubstituted derivatives
Among them 26-dimethyl-35-difurfuryloxycarbonyl-14-DHP showed the highest antioxidative activity In thegroup of 35-dialkoxycarbonyl derivatives the strongestactivity was attributed to compounds with medium lengthalkyl chains (i-butyl- t-butyl- and i-amyl- substituents) highlevel of lipophilicity minimal electron acceptor propertiesand moderate steric hindrance as contrasted to short or longalkyl chain ester derivatives (35-dimethoxycarbonyl- 35-diethoxycarbonyl derivatives and 35-didodecyloxycarbonylderivative) These data demonstrate the bell-shaped depen-dence of AOA on alkyl chain length [112] and are in accordwith results obtained in liposomes However these datadiffer from those obtained in emulsions where diludine wasthe most active compound Finally oxidized heteroaromaticderivatives showed only minimal activity
In both LP systems studied (AsA-dependent in mito-chondria and NADPH-dependent in microsomes) some of14-DHPs showed activity similar to classical antioxidantbutylated hydroxytoluene (ionol BHT) (Velena et al [112])However there was a significant difference related to con-centration and incubation time It allowed us to postu-late that 14-dihydropyridines (InH) acting as antioxidants-reductants and scavengers of reactive oxygen species and lipidfree radicals preferably influence initiation and propagation(prolongation) of lipid peroxidation chain reactions (1)ndash(5) according to Scheme 2 The phenomenon is particularlyprominent in the presence of Fe2+ and other ions of variablevalency
Chain break and termination reactions (6)ndash(10) of theLP reaction cascade [89] were influenced by 14-DHPs in alesser degree than were initiation and propagation steps This
may be important for their therapeutic effects even in theadvanced stages of LP
Scheme 2 (stages of initiation propagation and terminationof lipid peroxidation chain reactions (1ndash10)) Initiation andpropagation reactions are as follows
(8) RO∙ + In∙minus rarr Y (Y = molecular products)(9) ROO∙ + Fe2+ rarr Fe3+ + X (X = molecular products)(10) RO∙ + RO∙minus rarr Y (Y = molecular products)
In the reversible swelling of mitochondria accompanyingLP (initiated by mixture of 5mM GSSG1mM GSH) several14-DHPs showed low or no activity manifested only as adecrease of the swelling amplitude without a rate decreaseAn addition of GSH (4mM) or ATP to swollenmitochondriacaused their contraction in both control and tested systemIt may be suggested that 14-DHPs acting as antioxidantsin mitochondria preferably influence LP reactions initiatedby ions with variable valency or their complexes with hemetype compounds methemoglobin hemin hematin and soforth (Velena et al [112]) If the peroxidation process has amaximal velocity and 50 percent of initial O
2were consumed
14-DHPs cannot completely break the chain reactions andprevent subsequent membrane damage by addition of DHPsubstance at 10 120583M concentration at the moment of 50percent oxygen consumption the subsequent oxygen uptakeproceeded unchanged This observation is important for theapplication of DHPs as inhibitors of initiation and to a lesserdegree propagation stages of LP chain reactions
The influence of 14-DHPs on Mit swelling is not strictlyassociated with their own oxidation There is the possibilitythat the labilizing (or stabilizing) effect relates to surfaceactivity (connected with substituent lipophilicity) or may bethe consequence of complexation with some -OH (or -CH
3)
group sensitive receptors at the mitochondrial membraneNamely a bathochromic shift of the absorption band maxi-mum (about 10 nm) was observed in the visible region beforeswelling However after swelling in the presence of Na+linoleate the spectrum returns to its initial value [112]
Some 14-DHPs not only protect mitochondria againstswelling caused by AsA-dependent LP salts of fatty acids
14 Oxidative Medicine and Cellular Longevity
in vitro [112] but also have beneficial effects on repairingtheir integrity in vivo after exposure to irradiation hepato-toxins ischemia hypoxia or hypothermia Some of themwere shown to normalize the process of intracellular repara-tion and physiological regeneration of ultrastructures Theywere also shown to stimulate reparative processes If pre-treated with 14-DHPs irradiatedmitochondria will not swell(Ivanov et al [140 141])
Diludine ionol and some other AOs mitochondria pro-tectors act as anti-ischemic agents If applied prophylacticallyin vivo they may prevent ischemic and reperfusion lesionsin heart kidney and other organs (Bilenko et al [113]) Theeffect is dependent on applied dose timing and way ofapplicationWhen added onto the cryoconservationmediumfor mitochondria preservation 14-DHPs prevented decreaseof membrane potential normalized facilitated respirationand prevented loss of mitochondrial Na+ and Ca2+ ionsafter thawing ([112] see citation number 36 (Subbota et alKharkov 1984) therein) Diludine was stronger protectorwhen compared to ionol
CA drug foridone (riodipine) was shown to possesscardioprotective features primarily due to is protective effecton mitochondria exposed to OS [142 143]
Similarly the DHP water-soluble antiarrhythmic com-pound glutapyrone inhibits initiation of LP by free radicalsin erythrocytes and heart mitochondria Its cardioprotectiveeffect has been experimentally shown in heart mitochondrialmembranes especially during deep hypothermia (Utno et al[144])
Cerebrocrast was effective in several translation modelsmimicking pathological situations known to be associatedwith cellular OS The potential protective action of 14-DHP derivatives (4-substituted compounds cerebrocrastgammapyrone glutapyrone and 4-unsubstituted drug dieth-one) has been studied in rat liver in experimental modelsrelevant for oxidative stress and mitochondrial bioenergetics(Fernandes et al [145]) When succinate was used as therespiratory substrate higher concentrations (gt25 120583M) ofcerebrocrast depressed respiratory control ratio (RCR) ADPto oxygen ratio (ADPO) state 3 and uncoupled respirationrates transmembrane potential (deltapsi) and the phosphatecarrier rate At the same time state 4 respiration rate wasthree times increased At concentrations lower than 25120583Mcerebrocrast inhibited mitochondrial IMAC and partiallyprevented Ca2+-induced opening of the mitochondrial PTPGammapyrone glutapyrone and diethone did not inducethese phenomena When applied at concentrations up to100 120583M cerebrocrast gammapyrone and glutapyrone didnot affect ADPFe2+-induced LP of mitochondria in rat liver(as measured by oxygen consumption and TBARS forma-tion) On the other hand low diethone concentrations (upto 5 120583M) inhibited it in a dose-dependent manner Diethonealso prevented against deltapsi dissipation induced by LPinitiated by ADPFe2+ Based on these data it may bespeculated that cerebrocrast (inhibition of the IMAC) anddiethone (acting as an AO) may provide effective protectionof mitochondria during OS Cerebrocrast has shown sometherapeutic potential for treatment of several pathologicalconditions related to cellular OS [145]
5-Acetyl(carbamoyl)-6-methylsulfanyl-14-DHP-carbo-nitriles (Figure 3) with minor differences in their molecularstructure displaying antioxidant and antiradical activitiesin vitro show different biological activities Namely 4-p-chlorophenyl derivative OSI-1146 displays AO and anti-radical activities in cardiovascular OS models whereasOSI-3701 and OSI-3761 display hepatoprotective activityThus these compounds may be potentially useful for treat-ing several pathological processes including those associatedwith OS (Fernandes et al [146]) However besides mito-chondria the cellular targets for their pharmacologicalactions have not been fully investigated [146] All these com-pounds increase the susceptibility of Mit to MPT The mostpotent is OSI-3701 although it does not affect bioenergeticparameters
Although all these compounds protected mitochondriaagainst LP induced by the oxidant pair ADPFe2+ OSI-1146was shown to be the most potent Current data point outmitochondria as potential targets for protective and toxicactions of DHPs suggesting that the potential for their use astherapeutic agents should also take into consideration theirtoxic effects on mitochondria (Fernandes et al [146])
Several structurally different DHP derivatives (antioxi-dant diludine (diethone) as a 4-unsubstituted DHP 4-substi-tuted DHPs CA foridone (bicyclic compound) and the 4-phenyldiethone compound where phenyl group is joined tothe DHP in position 4) inhibited the 1-methyl-4-phenyl-pyridinium iodide (MPP+) induced ROS production incerebellar granule cells (CGC) with a distinct potency orderforidone (26-dimethyl-35-dimethoxycarbonyl-4-(o-difluo-romethoxyphenyl)-14-dihydropyridine) gt 26-dimethyl-35-diethoxycarbonyl-4-phenyl-14-dihydropyridine gt diludineThey also reversed the MPP+-induced decrease of the mito-chondrial membrane potential in the same order (Klimavi-ciusa et al [147]) Accordingly it was postulated that theclassical two-ring (bicyclic) structure of DHP derivativesrepresents an advantage in relation to neuroprotection andROS defense and is independent on compoundrsquos propertiesrelated to calcium ions
Novel adamantane-containing 14-DHP compounds (Kli-maviciusa et al [148]) were also found to improve mitochon-drial functions (MPP+ model) (Klimaviciusa et al [148])Klusa et al [149] have discovered antineurotoxic effects of14-DHP taurine derivative tauropyrone recorded as Mitfunction improvement
Many 14-DHPs including Ca2+ antagonists and AOmodify LP processes and influencemitochondrial function invarious organs (liver heart kidney and brain) in a differentway and degree Their beneficial action oxygen or lipidfree radical scavenging antioxidative effects binding withor intercalating into phospholipid bilayer regulation of iongating and regulation of mitochondrial permeability transi-tion pores (Tirzit and Duburs [39] Zilber et al [44] andDubur et al [45]) separately or in combination with eachother depends on two strong elements (1) their individ-ual structure including nature of substituents and theirpositions and (2) the nature of the biological system Forexample the direction of LP (inhibition of promotion) wasshown to depend on structure and concentration of applied
Oxidative Medicine and Cellular Longevity 15
14-DHPs as well as stages of chain reactions Accordinglymitochondrial swelling may be prolonged (retarded) accel-erated (promoted) or inhibited (Velena et al [112])
Therefore there is a ground for 14-dihydropyridineseither Ca2+ antagonists or antioxidants to be nominated asuseful tools in development of ldquomitochondrial drugsrdquo relatedto the control of OS
(c) DHPs as AOs in Endoplasmic Reticulum (Inhibition ofNADPH-Dependent LP System) Inhibition of NADPH Oxi-dase by DHPs Elevated level of NADPH oxidase 4- (NOX4-)derived hydrogen peroxide (H
2O2) joined with concomitant
decrease of nitric oxide (NO) mediated signaling and reac-tive oxygen species scavengers are considered to be centralfactor in molecular pathogenesis of fibrosis (Sampson etal [150]) Inhibition of microsomal NADPH-dependent LPwith particular focus on NADPH oxidases (NOX1ndash5 andDUOX1) may be very important for neuro- cardio- andhepatoprotection (Velena et al [112] Leto and Geiszt [151]Griendling et al [152] and Chen et al [153]) Endoplasmicreticulum may be an important target as this is where 14-DHPs could display their antioxidative properties (Velena etal [112] Leto and Geiszt [151] Griendling et al [152] andChen et al [153])
However the initiation of LP in the NADPH-dependentmicrosomal system does not appear to involve either super-oxide or hydrogen peroxide since neither SOD nor cata-lase can inhibit it On the other hand reduced iron playsan important role in both the initiation and propaga-tion of NADPH-dependent microsomal lipid peroxidation(Hochstein and Ernster [154] and Repetto et al [111])
Many DHPs possess inhibitory activity not only towardsAsA-dependent LP in mitochondria but also towardsNADPH-dependent LP as shown in isolated rat liver micro-somes (Velena et al [112]) This means that these compoundsinteract with the shared parts (nonenzymatic and enzymatic)of LP pathways
Microcalorimetry and fluorescent probes procedureswere used for studying the interaction of alpha-tocopheroland 14-DHPs with endoplasmic reticulum membranes andmodel systems human serum albumin and phospholipidbilayers [155] Modification of microviscosity of the endo-plasmatic reticular membranes depends on localization ofantioxidants within the protein structures or phospholipidphase Increase of membrane structuralization under theinfluence of 14-DHPs blocked their antioxidant action inspontaneous and induced lipid peroxidation
Inhibition of rat heart and liver microsomal lipid perox-idation by nifedipine was observed [156] while Goncalves etal [157] found antioxidant effect of calcium antagonists onmicrosomal membranes isolated from different brain areas
Nitroaryl-14-DHPs are both calcium channel antagonistsand antioxidant agents (Letelier et al [158 159]) commonlyused for treatment of cardiovascular diseases These drugsmust be metabolized through cytochrome P450 oxidativesystem (NADPH-cytochrome P450 reductase) mainly local-ized in the hepatic endoplasmic reticulum Several lipophilicdrugs generate OS while being metabolized by this cellularsystem Thus DHP antioxidant properties may prevent the
OS associated with hepatic biotransformation of drugs Var-ious commercial and new nitro-phenyl-DHPs were studiedagainst LP using rat liver microsomes under oxidative stress[159]
Incubation of rat liver microsomes with the 41015840-nitro-4-phenyl-14-DHP compounds (26-dimethyl-4-(41015840-nitro-phenyl)-14-dihydropyridin-35-diethyl-dicarboxylate andN-ethyl-26-dimethyl-4-(41015840-nitrophenyl)-14-dihydropyri-din-35-dimethyl-dicarboxylate) results in an inhibitionof LP the UDPGT (UDP-glucuronyltransferase) oxidativeactivation and the microsomal thiol oxidation induced byFe3+ascorbate a generator system of ROS This effect wasalso produced by nitrofurantoin and naphthalene in thepresence of NADPH
Interestingly IC50
ofDHPs obtained frommicrosomal LPassays decreased to the same extent as the microsomal thiolsoxidation provoked by Fe3+ascorbate [159] Neverthelessthe AO effects of a nitrophenyl-DHP compound in whichhydrogen at position one of the DHP ring was replaced bythe ethyl groupwere significantlyweaker Authors speculatedthat DHPs can resemble NADH transferring one hydrogenatom of 4-position (Hminus) to anion superoxide and another ofthe 1-position (H+) by way of a cationic radical intermediateto generate pyridine derivatives and water [159]
The AO effects of various tested DHP derivatives (m- andp-NO
2phenyl as well as methyl or ethyl and isopropyl-DHP
35-dicarboxylate derivatives) were not significantly differentThe authors assumed that the -NH- group of the dihydropy-ridine ring could contribute both to the development ofthe calcium channel antagonism and to the antioxidativeproperties of DHPs [159]
Prevention of the membrane LP seemingly depends onthe concentration of potential antioxidants such as vitaminE or even 14-DHP in lipids However only the differencesin synthetic DHPs lipophilicity cannot explain significantvariations of DHPs concentration in microsomal membraneand cannot clarify the strength of their antioxidative activityThis work [159] has further demonstrated that 14-DHPsmay prevent the OS induced by biotransformation of somedrugs for example antibiotic nitrofurantoin Simultaneousadministration of DHPs and nitrofurantoinmay be beneficialin reducing nitrofurantoin side effects
While most of Ca antagonist 14-DHPs are metabolizedby CYP3A4 (Guengerich et al [160]) not all of them are goodinhibitors of its activity Thus nicardipine but not nifedipineand nitrendipine inhibits CYP3A4 in vitro [53] Interactionof different DHPs with various types of cytochrome P450 wasdescribed by Carosati et al [53] It was also reported thatDHP class calcium channel blockers reduce the antiplateleteffect of clopidogrel (Park et al [161])This implies themutualinteractions of both drugs with CYP3A4
(3) In Vivo Evaluation of nifedipine effects on Saccharomycescerevisiaewas recently published (Asma andReda [162]) Sur-prisingly nifedipine exercised a toxic effect on Saccharomycescerevisiae shown through measuring cellular proliferationrespiratory activity and the level of some biomarkers (CATand MDA)
16 Oxidative Medicine and Cellular Longevity
However majority of data obtained on various animalcells and tissues by other authors show the protective role ofDHPs against both LP and oxidative stress [113 163 164]
The AOA attributed to many 14-DHPs Ca2+ antag-onists and other compounds reflecting on catalytic LDLperoxidation (see Section 331 (2) and Section 35) shouldencourage their testing for treating cardiovascular diseasesandor alterations of lipid metabolism
The possibility that 14-DHP-based calcium antagonistsexert an antiatherosclerotic action (via inhibition of LDLoxidation and other mechanisms) has been proved by manyexperimental data [165] and several clinical trials Besidesantihypertensive effect nicardipine was shown to possessantioxidative and antielastase activity [165 166] These prop-erties may be useful for prevention of inflammatory reactionwhich is relevant for hypertension pathogenesis
14-DHPs administration inhibits LDL oxidation medi-ated by oxygen radicals leading to decreased carotid inti-mal media thickness and reduced progression of coronaryatherosclerosis [130] It additionally preserves Apo B-100integrity against ROS Of importance antiatherogenic mech-anisms differ between animals and humans (primarily inthe stage of conversion of aldehydes to carboxylic acids)(Parthasarathy et al [167])
For example furyl-DHP compound (FDP-1 diethyl 26-dimethyl-4-(furyl)-14-dihydropyridine-35-dicarboxylate)was shown to act as an antioxidant (decreasing MDA GOTand FFA release of ischemic myocardium and inhibiting Ca-ATPase of erythrocyte membranes) preventing against heartmyocardium ischemia-reperfusion injury and arrhythmiawhen applied (in rats) at 10mgkg (Liu et al [168])
Similarly antioxidative effects of azelnidipine andamlodipine prevented neuronal damage by CCBs aftertransient focal ischemia in rats (Lukic-Panin et al [169])
Allanore et al [170] found that both nifedipine andnicardipine significantly decrease the mean level of plasmamarkers for oxidative stress in patients suffering from sys-temic sclerosis
Antioxidants may be considered as promising neuropro-tective compounds Still while experimental data demon-strate neuroprotective effect in vitro and in animal mod-els clinical evidence is still unsatisfactory and insufficient[171]
(a) Role of Metabolism of DHPs in Their AOA Metabolicpathways and ldquobioavailabilityrdquo of the probable AOA com-pound determine antioxidant activity in vivo Antioxidantmetabolites may vary in stability and activity leading to twoopposite scenarios lack or presence of activity substantiallycontributing to the overall AOA [172] Metabolic biotransfor-mation of DHPs includes oxidation (heteroaromatization)side chain ester group cleavage (deesterification) and 4-substituent abstraction ao [160] None of the DHPs metabo-lites was shown to be more toxic than original reduced formof the compound The commonly detected metabolites ofthe DHPs do not seem to possess the AO activity (withsome exceptions as in the case of metabolites of nifedipineand its analogues including nitrosonifedipine [173 174]) (seefurther in Section 35) Due to DHPs intrinsic instability
achieving andmaintaining an adequate concentrationmay beproblematic both in vitro and in vivo
(b) Role of Concentration and Lipophilicity (MembraneWateror LipidWater Partition Coefficients) of DHPs inTheir Actionas AOs and Antiradical Compounds Antioxidative effects ofany antioxidant depend on its concentration at the site ofaction This parameter is hardly measurable especially intwo-phase systems representing one of obstacles in com-parison to AOA upon applying various compounds [172]It is often incorrectly assumed that the concentrations inthe aqueous solution and at the site of action are the sameHowever even when the concentration in the aqueous phasemay be well controlled the concentration at the site ofaction in the lipid matrix of the membranes might fluctuatebetween different test compounds depending on a differencein lipophilicity [175] The prevention of the membrane LPalso seems to be dependent on the DHP concentration in thelipidmatrix (Mason andTrumbore [46]) and its amphiphilic-ity For example AOA of diludine is associated with itslipophilicity and consequential ability to be incorporatedinto liposomes (Panasenko et al [176]) It was also foundthat diludine easily incorporates into the outer monolayer oferythrocyte membranes [176]
Membranebuffer partition coefficients (lambda) weredirectly measured in the sarcolemma and sarcoplasmicreticulum membranes for three CA DHPs The obtainedvalues were in a broad range between 5000 and 150000(Herbette et al [177])These drugs interact primarily with themembrane bilayer component but may also bind to proteinsboth nonreceptors and receptors The intrinsic forward rateconstants for DHP binding to sarcolemmal calcium channelreceptors were apparently not strongly dependent on theirmembrane partition coefficients For example nimodipine(lambda = 6300) had a forward rate constant of 68 plusmn 06 times106Ms whereas the forward rate constant for Bay P 8857
(lambda = 149000) was 14plusmn08times107Ms Since these DHPsare highly liposoluble model calculations for this bindingreaction demonstrated that these rates on lipid solubilitywould probably not be reflected in the experimental forwardrate constants In addition the intrinsic forward rate constantfor nimodipine binding to sarcolemmal calcium channelreceptors was found not to be linearly dependent on theviscosity of the buffer medium over a fivefold range The rateof drug nonspecific binding to nonreceptor protein present inhighly purified sarcoplasmic reticulum membranes appearsto be extremely fast at least 103 times faster than specificdrug binding to the receptor in the sarcolemma Authorsconcluded that partitioning into the lipid bilayer matrix ofthe sarcolemma could be a general property of CA DHPsand may be a prerequisite for their binding to sarcolemmalmembrane receptors (Herbette et al [177])
The binding of DHP calcium channel agonists and antag-onists (including those with AO properties) to receptors incardiac sarcolemmal membranes is a complex reaction thatmay involve an interaction with the lipid bilayer matrix ofthe sarcolemma (Herbette et al [178]) Belevitch et al [179]studied the binding of DHP CCBs (riodipine and nifedip-ine) and verapamil to model and biological membranes by
Oxidative Medicine and Cellular Longevity 17
fluorescence analysis The consistent location of Ca agonistBay K 8644 was determined to be within the region ofthe first few methylene segments of the fatty acyl chains ofthe membranes (Mason et al [180]) This position is nearto that observed for the DHP calcium channel antagonistsnimodipine and Bay P 8857
Themajority of studies onOSwere performedwithDHPswith various lipophilicity but only a few studies reportedamphiphilicity ofDHPderivatives AmphiphilicDHPderiva-tive K-2-11 reduced the cellular generation of ROS It alsorevealed complete reversal of multidrug resistance (MDR) ofthe resistant cells K-2-11 was more efficient than well-knownMDR inhibitor verapamil Cytotoxic effects of anticancerdrug doxorubicin were enhanced by K-2-11 in bothMDR andparental nonresistant cell line (Cindric et al [181]) K-2-11suppresses increase of ROS and consequentially prevents NF-120581B activation leading to decreased expression of MDR1 andincreased expression of antiapoptotic genes This signalingswitch is necessary for restoring the chemosensitivity ofcancer cells This phenomenon is characteristic both for14-DHPs [182] (18 novel asymmetrical DHPs bearing 3-pyridyl methyl carboxylate and alkyl carboxylate moietiesat C3 and C5 positions resp as well as nitrophenyl orheteroaromatic rings at C4) and for their oxidized formspyridine compounds (Zhou et al [183])
34 Dependence of AOA of DHPs on the Experimental SystemAO effect of DHPs depends on their structure and theexperimental system used (in vitromodel system subcellularorganelle and cells ex vivo and in vivo) Ideally for theevaluation of the profile and value of DHPs AO propertieseach compound should be tested in as many systems aspossible (Dubur et al [45])
Lipidomics studies have been traditionally explored forstudying AOA of DHPs Proteomics methods are less rep-resented and are mostly focused on the properties of DHPsrelated to scavenging of protein free radicals So far there areno studies on the role of DHPs in scavenging nitrosoperoxy-carbonate the reactive species formed out of peroxynitrite inthe presence of carbon dioxide Although it was shown thatalbumin binds diludine no studies revealed the relevance ofthis effect for the AOA of diludine
There are findings showing that dihydropyridine calciumantagonists (DHPs CA) could indirectly play a beneficialprotective role during development of atherosclerosisNamely Berkels et al [184] have studied antioxidativeproperties of four substances the DHP prototype CAnifedipine the long-acting CA lacidipine the DHP calciumchannel agonist BayK8644 and the bulkyDHPderivate BayO 5572 in three different models (1) in an in vitro superoxideanion generating system (hypoxanthinexanthine oxidase)for testing the ldquopurerdquo antioxidative effect (2) in an artificialmembrane preparation (dimyristoylphosphatidylcholine) formimicking a more physiological environment and (3) underconditions of stimulated ROS release (hyperglycemia) fromnative endothelial cells derived from porcine coronary arter-ies
The study also revealed the potential correlation betweenlipophilic and AO properties of DHPs In the first model
Bay K 8644 was significantly more effective in scavengingsuperoxide anions than lacidipine Bay O 5572 or nifedipine(micro- to millimolar concentration range) Addition of anartificial membrane preparation resulted in an enhancedAO effect with lacidipine being the most effective DHP inquenching radicals (low micromolar concentration range)In the third model mimicking hyperglycemia (30mmolL)nifedipine was significantly more potent antioxidant (ther-apeutical nanomolar concentration range) than the otherDHPs Calculated lipophilicity of these four substances(lacidipine gt Bay O 5572 gt Bay K 8644 gt nifedipine) waspositively correlated with antioxidative potential only in thesecond experimental model It has been concluded that AOproperties of DHP substances need to be tested in variousmodels for demonstrating that nifedipine exhibits ROS-quenching properties in a therapeutic concentration range[184]
341 AOA of DHPs in Isolated Cells and Cell Cultures(Comparison with Other Simplest Systems) Although DHPspossess neuromodulatory andor antimutagenic propertiesthe mechanisms of action related to these phenomena arenot entirely elucidated Borovic et al [185] have studied 14-dihydroisonicotinic acid (14-DHINA) derivatives of 14-DHP water-soluble analogues of a well-known AO diludine(diethone) 26-dimethyl-35-diethoxycarbonyl-14-dihydro-isonicotinic acid sodium 2-(26-dimethyl-35-diethoxycar-bonyl-14-dihydropyridine-4-carboxamido)glutamate gluta-pyrone and sodium 2-(26-dimethyl-35-diethoxycarbonyl-14-dihydropyridine-4-carboxamido)ethane-sulphate tauro-pyrone as AO and bioprotectors (Figure 4)
14-DHINArsquos activities were studied in comparison toTrolox by NN-diphenyl-N1015840-picrylhydrazyl (DPPH∙) deoxy-ribose degradation ABTS∙ radical scavenging and AOA(antioxidative capacity method) assays copper-induced LPof cultured rat liver cells (MDA determination by HPLCand 4-hydroxynonenal-protein conjugates by dot-blot) 3H-thymidine incorporation and trypan blue assay for liver cellsgrowth and viability Ic decreased the amount of 4-HNE-protein adducts In all assays Ia was the most potent AOable to completely abolish copper induced LP of liver cellswhile Ic only slightly decreased it Thus AOA is importantactivity principle of Ia which was even superior to Trolox intreated cell cultures Ia (and its analogues) are easily oxidizedin the Fenton system (Rubene et al [186]) exerting ARA too
35 Peculiarities Related to Antioxidative and AntiradicalActivity of Some 14-DHPs Ca Antagonists Nine commer-cialized structurally and functionally different DHPs CAwill be discussed further Their common feature is ability toprevent OS This also counts for some of their metabolitesas already discussed The comparative effects of some DHPsCA on oxidative stress-induced modification of LDL werealready reviewed in Section 331 (2)-(a) AOA of CA DHPswas discussed in Sections 331 (2)-(b) and 331 (2)-(c)
351 Nifedipine and Its Close Analogues Nifedipine vera-pamil and antiarrhythmic-antihypoxic drug stobadin wereshown to depress lipid peroxidation of phosphatidylcholine
18 Oxidative Medicine and Cellular Longevity
NH
COOH
NH
COONa
Glutapyrone
NH
Gammapyrone
NH
C 2H5OOC COOC2H5
Tauropyrone
14-DHINA
H3C H3C
H3C
H3CCH3 CH3
CH3
CH3
COOC2H5COOC2H5
COOC2H5 C2H5OOCC2H5OOCC2H5OOC
CONHCH(CH2)2COONa CONH(CH2)3COONa
CONH(CH2)2SO3Na
Figure 4 Derivatives of 14-dihydroisonicotinic acid (14-DHINA)
liposomes (Ondrias et al [187]) However data obtained insome other experimental systems are conflicting
In an in vitromodel of sarcolemmal membrane lipid per-oxidation three calcium blockers (nifedipine verapamil anddiltiazem) exhibited concentration-dependent (10ndash400 120583M)inhibitory effects [188 189] Nifedipine the most effectivecalcium blocker was more than two-fold potent compared topropranolol achieving significant effect at 10 120583M Nifedipineprotective role on LP using reduced glutathione as modelmarker was recently described (Ray et al [190]) Antiper-oxidative properties of CA nifedipine and its analogueswere explored in different systemspathogenic processesatherogenesis (Henry [165]) brain focal ischemia (Yamatoet al [191]) nephroprotection related to cyclosporine intake(Chander and Chopra [192]) and hepatoprotection relatedto intake of diethyldithiocarbamate (Gaafa et al [193])Recent data suggest that nifedipine action as protector forendothelial cells proceeds independently from its CA proper-ties
The absence of antioxidant effects of nifedipine anddiltiazemonmyocardialmembrane lipid peroxidation oppo-site to nisoldipine and propranolol was also described[194] Nisoldipine and propranolol were shown to havea concentration-dependent antiperoxidant effect with IC
50
values of 282 and 501 120583M respectively Finally nisol-dipine appeared to possess dual antiperoxidant mecha-nisms involving both preventive and chain-breaking proper-ties
These findings were confirmed in some other studiesincluding reports on the lack of antioxidative activity ofnifedipine and nicardipine even at 500120583M concentrationin heart membrane lipid peroxidation tests [134] SimilarlyROS formation in bovine aorta smooth muscle cells was notaffected by addition of amlodipine nimodipine and nife-dipine [123]
(1) Metabolites of Nifedipine and Its Analogues as Antioxidantsand Regulators of OS Antioxidant activity of nifedipine35-dimethoxycarbonyl-26-dimethyl-4-(2-nitrophenyl)-14-dihydropyridine was originally studied in vitro by Kirule etal [195] and Tirzit et al [196] According to the kinetic dataof peroxide accumulation and the ESR spectra (inhibition ofthe autoxidation of methyl oleate in presence of nifedipine)AO action was exerted by the formation of nitroso analogueof the oxidized nifedipine nitroso nifedipine 26-dimethyl-4-(2-nitrosophenyl)-35-pyridine dicarboxylate (NO-NIF)This nitroso aromatic derivative can form nitroxyl radicalsexhibiting remarkable AOA in the presence of unsaturatedfatty acids and lipids [196]
The primary species of free radicals that have beenobtained and identified were ion radicals of the nitrophenyltype (Ogle et al [76]) Such a mechanism coincides withmechanisms proposed afterwards by Nunez-Vergara et al[96] Lopez-Alarcon et al [103] Valenzuela et al [104]Fukuhara et al [174] and Yanez et al [197]
There are also data showing that nitroso compounds mayinhibit LP by direct radical trapping and subsequent forma-tion of stable nitroxide radicals It was further found that thereactivity between the synthesized 14-DHP derivatives withalkylperoxyl radicals involves electron transfer reactionsThisis documented by the presence of pyridine as a final productof the reaction and complete oxidation of the nitroso groupin the case of the nitrosoaryl 14-dihydropyridine derivatives(Valenzuela et al [104]) Tested compounds reacted fastertoward alkylperoxyl radicals and ABTS radical cation thanalkyl ones (Lopez-Alarcon et al [103])
Nitrosonifedipine a photodegradation product of nifedi-pine significantly recovers cellular damage induced by tumornecrosis factor-alpha It also prevents toxic effects of cumeneperoxide which hampers integrity of cell membranes throughoxidative stress Its positive effects are equal to Trolox-C
Oxidative Medicine and Cellular Longevity 19
As a result nitrosonifedipine was already a long time agoclaimed as a candidate for a new class of antioxidative drugs(Kirule et al [195]) cellular protectors against oxidative stressin glomerular endothelial cells [174]
Moreover Misik et al [198] Ondrias et al [199] andStasko et al [200] studied AOA of nifedipine and its oxidizednitroso analogue NO-NIF prevents the progression of type2 diabetic nephropathy associated with endothelial dysfunc-tion through selective AO effects (Ishizawa et al [201]) NO-NIF administration reduces albuminuria and proteinuriaas well as glomerular expansion without affecting glucosemetabolism or systolic blood pressure NO-NIF also sup-presses renal and systemic OS and decreases the expressionof intercellular adhesion molecule-1 (ICAM-1) a marker ofendothelial cell injury in the glomeruli of the KKAy miceSimilar effects were achieved in endothelial nitric oxide syn-thase (eNOS) knockout mice Moreover NO-NIF suppressesurinary angiotensinogen (AGT) excretion and intrarenalAGT protein expression in proximal tubular cells in theKKAy mice On the other hand hyperglycemia-inducedmitochondrial superoxide production was not attenuated byNO-NIF in cultured endothelial cells
Fujii and Berliner found EPR evidence for free radicaladducts of nifedipine in vivo [202] The nature of these rad-icals was surmised by comparing the reaction of illuminatednitrosonifedipine with polyunsaturated fatty acids Surpris-ingly identical radical spectra were detected from excisedliver doped with nonilluminated nifedipine suggesting thatthis drug can be enzymatically converted in vivo to its nitrosoanalogue without the requirement for illumination This isone of the first reports of in vivo EPR evidence for a class ofunsaturated fatty acid radical conjugates resulting from thenormal metabolism of a common drug
Dıaz-Araya et al [173] studied some 4-nitrophenyl-DHPson Fe3+ initiated LP in rat brain slices LP as measuredby MDA formation was inhibited by all the tested nitro-aryl derivatives of 14-DHP over a wide range of concen-trations On the basis of both time course and IC
50experi-
ments the tentative order of AOA on rat brain slices wasnicardipine gt nisoldipine gt (RSSR)-furnidipine gt (RRSS)-furnidipine gt nitrendipine gt nimodipine gt nifedipine14-DHP derivatives that lack a nitro group in the mole-cule (isradipine and amlodipine) also inhibited LP in ratbrain slices but at higher concentrations than that of nitro-substituted derivatives All tested compounds reduced andoxidized nitrosoaryl derivatives (26-dimethyl-4-(2-nitro-sophenyl)-35-pyridinedicarboxylic acid dimethyl ester (pho-tooxidation product of nifedipine ndash NTP) ao) and weremore potent inhibitors of LP than their parent molecules(Valenzuela et al [104])
The electrooxidation process of 4-nitrosoaromatic DHPsis a strongly pH-dependent (two-electron two-proton mech-anism) ECEC type of mechanism that is the sequenceeminusH+eminusH+ at pH gt 85 ECCE mechanism (eminusH+H+eminus)at pH lt 85 dominates Reduction reaction of nitroso groupis as follows R-NO + 2eminus + 2H+ rarr RNHOH (Bollo et al[203])
352 Lacidipine It is a generic DHP type antihypertensiveCA 35-diethyl 4-2-[(1E)-3-(tert-butoxy)-3-oxoprop-1-en-1-yl]phenyl-26-dimethyl-14-dihydropyridine-35-dicarboxy-late
Ursini [204] described redox behaviour of lacidipine andshowed its tissue protective features Cristofori et al studiedantiatherosclerotic activity in addition to lacidipinersquos CAand AO properties [205] Lacidipine reduced the extent ofatherosclerotic area in hypercholesterolemic apoE-deficientmice (these mice show widespread vascular lesions whichclosely resemble the inflammatory fibrous plaques seen inhumans in atherosclerosis) The reduction may be associatedwith the capacity of the drug to maintain endothelial NOlevels at concentrations useful to protect against vasculardamage This work suggested that DHPs modulate vascularrelaxation via increased release of NO
Herbette et al [178] remarked optimal hydrophobicity oflacidipine due to cinnamic acid substituent so membraneinteractions and facilitation of the treatment of atherosclero-sis could proceed (see also Section 331 (2)-(a))
353 Amlodipine Amlodipine (Norvasc) (RS)-3-ethyl5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-14-dihydropyridine-35-dicarboxylate (AML) hasan antioxidant effect on vessels in vitro and is a 3rd genera-tion of charged dihydropyridine CCB that is widely used forthe treatment of hypertensive patients
Amlodipine was shown to have the highest affinity(amlodipine gt verapamil ≫ diltiazem) for the membranebilayer (119870
119901= 104) It produced the significant changes in
membrane thermodynamic properties including a reductionin the thermal phase transition temperature (minus11) enthalpy(minus14) and cooperative unit size (minus59) relative to thecontrol phosphatidylcholine liposomes (Mason et al [49])
Amlodipine AOA is related to its reductant nature orhydrogen donor properties respectively Its ability for donat-ing protons and electrons to the lipid peroxide moleculesblocks the LP process
Amlodipine and even its enantiomers (Zhang et al [206])act as ROS andNOS effectors in several model systems of OSAntioxidant properties of amlodipine were recently reviewedby Vitolina et al [32] Both in vitro and in vivo studiesof amlodipine AO properties revealed inhibition of lipidsoxidative damage primarily those associated with cellularmembranes and lipoprotein particles (LDL) (Mason et al[50])
Under controlled experimental conditions in vitro amlo-dipine showed AOA and ARA by inhibition of lipid peroxideformation and trapping ROS Its scavenging activity forhydroxyl and peroxyl radicals at concentrations as low as100 nmolL (which is remarkably less compared to the classi-cal antioxidants GSH uric acid and Trolox) was shown to beindependent of the calcium channel modulation (Franzoni etal [207])
AML showed efficiency as scavenger of peroxyl radicals(TOSC assay 5945 plusmn 544 unitsmg) significantly stronger(gt50 119875 lt 0001) than GSH (2733plusmn 636 unitsmg) and 70weaker (119875 lt 00001) than uric acid (18144 plusmn 696 unitsmg)and Trolox (17522 plusmn 734 unitsmg)
20 Oxidative Medicine and Cellular Longevity
Of interest the scavenging capacity of AML towardshydroxyl radicals (1455 plusmn 154 unitsmg) was 320 higher(119875 lt 000001) than that of GSH (358 plusmn 112 unitsmg) 20higher than that of uric acid (1198plusmn121 unitsmg) and 100higher than that of Trolox (759 plusmn 143 unitsmg)
Amlodipine was shown to increase enzyme activity ofparaoxonase (PON) and glutathione peroxidase (GSH-Px)However it also decreases glutathione reductase (GSSG-R)activity and diminishes the concentration of the endogenousantioxidant 120572-tocopherol (vitamin E) Moreover AML in aconcentration of 2 ngmL decreased the content of malonicdialdehyde and activity of superoxide dismutase in the blood(Gatsura [208])
Verapamil and amlodipine produced a potent anti-ischemic effect and reduced area of myocardial infarction inrats The observed changes were accompanied by inhibitionof LP In contrast to verapamil in vitro application of AML ina dose of 50 ngmL decreased hemoglobin affinity for oxygenWhen present in a concentration of 2 ngmLAMDdecreasedthe content of MDA and activity of SOD in the blood
On the other hand amlodipine shows no activity relatedto inhibition of macrophage superoxide release and cellmigration which occurs as a consequence of decreasedTNF120572induced O
2
∙ releaseAmlodipine-induced reduction of OS in the brain is
associated with sympathoinhibitory effects in stroke-pronespontaneously hypertensive rats (SHRSP) (Hirooka et al[209]) Antihypertensive treatment with amlodipine reducedOS in all examined areas of the brain and decreased bloodpressure without a reflex increase in sympathetic nerveactivity Nicardipine another CA DHP surprisingly wassignificantly less active than amlodipine
354 Lercanidipine Tomlinson and Benzie reported AOeffect of lercanidipine [210] which is well known as anti-hypertensive drug Zanidip 2[(33-diphenylpropyl)(methyl)-amino]-11-dimethylethyl methyl 26-dimethyl-4-(3-nitro-phenyl)-14-dihydropyridine-35-dicarboxylate Compara-tive data about this drug AOA were presented in parts of thispaper about other individual CA DHPs and in the part aboutthe ex vivo DHPs effects on LDL
355 Nimodipine Nimodipine (ND) commercially knownas Nimotop is 3-(2-methoxyethyl) 5-propan-2-yl 26-dim-ethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxy-late It is centrally active CA
Treatment with glutathione blocked andwith nimodipineattenuated neuronal cell death caused by prolonged exposureof cell culture to 4-HNE (Faraqui [211])
Nascimento et al [212] found AO effect of nimodipine inyoung rats after pilocarpine- (PIL-) induced (in 400mgkg)seizures The PIL administration increased the striatal cata-lase (CAT) activity The administration of ND 30mgkg30min before PIL preserved normal value of CAT activityOn the other hand no difference was detected in the animalstreated with lower dose 10mgkg These results confirmthe neuroprotectiveantiepileptic effect of ND in young ratssuggesting that this drug acts positively on lipid peroxidation
(in both doses) Nimodipine cannot induce these effects viablockade of Ca2+ channel
Ismailoglu et al [213] studied the therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjury These beneficial effects in rats after cerebral corticalinjury seemed to be related to AOA of nimodipine
356 Benidipine Licensed in Japan and South Asia as CA(CCB) benidipine possesses AO properties Chemically it is5-methyl 3-[(3R)-1-(phenylmethyl)piperidin-3-yl] 26-dim-ethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxy-late (or its hydrochloride (4R)-rel-35-pyridinedicarboxylicacid 14-dihydro-26-dimethyl-4-(3-nitrophenyl)- 3-methyl5-[(3R)-1-(phenylmethyl)-3-piperidinyl] ester hydrochloride(1 1))
Benidipine influences processes connected with OS inseveral ways It prevents lysophosphatidylcholine- (lysoPC)-induced injury and ROS production in human aorticendothelial cells (HAECs) (Matsubara and Hasegawa [214])Matsubara et al [215] explained this effect based on stimula-tion of nitric oxide release
LysoPC is a component of oxidized low-density lipopro-teins (oxLDLs) which plays an important role in the patho-genesis of atherosclerosis Pretreatmentwith benidipine (03ndash3 120583molL) for 24 h protected against lysoPC-induced cyto-toxicity in the HAECs through inhibition of both lysoPC-stimulated ROS production and caspase-37-like activationwith a similar potency Since caspase-37 is involved inexecuting the apoptotic process the reduction of the activityof this enzyme by benidipine may explain the antiapoptoticeffect of the drug However benidipine did not suppresslysoPC-induced phosphorylation of mitogen-activated pro-tein kinases and Ca2+ influx in HAECs These results suggestthat the antioxidant properties of benidipine may be respon-sible for its ability to inhibit ROS production a possiblereason for reduced activation of caspase-37 In conclusionbenidipine suppresses lysoPC-induced endothelial dysfunc-tion through inhibition of ROS production which is due atleast in part to its antioxidant effect and not through theinhibition of L-type voltage-dependent calcium channels
Matsubara and Hasegawa [216] examined the effectsof benidipine on cytokine-induced expression of adhesionmolecules and chemokines (chemoattractants) which areimportant for the adhesion of monocytes to endotheliumPretreatment of HAECs with benidipine (03ndash10 120583molL)for 24 h significantly suppressed cytokine-induced vascularcell adhesion molecule-1 (VCAM-1) and intracellular celladhesion molecule-1 (ICAM-1) mRNA and protein expres-sion resulting in reduced adhesion of THP-1 monocytesBenidipine also suppressed induction of monocyte chemoat-tractant protein-1 (MCP-1) and interleukin-8 Benidipinealso inhibited redox-sensitive transcriptional nuclear factor-120581B (NF-120581B) pathway as determined by Western blotting ofinhibitory 120581B (I120581B) phosphorylation and luciferase reporterassay Results of analysis using optical isomers of benidip-ine and antioxidants suggest that these inhibitory effectswere dependent on pharmacological effects other than Ca2+antagonism Benidipine may thus have anti-inflammatoryproperties and benefits for the treatment of atherosclerosis
Oxidative Medicine and Cellular Longevity 21
Benidipine was also shown to inhibit ROS production inpolymorphonuclear leukocytes and oxidative stress in salt-loaded stroke-prone spontaneously hypertensive rats (Mat-subara et al [217])
It should be mentioned that other DHPs also haveendothelial AO actions [218]
357 Azelnidipine (AZL) Azelnidipine 3-[1-[di(phen-yl)methyl]azetidin-3-yl] 5-propan-2-yl 2-amino-6-methyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate(AZL) CAS number 123524-52-7 is commercially available4-nitroaryl-DHP type calcium antagonist with long-actingantihypertensive action (long-acting CA (CCB)) and a lowreported incidence of tachycardia It additionally possessesbeneficial effects in OS and diabetic conditions
Azelnidipine prevents cardiac dysfunction in strepto-zotocin-diabetic rats by reducing intracellular calcium accu-mulation (altering intracellular Ca2+ handling proteins) OSand apoptosis (Kain et al [219]) AZL can reduce the superox-ide production It exerts its protective effects by targeting theNADPH oxidase and mitochondrial redox enzymes AZL-treated diabetic rats express enhanced level of bcl-2 in thelysates of heart muscle indicating that AZL plays protectiverole in cardiac apoptosis
It has been previously observed that azelnidipine inhibitstumor necrosis factor-alpha-induced endothelial cell (EC)oxidative stress through its AO properties (Nakamura etal [220]) Azelnidipine but not nitrendipine completelyinhibits the Ang II-induced ROS generation in ECs (Matsuiet al [221])
Furthermore azelnidipine but not nitrendipine wasfound to partially restore decreased pigment epithelium-derived factor (PEDF) mRNA levels in Ang II-exposed ECsThis study suggests that AZL influence depends on its antiox-idative properties Authors concluded that upregulation ofPEDF by azelnidipine may become a therapeutic targetfor the treatment of diabetic retinopathy associated withhypertension
Antihypertensive agents with AO effects are potentiallyuseful for diabetic patients with hypertension While DHPtypeCAare among themost frequently used antihypertensivedrugs azelnidipine has been reported to have a unique AOeffect in vitro and in vivo in experimental animals (Ohmuraet al [222]) In hypertensive diabetic patients azelnidipinetreatment for 12 weeks induced a more significant decreasein erythrocyte LOOH level than amlodipine although thevalues related to blood pressure during each treatmentremained comparable These data confirm the usefulness ofLOOH level in erythrocyte membrane as a marker of OS invivo and indicate that azelnidipine has a unique antioxidativeproperty in humans
Daikuhara et al [223] reported the results of the OLCAstudy based on combination of (1) olmesartan and a calciumchannel blocker (azelnidipine) or (2) candesartan and a CCBamlodipine in two groups of diabetic hypertensive patientsPatients treated with the first combination presented highlypersistent early morning antihypertensive effect and strongerdecrease in heart rate fasting blood glucose andHbA1c levels
and microalbuminuria when compared to patients treatedwith the combination (2) Because diabetes is associated withsevere chronic OS the observed results might be at least in apart due to the AOA of azelnidipine
In favor of this are findings of Abe et al [224] who foundadditive antioxidative effects of azelnidipine on angiotensinreceptor blocker olmesartan treatment for type 2 diabeticpatients with albuminuria
Similarly the AOA of thiazolidinediones (insulin sensi-tizer) and their effect on cardiovascular function in type 2diabetic model rats and also those of some DHPs (nifedipineamlodipine or AZL commonly used antianginal and anti-hypertensive agents) in cultured human endothelial cells LPwere examined (Mizushige [225]) The AOA was evaluatedby measuring 8-iso-prostaglandine F
2120572concentration and
azelnidipine exhibited potent AOAInsulin (INS) resistance combined with hyperinsuline-
mia is involved in the generation of OS A relation-ship exists between increased production of ROS and thediverse pathogenic mechanisms involved in diabetic vascularcomplications including nephropathy Manabe et al [226]revealed that high doses of INS augmented mesangial cellproliferation through generation of intracellular ROS andactivation of redox signaling pathways Cell proliferation wasincreased in a dose-dependent manner by high doses of INS(01ndash10 120583M) but was inhibited by 01120583M AZL Namely theINS-increased phosphorylation of mitogen activated proteinkinaseextracellular signal-regulated kinase 12 (MAPKERK12) was inhibited by 01 120583MAZL The same AZL concen-tration blocked intracellular ROS production more effec-tively than 01 120583M nifedipine The NADPH oxidase inhibitorapocynin (001ndash01120583M) prevented INS-induced mesangialcell proliferation So azelnidipine inhibits insulin-inducedmesangial cell proliferation by inhibiting the productionof ROS Therefore azelnidipine may have the potential toprotect against the onset of diabetic nephropathy and slowits progression
Azelnidipine inhibited H2O2-induced cell death in
neonatal rat cardiomyocytes (Koyama et al [227]) Azelnidip-ine and nifedipine did not affect theH
2O2-induced activation
of extracellular signal-regulated protein kinases (ERK) andp38 MAPK (mitogen-activated protein kinase) In contrastazelnidipine but not nifedipine inhibited H
2O2-induced c-
Jun NH2-terminal kinases (JNK) activation Authors con-
cluded that azelnidipine has inhibited theH2O2-induced JNK
activation and cardiac cell death Therefore azelnidipine mayhave cardioprotective effects against OS
A specific atheroprotection activity of azelnidipine relatesto inhibition of TNF-120572-induced activator protein-1 activa-tion and interleukin-8 expression in human umbilical veinendothelial cells (HUVEC) through suppression of NADPHoxidase-mediated reactive oxygen species generation (Naka-mura et al [220]) TNF-120572 could play a central role in patho-genesis of insulin resistance and accelerated atherosclerosis inthe metabolic syndrome The concentration of AZL found tobe effective in these in vitro experiments is within therapeuticrange As EC do not possess voltage-operated L-type calciumchannels it is suggested that the beneficial effects of azelni-dipine are not likely due to CA property but to its unique AO
22 Oxidative Medicine and Cellular Longevity
ability Furthermore it has been recently found that serumlevels of monocyte chemoattractant protein-1 a biomarkerfor subclinical atherosclerosis were significantly decreased bythe AZL treatment in patients with essential hypertension Inthis paper [220] authors hypothesize that due to its uniqueTNF-120572 signalmodulatory activity and antioxidative propertyazelnidipine may be a promising DHP for targeting diabetesand cardiovascular diseases in hypertensive patients withmetabolic syndrome
Shinomiya et al [228] evaluated its AOA in culturedhuman arterial EC under OS Azelnidipine has shown apotent antioxidative effect that could be of significant clinicalbenefit when combined with its long-lasting antihypertensiveaction and low incidence of tachycardia
Azelnidipine inhibited TGF-1205731 and angiotensin II- (AngII-) activated 1205721(I) collagen mRNA expression in hepaticstellate cells (HSCs) (Ohyama et al [229]) FurthermoreTGF-1205731- and Ang II-induced OS and TGF-1205731-induced p38and JNK phosphorylation were reduced inHSCs treated withAZL Azelnidipine significantly decreased inflammatory cellinfiltration profibrotic genes expression HSC activation LPoxidative DNA damage and fibrosis in liver of CCl
4- or
TAA-treated mice Finally AZL prevented decrease of theexpression of some AO enzymes and accelerated regressionof liver fibrosis in CCl
4-treated mice Hence the antifibrotic
mechanism of AZL against CCl4-induced liver fibrosis in
mice may have been due to an increased level of AO defenseAs azelnidipine is widely used in clinical practice withoutserious adverse effects it may provide an effective newstrategy for antifibrotic therapy
358 Manidipine Manidipine (2-[4-(diphenylmethyl)pip-erazin-1-yl]ethyl methyl 26-dimethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate) is a DHP CCB withreported nephroprotective properties Calo et al [230] stud-ied effect of manidipine on gene expression and proteinlevel of OS related proteins p22(phox) (human neutrophilcytochrome b light chain (CYBA)) and heme oxygenase-1HO-1 Relevance for antihypertensive effects was revealedThe study assessed the effect of manidipine on normalsubjectsrsquo monocyte gene and protein expression of OS relatedproteins such as p22phox a NADPH oxidase system subunitcritical in generating O
2
∙minus and HO-1 induced by and pro-tective against OS Manidipine was compared with the ACEinhibitor captopril and the CCB nifedipine in the presenceand in the absence of sodiumarsenite (NaAsO
2) as an inducer
of OS Monocyte p22phox (CYBA) mRNA production wasreduced by both manidipine and captopril while no changeswere induced by nifedipine Manidipine increased monocyteHO-1 mRNA production while nifedipine and captoprilshowed no effect The effects of manidipine on p22phoxand HO-1 gene expression in the presence of OS were alsoconfirmed at the protein level Thus manidipine seems tosuppress p22phox and to increase the HO-1 mRNA produc-tion and protein level The manidipine-induced increase ofHO-1 gene and protein expression seems to be a peculiareffect of this drug since it is not observed with captopriland nifedipine This effect together with the reduction of
p22phoxmRNAproduction could play a role in its protectivemechanism against OS
359 Mebudipine The protective effect of mebudipine (14-dihydro-26-dimethyl-4-(3-nitrophenyl)-35-pyridinedicar-boxylic acid 3-methyl-5-tert-butyl ester BAY-n-6391) wasrevealed on OS and LP (MDA decrease SOD GPX andcatalase increase) in myocardial ischemic-reperfusion injuryin male rats (Ghyasi et al [231])
There are articles about other commercial and experi-mental DHPs on OS but we have reviewed only the mostcommonly studied compounds Effects of other commercialCA DHPs on OS are also mentioned in several parts of thisreview
36 14-DHPs Ca Agonists andTheir AOA and ARA For themost popular calcium agonist DHP Bay K 8644 no reactionwith peroxyl radicals was registered (Toniolo et al [114])However interactionwith other compounds possessing AOAand ARA (quercetin) was found
Opposite to that AON-acetylcysteine (NAC) diminishedincrease in Ca2+ transient amplitude and cell shorteninginduced by ISO and forskolin whereas NAC had no effecton the (S)-(minus)-methyl-14-dihydro-26-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylatemdash(minus)-BayK 8644-induced increases (Andersson et al [232])
Increased vasoconstriction responses to Bay K 8644 (3 times10minus7ndash3times 10minus5M)were significantly decreased by pyridoindoleantioxidant stobadine treatment in diabetes (Ceylan-Isik etal [233])
The functional interaction between two L-type Ca2+channel activators quercetin and Bay K 8644 has beeninvestigated in vascular smooth muscle cells Biological ARAcompound quercetin at nutritionally meaningful concen-trations limited the responsiveness of vascular L-type Ca2+channels to the pharmacological stimulation operated by BayK 8644 These data contribute to a better understanding ofquercetin effects on experimental in vivo cardioprotection(Saponara et al [234]) Thus these findings indicated thatalthough Bay K 8644 does not exert potent and direct AOAyet acting as calcium agonist it may affect efficiency of AOsubstances and vice versa
Interaction of grapefruit juice (containing quercetin andits analogues) with DHPs CA diminished effectiveness of CAaction of DHPs (Sica [235])
37 Interpretations of the Mechanism(s) of RadicalScavenging and AOA by DHPs
371 Molecular Mechanism(s) of Radical Scavenging andAOA of DHPs in the Model Systems 35-Dicarbonyl-14-di-hydropyridine derivatives possess powerful bis-120573-carbony-lvinyl-amino conjugation and for that reason cannot be con-sidered as ordinary amino antioxidants The electron andorH donation from DHPs ensures their reductant role andresults in AOA and ARA Oxidation reaction from DHPsresults in production of corresponding heteroaromatic pyri-dine derivatives
Oxidative Medicine and Cellular Longevity 23
Detailed studies were made about substituent in DHPring positions 14- namely 4-unsubstituted- 4-substituted4-alkyl- 4-aryl- 4-alkylaryl- ao 26- 35- (diacetyl ordialkoxycarbonyl chain ao) electronic and steric effects onAOA and ARA of DHPs [44 45 51] see Sections 331and 35 The bell-shaped dependence of DHPs AOA onthe 35-dialkoxycarbonyl- chain length was observed [4445 107 109 112] with the maximum activity at C
2H5ndash
C4H9 Decrease of AOA and incorporation into liposomes for
DHPs with alkyl chains longer than R gt C4H9further were
clarified as probable tendency to self-aggregation of thesecompounds ([51] and citation number 245 therein) Electronacceptorelectron donor properties are relevant for expres-sion of AOA or ARA of 35-disubstituted DHPs 35-Diacyl-substituted and 35-dicarbanilido- and 35-dipyridylamido-substituted DHPs are more active as AOs as their 35-dicyano-substituted analogues which have electron acceptorproperties [186]
Dubur et al [89] observed overwhelming steric influenceof substituents in position 4 of the DHP ring Gaviraghiet al [163 164] proposed that AO activity of DHPs ispartly dependent on capacity of the 14-DHP ring to donateelectrons to the propagating radical (ROO∙ or RO∙) and toreduce it to a less reactive form The abstraction (donation)of electron andor H in the oxidation and LP reactionstakes place from all 35-dicarbonyl-14-DHP systems andresults in the formation of corresponding pyridine derivatives(Augustyniak et al [51]) The physicochemical mechanism ofARA and AOA of 14-DHP has been extensively studied anddiscussed (Mulder et al [236]) but precise mechanisms oftheir activity need further clarification
The reactivity of C-4 substituted 14-DHPs possessingeither secondary or tertiary nitrogen atom in the DHP ringtoward alkyl alkylperoxyl radicals and ABTS radical cationwas determined in aqueous media at pH 74 [103] Thesecompounds reacted faster toward alkylperoxyl radicals andABTS radical cation than alkyl ones N-Ethyl-substitutedDHPs showed the lowest reactivity
The 4-methyl substituted DHP was the most reac-tive compound in previously mentioned reactions (Lopez-Alarcon et al [103]) However it was less active (068versus 10) than Trolox-C DHPs having electron-donatingsubstituents (4-Me-DHP and p-MeO-Phe-DHP) showed thehighest kinetic rate constants toward ABTS radical cation p-nitro-Phe-DHP a compound with an electron-withdrawingsubstituent showed a lower kinetic rate constant and N-alkyl-DHP compounds show kinetic rate constants lowerthan the -NH-DHP
Hydrogen at the 1-position of the DHP ring was revealedaccording to the deuteriumkinetic isotope effect studies to beinvolved in the proposedARAmechanismThis fact ismostlynoticeable in the case of alkyl radicals N-Ethyl-substitutedDHPs show the lowest reactivity when compared to Troloxor nisoldipine In all cases the respective pyridine derivativewas detected as the main product of the reaction (Lopez-Alarcon et al [103]) Authors indicate that the kinetic rateconstants toward alkyl alkylperoxyl andABTS radical cationdepend on the nature of the substituents in the C-4 positionof DHP and the presence of the secondary amine group in the
dihydropyridine ring that is the presence of the hydrogen in1-position
Yanez et al [197] have studied the reactivity of 11derivatives of 14-DHPs (including commercial CA) withalkylperoxyl radicals and ABTS radical cation The tested14-DHPs were 83-fold more reactive towards alkylperoxylradicals than to the ABTS cation radical All commercial14-DHP type CCBs were weaker than Trolox-C The par-ticipation of the hydrogen atom in the 1-position appearsto be very relevant for exhibited reactivity Hantzsch ester(diludine)was again found to be themost active compound inthe reaction with alkylperoxyl radicals 23-fold more activethan Trolox The photodegradation product of nifedipine(nitrosophenyl derivative of pyridine) also showed a highactivity Kinetic rate constants for the reaction between 14-DHP compounds and alkylperoxyl radicals exhibited a fairlygood linear correlation with the oxidation peak potentialof DHP derivatives However the activity of tested 14-DHPs towards ABTS radical cation showed an independencebetween kinetic rate constants and oxidation peak potentials
Kirule et al [195] andTirzit et al [196] studiedmechanismof AOA of 4-nitrophenyl-14-DHPs nifedipine and its ana-logues involving formation of 4-(21015840-nitrosophenyl)-pyridinederivative (as active principle) as a result of intramolecularredox reaction using chemical electrochemical and bio-chemical approaches (see Sections 331 and 351)
Nunez-Vergara et al [237] reported the electrochemicaloxidation of C4-hydroxyphenyl-substituted 14-DHP deriva-tives The oxidation proceeds via formation of the unstabledihydropyridyl radical as confirmed by controlled-potentialelectrolysis (CPE) and ESR experiments This type of 14-DHPs has significant activity towards the radicals even whencompared with commercial 14-DHP drugs with well-knownantioxidant ability
It was observed that nicardipine preferentially targets RO∙radicals and is inactive against ROO∙ Lacidipine on theother hand is equally active towards both types of radicals(Gaviraghi et al [164]) The cytoprotective effect againstexposure to H
2O2was more significant for lacidipine (ID
50=
14 nM its log119875 = 54 membrane partition = 136000 assumesposition located 7 A near to the membrane center otherless lipophilic DHPs located 12ndash16 A far from the center)as compared to amlodipine nifedipine and nicardipine insmooth muscle cell culture (Gaviraghi et al [164]) Oxidativeeffect of H
2O2shifts the Ca channel toward an open state
Thus the redox property of CCBs DHPs may augment theirCCB properties
Oxidation of pharmacologically active Hantzsch 14-dihydropyridines was found by electrogenerated superoxideusing a voltammetric approach in DMSO solutions (Ortiz etal [238] and Ortiz et al [239]) Raghuvanshi and Singh [240]have also reported oxidative aromatization of these DHPsinduced by superoxide
Chemiluminescence (CL) was used in the studies ana-lyzing the antioxidant activity of 12 various 4-flavonil-14-dihydropyridine derivatives (Kruk et al [241]) on a chemicalsystem involving a superoxide radical anion These deriva-tives showed structural similarity to flavonoids with respectto the presence of rings A B and C The results obtained in
24 Oxidative Medicine and Cellular Longevity
this study indicate that the tested derivatives may catalyzeconversion of superoxide radicals through mimicking theactivity of superoxide dismutase by delivering H+ for reac-tion
O2
minus∙+O2
minus∙+ 2H+ 997888rarr H
2O2+1O2
(3)
The enhanced emission of the light in the presence oftested compounds was significant and related to stimulatedproduction ofH
2O2and 1O
2fromO
2
∙The latter specieswereremoved from the reactionmixture by the following sequenceof reactions
H+
O2
minus∙997888rarr HO
2
∙
HO2
∙+O2
∙minus997888rarr HO
2
minus+1O2
2HO2
∙997888rarr H
2O2+1O2
2 (1O2) 997888rarr (O
2)2+ h]lowast
(4)
or to take part in spontaneous dismutation of H2O2
2H2O2997888rarr 2H
2O + 1O
2(5)
The authors have offered an original concept of action for 4-flavonil-14-dihydropyridine derivatives unrelated to that ofO2
∙ radical-trapping chain-breaking antioxidants Insteadthey showed that these compounds act similar to superoxidedismutases converting O
2
∙ to H2O2 Hydrogen peroxide
is less toxic for cells than O2
∙ because it is predominantlyremoved by peroxidases and catalases Finally AO effect ofthese DHPs differed from those mediated by flavonoids witha catechol structure of ring B which are well-known 1O
2
quenchersMulder and collaborators came to similar conclusions
especially related to molecular mechanisms of antioxidativeactivity of DHPs [236]TheAOproperties of Hantzsch 14-di-hydropyridine esters and two dibenzo-14-dihydropyridines910-dihydroacridine (DHAC) and N-methyl-910-dihydro-acridine (N-Me-DHAC) have been explored by determin-ing the autoxidation of styrene or cumene at 30∘C Theseexperiments showed that Hantzsch esters are virtually inac-tive as chain-breaking antioxidants (CB-AOs) contrary tothe findings observed by Lopez-Alarcon et al [103] whoused CB-AOA in aqueous media at pH 74 Their reactivitytoward peroxyl radicals was shown to be some 5 orders ofmagnitude lower than that of the excellent CB-AO 22578-pentamethyl-6-hydroxy-chroman (PMHC)
DHAC was found to be sim10 times less reactive thanPMHC kinetic measurements using DHAC N-deuterio-DHAC and N-Me-DHAC pointing out the abstraction ofN-H hydrogen in DHAC by peroxyl radicals despite the factthat the calculated C-H bond dissociation enthalpy (BDE) inDHAC is about 11 kcalmol lower than the N-H BDE Therates of hydrogen atom abstraction by the 22-diphenyl-1-picrylhydrazyl radical (DPPH∙) have also been determined
for the same series of compounds The trends in the peroxyl∙and DPPH∙ rate constants were found to be similar [236]
Tirzit et al [242] have observed quenching of singletoxygen by DHPs This observation paved the ground forfurther research related to reactions of DHPs with hydroxylradicals (Tirzit et al [243]) singlet oxygen (Kazush etal [94]) and mechanisms of action A series of 14-DHPderivatives in NAD-H-Cu2+-H
2O2system inhibited forming
of the hydroxyl radical (HO∙) while 14-DHP derivativeswith electron donor substituents in the molecule were shownto be capable themselves of generating HO∙ in the presenceof Cu2+ and H
2O2 Rubene et al [186] also described
interaction of 14-DHP derivatives with Fentonrsquos reagentwhich produces hydroxyl radical (HO∙) Rate constants ofthe DHPs reaction (1st order) with HO∙ radical were highin the range 109 L times mol times secminus1 close to that of NADHcysteine and thiourea 35-Diacetyl- derivatives reacted fastercompared to 35-dialkoxycarbonyl- ones The reaction ratedecrease was observed in the case of substitution at position4 as compared to 4-unsubstituted DHPs Some DHPs havingelectron donor -COOminus groups in the 35- or 26- positionsof DHP ring reacted immediately (having rate constantshigher as 109 L times mol times secminus1) Rate constants with HO
2
∙
and O2
∙minus radicals were of lower degree Thus DHPs actingas oxygen radical scavengers could effectively inhibit ROSrelated reactions of LP initiation stage
Nifedipine and nitrendipine reactivity toward singletoxygen was also studied [244] Nifedipine was shown tobe a good scavenger of excited oxygen mainly via physicaldeactivation with values of the total rate constant rangingfrom 208 times 105Mminus1 sminus1 (in dioxane) to 930 times 105Mminus1 sminus1(in propylene carbonate)The less reactive pathway generateda photooxidation product For that reason a mechanisminvolving a perepoxide-like encounter complex in the firststep of the reaction path was proposed (see [244] Figures8 and 9 therein) The dependence was observed on solventmicroscopic parameters of the total rate constant for the reac-tion between singlet oxygen and 14-DHPs These findingsshow that nifedipine possesses stronger protective activity inbiological systems than nitrendipine
Density-functional-theory (DFT) calculations made byWang et al [245] confirmed the former experimental obser-vations that Hantzsch ester diludine is potent antioxi-dant with high H atom-donating ability and relatively lowprooxidant activity Possible reaction pathways for radicalsderived from 14-dihydropyridine and the resonance modesfor radical species were given [245]
Moreover two ethoxycarbonyl (EtOCO) substituentsat C(2) and C(6) should further enhance Hantzsch esterdiludine H-atom-donating ability due to resonance effectsHowever DHPs should be used in nonpolar rather than inpolar solvents since in the latter not H-atom but electrontransfer is preferred in the radical scavenging process [245]
Mulder et al [246] proposed that quantum-thermochem-ical calculations must be used with caution to indicate ldquoapromising lead antioxidantrdquo as they criticized the density-functional-theory (DFT) calculations made by Wang et al[245]
Oxidative Medicine and Cellular Longevity 25
372 Possible Mechanisms of DHPs ARA and AOA in the Bio-logical Systems Interaction with Other OSModifiers Some ofthese mechanisms were already described (Sections 331 (2)-(b) 331 (2)-(c) 331 (3)-(b) 35)
Enzymatic sources of ROSwith confirmed functional rolein hypertension are NADPH oxidase NO synthase (NOS)xanthine oxidase and cyclooxygenase Godfraind [3] hasreviewed AO effects and protective action of calcium channelblockers (CCBs) Yao et al [247] observed antioxidant effects(as inhibition of LP) for cardio- and neuroprotective CCBs(3ndash300 120583molL) including 7 DHPs in homogenates of ratbrain IC
50values (120583M) were as follows nifedipine (515) gt
barnidipine (586) gt benidipine (712) gt nicardipine (1293)gt amlodipine (1355) gt nilvadipine (1673) gt nitrendipine(2521) gt diltiazem (gt300) = verapamil (gt300) There arealso research articles describing the AO properties of CCBsthrough direct scavenging effect or through preservationof the endogenous SOD activity These findings indicatethat CCBs may also act by reducing the production ofvasoconstrictors angiotensin and endothelin
When present in concentrations that can be achievedin plasma CCBs may inhibit LP formation [3] This AOactivity seems to be typical for high lipophilic CCBs becausetheir chemical structure facilitates proton-donating andresonance-stabilization mechanisms that quench the freeradical reaction Their insertion in the membrane nearpolyunsaturated fatty acids at relatively high concentrationspotentiates proton donation (or atomary H) to lipid peroxidemolecules thereby blocking the peroxidation process Theremaining unpaired free electron associated with the CCBmolecule can be stabilized in well-defined resonance struc-tures associated with the DHP ring (Mason et al [48])
The radical reaction (according to Godfraind [3]) thatdescribes the AO effects of a DHP CCBs is LOOlowast + DHPrarr LOOH + DHPlowast (where LOOlowast is lipid peroxide radical)which in general is reaction (7) of the LP reaction cascadeconsisting of sim10 reactions (Scheme 2) [89]
As the rate constants of in vitro interaction of 4-substituted DHPs with peroxyl radicals are three ordersof magnitude lower than that of the vitamin E derivativethese DHPs must be considered as weak AO (Ursini [204])However due to partition coefficient of DHPs in membranesand in case of specific binding high local concentration ofDHPs may be obtained
DHPs without CCB properties for instance Bay w 9798although structurally related to nifedipine inhibit TNF-120572-induced vascular cell adhesion molecule-1 expression inendothelial cells by suppressing reactive oxygen speciesgeneration [248]
Mitrega et al [249] have discovered that antiarrhythmicand hemodynamic effects of oxidized heteroaromatic DHPsoxy nifedipine oxy nimodipine oxy nitrendipine and oxynisoldipine suggest that CCB DHPs and their metabolitescould act at least in two ways targeting OS related eventsas reductants (see Section 351 (1)) andor bypassing OSrelatedmetabolic routes Authors postulated that contrary tocurrent belief NIF metabolites are pharmacologically activeATP sensitive potassium channels were mentioned as a tar-get
38 DHPs Anti- or Prooxidants Several substances (ascorbicacid being the most commonly studied) can serve either asantioxidants or as prooxidants depending on given condi-tions (Herbert [250]) Therefore Halliwell [251] has reporteddilemma related to polyphenols as possible antioxidantsand prooxidants causing experimental artifacts (about 25)by oxidation of antioxidant compounds in the cell culturemedia Nevertheless it is generally accepted opinion thatpolyphenols act as antioxidants in vivo Studies on DHPs alsoface such a dilemmaThe exact roles (anti- or prooxidative) ofany specific DHP depend on its structure appliedachievedconcentration and specificity of the targetexperimentaltesting system
This situation resembles the case of antioxidative effectsof tocopherol which depends on the fate of the secondaryradical as proposed by Winterbourn [252] The question wasldquoVitamin E - Pro- or Antioxidantrdquo
997888rarr chain termination of lipid peroxidation
(6)
Prooxidant
Toc∙ + Lipid-H 997888rarr Lipid∙ (in LDL particles) (7)
This example shows that generally speaking any AO mustfulfil several criteria to be considered as an effective com-pound physiologically
(i) It must be able to functionally interact with endoge-nous scavengers even at low concentrations
(ii) It must affect endogenous pathways of OS(iii) It should not have undesirable adverse effect(iv) It should manifest the antioxidant efficacy dependent
on the oxidant(v) It must discriminate among different strategies
needed for 1-electron and 2-electron processes(vi) Radical scavengers can be prooxidant unless linked to
a radical sink (Winterbourn [252])
According to these statements DHPs could be effective asAO under physiological conditions in vivo (Godfraind [3]and others [30 31 38]) and in vitro in various experimentalsystems (cell and tissue) (see Sections 33 34 35)
Hence calcium antagonists appeared to disrupt thefine balance between the production and scavenging ofROS Nifedipine verapamil and diltiazem were shown toinduce significant oxidative stress in the epididymal sperm(increased MDA and decreased catalase and superoxidedismutase activity) This may be the reason for the inductionof male infertility [253]
The dualism of 14-DHP effects has been recorded asinhibition or promotion of LP as quenching or initiating
26 Oxidative Medicine and Cellular Longevity
oxygen and nitrogen free radical chain reactions radiopro-tecting or radiosensitizing antagonizing or synergizing Ca2+in electromechanical coupling as well as in the membranestabilization or labilization
39 Could DHPs Be Involved in Antioxidative Stress Beforebeing applied in vivo the optimal dose and optimal timeintervals forDHPs applicationmust be knownNamely whileROS have been traditionally considered as toxic byproductsof aerobic metabolism we know nowadays that ROS may actas essential signaling molecules needed for the control ofmany different physiological processes Whether the role ofROS will be damaging protective or signaling depends onthe delicate equilibrium between time- and location-specificROS production and scavenging Accordingly the imbalanceof the increased AO potential so-called antioxidative stresscould be dangerous similar to chronic OS in particular incase of extended exposure Inappropriate interventions inthe oxidative homeostasis by excessive antioxidants especiallyin case of chronic exposure to antioxidants might havevery negative effects as was published in the ATBC studyshowing an increased cancer incidence in smokers treatedby excessive beta-carotene [254] Therefore overconsump-tion of any natural or synthetic AO including DHPs asdietary supplements or drugs must be avoided in order tosuppress oxidative damage and must not disrupt the well-integrated antioxidant defense network (Poljsak [255] andPoljsak and Milisav [256]) This is especially important whenadministrating lipid-soluble antioxidants that can be storedin biomembranes thus not only attenuating or preventing LPbut also affecting physiological effects of the natural antiox-idants in particular tocopherol The interrelationship withthe status of endogenous antioxidantsprooxidants should befollowed
DHPs primarily suppress the initiation stages of LPprocessThey do not entirely stop the LP propagation Actingsynergistically with tocopherol diludine may prevent patho-logical excess of ROS production within the lipid moiety ofthe cellular membranes and LDL However due to its lowsolubility and fast metabolism its concentration in the cellsis low For that reason it cannot cause antioxidative stresseven if used for an extended period of time Thus diludine(diethone) could be only a mild antioxidant it has potentialfor restoring the pool of natural antioxidants (as synergist of120572-tocopherol and polyphenols) in the cells
Moreover DHPs CA used for cardioprotection andvasodilatation as commercial drugs in low concentrationsare fast metabolized via CYP3A4 and for that reason theirapplication does not induce cellular AO stress [53 160]However Godfraind and Salomone [257] have postulated noevidence that allows recommending dietary supplementationwith antioxidants for the primary or secondary prevention ofcardiovascular disease
So far there are no reports on antioxidative stress causedby some DHPs diludine and its analogues Diludine andits analogues therefore could act as adaptogens supportinghormetic effects of mild oxidative stress These compoundsmay act as potential multisided modulators of Yin-Yang
cycles of redox and cell functions (the electroplasmic cycle)(Wagner et al [258])
4 Conclusions
14-Dihydropyridines (14-DHPs) have broad spectrum ofOS modulating activities DHPs have reducing and lipidperoxidation inhibitor properties act as reductants in simplechemical systems and stabilize various biological systems(LDL mitochondria microsomes cells and tissues) againstOS Examples and peculiarities and mechanisms of antiox-idant activity (AOA) and antiradical activity (ARA) as wellas stress-protective effect of DHPs including commercialcalcium antagonists (CA) were highlighted These activitiesdepend on various structural parameters related to DHPs(presence and character of substituents) lipophilicity anddepth of the incorporation in the biologicalmembranesTheyalso depend on the experimental model system for exploringthe lipid peroxidation or oxidative stress Stress-protectiveeffect of some metabolites of CA (nifedipine) is reviewedAlthough some DHPs including CA have prooxidant prop-erties (on epididymal sperm cells) they can generally beconsidered as potent antioxidants Therefore comparisonof the AOA and ARA of different DHPs (mutually andwith other AOs) was described in detail According to thedata presented the DHPs might be considered as bellwetheramong synthetic compounds targeting OS and as a kind ofpharmacological measure for respective field of organic andmedicinal chemistry
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
Authors from Latvian IOS acknowledge ESF 201300021DP1112013APIAVIAA011 and National Research Pro-gramme PUBLIC HEALTHBiomedicine of the Republicof Latvia for financial support administration of the Insti-tute for technical support and Rufus Smits PhD for con-sultations in English The support of Cooperation in Euro-pean System of Science and Technology (COST) Domain ofChemistry Molecular Sciences and Technologies (CMST)was of highest importance for preparation of this paper
[2] D J Triggle ldquo14-Dihydropyridines as calcium channel ligandsand privileged structuresrdquoCellular andMolecular Neurobiologyvol 23 no 3 pp 293ndash303 2003
[3] T Godfraind ldquoAntioxidant effects and the therapeutic modeof action of calcium channel blockers in hypertension andatherosclerosisrdquo Philosophical Transactions of the Royal SocietyB Biological Sciences vol 360 no 1464 pp 2259ndash2272 2005
[4] E Cadenas ldquoMitochondrial free radical production and cellsignalingrdquoMolecular Aspects of Medicine vol 25 no 1-2 pp 17ndash26 2004
[5] E Cadenas ldquoFree radicals oxidative stress and diseasesrdquo inLecture PSC 616 p 38 Missouri University of Science andTechnology Rolla Mo USA httpwwwcarnicominstituteorgarticlesenrique cadenaspdf
[6] K Rahman ldquoStudies on free radicals antioxidants and co-fac-torsrdquo Clinical Interventions in Aging vol 2 no 2 pp 219ndash2362007
[7] V Bocci and G Valacchi ldquoFree radicals and antioxidants howto reestablish redox homeostasis in chronic diseasesrdquo CurrentMedicinal Chemistry vol 20 no 27 pp 3397ndash3415 2013
[8] M Valko C J Rhodes J Moncol M Izakovic and M MazurldquoFree radicals metals and antioxidants in oxidative stress-induced cancerrdquo Chemico-Biological Interactions vol 160 no 1pp 1ndash40 2006
[9] G Bartosz ldquoReactive oxygen species destroyers or messen-gersrdquo Biochemical Pharmacology vol 77 no 8 pp 1303ndash13152009
[10] R Visconti and D Grieco ldquoNew insights on oxidative stress incancerrdquo Current Opinion in Drug Discovery and Developmentvol 12 no 2 pp 240ndash245 2009
[11] R N Kujundzic N Zarkovic and K G Troselj ldquoPyridinenucleotides in regulation of cell death and survival by redoxand non-redox reactionsrdquo Critical Reviews in Eukaryotic GeneExpression vol 24 no 4 pp 287ndash309 2014
[12] B Halliwell and J M C Gutteridge ldquoThe definition and mea-surement of antioxidants in biological systemsrdquo Free RadicalBiology and Medicine vol 18 no 1 pp 125ndash126 1995
[13] V D Kancheva and O T Kasaikina ldquoBio-antioxidantsmdashachemical base of their antioxidant activity and beneficial effect
on human healthrdquo Current Medicinal Chemistry vol 20 no 37pp 4784ndash4805 2013
[14] H V Panglossi Ed Frontiers in Antioxidants Research NovaScience Publishers New York NY USA 2006
[15] E B Burlakova E M Molochkina and G A NikiforovldquoHybrid antioxidantsrdquo Oxidation Communications vol 31 no4 pp 739ndash757 2008 httpmembraneustceducnpaperpdfHybrid20Antioxidantspdf
[16] A Bast and G R M M Haenen ldquoTen misconceptions aboutantioxidantsrdquo Trends in Pharmacological Sciences vol 34 no 8pp 430ndash436 2013
[17] E B Burlakova A V 0lesenko E M Molochkina N PPalmina and N G Khrapova Bioantioxidants for RadiationDamage and Malignant Growth Nauka Moscow Russia 1975(Russian)
[18] J Fang T Seki and H Maeda ldquoTherapeutic strategies by mod-ulating oxygen stress in cancer and inflammationrdquo AdvancedDrug Delivery Reviews vol 61 no 4 pp 290ndash302 2009
[19] M Valko D Leibfritz J Moncol M T D Cronin M Mazurand J Telser ldquoFree radicals and antioxidants in normal physi-ological functions and human diseaserdquo International Journal ofBiochemistry and Cell Biology vol 39 no 1 pp 44ndash84 2007
[20] M Jimenez-Del-Rio and C Velez-Pardo ldquoThe bad the goodand the ugly about oxidative stressrdquo Oxidative Medicine andCellular Longevity vol 2012 Article ID 163913 13 pages 2012
[21] C D Kamat S Gadal M Mhatre K S Williamson Q N Pyeand K Hensley ldquoAntioxidants in central nervous system dis-eases preclinical promise and translational challengesrdquo Journalof Alzheimerrsquos Disease vol 15 no 3 pp 473ndash493 2008
[22] A Pompella H Sies R Wacker et al ldquoThe use of totalantioxidant capacity as surrogate marker for food quality andits effect on health is to be discouragedrdquo Nutrition vol 30 no7-8 pp 791ndash793 2014
[23] Z Ye and H Song ldquoAntioxidant vitamins intake and the risk ofcoronary heart disease meta-analysis of cohort studiesrdquo Euro-pean Journal of Cardiovascular Prevention and Rehabilitationvol 15 no 1 pp 26ndash34 2008
[24] P Knekt J Ritz M A Pereira et al ldquoAntioxidant vitamins andcoronary heart disease risk a pooled analysis of 9 cohortsrdquoTheAmerican Journal of Clinical Nutrition vol 80 no 6 pp 1508ndash1520 2004
[25] A C Carr and M C M Vissers ldquoSynthetic or food-derivedvitamin Cmdashare they equally bioavailablerdquo Nutrients vol 5 no11 pp 4284ndash4304 2013
[26] R Tabrizchi ldquoEdaravoneMitsubishi-TokyordquoCurrentOpinion inInvestigational Drugs vol 1 no 3 pp 347ndash354 2000
[27] K Kikuchi S Tancharoen N Takeshige et al ldquoThe efficacy ofedaravone (radicut) a free radical scavenger for cardiovasculardiseaserdquo International Journal of Molecular Sciences vol 14 no7 pp 13909ndash13930 2013
[28] D Mauzerall and F H Westheimer ldquo1-Benzyldihydronicoti-namidemdasha model for reduced DPNrdquo Journal of the AmericanChemical Society vol 77 no 8 pp 2261ndash2264 1955 ChemicalAbstracts vol 50 Article ID 2588i 1956
[29] F Bossert and W Vater ldquo14-Dihydropyridinesmdasha basis fordeveloping new drugsrdquo Medicinal Research Reviews vol 9 no3 pp 291ndash324 1989
[30] G Swarnalatha G Prasanthi N Sirisha and CMadhusudhanaChetty ldquo14-Dihydropyridines a multtifunctional moleculemdash areviewrdquo International Journal of ChemTech Research vol 3 no1 pp 75ndash89 2011
28 Oxidative Medicine and Cellular Longevity
[31] M Cataldi and F Bruno ldquo14-Dihydropyridines the multiplepersonalities of a blockbuster drug familyrdquo Translational Medi-cine UniSa vol 4 no 2 pp 12ndash26 2012 httpwwwncbinlmnihgovpmcarticlesPMC3728803
[32] R Vitolina A Krauze G Duburs and A Velena ldquoAspects ofthe amlodipine pleiotropy in biochemistry pharmacology andclinicsrdquo International Journal of Pharmaceutical Sciences andResearch vol 3 no 5 pp 1215ndash1232 2012
[33] D Grover S N Mokale and M T Shete ldquoDihydropyridinea novel pharmacophorerdquo International Journal of Pharmaceu-tical Erudition vol 1 no 2 pp 16ndash29 2011 httppharmaeru-ditionorgContentPaper20111-RV-320Final2016-29pdf
[34] A M Vijesh A M Isloor S K Peethambar K N ShivanandaT Arulmoli and N A Isloor ldquoHantzsch reaction synthesis andcharacterization of somenew 14-dihydropyridine derivatives aspotent antimicrobial and antioxidant agentsrdquo European Journalof Medicinal Chemistry vol 46 no 11 pp 5591ndash5597 2011
[35] P Mehta and P Verma ldquoAntimicrobial activity of some deriva-tives of 14-dihydropyridinesrdquo Journal of Chemistry vol 2013Article ID 865128 4 pages 2013
[36] P Olejnıkova L Svorc D Olsovska et al ldquoAntimicrobialactivity of novel C2-substituted 14-dihydropyridine analoguesrdquoScientia Pharmaceutica vol 82 no 2 pp 221ndash232 2014
[37] S Sepehri H Perez Sanchez and A Fassihi ldquoHantzsch-typedihydropyridines and biginelli-type tetra-hydropyrimidinesa review of their chemotherapeutic activitiesrdquo Journal of Phar-macy amp Pharmaceutical Sciences vol 18 no 1 pp 1ndash52 2015httpsejournalslibraryualbertacaindexphpJPPSarticleview2383617863
[38] S A Khedkar and P B Auti ldquo14-Dihydropyridines a classof pharmacologically important moleculesrdquo Mini-Reviews inMedicinal Chemistry vol 14 no 3 pp 282ndash290 2014
[39] G D Tirzit and G Ya Duburs ldquo14-dihydropyridines as inhi-bitors of free-radical reactionsrdquo Chemistry of Heterocyclic Com-pounds vol 8 no 1 pp 126ndash127 1972 Translated from KhimiyaGeterotsiklicheskikh Soedinenii no1 pp 133ndash134 1972 (Rus-sian)
[40] I Bogeski R Kappl C Kummerow R Gulaboski M Hothand B A Niemeyer ldquoRedox regulation of calcium ion channelschemical and physiological aspectsrdquoCell Calcium vol 50 no 5pp 407ndash423 2011
[41] S A Giller G Y Dubur Y R Uldrikis et al ldquoDiludine [Themethod to obtain 35-dicarbonylderivatives of 26-dimethyl-14-dihydropyridines]rdquo Authors certificate of USSR no 3004651971 [Byull Izobret no13 p 95 1971] and following patentsPatent of England no 1294650 1973 Patent of France no2055458 1971 Patent of Japan no 702883 1973 Patent ofHolland no 149787 1976 Patent of Italy no 969022 1974 Patentof FRG no 2036403 1978 US Patent no 3883673 1975 USPatent no 3948924 1976
[42] S A Giller G Y Dubur Y R Uldrikis et al ldquoImprovementsin or relating to the stabilization of carotenerdquo GB Patent no1294650 1972
[43] S A Giller G Y Dubur Y R Uldrikis et al ldquoStabilization ofcarotenerdquo US Patent no 3883673 1975 Chemical Abstracts vol83 Article ID 95193 1975
[44] Yu A Zilber G Ya Dubur K K Kumsar and A Kh VelenaldquoThe effect of antioxidants on the peroxidation of bimole-cular phospholipid membranesrdquo Latvijas PSR ZA Vestis Izves-tia Akademii Nauk Latviyskoy SSR vol 6 pp 80ndash82 1971(Russian) translated from the original Russian Doc Accesion
No AD0771751 distributed by NTIS US Department of Com-merce httpwwwdticmildtictrfulltextu2771751pdf
[45] G Ya Dubur Yu A Zilbers A Kh Velena A O Kumerovaand G D Tirzitis ldquoMultistage study of regulation of peroxida-tion processes in biological membranes by antioxidants of 14-dihydropyridine grouprdquo Izvestiya Akademii Nauk LatviyskoySSR vol 336 no 7 pp 65ndash68 1975 (Russian)
[46] R P Mason and M W Trumbore ldquoDifferential membraneinteractions of calcium channel blockers Implications forantioxidant activityrdquo Biochemical Pharmacology vol 51 no 5pp 653ndash660 1996
[47] R P Mason M F Walter M W Trumbore E G Olmstead Jrand P E Mason ldquoMembrane antioxidant effects of the chargeddihydropyridine calcium antagonist amlodipinerdquo Journal ofMolecular and Cellular Cardiology vol 31 no 1 pp 275ndash2811999
[48] R PMason I T MakMW Trumbore and P EMason ldquoAnti-oxidant properties of calcium antagonists related to membranebiophysical interactionsrdquo American Journal of Cardiology vol84 no 4 pp 16ndash22 1999
[49] R PMasonMW Trumbore and P EMason ldquoMembrane bio-physical interaction of amlodipine and antioxidant propertiesrdquoDrugs vol 59 no 2 pp 9ndash16 2000 (French)
[50] R P Mason P Marche and T H Hintze ldquoNovel vascularbiology of third-generation L-type calcium channel antagonistsAncillary actions of amlodipinerdquo Arteriosclerosis Thrombosisand Vascular Biology vol 23 no 12 pp 2155ndash2163 2003
[51] A Augustyniak G Bartosz A Cipak et al ldquoNatural andsynthetic antioxidants an updated overviewrdquo Free RadicalResearch vol 44 no 10 pp 1216ndash1262 2010
[52] T Grune N Zarkovic and K Kostelidou ldquoLipid peroxidationresearch in Europe and the COST B35 action lsquoLipid Peroxida-tion Associated Disordersrsquordquo Free Radical Research vol 44 no10 pp 1095ndash1097 2010
[53] E Carosati P Ioan M Micucci et al ldquo14-Dihydropyridinescaffold in medicinal chemistry the story so far and perspec-tives (part 2) action in other targets and antitargetsrdquo CurrentMedicinal Chemistry vol 19 no 25 pp 4306ndash4323 2012
[54] U Eisner and J Kuthan ldquoThe chemistry of dihydropyridinesrdquoChemical Reviews vol 72 no 1 pp 1ndash42 1972 httpwwwsci-encemadnessorgtalkfilesphppid=138742ampaid=6475
[55] J Kuthan and A Kurfurst ldquoDevelopment in dihydropyri-dine chemistryrdquo Industrial amp Engineering Chemistry ProductResearch and Development vol 21 no 2 pp 191ndash261 1982
[56] A Sausins and G Duburs ldquoSynthesis of 14-dihydropyridinesby cyclocondensation reactionsrdquo Heterocycles vol 27 no 1 pp269ndash289 1988
[57] A E Sausins and G Y Duburs ldquoSynthesis of 14-dihydro-pyridines in cyclocondensation reactions (review)rdquo Chemistryof Heterocyclic Compounds vol 28 no 4 pp 363ndash391 1992Translated from Khimiya Geterotsiklicheskikh Soedinenii no 4pp 435ndash467 1992 (Russian)
[58] S Kazda ldquoTwenty years of dihydropyridinesrdquo in Dihydropy-ridines Progress in Pharmacology and Therapy W-D Busse BGarthoff and F Seuter Eds pp 1ndash12 Springer Verlag BerlinGermany 1993
[59] J-P Wan and Y Liu ldquoRecent advances in new multicomponentsynthesis of structurally diversified 14-dihydropyridinesrdquo RSCAdvances vol 2 no 26 pp 9763ndash9777 2012
[61] Reaxys Database[62] J Tuttle ldquoStructure mechanism and reactivity of hantzsch
estersrdquo in MacMillan Lab Group Meeting (082504) p 332004 httpwwwprincetoneduchemistrymacmillangroup-meetingsJBT20Hantzschpdf
[63] A Saini S Kumar and J S Sandhu ldquoHantzsch reaction recentadvances in Hantzsch 14-dihydropyridinesrdquo Journal of Sci-entific amp Industrial Research vol 67 pp 95ndash111 2008
[64] L LW Cheung S A Styler and A P Dicks ldquoRapid and conve-nient synthesis of the 14-dihydropyridine privileged structurerdquoJournal of Chemical Education vol 87 no 6 pp 628ndash630 2010
[65] A Kumar R A Maurya S Sharma M Kumar and G BhatialdquoSynthesis and biological evaluation of N-aryl-14-dihydro-pyridines as novel antidyslipidemic and antioxidant agentsrdquoEuropean Journal of Medicinal Chemistry vol 45 no 2 pp 501ndash509 2010
[66] R S Kumar A Idhayadhulla A J Abdul Nasser and J SelvinldquoSynthesis and anticoagulant activity of a new series of 14-dihydropyridine derivativesrdquo European Journal of MedicinalChemistry vol 46 no 2 pp 804ndash810 2011
[67] H A Stefani C B Oliveira R B Almeida et al ldquoDihydro-pyrimidin-(2H)-ones obtained by ultrasound irradiation anew class of potential antioxidant agentsrdquo European Journal ofMedicinal Chemistry vol 41 no 4 pp 513ndash518 2006
[68] H Sun C Shang L Jin and J Zhang ldquoSynthesis and antiox-idant activity of a series of novel 3-chalcone-substituted 14-dihydropyridine derivativesrdquoHeterocyclic Communications vol18 no 5-6 pp 239ndash243 2012
[69] D B Tikhonov and B S Zhorov ldquoStructural model for dihy-dropyridine binding to L-type calcium channelsrdquo The Journalof Biological Chemistry vol 284 no 28 pp 19006ndash19017 2009
[70] G Y Dubur and Y R Uldrikis ldquoThe oxidation of 14-dihydro-pyridinesrdquo Chemistry of Heterocyclic Compounds vol 6 no 1pp 80ndash84 1970 Translated from Khimiya GeterotsiklicheskikhSoedinenii no 1 pp 83ndash88 1970 (Russian)
[71] G Ya Duburs A O Kumerova and Ya R Uldrikis ldquoEnzymicoxidation of hydrogenated pyridines with peroxidase-hydrogenperoxide systemrdquoLatvijas PSRZAVestis vol 73 no 7 pp 73ndash771970 (Russian) Chemical Abstracts vol 73 Article ID 94913g1970
[72] K Xie Y-C Liu Y Cui J-GWang Y Fu andT CWMak ldquoN-methyl-(R)-3-(tert-butyl)-sulfinyl-14-dihydropyridine a novelNADHmodel compoundrdquoMolecules vol 12 no 3 pp 415ndash4222007
[73] S Tamagaki T Mimura and W Tagaki ldquoMetal-ion-facilitatedoxidations of dihydropyridines with molecular oxygen andhydrogen peroxiderdquo Journal of the Chemical Society PerkinTransactions 2 no 10 pp 1645ndash1650 1990
[74] D Tirzite G Tirzitis andD Antipova ldquoReductive ability of 14-dihydropyridine derivatives in relation to ions of trivalent ironrdquoChemistry of Heterocyclic Compounds vol 35 no 5 pp 592ndash594 1999
[76] J Ogle J Stradins and L Baumane ldquoFormation and decay offree cation-radicals in the course of electro-oxidation of 12- and14-dihydropyridines (Hantzsch esters)rdquo Electrochimica Actavol 39 no 1 pp 73ndash79 1994
[77] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for the
synthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts C Wittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Berlin Germany 2010
[78] WDu and Zh Yu ldquoBiomimetic in situ regeneration of cofactorsNAD(P)+ and NAD(P)H models hantzsch esters and dihy-drophenanthridinerdquo Synlett vol 23 no 9 pp 1300ndash1304 2012
[79] H K Chenault and G M Whitesides ldquoRegeneration ofnicotinamide cofactors for use in organic synthesisrdquo AppliedBiochemistry and Biotechnology vol 14 no 2 pp 147ndash197 1987
[80] Y R Uldrikis A A Zidermane E A Biseniex I E Preisa GY Dubur and G D Tirzit ldquoEsters of 26-dimethyl-14-dihydro-pyridine-35-dicarboxylic acid and method of obtainingthereofrdquo WO 8000345 A1 1978 httpworldwideespacenetcompublicationDetailsbiblioDB=EPODOCampII=1ampND=3ampadjacent=trueamplocale=en EPampFT=Dampdate=19800306ampCC=WOampNR=8000345A1ampKC=A1
[81] Y Sambongi H Nitta K Ichihashi M Futai and I Ueda ldquoAnovel water-soluble Hantzsch 14-dihydropyridine compoundthat functions in biological processes through NADH regener-ationrdquo Journal of Organic Chemistry vol 67 no 10 pp 3499ndash3501 2002
[82] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for thesynthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts ChWittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Verlag Berlin Germany 2010
[83] T Okamura T Kikuchi A Nagamine et al ldquoAn approach formeasuring in vivo cerebral redox states using the oxidative con-version of dihydropyridine to pyridinium ion and themetabolictrapping principlerdquo Free Radical Biology and Medicine vol 38no 9 pp 1197ndash1205 2005
[84] K A Schellenberg and F H Westheimer ldquoA free-radicaloxidation of a dihydropyridine1ardquo The Journal of OrganicChemistry vol 30 no 6 pp 1859ndash1862 1965
[85] K A Schellenberg ldquoReaction of hydroxyl radical with thymi-dine Scavenging by a dihydropyridinerdquo Federation Proceedingsvol 38 no 3 I p 1433 1979
[86] E S Huyser J A K Harmony and F L McMillian ldquoPeroxideoxidations of dihydropyridine derivativesrdquo Journal of the Amer-ican Chemical Society vol 94 no 9 pp 3176ndash3180 1972
[87] A Sakamoto S T Ohnishi and R Ogawa ldquoInhibition of lipidperoxidation by some dihydropyridine derivativesrdquo Journal ofAnesthesia vol 7 no 2 pp 193ndash197 1993
[88] R Hardeland ldquoReview Neuroprotection by radical avoidancesearch for suitable agentsrdquo Molecules vol 14 no 12 pp 5054ndash5102 2009
[89] G Ya Dubur A Kh Velena V M Gukasov and Yu AVladimirov ldquoRegulation of peroxidation of mitochondrialmembrane lipids initiated by Fe2+ ions by antoxidants of the14-dihydropyridine series in experiments in vitrordquo Biomed-itsinskaya Khimiya vol 22 no 5 pp 665ndash673 1976 (Russian)Chemical Abstracts vol 88 Article ID 2640 1977
[90] G RMMHaenenM J T J Arts A Bast andMD ColemanldquoStructure and activity in assessing antioxidant activity in vitroand in vivo a critical appraisal illustrated with the flavonoidsrdquoEnvironmental Toxicology and Pharmacology vol 21 no 2 pp191ndash198 2006
[91] G Tirzitis and G Bartosz ldquoDetermination of antiradical andantioxidant activity basic principles and new insightsrdquo ActaBiochimica Polonica vol 57 no 2 pp 139ndash142 2010
30 Oxidative Medicine and Cellular Longevity
[92] G R Buettner and R P Mason ldquoSpin-trapping methods fordetecting superoxide and hydroxyl free radicals in vitro and invivordquo inCritical Reviews of Oxidative Stress and Aging Advancesin Basic Science Diagnostics and Intervention R G Cutler andH Rodriguez Eds vol 1 chapter 2 pp 27ndash38World ScientificLondon UK 2003
[93] M M Tarpey and I Fridovich ldquoMethods of detection ofvascular reactive species Nitric oxide superoxide hydrogenperoxide and peroxynitriterdquo Circulation Research vol 89 no3 pp 224ndash236 2001
[94] E Y Kazush E I Sagun G D Tirzit and G Y DaburldquoQuenching of singlet oxygen by electron donating derivativesof 14-dihydropyridinerdquo Chemistry of Heterocyclic Compoundsvol 30 no 5 pp 562ndash563 1994
[95] G Tirzitis E Kazush and G Duburs ldquoReaction of 14-dihydropyridine derivatives with peroxynitrite anionrdquo Chem-istry of Heterocyclic Compounds vol 34 no 3 pp 321ndash3231998 (Russian) Translated from Khimiya GeterotsiklicheskikhSoedinenii no 3 pp 355ndash357 1998
[96] L J Nunez-Vergara C Lopez-Alarcon P A Navarrete-EncinaA M Atria C Camargo and J A Squella ldquoElectrochemicaland EPR characterization of 14-dihydropyridines Reactivitytowards alkyl radicalsrdquo Free Radical Research vol 37 no 1 pp109ndash120 2003
[97] D Tirzite A Krauze A Zubareva G Tirzitis and G DubursldquoSynthesis and antiradical activity of 5-acetyl-2-alkylthio-4-aryl-6-methyl-14-dihydropyridine-3-carboxylic acid nitrilesrdquoChemistry of Heterocyclic Compounds vol 38 no 7 pp 795ndash800 2002
[98] H Ohkawa N Ohishi and K Yagi ldquoAssay for lipid peroxidesin animal tissues by thiobarbituric acid reactionrdquo AnalyticalBiochemistry vol 95 no 2 pp 351ndash358 1979
[99] N Zarkovic ldquo4-Hydroxynonenal as a bioactive marker ofpathophysiological processesrdquo Molecular Aspects of Medicinevol 24 no 4-5 pp 281ndash291 2003
[100] M Parola G Bellomo G Robino G Barrera and M UDianzani ldquo4-Hydroxynonenal as a biological signal molecularbasis and pathophysiological implicationsrdquo Antioxidants andRedox Signaling vol 1 no 3 pp 255ndash284 1999
[101] T Lovakovic M Poljak-Blazi G Duburs et al ldquoGrowthmodulation of human cells in vitro by mild oxidative stressand 14-dihydropyridine derivative antioxidantsrdquo CollegiumAntropologicum vol 35 no 1 pp 137ndash141 2011
[102] R van den Berg G R M M Haenen H van den Bergand A Bast ldquoApplicability of an improved Trolox equivalentantioxidant capacity (TEAC) assay for evaluation of antioxidantcapacity measurements of mixturesrdquo Food Chemistry vol 66no 4 pp 511ndash517 1999
[103] C Lopez-Alarcon P Navarrete C Camargo J A Squella andL J Nunez-Vergara ldquoReactivity of 14-dihydropyridines towardalkyl alkylperoxyl radicals and ABTS radical cationrdquo ChemicalResearch in Toxicology vol 16 no 2 pp 208ndash215 2003
[104] V Valenzuela P Santander C Camargo J A Squella C Lopez-Alarcon and L J Nunez-Vergara ldquo14-Dihydropyridines reac-tivity of nitrosoaryl and nitroaryl derivatives with alkylperoxylradicals andABTS radical cationrdquo Free Radical Research vol 38no 7 pp 715ndash727 2004
[105] L G Tsetlin N A Chebotareva B I Kurganov A K VelenaG Y Dubur and V Z Lankin ldquoStudy of 14-dihydropyridinesas lipoxygenase inhibitors with the use of hydrated reversedmicellesrdquo Pharmaceutical Chemistry Journal vol 22 no 6 pp425ndash428 1988 (Russian)
[106] J Panek Z Reblova L Kocirkova et al ldquoAntioxidant activityof dihydropyridine derivativesrdquo Czech Journal of Food Sciencesvol 18 pp 144ndash145 2000
[107] G Tirzitis I Kirule and G Duburs ldquoAntioxidationsaktivitatder 35-dicarbonylderivate des 26-demethyl-14-dihydropyri-dinsrdquo Fett Wissenschaft TechnologieFat Science Technology vol90 no 10 pp 411ndash413 1988
[108] M Plotniece G Tirzitis Y Uldrikis et al ldquoSynthesis of 14-dihydropyridine derivatives having an oxy- alkoxy- or dimeth-ylaminophenyl substituent in the 4 position their antioxidantactivity and their binding to phospholipid membranesrdquo Chem-istry of Heterocyclic Compounds vol 32 no 10 pp 1166ndash11721996 Translated from Khimiya Geterotsiklicheskikh Soedineniino 10(352) pp 1358ndash1365 1996 (Russian)
[109] D Y Rubene V S Sharov V I Olenev G D Tirzit G Y Duburand Y A Vladimirov ldquoUse of chemiluminescent method forthe evaluation of antioxidant activity of some derivatives of 14-dihydropyridinerdquo Russian Journal of Physical Chemistry A vol55 no 2 pp 511ndash512 1981 (Russian)
[110] M C R Symons and JM C Gutteridge Free Radicals and IronChemistry Biology and Medicine Oxford Science PublicationsOxford University Press Oxford UK 1998
[111] M Repetto J Semprine and A Boveris ldquoLipid peroxidationchemical mechanism biological implications and analyticaldeterminationrdquo in Lipid Peroxidation A Catala Ed Section ILipid Peroxidation Chemical Mechanisms Antioxidants Bio-logical Implications of Biochemistry Genetics and MolecularBiology chapter 1 pp 3ndash30 InTech Rijeka Croatia 2012
[112] A Velena J Zilbers and G Duburs ldquoDerivatives of 14-dihydropyridines asmodulators of ascorbate-induced lipid per-oxidation and high-amplitude swelling ofmitochondria causedby ascorbate sodium linoleate and sodiumpyrophosphaterdquoCellBiochemistry and Function vol 17 no 4 pp 237ndash252 1999
[113] M V Bilenko L N Shelenkova G Y Dubur and A K VelenaldquoUse of antioxidants to prevent renal damage during acuteischemia and reperfusionrdquo Bulletin of Experimental Biology andMedicine vol 96 no 3 pp 1195ndash1198 1983 Translated fromByulletenrsquo Eksperimentalrsquonoi Biologii i Meditsiny vol 96 no 9pp 8ndash11 1983 (Russian)
[114] R Toniolo F Tubaro F Ursini and G Bontempelli ldquoAn elec-troanalytical investigation on the redox properties of calciumantagonist dihydropyridinesrdquo Electroanalysis vol 15 no 10 pp855ndash861 2003
[115] L Kourimska J Pokorny and G Tirzitis ldquoThe antioxidant aci-tivity of 26-dimethyl-35-diethoxycarbonyl-14-dihydropyri-dine in edible oilsrdquo Nahrung vol 37 no 1 pp 91ndash93 1993
[116] C Lopez-Alarcon H Speisky J A Squella C Olea-Azar CCamargo and L J Nunez-Vergara ldquoReactivity of 14-dihydro-pyridines toward SIN-1-derived peroxynitriterdquo PharmaceuticalResearch vol 21 no 10 pp 1750ndash1757 2004
[117] R A Olek W Ziolkowski J J Kaczor L Greci J Popinigisand J Antosiewicz ldquoAntioxidant activity of NADH and its ana-loguemdashan in vitro studyrdquo Journal of Biochemistry andMolecularBiology vol 37 no 4 pp 416ndash421 2004
[118] E Niki N Noguchi and N Gotoh ldquoInhibition of oxidativemodification of low density lipoprotein by antioxidantsrdquo Jour-nal of Nutritional Science andVitaminology vol 39 supplementpp S1ndashS8 1993
[119] N Rojstaczer and D J Triggle ldquoStructure-function relation-ships of calcium antagonists effect on oxidative modificationof low density lipoproteinrdquo Biochemical Pharmacology vol 51no 2 pp 141ndash150 1996
Oxidative Medicine and Cellular Longevity 31
[120] A Sevanian L Shen and FUrsini ldquoInhibition of LDLoxidationand oxidized LDL-induced cytotoxicity by dihydropyridinecalcium antagonistsrdquo Pharmaceutical Research vol 17 no 8 pp999ndash1006 2000
[121] A Negre-Salvayre and R Salvayre ldquoProtection by Ca2+ channelblockers (nifedipine diltiazem and verapamil) against the tox-icity of oxidized low density lipoprotein to cultured lymphoidcellsrdquo British Journal of Pharmacology vol 107 no 3 pp 738ndash744 1992
[122] A Negre-Salvayre G FitoussiM Troly and R Salvayre ldquoCom-parative cytoprotective effect of dihydropyridine calcium chan-nel blockers against the toxicity of oxidized low density lipopro-tein for cultured lymphoid cellsrdquo Biochemical Pharmacologyvol 44 no 12 pp 2379ndash2386 1992
[123] L Cominacini A F Pasini U Garbin et al ldquoAntioxidant activ-ity of different dihydropyridinesrdquo Biochemical and BiophysicalResearch Communications vol 302 no 4 pp 679ndash684 2003
[124] L Cominacini U Garbin A Fratta Pasini et al ldquoOxidized low-density lipoprotein increases the production of intracellularreactive oxygen species in endothelial cells inhibitory effect oflacidipinerdquo Journal of Hypertension vol 16 no 12 part 2 pp1913ndash1919 1998
[125] H M Lander ldquoAn essential role for free radicals and derivedspecies in signal transductionrdquo The FASEB Journal vol 11 no2 pp 118ndash124 1997
[126] M L L Martinez E Rizzi M M Castro et al ldquoLercanidipinedecreases vascular matrix metalloproteinase-2 activity andprotects against vascular dysfunction in diabetic ratsrdquo EuropeanJournal of Pharmacology vol 599 no 1ndash3 pp 110ndash116 2008
[127] P Lesnik C Dachet L Petit et al ldquoImpact of a combinationof a calcium antagonist and a 120573-blocker on cell- and copper-mediated oxidation of LDL and on the accumulation and effluxof cholesterol in human macrophages and murine J774 cellsrdquoArteriosclerosis Thrombosis and Vascular Biology vol 17 no 5pp 979ndash988 1997
[128] G Sobal E J Menzel and H Sinzinger ldquoCalcium antagonistsas inhibitors of in vitro low density lipoprotein oxidation andglycationrdquoBiochemical Pharmacology vol 61 no 3 pp 373ndash3792001
[129] E Lupo R Locher B Weisser and W Vetter ldquoIn vitro antiox-idant activity of calcium antagonists against LDL oxidationcompared with 120572-tocopherolrdquo Biochemical and BiophysicalResearch Communications vol 203 no 3 pp 1803ndash1808 1994
[130] J Zou Y Li H-Q Fan and J-G Wang ldquoEffects of dihydropy-ridine calcium channel blockers on oxidized low-density lipo-protein induced proliferation and oxidative stress of vascularsmooth muscle cellsrdquo BMC Research Notes vol 5 article 1682012
[131] C Napoli S Salomone T Godfraind et al ldquo14-Dihydro-pyridine calcium channel blockers inhibit plasma and LDL oxi-dation and formation of oxidation-specific epitopes in the arte-rial wall and prolong survival in stroke-prone spontaneouslyhypertensive ratsrdquo Stroke vol 30 no 9 pp 1907ndash1915 1999
[132] G Zernig I Graziadei T Moshammer C Zech N Reider andH Glossmann ldquoMitochondrial Ca2+ antagonist binding sitesare associated with an inner mitochondrial membrane anionchannelrdquo Molecular Pharmacology vol 38 no 3 pp 362ndash3691990
[133] F E Hunter Jr A Scott P E Hochstein et al ldquoStudies of themechanism of ascorbate-induced swelling and lysis of isolatedliver mitochondriardquo The Journal of Biological Chemistry vol239 pp 604ndash613 1964
[134] D R Janero B Burghardt and R Lopez ldquoProtection of cardiacmembrane phospholipid against oxidative injury by calciumantagonistsrdquoBiochemical Pharmacology vol 37 no 21 pp 4197ndash4203 1988
[135] A Karadag B Ozcelik and S S Saner ldquoReview of methods todetermine antioxidant capacitiesrdquo FoodAnalyticalMethods vol2 no 1 pp 41ndash60 2009
[136] Y I Gubskiı N V Litvinova and E V Shnurko-TabakovaldquoAntioxidant and antiradical activity of various classes of antiox-idantsrdquo Ukrainskiı Biokhimicheskiı Zhurnal vol 66 no 4 pp114ndash116 1994 (Russian)
[137] M Takei M Hiramatsu and A Mori ldquoInhibitory effects ofcalcium antagonists onmitochondrial swelling induced by lipidperoxidation or arachidonic acid in the rat brain in vitrordquoNeurochemical Research vol 19 no 9 pp 1199ndash1206 1994
[138] M Takei M Hiramatsu R Edamatsu and A Mori ldquoFreeradical scavenging by calcium antagonistsrdquo Neurosciences vol20 no 2 pp 75ndash82 1994
[139] Ya P Stradin G Ya Dubur Yu A Beilis Ya R Uldrikis andA F Korotkova ldquoVoltammetry of 14-dihydropyridine deriva-tives I Potentials of electrochemical oxidation of 35-diacyl-and 35-di(alkoxycarbonyl)-14-dihydropyridines in acetoni-trilerdquo Chemistry of Heterocyclic Compounds no 1 pp 84ndash871972 (Russian)
[140] E V Ivanov T V Ponomarjova G N Merkusev et al ldquoEinneuer Haut-Radioprotektor Diethon (experimentelle Unter-suchung)rdquo Radiobiologia Radiotherapia vol 31 no 1 pp 69ndash78 1990
[141] E V Ivanov T V Ponomareva G N Merkushev et al ldquoRadia-tion modulating properties of derivates of 14-dihydropyridineand 12345678910-decahydroacridine-18 dionerdquo Radiat-sionnaia Biologiia Radioecologiia vol 44 no 5 pp 550ndash5592004 (Russian)
[142] R O Vitolinia D A Berzinia A K Velena I A Vutsina A AKimenis and G Y Duburs ldquoThe protective effects of the cal-cium antagonist foridon in acute myocardial ischaemiardquo Kardi-ologiya vol 27 no 3 pp 90ndash93 1987 (Russian)
[143] A H Velena G Ya Duburs R O Vitolina et al ldquoEffect ofryodipine on electromechanical parameters of heart and vesselscAMP phosphodiesterase activity and swelling-contractioncycle of mitochondriardquo Arzneimittelforschung vol 35 no 6 pp907ndash914 1985
[144] L I Utno Z E Lipsberga A A Silova M I Girgensone EA Bisenieks and G I Ia ldquoCardioprotective properties of a 14-dihydropyridine derivative glutapyrone in deep hypothermiardquoBiulletenrsquo Eksperimentalrsquonoı Biologii i Meditsiny vol 108 no 11pp 558ndash561 1989 (Russian)
[145] M A S FernandesM S Santos J A F Vicente et al ldquoEffects of14-dihydropyridine derivatives (cerebrocrast gammapyroneglutapyrone and diethone) onmitochondrial bioenergetics andoxidative stress a comparative studyrdquoMitochondrion vol 3 no1 pp 47ndash59 2003
[146] M A S Fernandes M S Santos A J M Moreno et al ldquoEffectsof 5-acetyl(carbamoyl)-6-methylsulfanyl-14-dihydropyridine-5-carbonitriles on rat liver mitochondrial functionrdquo Toxicologyin Vitro vol 23 no 7 pp 1333ndash1341 2009
[147] L Klimaviciusa A Kalda A Kaasik et al ldquoNeuroprotectiveactivity of 14-dihydropyridine derivatives structure determi-nantsrdquo Proceedings of the Latvian Academy of Sciences BNatural Exact and Applied Sciences vol 61 no 1-2 pp 33ndash372007
32 Oxidative Medicine and Cellular Longevity
[148] L Klimaviciusa M A S Fernandes N Lencberga et alldquoTargeting the mitochondria by novel adamantane-containing14-dihydropyridine compoundsrdquo in Bioenergetics K B ClarkEd pp 257ndash272 InTech 2012
[149] V Klusa L Klimaviciusa G Duburs J Poikans and AZharkovsky ldquoAnti-neurotoxic effects of tauropyrone a taurineanaloguerdquo Advances in Experimental Medicine and Biology vol583 pp 499ndash508 2006
[150] N Sampson P Berger and Ch Zenzmaier ldquoRedox signalingas a therapeutic target to inhibit myofibroblast activation indegenerative fibrotic diseaserdquo BioMed Research Internationalvol 2014 Article ID 131737 14 pages 2014
[151] T L Leto and M Geiszt ldquoRole of Nox family NADPH oxidasesin host defenserdquoAntioxidantsampRedox Signaling vol 8 no 9-10pp 1549ndash1561 2006
[152] K K Griendling D Sorescu and M Ushio-Fukai ldquoNAD(P)Hoxidase role in cardiovascular biology and diseaserdquo CirculationResearch vol 86 no 5 pp 494ndash501 2000
[153] H Chen Y S Song and P H Chan ldquoInhibition of NADPHoxi-dase is neuroprotective after ischemia-reperfusionrdquo Journal ofCerebral Blood Flow and Metabolism vol 29 no 7 pp 1262ndash1272 2009
[154] P Hochstein and L Ernster ldquoADP-activated lipid peroxidationcoupled to the TPNH oxidase system of microsomesrdquo Biochem-ical and Biophysical Research Communications vol 12 no 5 pp388ndash394 1963
[155] I I Gubskiı AGGoriushkoNV Litvinova et al ldquoAntioxidantproperties and membranotropic effect of certain derivatives of14-dihydropyridinerdquo Ukrainskiı Biokhimicheskiı Zhurnal vol71 no 4 pp 35ndash39 1999 (Russian)
[156] F Engineer and R Sridhar ldquoInhibition of rat heart andliver microsomal lipid peroxidation by nifedipinerdquo BiochemicalPharmacology vol 38 no 8 pp 1279ndash1285 1989
[157] T Goncalves A P Carvalho and C R Oliveira ldquoAntioxidanteffect of calcium antagonists on microsomai membranes iso-lated from different brain areasrdquo European Journal of Pharma-cology vol 204 no 3 pp 315ndash322 1991
[158] M E Letelier P Izquierdo L Godoy A M Lepe and MFaundez ldquoLiver microsomal biotransformation of nitro-aryldrugs mechanism for potential oxidative stress inductionrdquoJournal of Applied Toxicology vol 24 no 6 pp 519ndash525 2004
[159] M E Letelier P Entrala C Lopez-Alarcon et al ldquoNitroaryl-14-dihydropyridines as antioxidants against rat liver microsomesoxidation induced by ironascorbate Nitrofurantoin and naph-thalenerdquo Toxicology in Vitro vol 21 no 8 pp 1610ndash1618 2007
[160] F P Guengerich W R Brian M Iwasaki M-A Sari CBaarnhielm and P Berntsson ldquoOxidation of dihydropyridinecalcium channel blockers and analogues by human liver cyto-chrome P-450 IIIA4rdquo Journal of Medicinal Chemistry vol 34no 6 pp 1838ndash1844 1991
[161] S H Park S-W RhaW-Y Shin et al ldquoAS-160 Calcium channelblockers of dihydropyridine class reduce the antiplatelet effectof Clopidogrel what is clinical impactrdquo The American Journalof Cardiology vol 107 no 8 supplement p 47A 2011
[162] C Asma and D M Reda ldquoEvaluation of dihydropyridinecalcium antagonist effects on the stress bioindicator orga-nism Saccharomyces cerevisiaerdquo Annals of Biological Researchvol 4 no 10 pp 40ndash46 2013 httpscholarsresearchlibrarycomABR-vol4-iss10ABR-2013-4-10-40-46pdf
[163] G Gaviraghi A M Pastorino E Ratti and D G TristldquoCalcium channel blockers with antioxidant activityrdquo in Free
Radicals Lipoprotein Oxidation andAtherosclerosis G BellomoG Finardi E Maggi and E Rice-Evans Eds pp 431ndash456Richelieu Press London UK 1995
[164] G Gaviraghi AM Pastorino E Ratti and D G Trist ldquoAntiox-idant dihydropyridines a new and comprehensive therapy forfree radical-induced cardiovascular diseasesrdquo in Free Radicalsin Biology and Environment F Minisci Ed vol 27 of NATOASI Series pp 193ndash221 Springer Dordrecht The Netherlands1997
[165] P D Henry ldquoAntiperoxidative actions of calcium antagonistsand atherogenesisrdquo Journal of Cardiovascular Pharmacologyvol 18 supplement 1 pp S6ndashS10 1991
[166] F Kouoh B Gressier T Dine et al ldquoAntioxidant effects andanti-elastase activity of the calcium antagonist nicardipine onactivated human and rabbit neutrophilsmdasha potential antiath-erosclerotic property of calcium antagonistsrdquo CardiovascularDrugs andTherapy vol 16 no 6 pp 515ndash520 2002
[167] S Parthasarathy D Litvinov K Selvarajan and M GarelnabildquoLipid peroxidation and decompositionmdashconflicting roles inplaque vulnerability and stabilityrdquo Biochimica et BiophysicaActa vol 1781 no 5 pp 221ndash231 2008
[168] D-Q Liu Z-Q Pang D-H Zhao and B-H Sheng ldquoEffects offuryl-dihydropyridines I on lipid peroxides of ischemic myo-cardium and ATPases activity of erythrocyte membranes inratsrdquo Acta Pharmacologica Sinica vol 12 no 3 pp 253ndash2561991
[169] V Lukic-Panin T Kamiya H Zhang et al ldquoPrevention of neu-ronal damage by calcium channel blockers with antioxidativeeffects after transient focal ischemia in ratsrdquo Brain Research vol1176 no 1 pp 143ndash150 2007
[170] Y Allanore D Borderie H Lemarechal O G Ekindjian andA Kahan ldquoAcute and sustained effects of dihydropyridine-typecalcium channel antagonists on oxidative stress in systemicsclerosisrdquo American Journal of Medicine vol 116 no 9 pp 595ndash600 2004
[171] I Casetta V Govoni and E Granieri ldquoOxidative stress antioxi-dants and neurodegenerative diseasesrdquo Current PharmaceuticalDesign vol 11 no 16 pp 2033ndash2052 2005
[172] M J T J Arts Assessing antioxidant activity [PhD the-sis] Maastricht University Maastricht The Netherlands 2007httparnounimaasnlshowcgifid=8676
[173] G Dıaz-Araya L Godoy L Naranjo A Squella M E Letelierand L J Nunez-Vergara ldquoAntioxidant effects of 14-dihydro-pyridine and nitroso aryl derivatives on the Fe+3ascorbate-stimulated lipid peroxidation in rat brain slicesrdquo General Phar-macology The Vascular System vol 31 no 3 pp 385ndash391 1998
[174] Y Fukuhara K Tsuchiya Y Horinouchi et al ldquoProtectiveeffect of photodegradation product of nifedipine against tumornecrosis factor 120572-induced oxidative stress in human glomerularendothelial cellsrdquo Journal of Medical Investigation vol 58 no1-2 pp 118ndash126 2011
[175] W Stengel M Jainz and K Andreas ldquoDifferent potencies ofdihydropyridine derivatives in blocking T-type but not L-typeCa2+ channels in neuroblastoma-glioma hybrid cellsrdquo EuropeanJournal of Pharmacology vol 342 no 2-3 pp 339ndash345 1998
[176] O M Panasenko D J Tirzite G D Tirzitis and G J DubursldquoEffect of some 14-dihydropyridine derivatives on structuralorganization of erythrocyte membranesrdquo Biologicheskie Mem-brany (Biochemistry (Moscow) Series A Membrane and CellBiology) vol 1 pp 919ndash925 1984 (Russian)
[177] L G Herbette Y M H Vant Erve and D G Rhodes ldquoInter-action of 14 dihydropyridine calcium channel antagonists with
Oxidative Medicine and Cellular Longevity 33
biological membranes lipid bilayer partitioning could occurbefore drug binding to receptorsrdquo Journal of Molecular andCellular Cardiology vol 21 no 2 pp 187ndash201 1989
[178] L G Herbette P E Mason G Gaviraghi T N Tulenko andR P Mason ldquoThe molecular basis for lacidipinersquos unique phar-macokinetics optimal hydrophobicity results in membraneinteractions that may facilitate the treatment of atherosclerosisrdquoJournal of Cardiovascular Pharmacology vol 23 supplement 5pp S16ndashS25 1994
[179] G V Belevitch G Y Dubur G E Dobretsov N K Kurek andM M Spirin ldquoCalcium antagonists riodipine nifedipine andverapamil binding to model and biological membranes fluore-scence analysisrdquo Biologicheskie Membrany (Biochemistry(Moscow) Series A Membrane and Cell Biology) vol 5 pp768ndash776 1988 (Russian)
[180] R P Mason G E Gonye D W Chester and L G HerbetteldquoPartitioning and location of Bay K 8644 14-dihydropyridinecalcium channel agonist in model and biological membranesrdquoBiophysical Journal vol 55 no 4 pp 769ndash778 1989
[181] M Cindric A Cipak J Serly et al ldquoReversal of multidrugresistance inmurine lymphoma cells by amphiphilic dihydropy-ridine antioxidant derivativerdquo Anticancer Research vol 30 no10 pp 4063ndash4070 2010
[182] F Shekari H Sadeghpour K Javidnia et al ldquoCytotoxic andmultidrug resistance reversal activities of novel 14-dihydro-pyridines against human cancer cellsrdquo European Journal ofPharmacology vol 746 no 1 pp 233ndash244 2015
[183] X-F Zhou Q Shao R A Coburn and M E Morris ldquoQuanti-tative structure-activity relationship and quantitative structure-pharmacokinetics relationship of 14-dihydropyridines andpyridines as multidrug resistance modulatorsrdquo PharmaceuticalResearch vol 22 no 12 pp 1989ndash1996 2005
[184] R Berkels T Breitenbach H Bartels et al ldquoDifferent antioxida-tive potencies of dihydropyridine calcium channel modulatorsin various modelsrdquo Vascular Pharmacology vol 42 no 4 pp145ndash152 2005
[185] S Borovic G Tirzitis D Tirzite et al ldquoBioactive 14-dihydro-isonicotinic acid derivatives prevent oxidative damage of livercellsrdquo European Journal of Pharmacology vol 537 no 1ndash3 pp12ndash19 2006
[186] D Ya Rubene G D Tirzitis and G Ya Duburs ldquoInteractionof some 14-dihydropyridine derivatives with Fentonrsquos reagentrdquoLatvijas PSRZinatnuAkademijas Vestis Kimijas Serija Proceed-ings of the Latvian SSR Academy of Sciences Chemistry Seriespp 212ndash216 1982 (Russian)
[187] K Ondrias V Misık D Gergel and A Stasko ldquoLipid per-oxidation of phosphatidylcholine liposomes depressed by thecalcium channel blockers nifedipine and verapamil and bythe antiarrhythmic-antihypoxic drug stobadinerdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1003 no 3pp 238ndash245 1989
[188] I T Mak and W B Weglicki ldquoComparative antioxidant acti-vities of propranolol nifedipine verapamil and diltiazemagainst sarcolemmal membrane lipid peroxidationrdquoCirculationResearch vol 66 no 5 pp 1449ndash1452 1990
[189] I T Mak P Boehme and W B Weglicki ldquoProtective effects ofcalcium channel blockers against free radical-impaired endo-thelial cell proliferationrdquo Biochemical Pharmacology vol 50 no9 pp 1531ndash1534 1995
[190] S Ray S Mondal and N Dana ldquoEvaluation of protective roleof nifedipine on lipid peroxidation using reduced glutathione as
model markerrdquo Oxidants and Antioxidants in Medical Sciencevol 1 no 2 pp 97ndash100 2012
[191] M Yamato T Shiba T Ide Y Honda K-I Yamada andH Tsutsui ldquoNifedipine treatment reduces brain damage aftertransient focal ischemia possibly through its antioxidativeeffectsrdquoHypertension Research vol 34 no 7 pp 840ndash845 2011
[192] V Chander and K Chopra ldquoNifedipine attenuates changes innitric oxide levels renal oxidative stress and nephrotoxicityinduced by cyclosporinerdquo Renal Failure vol 27 no 4 pp 441ndash450 2005
[193] K M Gaafa M M Badawy and A A Hamza ldquoThe protectiveeffects of ascorbic acid cimetidine and nifedipine on diethyl-dithiocarbamate-induced hepatic toxicity in albino ratsrdquo Drugand Chemical Toxicology vol 34 no 4 pp 405ndash419 2011
[194] H Sugawara K Tobise and S Onodera ldquoAbsence of antiox-idant effects of nifedipine and diltiazem on myocardial mem-brane lipid peroxidation in contrast with those of nisoldipineand propranololrdquo Biochemical Pharmacology vol 47 no 5 pp887ndash892 1994
[195] I E Kirule D Y Rubene E A Bisenieks G D Tirzit and GY Dubur ldquo4-Nitrophenyl-14-dihydropyridinesmdasha new groupof inhibitors of peroxide oxidationrdquo Chemistry of HeterocyclicCompounds vol 18 no 3 p 316 1982
[196] G D Tirzit I E Kirule L K Baumane R A Gavar Y PStradynrsquo andG YDubur ldquoMechanism of the antioxidant actionof 26-dimethyl-35-dimethoxy-carbonyl-4-(2-nitrophenyl)14-dihydropyridinerdquoChemistry ofHeterocyclic Compounds vol 20no 8 pp 915ndash918 1984
[197] C Yanez C Lopez-Alarcon C Camargo V Valenzuela J ASquella and L J Nunez-Vergara ldquoStructural effects on thereactivity 14-dihydropyridines with alkylperoxyl radicals andABTS radical cationrdquo Bioorganic and Medicinal Chemistry vol12 no 9 pp 2459ndash2468 2004
[198] VMisik A J Stasko D Gergel and K Ondrias ldquoSpin-trappingand antioxidant properties of illuminated and nonilluminatednifedipine and nimodipine in heart homogenate and modelsystemrdquo Molecular Pharmacology vol 40 no 3 pp 435ndash4391991
[199] K Ondrias V Misık A Stasko D Gergelrsquo and M HromadovaldquoComparison of antioxidant properties of nifedipine and illu-minated nifedipine with nitroso spin traps in low densitylipoproteins and phosphatidylcholine liposomesrdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1211 no 1pp 114ndash119 1994
[200] A Stasko V Brezova S Biskupic K Ondrias and V MisıkldquoReactive radical intermediates formed from illuminated nife-dipinerdquoFree Radical Biology andMedicine vol 17 no 6 pp 545ndash556 1994
[201] K Ishizawa Y Izawa-Ishizawa N Yamano et al ldquoNitrosoni-fedipine ameliorates the progression of type 2 diabetic nephro-pathy by exerting antioxidative effectsrdquo PLoS ONE vol 9 no 1Article ID e86335 2014
[202] H Fujii and L J Berliner ldquoIn vivo EPR evidence for free radicaladducts of nifedipinerdquoMagnetic Resonance in Medicine vol 42no 4 pp 691ndash694 1999
[203] S Bollo S Finger J C Sturm L J Nunez-Vergara and JA Squella ldquoCyclic voltammetry and scanning electrochemicalmicroscopy studies of the heterogeneous electron transferreaction of some nitrosoaromatic compoundsrdquo ElectrochimicaActa vol 52 no 15 pp 4892ndash4898 2007
34 Oxidative Medicine and Cellular Longevity
[204] F Ursini ldquoTissue protection by lacidipine insight from redoxbehaviorrdquo Journal of Cardiovascular Pharmacology vol 30supplement 2 pp S28ndashS30 1997
[205] P G Cristofori F A Crivellente I Faustinelli et al ldquoInvolve-ment of the nitric oxide system in the anti-atheroscleroticpotential of lacidipine in the apoE-deficient mouse a mor-phological functional and electrochemical studyrdquo ToxicologicPathology vol 32 no 4 pp 493ndash499 2004
[206] X-P Zhang E L Kit S Mital S Chahwala and T HHintze ldquoParadoxical release of nitric oxide by an L-type calciumchannel antagonist the R+ enantiomer of amlodipinerdquo Journalof Cardiovascular Pharmacology vol 39 no 2 pp 208ndash2142002
[207] F Franzoni G Santoro F Regoli et al ldquoAn in vitro study of theperoxyl and hydroxyl radical scavenging capacity of the calciumantagonist amlodipinerdquo Biomedicine and Pharmacotherapy vol58 no 8 pp 423ndash426 2004
[208] S V Gatsura ldquoOxygen-dependent mechanisms underlying theantiischemic effect of verapamil and amlodipinerdquo Bulletin ofExperimental Biology and Medicine vol 137 no 1 pp 40ndash422004
[209] Y Hirooka Y Kimura M Nozoe Y Sagara K Ito and KSunagawa ldquoAmlodipine-induced reduction of oxidative stressin the brain is associated with sympatho-inhibitory effects instroke-prone spontaneously hypertensive ratsrdquo HypertensionResearch vol 29 no 1 pp 49ndash56 2006
[210] B Tomlinson and I F F Benzie ldquoAntioxidant effect of lercani-dipine (note)rdquo Hypertension vol 42 no 4 pp e10ndashe11 2003
[211] A A Faraqui ldquoNeurochemical aspects of 4-hydroxynonenalrdquoin Lipid Mediators and Their Metabolism in the Brain A AFaraqui Ed chapter 6 pp 159ndash191 Springer New York NYUSA 2011
[212] V S NascimentoM S DrsquoAlva A AOliveira et al ldquoAntioxidanteffect of nimodipine in young rats after pilocarpine-inducedseizuresrdquo Pharmacology Biochemistry and Behavior vol 82 no1 pp 11ndash16 2005
[213] O Ismailoglu P Atilla S Palaoglu et al ldquoThe therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjuryrdquo Turkish Neurosurgery vol 22 no 6 pp 740ndash746 2012
[214] M Matsubara and K Hasegawa ldquoBenidipine a dihydropy-ridine-calcium channel blocker prevents lysophosphatidyl-choline-induced injury and reactive oxygen species productionin human aortic endothelial cellsrdquo Atherosclerosis vol 178 no1 pp 57ndash66 2005
[215] M Matsubara K Yao and K Hasegawa ldquoBenidipine adihydropyridine-calcium channel blocker inhibits lysophos-phatidylcholine-induced endothelial injury via stimulation ofnitric oxide releaserdquo Pharmacological Research vol 53 no 1 pp35ndash43 2006
[216] MMatsubara and K Hasegawa ldquoEffects of benidipine a dihyd-ropyridine-Ca2+ channel blocker on expression of cytokine-induced adhesion molecules and chemoattractants in humanaortic endothelial cellsrdquo European Journal of Pharmacology vol498 no 1ndash3 pp 303ndash314 2004
[217] M Matsubara O Akizuki J-I Ikeda K Saeki K Yao and KSasaki ldquoBenidipine an anti-hypertensive drug inhibits reactiveoxygen species production in polymorphonuclear leukocytesand oxidative stress in salt-loaded stroke-prone spontaneouslyhypertensive ratsrdquo European Journal of Pharmacology vol 580no 1-2 pp 201ndash213 2008
[218] A C Rosenkranz H Lob T Breitenbach R Berkels and RRoesen ldquoEndothelial antioxidant actions of dihydropyridines
and angiotensin converting enzyme inhibitorsrdquo European Jour-nal of Pharmacology vol 529 no 1ndash3 pp 55ndash62 2006
[219] V Kain S Kumar and S L Sitasawad ldquoAzelnidipine preventscardiac dysfunction in streptozotocin-diabetic rats by reducingintracellular calcium accumulation oxidative stress and apop-tosisrdquo Cardiovascular Diabetology vol 10 article 97 2011
[220] K Nakamura S Yamagishi and H Inoue ldquoUnique atheropro-tective property of azelnidipine a dihydropyridine-based cal-cium antagonistrdquoMedical Hypotheses vol 65 no 1 pp 155ndash1572005
[221] TMatsui S Yamagishi K Nakamura S Kikuchi andH InoueldquoAzelnidipine a dihydropyridine-based calcium antagonistinhibits angiotensin II-induced oxidative stress generation anddownregulation of pigment epithelium-derived factor mRNAlevels in microvascular endothelial cellsrdquo Drugs under Experi-mental and Clinical Research vol 31 no 5-6 pp 215ndash219 2005
[222] C Ohmura H Watada T Shimizu et al ldquoCalcium channelblocker azelnidipine reduces lipid hydroperoxides in patientswith type 2 diabetes independent of blood pressurerdquo EndocrineJournal vol 54 no 5 pp 805ndash811 2007
[223] H Daikuhara F Kikuchi and T Ishida ldquoThe combination ofOLmesartan and a CAlcium channel blocker (azelnidipine) orcandesartan and a calcium channel blocker (amlodipine) intype 2 diabetic hypertensive patients theOLCA studyrdquoDiabetesand Vascular Disease Research vol 9 no 4 pp 280ndash286 2012
[224] MAbe NMaruyama KOkada SMatsumoto KMatsumotoand M Soma ldquoAdditive antioxidative effects of azelnidipine onangiotensin receptor blocker olmesartan treatment for type 2diabetic patients with albuminuriardquoHypertension Research vol34 no 8 pp 935ndash941 2011
[225] K Mizushige ldquoAntioxidative activities of thiazolidinedionesand dihydropyridine-type calcium antagonistsrdquo IRYOmdashJapa-nese Journal of National Medical Services vol 59 no 11 pp 581ndash592 2005
[226] S Manabe T Okura T Fukuoka and J Higaki ldquoAntioxidativeeffects of azelnidipine on mesangial cell proliferation inducedby highly concentrated insulinrdquo European Journal of Pharma-cology vol 567 no 3 pp 252ndash257 2007
[227] Y Koyama Y Takeishi H Takahashi et al ldquoAzelnidipine inhi-bits H
2O2-induced cell death in neonatal rat cardiomyocytesrdquo
CardiovascularDrugs andTherapy vol 21 no 1 pp 69ndash72 2007[228] K Shinomiya K Mizushige M Fukunaga et al ldquoAntioxidant
effect of a new calcium antagonist azelnipidine in culturedhuman arterial endothelial cellsrdquo Journal of International Med-ical Research vol 32 no 2 pp 170ndash175 2004
[229] T Ohyama K Sato K Kishimoto et al ldquoAzelnidipine is acalcium blocker that attenuates liver fibrosis and may increaseantioxidant defencerdquo British Journal of Pharmacology vol 165no 4 pp 1173ndash1187 2012
[230] L A Calo F Zaghetto E Pagnin P A Davis A Sempliciniand A C Pessina ldquoEffect of manidipine on gene expressionand protein level of oxidative stress-related proteins p22phoxand HO-1 Relevance for antihypertensive and anti-remodelingeffectsrdquo Journal of Cardiovascular Pharmacology vol 43 no 4pp 531ndash538 2004
[231] R Ghyasi G Sepehri M Mohammadi R Badalzadeh and AGhyasi ldquoEffect of mebudipine on oxidative stress and lipid per-oxidation in myocardial ischemic-reperfusion injury in maleratrdquo Journal of Research in Medical Sciences vol 17 no 12 pp1150ndash1155 2012
Oxidative Medicine and Cellular Longevity 35
[232] DCAndersson J Fauconnier T Yamada et al ldquoMitochondrialproduction of reactive oxygen species contributes to the 120573-adrenergic stimulation of mouse cardiomycytesrdquoThe Journal ofPhysiology vol 589 no 7 pp 1791ndash1801 2011
[233] A F Ceylan-Isik N Ari M Stefek et al ldquoEffects of a long-term treatment with an antioxidant pyridoindole on vascularresponsiveness in diabetes-induced aging ratsrdquo Current AgingScience vol 4 no 2 pp 150ndash157 2011
[234] S Saponara G Sgaragli and F Fusi ldquoQuercetin antagonismof Bay K 8644 effects on rat tail artery L-type Ca2+ channelsrdquoEuropean Journal of Pharmacology vol 598 no 1ndash3 pp 75ndash802008
[235] D A Sica ldquoInteraction of grapefruit juice and calcium channelblockersrdquo American Journal of Hypertension vol 19 no 7 pp768ndash773 2006
[236] P Mulder G Litwinienko S Lin P D MacLean L R CBarclay and K U Ingold ldquoThe L-type calcium channel block-ers Hantzsch 14-dihydropyridines are not peroxyl radical-trapping chain-breaking antioxidantsrdquo Chemical Research inToxicology vol 19 no 1 pp 79ndash85 2006
[237] L J Nunez-Vergara R Salazar C Camargo et al ldquoOxidation ofC4-hydroxyphenyl 14-dihydropyridines in dimethylsulfoxideand its reactivity towards alkylperoxyl radicals in aqueousmediumrdquo Bioorganic and Medicinal Chemistry vol 15 no 12pp 4318ndash4326 2007
[238] M E Ortiz L J Nunez-Vergara and J A Squella ldquoRelativereactivity of dihydropyridine derivatives to electrogeneratedsuperoxide ion in DMSO solutions a voltammetric approachrdquoPharmaceutical Research vol 20 no 2 pp 292ndash296 2003
[239] M E Ortiz L J Nunez-Vergara C Camargo and J A SquellaldquoOxidation of Hantzsch 14-dihydropyridines of pharmacolog-ical significance by electrogenerated superoxiderdquo Pharmaceuti-cal Research vol 21 no 3 pp 428ndash435 2004
[240] R S Raghuvanshi and K N Singh ldquoSuperoxide induced oxida-tive aromatization of Hantzsch 14-dihydropyridinesrdquo IndianJournal of Chemistry Section B Organic and Medicinal Chem-istry vol 47 no 11 pp 1735ndash1738 2008
[241] I Kruk A Kladna K Lichszteld et al ldquoAntioxidant activityof 4-flavonil-14-dihydropyridine derivativesrdquo Biopolymers vol62 no 3 pp 163ndash167 2001
[242] G D Tirzit I M Byteva K I Salokhiddinov G P Gurinovichand G Y Dubur ldquo14-Dihydropyridine derivatives as deactiva-tors of singlet oxygenrdquo Chemistry of Heterocyclic Compoundsvol 17 no 7 pp 682ndash684 1981
[243] G D Tirzit E Y Kazush and G Y Dubur ldquoInfluence of14-dihydropyridine derivatives on the generation of hydroxylradicalsrdquo Chemistry of Heterocyclic Compounds vol 28 no 4pp 435ndash437 1992
[244] N A Pizarro-Urzua and L J Nunez-Vergara ldquoNifedipine andnitrendipine reactivity toward singlet oxygenrdquo Journal of Photo-chemistry and Photobiology A Chemistry vol 175 no 2-3 pp129ndash137 2005
[245] L-F Wang H-Y Zhang L Konga Z-W Chena and J-G ShildquoDFT calculations indicate that 14-dihydropyridine is a promis-ing lead antioxidantrdquo Helvetica Chimica Acta vol 87 no 6 pp1515ndash1521 2004
[246] P Mulder H-G Korth and K U Ingold ldquoWhy quantum-thermochemical calculations must be used with caution toindicate lsquoa promising lead antioxidantrsquordquoHelvetica Chimica Actavol 88 no 2 pp 370ndash374 2005
[247] K Yao Y Ina K Nagashima K Ohmori and T Ohno ldquoAntiox-idant effects of calcium antagonists in rat brain homogenatesrdquo
Biological and Pharmaceutical Bulletin vol 23 no 6 pp 766ndash769 2000
[248] T Matsui S-I Yamagishi K Nakamura and H Inoue ldquoBayw 9798 a dihydropyridine structurally related to nifedipinewith no calcium channel-blocking properties inhibits tumournecrosis factor-120572-induced vascular cell adhesion molecule-1expression in endothelial cells by suppressing reactive oxygenspecies generationrdquo Journal of International Medical Researchvol 35 no 6 pp 886ndash891 2007
[249] K AMitrega B VargheseM Porc and T F Krzeminski ldquoAnti-arrhythmic and hemodynamic effects of oxy nifedipine oxynimodipine oxy nitrendipine and oxy nisoldipinerdquo Pharmaco-logical Research vol 66 no 4 pp 300ndash308 2012
[250] V Herbert ldquoSymposium prooxidant effects of antioxidantvitamins Introductionrdquo The Journal of Nutrition vol 126 no4 supplement pp 1197Sndash1200S 1996 httpjnnutritionorgcontent1264 Suppl1197Sfullpdf
[251] B Halliwell ldquoAre polyphenols antioxidants or pro-oxidantsWhat do we learn from cell culture and in vivo studiesrdquoArchives of Biochemistry and Biophysics vol 476 no 2 pp 107ndash112 2008
[252] C Winterbourn Pro-Oxidants or Antioxidants ChristchurchSchool of Medicine Depatment of Pathology Free RadicalSchool SFRBMUniversity of Otago San Francisco Calif USA2009 httpwwwsfrbmorgfrsWinterbournpdf
[253] A Morakinyo B Iranloye and O Adegoke ldquoCalcium antag-onists modulate oxidative stress and acrosomal reaction in ratspermatozoardquo Archives of Medical Science vol 7 no 4 pp 613ndash618 2011
[254] The Alpha-Tocopherol Beta Carotene Cancer Prevention StudyGroup ldquoThe effect of vitamin E and beta carotene on theincidence of lung cancer and other cancers in male smokersrdquoTheNew England Journal of Medicine vol 330 no 15 pp 1029ndash1035 1994
[255] B Poljsak ldquoStrategies for reducing or preventing the generationof oxidative stressrdquo Oxidative Medicine and Cellular Longevityvol 2011 Article ID 194586 15 pages 2011
[256] B Poljsak and I Milisav ldquoThe neglected significance of lsquoanti-oxidative stressrsquordquoOxidativeMedicine and Cellular Longevity vol2012 Article ID 480895 12 pages 2012
[257] T Godfraind and S Salomone ldquoAmbiguities in dietary antiox-idant supplementation compared to calcium channel blockerstherapyrdquo Frontiers in Pharmacology vol 6 article 10 2015
[258] H Wagner H Norr and H Winterhoff ldquoDrugs with adap-togenic effects for strengthening the powers of resistancerdquoZeitschrift fur Phytotherapie vol 13 no 2 pp 42ndash54 1992
10 Oxidative Medicine and Cellular Longevity
Table 4 Normolipidemic human blood LDL (025mgmL) in vitro oxidation in the presence of 5 120583M CuSO4and CA of 3 types (DHPs
verapamil and diltiazem) and vitamin E Compiled according to Lupo et al [129]
Compound
MethodsTBARS method (fluorimetry at 515 nm533 nm 4 hours
preincubation of LDL with compounds and copper (II)ions 320 TBARS increase in control during 4 h
period)
Inhibition of conjugated diene formation (at 234 nm)expressed as prolongation of induction period (in
of control) 119905contr = 368min
Effective [IC] (in 120583M)1 120583M 10120583M 50 120583M
Activity rank order (ARO= I for the highest activity
ARO = VII for themindest activity)
Effective [IC] (in 120583M)1 120583M 5 120583M 10120583M 50 120583M
Activity rank order (ARO= I for the highest activity
ARO = VII for themindest activity)
Nifedipine 10120583M50 120583M ARO = III
5 120583M10120583M 15050 120583M 213
ARO = III
Amlodipine 50 120583M ARO = IV5 120583M
10120583M 12250120583M 138
ARO = IVndashVI
Isradipine 50 120583M ARO = VI 10120583M 15050 120583M 183 ARO = IVndashVI
Lacidipine1 120583M10120583M50 120583M
ARO = II5 120583M
10120583M 19250 120583M 283
ARO = II
Verapamil 50 120583M ARO = V 10120583M 15050 120583M 178 ARO = IVndashVI
Diltiazem No effect No effect (ARO = VII) No effect No effect (ARO = VII)
Vitamin E1 120583M
10120583M (IC50)
50 120583M (20 of control)ARO = I
5 120583M10 120583M 23050 120583M 370
ARO = I
Table 5 Antiproliferative effect (oxLDL-induced HUVSMCs proliferation) of CA DHPs and simultaneous oxLDL-induced ROS productionscavenging Comparison with N-acetyl-L-cysteine NAC (intracellular ROS scavenger) Compiled according to data presented by Zou et al2012 [130]
DHP compound
MethodsAntiproliferative effect against proproliferative effectinduced by oxLDL (50 120583gmL) (UV detection of
formazan production from tetrazolium salt)
oxLDL-induced ROS production (fluorescent DCF(2101584071015840-dichlorofluorescein) production)
Effective [IC] in120583M and I in
Amlodipine 3 120583M I = 18 3 120583M 10 120583M No effectI = 20
S(minus)-Amlodipine No effect No effect
Lacidipine 10 120583M30 120583M
I = 21I = 27 10120583M Isim23 of control
N-Acetyl-L-cysteineNAC
mdash 5000 120583M(5mM) I = 28
As presented (Table 4 according to [129]) for diltiazem(poor lipid solubility) noAOwas detected whereas the otherCA and 120572-tocopherol have demonstrated AOA at least atconcentrations of 10 and 50120583M 120572-tocopherol gt lacidipinegt nifedipine gt isradipine verapamil and amlodipine Addi-tionally120572-tocopherol and lacidipinewere able to significantlyattenuate in vitro LDL oxidation at 1 and 5120583M Theseresults have confirmed the highest activity for the stronglylipophilic DHP type CA compound lacidipine This might be
a possible antiatherogenic mechanism of CA since oxidativemodification enhances the atherogenic potential of LDL
The lipid peroxidation of LDL promoted either by UVradiation or by copper ions was inhibited (antioxidant effect)by nisoldipine in a dose-dependentmanner (IC
50values were
evaluated at around 10 120583M) nimodipine was less potent (IC50
around 50ndash100 120583M) and nicardipine almost inactive In addi-tion to this indirect protective effect CA DHPs nisoldipineand nimodipine exerted direct protective effect on lymphoid
Oxidative Medicine and Cellular Longevity 11
cells against toxicity of previously oxidized LDL The IC50
values were 6 plusmn 2 and 80 plusmn 20 120583M respectively [122] Theinhibition of the cytotoxic effect of LDL oxidized in thepresence of DHP type Ca2+ channel blockers correlated wellwith protection from oxidation by these compounds Com-plete protection cannot be obtained because the DHPs arecytotoxic themselves The potential relevance to the preven-tion of atherogenesis is envisaged
DHP typeCCBnifedipinewas themost effective inhibitorof oxidation promoted either by UV radiation or by copperions in experiments with cultured lymphoid cells LDL (2mgapoBmL) CCBs from other two CCB classes diltiazem andverapamil were only poorly active or completely ineffective[121] The protective effect of nifedipine occurs at two levelsbesides its direct antioxidant effect by inhibition of LDLoxidation it also exhibits a direct cytoprotective effect againstcytotoxicity of oxidized LDL by yet unknown mechanismsThe protective effect of CCBs was not due to an inhibitionof LDL uptake This effect seems to be independent of theinhibition of LDL oxidation per se since LDL was oxidizedin the absence of the drug before the incubation withcells Moreover this direct protective effect was observedat lower concentrations (IC
50of 1 plusmn 02 120583M) compared to
the antioxidant effect (IC50
of TBARS inhibition is around10 plusmn 2 120583M at UV promoted and 4 plusmn 05 120583M by Cu2+ ionsinitiated) The AO effect of nifedipine is also correlated withthe protection of endogenous tocopherols (IC
50= 50 120583M)
It was suggested that the AO effect of CCBs protected cellsindirectly from the cytotoxic effect of oxidized LDL [121]
A recent study has reported that beneficial vascular effectsof lercanidipine in diabetic rats depend on its antioxidantactivity related to attenuating the increase in oxidativestress and in vascular matrix metalloproteinase-2 (MMP-2) (Martinez et al [126]) Lesnik et al [127] studied theimpact of a combination of this calcium antagonist and a120573-blocker atenolol on cell- and copper-mediated oxidationof LDL and on the accumulation and efflux of cholesterolin human macrophages and murine J774 cells They realizedthat lercanidipine reduced the oxidative modification of LDLrather than diminished cholesterol accumulation in humanfoam cells
Comparing the antioxidative action of CA (DHPs amlo-dipine lacidipine nifedipine and isradipine as well as diltia-zem and semotiadil) in the copper-catalyzed oxidation oflow-density lipoprotein (LDL) with that of glycated (g)gly-coxidated (go) LDL demonstrated that the strongest AOeffects during long-term LDL glycation are seen for isradip-ine lacidipine nifedipine and semotiadil [128] Inhibitoryeffects were in the range 10minus5ndash10minus3MAuthors suggested thatdue to the increased generation of ROS by glucose-modifiedLDL the chain-breaking capacity of CA may be overriddenThe AOA of CA depends on their lipophilicity and theirability to incorporate into the LDL particle that is to reachthe site of peroxidation CA like other AOs significantlyretards advanced glycation end products (AGE) formationwhereas initial glycation reactions such as Amadori productformation are only weakly inhibited The observation thatboth oxidative changes and at least long-termglycation effectsare indeed drastically reduced by CA is corroborated by
fluorescence analysis AGE-ELISA quantitation of lipid per-oxidation and TBARS measurement of long-term ggo LDL
The effects of lipophilic DHP calcium channel blockerson oxidized LDL-induced proliferation and oxidative stressof vascular smooth muscle cells were also studied [130] (seeTable 5)
Lacidipine and amlodipine reduced carotid intima-media thickness by decreasing proliferative effect of oxLDLwhereas (S-)-amlodipine had no antiproliferative effect ROS-MAPKs (mitogen-activated protein kinases) pathway mightbe involved in the mechanism
Both 14-DHP CCBs lacidipine and nifedipine reduceplasma and LDL oxidation and formation of oxidation-specific epitopes Their application may also relate to pro-longed survival of rats independently of blood pressuremod-ifications (in the SPSHR model 1mgkg per day lacidipineand 80mgkg per day nifedipine) These results suggestedthat the protective effect of these two 14-DHP drugs invivo as shown in cerebral ischemia and stroke may in partresult from inhibition of LDL oxidative process althoughthese two drugs possess different lipophilic properties [131]Both lacidipine (03 and 10mgkg) andnifedipine (80mgkg)prolonged lag time of the conjugated diene formation inLDL isolated from arterial wall and 119905max These drugssignificantly reduced electrophoreticmobility of oxLDL fromSPSHR subjected to XXO oxidation system 14-DHP CCBsalso protected apolipoprotein B which is important for thebinding with macrophage LDL receptor lysine residues Thedoses used (gt10minus6molL for SPSHR and normotensive WKYrats) however are 2 to 3 orders of magnitude higher thanthose inhibiting vascular smooth muscle contraction in vitroand in vivo They also exceed values that are commonlyused in clinical practice The daily dose of lacidipine forhypertensive patients is 007mgkg asymp4- to 14-fold lower thanthe 2 doses used in SPSHR The maximum daily dose ofnifedipine given to hypertensive patients is 20mgkg asymp40-fold lower thanwhatwere used [131]These discrepanciesmaybe related to differences in bioavailability of CA between ratsand humans [131]
Accordingly in routine clinical use 14-DHPCCBs donotreach the concentrations required for antioxidant activity invitro [131]
Another data concerning the effect of CA DHPs on OSrelated to LDL is presented under Section 35
(b) Effect of DHPs on Isolated Rat Liver and Heart Mitochon-dria As a major cellular source of oxygen radicals (Cadenas[4 5]) mitochondria are promising targets for pharmaco-logical and toxicological actions of various membrane-activecompounds including several 14-DHP derivatives Zernig etal [132] have discovered CA binding sites associated with aninner mitochondrial membrane anion channel
More than 40-year long research onmitochondrial effectsof the DHPs (on their bioenergetics chemiosmotic proper-ties and ion fluxes) clearly points them out as mitochondri-otropic compounds
The activity of the first 35 synthesized compounds(derivatives of 14-DHP their heteroaromatic analogues
12 Oxidative Medicine and Cellular Longevity
NAD-H+ and butylated hydroxytoluene (BHT BOT)) orig-inally was examined in rat liver mitochondrial LP system inthe presence of Fe2+ ions and using the ultraweak chemilu-minescence method (Dubur et al [89])
Several 14-DHP derivatives Hantzsch ester diludine andits analogues were found to be effective antioxidants in thisexperimental system changing the kinetics of LP lengtheningthe time of the appearance of the maximum of the slowburst of the chemiluminescence (latency latent period) anddiminishing the reaction rate (the tangent of the slope angleduring the time in which the amplitude of the slow burstcharacterizing LP rate increases) and its peak value Theirpresence has influenced the reaction constant 119870
6 in relation
to a very significant reduction of lipid hydroperoxides andorinactivation of free radicals as follows
ROO∙ + ROO∙ 997888rarr P + h]lowast termination (1)
(P = molecular products) or
ROO∙ + ROO∙ +H2O 997888rarr ROH + RO∙ + 1O
2
lowast (2)
In this study diludine was one of themost active compoundsDHPs had activity similar to the standard synthetic AO-BHT(ionol) However when plotted against applied concentrationand time window diludinersquos activity profile differed from thatof BHT
There were also similar studies (using different LP rateexperimental detection system and method Hunter et al[133]) based on exploring a group of 26 26-dimethyl-35-disubstituted- and 26-dimethyl-345-trisubstituted-14-dihydropyridines (14-H
2Py=14-DHPs) and five related pyri-
dines as inhibitors of rat liver Mit swelling (Δ119860520119905) and O
2
uptake by ascorbic acid- (AsA-) dependent lipid peroxidationand as modulators of Mit swelling induced by Na+-linoleateor Na+-pyrophosphate (Velena et al [112])
Some of tested 4-DHPs (4-unsubstituted 35-dialkoxy-carbonyl-26-dimethyl-14-DHPs and 35-diamido-26-dim-ethyl-14-DHPs both 4-unsubstituted or those possessinglipophilic 4-aryl- groups) have shown significant AO andmembrane stabilizing activity These studies further revealedthat 14-DHPs preferably act as AO during the stages ofinitiation and prolongation of LP chain reactions at lowconcentrations The studied 14-DHPs had IC
50(when 119881
0119881
or 1205911205910= 2) 01 120583M to 100 120583M and the minimal activity was
scored for oxidized (heteroaromatized) derivativesAt the concentration of 100120583M 35-di-n-butyloxycarbo-
nyl-26-dimethyl-14-DHP entirely stops mitochondrialswelling in the presence of 08mM Na+-pyrophosphateAt the same concentration the following compoundsalter the mitochondrial swelling rate in the presence ofnatural protonophore Na+-linoleate 35-di-p-hydroxyphen-oxycarbonyl- and 35-di-p-tolyloxycarbonyl-26-dimethyl-14-DHPs 35-diethoxycarbonyl-26-dimethyl-pyridine (oxi-dized form of Hantzsch ester) and more lipophilic 35-diamyloxycarbonyl-26-dimethyl-pyridine The alteration ofswelling may be scored as prolonged promoted acceleratedor inhibited The type of alteration depends on the structureand concentration of 14-DHPs the type of initiators of theswelling process and the medium composition
In accord with previously published Janerorsquos results (lackof AO for Ca2+ antagonists nifedipine and nicardipine evenat 500120583M concentration in LP tests performed on heartmembrane [134]) no antioxidative activity for 4-phenyl sub-stituted derivatives of 35-dialkoxycarbonyl 14-DHP (closeanalogues of Ca2+ antagonists) was found contrary to various4-nitrophenyl 14-DHP derivatives calcium antagonists forwhich the significant antioxidant activity was reported [3146ndash53]
Studies made on phosphatidylcholine liposomes (ourunpublished data) suggest approximately three and twotimes more antioxidative activity for 100 120583M 4-unsubstitutedDHP compound diludine when compared to 4-substitutedDHPs riodipinenifedipine and nicardipine respectively atmethemoglobin-induced LP (oxygraphy)
Inhibition of mitochondrial AsA-dependent LP and sta-bilization ofmitochondriawere shown to be characteristic fora large group of 14-DHP compounds [112] showing to pos-sess the AOA in simplest in vitro systems (Tirzit andDuburs [39] Zilber et al [44] and Dubur et al [45])based on reactions with the stable free radical 11-diphenyl-2-picrylhydrazyl (DPPH) LP of fatty acid ester (linethole andmethyloleate) emulsions and phospholipid (phosphatidyl-choline) liposomes Generally these properties did not coin-cide with Ca2+ antagonism Depending on DHP structure itseems that AOA properties are less specific than Ca2+ antago-nist properties Both properties may be interrelated but notinterdependent
These data show that the presence and the nature ofa substituent in position 4 as well as 35-substituentsare important factors for 14-DHP antioxidant effects invarious systems that is AsA-dependent nonenzymatic aswell as enzymatic NADPH-dependent lipid peroxidationSometimes the efficacy of inhibition of nonenzymatic LPby 14-DHPs is higher than the inhibition of the enzymaticLP However the action may be opposite stimulation of theLP Hantzsch ester (HEH diludine) and its close analoguesexhibited significant AOA and membrane stabilizing prop-erties in both AsA-dependent nonenzymatic peroxidationof mitochondria and NADPH-dependent enzymatic LP ofmicrosomes usually at similar 10 to 100120583M concentrations[112]
The order of AOpotency (IC50
values) in vitro depends ondrug structure as well as on the experimental conditions andspecificity of the biological system Eachmethod for determi-nation of AOA and ARA has advantages and disadvantages(Karadag et al [135])
Accordingly as reported by Gubskiı et al [136] IC50
forthe AsA-dependent LP was 025 120583M and 20 120583M for 14-DHPCa2+ antagonists nitrepine (nitrendipine) and nifedipinerespectively Takei et alrsquos [137 138] studies on mitochondrialswelling induced by LP or arachidonic acid in the rat braindetermined the IC
50values of 127 105 1568 and 384 120583Mfor
efonidipine nicardipine nifedipine and nimodipine respec-tively For LDL in the copper-induced oxidation system theorder of potencywas vitamin Egt felodipinegt 2-chlorophenylanalogue of nifedipine gt nifedipine gt amlodipine nitrendip-ine verapamil and diltiazem (Rojstaczer and Triggle [119])
Oxidative Medicine and Cellular Longevity 13
It was interesting to compare the AOAofDHPswith theirsusceptibility to oxidation that is electron and hydrogendonating properties
It has been estimated that electron donor substituentsin positions 2 and 6 of 14-DHP cycle usually promoteoxidation while electron acceptor substituents promotequench oxidation Stronger electron acceptors in positions 3and 5 also significantly quench oxidation These estimationsare based on studies including chemical enzymatic andelectrochemical oxidation of 14-DHPderivatives (Dubur andUldrikis [70] Duburs et al [71] and Stradin et al [139])
On the other hand diminished AOA of 14-DHP relatesto presence of substituents in position 4 (both electron donorand electron acceptor) (Velena et al [112])
35-Dicarbamoyl substituents possess minimal quench-ing feature and are followed by benzoyl- acetyl- andalkoxycarbonyl- groups Maximal decrease was obtainedwith condensed substituents (ie oxoindeno- or oxocyclo-hexeno- groups) and a CN-group 4-Unsubstituted 35-dicar-bamoyl derivatives can be easily oxidized and consequen-tially inactivated whereas 4-substituted 35-dicarbamoyl-14-DHPs possess an oxidation potential analogous to the 4-unsubstituted 35-COOR derivatives Therefore they haveadequate electron donor properties and are considerablystableThismay be the reason for significantmembrane stabi-lization upon exposure to 4-substituted derivatives Ofimportance their AOA was usually more pronounced incomparison to 4-unsubstituted derivatives
Among them 26-dimethyl-35-difurfuryloxycarbonyl-14-DHP showed the highest antioxidative activity In thegroup of 35-dialkoxycarbonyl derivatives the strongestactivity was attributed to compounds with medium lengthalkyl chains (i-butyl- t-butyl- and i-amyl- substituents) highlevel of lipophilicity minimal electron acceptor propertiesand moderate steric hindrance as contrasted to short or longalkyl chain ester derivatives (35-dimethoxycarbonyl- 35-diethoxycarbonyl derivatives and 35-didodecyloxycarbonylderivative) These data demonstrate the bell-shaped depen-dence of AOA on alkyl chain length [112] and are in accordwith results obtained in liposomes However these datadiffer from those obtained in emulsions where diludine wasthe most active compound Finally oxidized heteroaromaticderivatives showed only minimal activity
In both LP systems studied (AsA-dependent in mito-chondria and NADPH-dependent in microsomes) some of14-DHPs showed activity similar to classical antioxidantbutylated hydroxytoluene (ionol BHT) (Velena et al [112])However there was a significant difference related to con-centration and incubation time It allowed us to postu-late that 14-dihydropyridines (InH) acting as antioxidants-reductants and scavengers of reactive oxygen species and lipidfree radicals preferably influence initiation and propagation(prolongation) of lipid peroxidation chain reactions (1)ndash(5) according to Scheme 2 The phenomenon is particularlyprominent in the presence of Fe2+ and other ions of variablevalency
Chain break and termination reactions (6)ndash(10) of theLP reaction cascade [89] were influenced by 14-DHPs in alesser degree than were initiation and propagation steps This
may be important for their therapeutic effects even in theadvanced stages of LP
Scheme 2 (stages of initiation propagation and terminationof lipid peroxidation chain reactions (1ndash10)) Initiation andpropagation reactions are as follows
(8) RO∙ + In∙minus rarr Y (Y = molecular products)(9) ROO∙ + Fe2+ rarr Fe3+ + X (X = molecular products)(10) RO∙ + RO∙minus rarr Y (Y = molecular products)
In the reversible swelling of mitochondria accompanyingLP (initiated by mixture of 5mM GSSG1mM GSH) several14-DHPs showed low or no activity manifested only as adecrease of the swelling amplitude without a rate decreaseAn addition of GSH (4mM) or ATP to swollenmitochondriacaused their contraction in both control and tested systemIt may be suggested that 14-DHPs acting as antioxidantsin mitochondria preferably influence LP reactions initiatedby ions with variable valency or their complexes with hemetype compounds methemoglobin hemin hematin and soforth (Velena et al [112]) If the peroxidation process has amaximal velocity and 50 percent of initial O
2were consumed
14-DHPs cannot completely break the chain reactions andprevent subsequent membrane damage by addition of DHPsubstance at 10 120583M concentration at the moment of 50percent oxygen consumption the subsequent oxygen uptakeproceeded unchanged This observation is important for theapplication of DHPs as inhibitors of initiation and to a lesserdegree propagation stages of LP chain reactions
The influence of 14-DHPs on Mit swelling is not strictlyassociated with their own oxidation There is the possibilitythat the labilizing (or stabilizing) effect relates to surfaceactivity (connected with substituent lipophilicity) or may bethe consequence of complexation with some -OH (or -CH
3)
group sensitive receptors at the mitochondrial membraneNamely a bathochromic shift of the absorption band maxi-mum (about 10 nm) was observed in the visible region beforeswelling However after swelling in the presence of Na+linoleate the spectrum returns to its initial value [112]
Some 14-DHPs not only protect mitochondria againstswelling caused by AsA-dependent LP salts of fatty acids
14 Oxidative Medicine and Cellular Longevity
in vitro [112] but also have beneficial effects on repairingtheir integrity in vivo after exposure to irradiation hepato-toxins ischemia hypoxia or hypothermia Some of themwere shown to normalize the process of intracellular repara-tion and physiological regeneration of ultrastructures Theywere also shown to stimulate reparative processes If pre-treated with 14-DHPs irradiatedmitochondria will not swell(Ivanov et al [140 141])
Diludine ionol and some other AOs mitochondria pro-tectors act as anti-ischemic agents If applied prophylacticallyin vivo they may prevent ischemic and reperfusion lesionsin heart kidney and other organs (Bilenko et al [113]) Theeffect is dependent on applied dose timing and way ofapplicationWhen added onto the cryoconservationmediumfor mitochondria preservation 14-DHPs prevented decreaseof membrane potential normalized facilitated respirationand prevented loss of mitochondrial Na+ and Ca2+ ionsafter thawing ([112] see citation number 36 (Subbota et alKharkov 1984) therein) Diludine was stronger protectorwhen compared to ionol
CA drug foridone (riodipine) was shown to possesscardioprotective features primarily due to is protective effecton mitochondria exposed to OS [142 143]
Similarly the DHP water-soluble antiarrhythmic com-pound glutapyrone inhibits initiation of LP by free radicalsin erythrocytes and heart mitochondria Its cardioprotectiveeffect has been experimentally shown in heart mitochondrialmembranes especially during deep hypothermia (Utno et al[144])
Cerebrocrast was effective in several translation modelsmimicking pathological situations known to be associatedwith cellular OS The potential protective action of 14-DHP derivatives (4-substituted compounds cerebrocrastgammapyrone glutapyrone and 4-unsubstituted drug dieth-one) has been studied in rat liver in experimental modelsrelevant for oxidative stress and mitochondrial bioenergetics(Fernandes et al [145]) When succinate was used as therespiratory substrate higher concentrations (gt25 120583M) ofcerebrocrast depressed respiratory control ratio (RCR) ADPto oxygen ratio (ADPO) state 3 and uncoupled respirationrates transmembrane potential (deltapsi) and the phosphatecarrier rate At the same time state 4 respiration rate wasthree times increased At concentrations lower than 25120583Mcerebrocrast inhibited mitochondrial IMAC and partiallyprevented Ca2+-induced opening of the mitochondrial PTPGammapyrone glutapyrone and diethone did not inducethese phenomena When applied at concentrations up to100 120583M cerebrocrast gammapyrone and glutapyrone didnot affect ADPFe2+-induced LP of mitochondria in rat liver(as measured by oxygen consumption and TBARS forma-tion) On the other hand low diethone concentrations (upto 5 120583M) inhibited it in a dose-dependent manner Diethonealso prevented against deltapsi dissipation induced by LPinitiated by ADPFe2+ Based on these data it may bespeculated that cerebrocrast (inhibition of the IMAC) anddiethone (acting as an AO) may provide effective protectionof mitochondria during OS Cerebrocrast has shown sometherapeutic potential for treatment of several pathologicalconditions related to cellular OS [145]
5-Acetyl(carbamoyl)-6-methylsulfanyl-14-DHP-carbo-nitriles (Figure 3) with minor differences in their molecularstructure displaying antioxidant and antiradical activitiesin vitro show different biological activities Namely 4-p-chlorophenyl derivative OSI-1146 displays AO and anti-radical activities in cardiovascular OS models whereasOSI-3701 and OSI-3761 display hepatoprotective activityThus these compounds may be potentially useful for treat-ing several pathological processes including those associatedwith OS (Fernandes et al [146]) However besides mito-chondria the cellular targets for their pharmacologicalactions have not been fully investigated [146] All these com-pounds increase the susceptibility of Mit to MPT The mostpotent is OSI-3701 although it does not affect bioenergeticparameters
Although all these compounds protected mitochondriaagainst LP induced by the oxidant pair ADPFe2+ OSI-1146was shown to be the most potent Current data point outmitochondria as potential targets for protective and toxicactions of DHPs suggesting that the potential for their use astherapeutic agents should also take into consideration theirtoxic effects on mitochondria (Fernandes et al [146])
Several structurally different DHP derivatives (antioxi-dant diludine (diethone) as a 4-unsubstituted DHP 4-substi-tuted DHPs CA foridone (bicyclic compound) and the 4-phenyldiethone compound where phenyl group is joined tothe DHP in position 4) inhibited the 1-methyl-4-phenyl-pyridinium iodide (MPP+) induced ROS production incerebellar granule cells (CGC) with a distinct potency orderforidone (26-dimethyl-35-dimethoxycarbonyl-4-(o-difluo-romethoxyphenyl)-14-dihydropyridine) gt 26-dimethyl-35-diethoxycarbonyl-4-phenyl-14-dihydropyridine gt diludineThey also reversed the MPP+-induced decrease of the mito-chondrial membrane potential in the same order (Klimavi-ciusa et al [147]) Accordingly it was postulated that theclassical two-ring (bicyclic) structure of DHP derivativesrepresents an advantage in relation to neuroprotection andROS defense and is independent on compoundrsquos propertiesrelated to calcium ions
Novel adamantane-containing 14-DHP compounds (Kli-maviciusa et al [148]) were also found to improve mitochon-drial functions (MPP+ model) (Klimaviciusa et al [148])Klusa et al [149] have discovered antineurotoxic effects of14-DHP taurine derivative tauropyrone recorded as Mitfunction improvement
Many 14-DHPs including Ca2+ antagonists and AOmodify LP processes and influencemitochondrial function invarious organs (liver heart kidney and brain) in a differentway and degree Their beneficial action oxygen or lipidfree radical scavenging antioxidative effects binding withor intercalating into phospholipid bilayer regulation of iongating and regulation of mitochondrial permeability transi-tion pores (Tirzit and Duburs [39] Zilber et al [44] andDubur et al [45]) separately or in combination with eachother depends on two strong elements (1) their individ-ual structure including nature of substituents and theirpositions and (2) the nature of the biological system Forexample the direction of LP (inhibition of promotion) wasshown to depend on structure and concentration of applied
Oxidative Medicine and Cellular Longevity 15
14-DHPs as well as stages of chain reactions Accordinglymitochondrial swelling may be prolonged (retarded) accel-erated (promoted) or inhibited (Velena et al [112])
Therefore there is a ground for 14-dihydropyridineseither Ca2+ antagonists or antioxidants to be nominated asuseful tools in development of ldquomitochondrial drugsrdquo relatedto the control of OS
(c) DHPs as AOs in Endoplasmic Reticulum (Inhibition ofNADPH-Dependent LP System) Inhibition of NADPH Oxi-dase by DHPs Elevated level of NADPH oxidase 4- (NOX4-)derived hydrogen peroxide (H
2O2) joined with concomitant
decrease of nitric oxide (NO) mediated signaling and reac-tive oxygen species scavengers are considered to be centralfactor in molecular pathogenesis of fibrosis (Sampson etal [150]) Inhibition of microsomal NADPH-dependent LPwith particular focus on NADPH oxidases (NOX1ndash5 andDUOX1) may be very important for neuro- cardio- andhepatoprotection (Velena et al [112] Leto and Geiszt [151]Griendling et al [152] and Chen et al [153]) Endoplasmicreticulum may be an important target as this is where 14-DHPs could display their antioxidative properties (Velena etal [112] Leto and Geiszt [151] Griendling et al [152] andChen et al [153])
However the initiation of LP in the NADPH-dependentmicrosomal system does not appear to involve either super-oxide or hydrogen peroxide since neither SOD nor cata-lase can inhibit it On the other hand reduced iron playsan important role in both the initiation and propaga-tion of NADPH-dependent microsomal lipid peroxidation(Hochstein and Ernster [154] and Repetto et al [111])
Many DHPs possess inhibitory activity not only towardsAsA-dependent LP in mitochondria but also towardsNADPH-dependent LP as shown in isolated rat liver micro-somes (Velena et al [112]) This means that these compoundsinteract with the shared parts (nonenzymatic and enzymatic)of LP pathways
Microcalorimetry and fluorescent probes procedureswere used for studying the interaction of alpha-tocopheroland 14-DHPs with endoplasmic reticulum membranes andmodel systems human serum albumin and phospholipidbilayers [155] Modification of microviscosity of the endo-plasmatic reticular membranes depends on localization ofantioxidants within the protein structures or phospholipidphase Increase of membrane structuralization under theinfluence of 14-DHPs blocked their antioxidant action inspontaneous and induced lipid peroxidation
Inhibition of rat heart and liver microsomal lipid perox-idation by nifedipine was observed [156] while Goncalves etal [157] found antioxidant effect of calcium antagonists onmicrosomal membranes isolated from different brain areas
Nitroaryl-14-DHPs are both calcium channel antagonistsand antioxidant agents (Letelier et al [158 159]) commonlyused for treatment of cardiovascular diseases These drugsmust be metabolized through cytochrome P450 oxidativesystem (NADPH-cytochrome P450 reductase) mainly local-ized in the hepatic endoplasmic reticulum Several lipophilicdrugs generate OS while being metabolized by this cellularsystem Thus DHP antioxidant properties may prevent the
OS associated with hepatic biotransformation of drugs Var-ious commercial and new nitro-phenyl-DHPs were studiedagainst LP using rat liver microsomes under oxidative stress[159]
Incubation of rat liver microsomes with the 41015840-nitro-4-phenyl-14-DHP compounds (26-dimethyl-4-(41015840-nitro-phenyl)-14-dihydropyridin-35-diethyl-dicarboxylate andN-ethyl-26-dimethyl-4-(41015840-nitrophenyl)-14-dihydropyri-din-35-dimethyl-dicarboxylate) results in an inhibitionof LP the UDPGT (UDP-glucuronyltransferase) oxidativeactivation and the microsomal thiol oxidation induced byFe3+ascorbate a generator system of ROS This effect wasalso produced by nitrofurantoin and naphthalene in thepresence of NADPH
Interestingly IC50
ofDHPs obtained frommicrosomal LPassays decreased to the same extent as the microsomal thiolsoxidation provoked by Fe3+ascorbate [159] Neverthelessthe AO effects of a nitrophenyl-DHP compound in whichhydrogen at position one of the DHP ring was replaced bythe ethyl groupwere significantlyweaker Authors speculatedthat DHPs can resemble NADH transferring one hydrogenatom of 4-position (Hminus) to anion superoxide and another ofthe 1-position (H+) by way of a cationic radical intermediateto generate pyridine derivatives and water [159]
The AO effects of various tested DHP derivatives (m- andp-NO
2phenyl as well as methyl or ethyl and isopropyl-DHP
35-dicarboxylate derivatives) were not significantly differentThe authors assumed that the -NH- group of the dihydropy-ridine ring could contribute both to the development ofthe calcium channel antagonism and to the antioxidativeproperties of DHPs [159]
Prevention of the membrane LP seemingly depends onthe concentration of potential antioxidants such as vitaminE or even 14-DHP in lipids However only the differencesin synthetic DHPs lipophilicity cannot explain significantvariations of DHPs concentration in microsomal membraneand cannot clarify the strength of their antioxidative activityThis work [159] has further demonstrated that 14-DHPsmay prevent the OS induced by biotransformation of somedrugs for example antibiotic nitrofurantoin Simultaneousadministration of DHPs and nitrofurantoinmay be beneficialin reducing nitrofurantoin side effects
While most of Ca antagonist 14-DHPs are metabolizedby CYP3A4 (Guengerich et al [160]) not all of them are goodinhibitors of its activity Thus nicardipine but not nifedipineand nitrendipine inhibits CYP3A4 in vitro [53] Interactionof different DHPs with various types of cytochrome P450 wasdescribed by Carosati et al [53] It was also reported thatDHP class calcium channel blockers reduce the antiplateleteffect of clopidogrel (Park et al [161])This implies themutualinteractions of both drugs with CYP3A4
(3) In Vivo Evaluation of nifedipine effects on Saccharomycescerevisiaewas recently published (Asma andReda [162]) Sur-prisingly nifedipine exercised a toxic effect on Saccharomycescerevisiae shown through measuring cellular proliferationrespiratory activity and the level of some biomarkers (CATand MDA)
16 Oxidative Medicine and Cellular Longevity
However majority of data obtained on various animalcells and tissues by other authors show the protective role ofDHPs against both LP and oxidative stress [113 163 164]
The AOA attributed to many 14-DHPs Ca2+ antag-onists and other compounds reflecting on catalytic LDLperoxidation (see Section 331 (2) and Section 35) shouldencourage their testing for treating cardiovascular diseasesandor alterations of lipid metabolism
The possibility that 14-DHP-based calcium antagonistsexert an antiatherosclerotic action (via inhibition of LDLoxidation and other mechanisms) has been proved by manyexperimental data [165] and several clinical trials Besidesantihypertensive effect nicardipine was shown to possessantioxidative and antielastase activity [165 166] These prop-erties may be useful for prevention of inflammatory reactionwhich is relevant for hypertension pathogenesis
14-DHPs administration inhibits LDL oxidation medi-ated by oxygen radicals leading to decreased carotid inti-mal media thickness and reduced progression of coronaryatherosclerosis [130] It additionally preserves Apo B-100integrity against ROS Of importance antiatherogenic mech-anisms differ between animals and humans (primarily inthe stage of conversion of aldehydes to carboxylic acids)(Parthasarathy et al [167])
For example furyl-DHP compound (FDP-1 diethyl 26-dimethyl-4-(furyl)-14-dihydropyridine-35-dicarboxylate)was shown to act as an antioxidant (decreasing MDA GOTand FFA release of ischemic myocardium and inhibiting Ca-ATPase of erythrocyte membranes) preventing against heartmyocardium ischemia-reperfusion injury and arrhythmiawhen applied (in rats) at 10mgkg (Liu et al [168])
Similarly antioxidative effects of azelnidipine andamlodipine prevented neuronal damage by CCBs aftertransient focal ischemia in rats (Lukic-Panin et al [169])
Allanore et al [170] found that both nifedipine andnicardipine significantly decrease the mean level of plasmamarkers for oxidative stress in patients suffering from sys-temic sclerosis
Antioxidants may be considered as promising neuropro-tective compounds Still while experimental data demon-strate neuroprotective effect in vitro and in animal mod-els clinical evidence is still unsatisfactory and insufficient[171]
(a) Role of Metabolism of DHPs in Their AOA Metabolicpathways and ldquobioavailabilityrdquo of the probable AOA com-pound determine antioxidant activity in vivo Antioxidantmetabolites may vary in stability and activity leading to twoopposite scenarios lack or presence of activity substantiallycontributing to the overall AOA [172] Metabolic biotransfor-mation of DHPs includes oxidation (heteroaromatization)side chain ester group cleavage (deesterification) and 4-substituent abstraction ao [160] None of the DHPs metabo-lites was shown to be more toxic than original reduced formof the compound The commonly detected metabolites ofthe DHPs do not seem to possess the AO activity (withsome exceptions as in the case of metabolites of nifedipineand its analogues including nitrosonifedipine [173 174]) (seefurther in Section 35) Due to DHPs intrinsic instability
achieving andmaintaining an adequate concentrationmay beproblematic both in vitro and in vivo
(b) Role of Concentration and Lipophilicity (MembraneWateror LipidWater Partition Coefficients) of DHPs inTheir Actionas AOs and Antiradical Compounds Antioxidative effects ofany antioxidant depend on its concentration at the site ofaction This parameter is hardly measurable especially intwo-phase systems representing one of obstacles in com-parison to AOA upon applying various compounds [172]It is often incorrectly assumed that the concentrations inthe aqueous solution and at the site of action are the sameHowever even when the concentration in the aqueous phasemay be well controlled the concentration at the site ofaction in the lipid matrix of the membranes might fluctuatebetween different test compounds depending on a differencein lipophilicity [175] The prevention of the membrane LPalso seems to be dependent on the DHP concentration in thelipidmatrix (Mason andTrumbore [46]) and its amphiphilic-ity For example AOA of diludine is associated with itslipophilicity and consequential ability to be incorporatedinto liposomes (Panasenko et al [176]) It was also foundthat diludine easily incorporates into the outer monolayer oferythrocyte membranes [176]
Membranebuffer partition coefficients (lambda) weredirectly measured in the sarcolemma and sarcoplasmicreticulum membranes for three CA DHPs The obtainedvalues were in a broad range between 5000 and 150000(Herbette et al [177])These drugs interact primarily with themembrane bilayer component but may also bind to proteinsboth nonreceptors and receptors The intrinsic forward rateconstants for DHP binding to sarcolemmal calcium channelreceptors were apparently not strongly dependent on theirmembrane partition coefficients For example nimodipine(lambda = 6300) had a forward rate constant of 68 plusmn 06 times106Ms whereas the forward rate constant for Bay P 8857
(lambda = 149000) was 14plusmn08times107Ms Since these DHPsare highly liposoluble model calculations for this bindingreaction demonstrated that these rates on lipid solubilitywould probably not be reflected in the experimental forwardrate constants In addition the intrinsic forward rate constantfor nimodipine binding to sarcolemmal calcium channelreceptors was found not to be linearly dependent on theviscosity of the buffer medium over a fivefold range The rateof drug nonspecific binding to nonreceptor protein present inhighly purified sarcoplasmic reticulum membranes appearsto be extremely fast at least 103 times faster than specificdrug binding to the receptor in the sarcolemma Authorsconcluded that partitioning into the lipid bilayer matrix ofthe sarcolemma could be a general property of CA DHPsand may be a prerequisite for their binding to sarcolemmalmembrane receptors (Herbette et al [177])
The binding of DHP calcium channel agonists and antag-onists (including those with AO properties) to receptors incardiac sarcolemmal membranes is a complex reaction thatmay involve an interaction with the lipid bilayer matrix ofthe sarcolemma (Herbette et al [178]) Belevitch et al [179]studied the binding of DHP CCBs (riodipine and nifedip-ine) and verapamil to model and biological membranes by
Oxidative Medicine and Cellular Longevity 17
fluorescence analysis The consistent location of Ca agonistBay K 8644 was determined to be within the region ofthe first few methylene segments of the fatty acyl chains ofthe membranes (Mason et al [180]) This position is nearto that observed for the DHP calcium channel antagonistsnimodipine and Bay P 8857
Themajority of studies onOSwere performedwithDHPswith various lipophilicity but only a few studies reportedamphiphilicity ofDHPderivatives AmphiphilicDHPderiva-tive K-2-11 reduced the cellular generation of ROS It alsorevealed complete reversal of multidrug resistance (MDR) ofthe resistant cells K-2-11 was more efficient than well-knownMDR inhibitor verapamil Cytotoxic effects of anticancerdrug doxorubicin were enhanced by K-2-11 in bothMDR andparental nonresistant cell line (Cindric et al [181]) K-2-11suppresses increase of ROS and consequentially prevents NF-120581B activation leading to decreased expression of MDR1 andincreased expression of antiapoptotic genes This signalingswitch is necessary for restoring the chemosensitivity ofcancer cells This phenomenon is characteristic both for14-DHPs [182] (18 novel asymmetrical DHPs bearing 3-pyridyl methyl carboxylate and alkyl carboxylate moietiesat C3 and C5 positions resp as well as nitrophenyl orheteroaromatic rings at C4) and for their oxidized formspyridine compounds (Zhou et al [183])
34 Dependence of AOA of DHPs on the Experimental SystemAO effect of DHPs depends on their structure and theexperimental system used (in vitromodel system subcellularorganelle and cells ex vivo and in vivo) Ideally for theevaluation of the profile and value of DHPs AO propertieseach compound should be tested in as many systems aspossible (Dubur et al [45])
Lipidomics studies have been traditionally explored forstudying AOA of DHPs Proteomics methods are less rep-resented and are mostly focused on the properties of DHPsrelated to scavenging of protein free radicals So far there areno studies on the role of DHPs in scavenging nitrosoperoxy-carbonate the reactive species formed out of peroxynitrite inthe presence of carbon dioxide Although it was shown thatalbumin binds diludine no studies revealed the relevance ofthis effect for the AOA of diludine
There are findings showing that dihydropyridine calciumantagonists (DHPs CA) could indirectly play a beneficialprotective role during development of atherosclerosisNamely Berkels et al [184] have studied antioxidativeproperties of four substances the DHP prototype CAnifedipine the long-acting CA lacidipine the DHP calciumchannel agonist BayK8644 and the bulkyDHPderivate BayO 5572 in three different models (1) in an in vitro superoxideanion generating system (hypoxanthinexanthine oxidase)for testing the ldquopurerdquo antioxidative effect (2) in an artificialmembrane preparation (dimyristoylphosphatidylcholine) formimicking a more physiological environment and (3) underconditions of stimulated ROS release (hyperglycemia) fromnative endothelial cells derived from porcine coronary arter-ies
The study also revealed the potential correlation betweenlipophilic and AO properties of DHPs In the first model
Bay K 8644 was significantly more effective in scavengingsuperoxide anions than lacidipine Bay O 5572 or nifedipine(micro- to millimolar concentration range) Addition of anartificial membrane preparation resulted in an enhancedAO effect with lacidipine being the most effective DHP inquenching radicals (low micromolar concentration range)In the third model mimicking hyperglycemia (30mmolL)nifedipine was significantly more potent antioxidant (ther-apeutical nanomolar concentration range) than the otherDHPs Calculated lipophilicity of these four substances(lacidipine gt Bay O 5572 gt Bay K 8644 gt nifedipine) waspositively correlated with antioxidative potential only in thesecond experimental model It has been concluded that AOproperties of DHP substances need to be tested in variousmodels for demonstrating that nifedipine exhibits ROS-quenching properties in a therapeutic concentration range[184]
341 AOA of DHPs in Isolated Cells and Cell Cultures(Comparison with Other Simplest Systems) Although DHPspossess neuromodulatory andor antimutagenic propertiesthe mechanisms of action related to these phenomena arenot entirely elucidated Borovic et al [185] have studied 14-dihydroisonicotinic acid (14-DHINA) derivatives of 14-DHP water-soluble analogues of a well-known AO diludine(diethone) 26-dimethyl-35-diethoxycarbonyl-14-dihydro-isonicotinic acid sodium 2-(26-dimethyl-35-diethoxycar-bonyl-14-dihydropyridine-4-carboxamido)glutamate gluta-pyrone and sodium 2-(26-dimethyl-35-diethoxycarbonyl-14-dihydropyridine-4-carboxamido)ethane-sulphate tauro-pyrone as AO and bioprotectors (Figure 4)
14-DHINArsquos activities were studied in comparison toTrolox by NN-diphenyl-N1015840-picrylhydrazyl (DPPH∙) deoxy-ribose degradation ABTS∙ radical scavenging and AOA(antioxidative capacity method) assays copper-induced LPof cultured rat liver cells (MDA determination by HPLCand 4-hydroxynonenal-protein conjugates by dot-blot) 3H-thymidine incorporation and trypan blue assay for liver cellsgrowth and viability Ic decreased the amount of 4-HNE-protein adducts In all assays Ia was the most potent AOable to completely abolish copper induced LP of liver cellswhile Ic only slightly decreased it Thus AOA is importantactivity principle of Ia which was even superior to Trolox intreated cell cultures Ia (and its analogues) are easily oxidizedin the Fenton system (Rubene et al [186]) exerting ARA too
35 Peculiarities Related to Antioxidative and AntiradicalActivity of Some 14-DHPs Ca Antagonists Nine commer-cialized structurally and functionally different DHPs CAwill be discussed further Their common feature is ability toprevent OS This also counts for some of their metabolitesas already discussed The comparative effects of some DHPsCA on oxidative stress-induced modification of LDL werealready reviewed in Section 331 (2)-(a) AOA of CA DHPswas discussed in Sections 331 (2)-(b) and 331 (2)-(c)
351 Nifedipine and Its Close Analogues Nifedipine vera-pamil and antiarrhythmic-antihypoxic drug stobadin wereshown to depress lipid peroxidation of phosphatidylcholine
18 Oxidative Medicine and Cellular Longevity
NH
COOH
NH
COONa
Glutapyrone
NH
Gammapyrone
NH
C 2H5OOC COOC2H5
Tauropyrone
14-DHINA
H3C H3C
H3C
H3CCH3 CH3
CH3
CH3
COOC2H5COOC2H5
COOC2H5 C2H5OOCC2H5OOCC2H5OOC
CONHCH(CH2)2COONa CONH(CH2)3COONa
CONH(CH2)2SO3Na
Figure 4 Derivatives of 14-dihydroisonicotinic acid (14-DHINA)
liposomes (Ondrias et al [187]) However data obtained insome other experimental systems are conflicting
In an in vitromodel of sarcolemmal membrane lipid per-oxidation three calcium blockers (nifedipine verapamil anddiltiazem) exhibited concentration-dependent (10ndash400 120583M)inhibitory effects [188 189] Nifedipine the most effectivecalcium blocker was more than two-fold potent compared topropranolol achieving significant effect at 10 120583M Nifedipineprotective role on LP using reduced glutathione as modelmarker was recently described (Ray et al [190]) Antiper-oxidative properties of CA nifedipine and its analogueswere explored in different systemspathogenic processesatherogenesis (Henry [165]) brain focal ischemia (Yamatoet al [191]) nephroprotection related to cyclosporine intake(Chander and Chopra [192]) and hepatoprotection relatedto intake of diethyldithiocarbamate (Gaafa et al [193])Recent data suggest that nifedipine action as protector forendothelial cells proceeds independently from its CA proper-ties
The absence of antioxidant effects of nifedipine anddiltiazemonmyocardialmembrane lipid peroxidation oppo-site to nisoldipine and propranolol was also described[194] Nisoldipine and propranolol were shown to havea concentration-dependent antiperoxidant effect with IC
50
values of 282 and 501 120583M respectively Finally nisol-dipine appeared to possess dual antiperoxidant mecha-nisms involving both preventive and chain-breaking proper-ties
These findings were confirmed in some other studiesincluding reports on the lack of antioxidative activity ofnifedipine and nicardipine even at 500120583M concentrationin heart membrane lipid peroxidation tests [134] SimilarlyROS formation in bovine aorta smooth muscle cells was notaffected by addition of amlodipine nimodipine and nife-dipine [123]
(1) Metabolites of Nifedipine and Its Analogues as Antioxidantsand Regulators of OS Antioxidant activity of nifedipine35-dimethoxycarbonyl-26-dimethyl-4-(2-nitrophenyl)-14-dihydropyridine was originally studied in vitro by Kirule etal [195] and Tirzit et al [196] According to the kinetic dataof peroxide accumulation and the ESR spectra (inhibition ofthe autoxidation of methyl oleate in presence of nifedipine)AO action was exerted by the formation of nitroso analogueof the oxidized nifedipine nitroso nifedipine 26-dimethyl-4-(2-nitrosophenyl)-35-pyridine dicarboxylate (NO-NIF)This nitroso aromatic derivative can form nitroxyl radicalsexhibiting remarkable AOA in the presence of unsaturatedfatty acids and lipids [196]
The primary species of free radicals that have beenobtained and identified were ion radicals of the nitrophenyltype (Ogle et al [76]) Such a mechanism coincides withmechanisms proposed afterwards by Nunez-Vergara et al[96] Lopez-Alarcon et al [103] Valenzuela et al [104]Fukuhara et al [174] and Yanez et al [197]
There are also data showing that nitroso compounds mayinhibit LP by direct radical trapping and subsequent forma-tion of stable nitroxide radicals It was further found that thereactivity between the synthesized 14-DHP derivatives withalkylperoxyl radicals involves electron transfer reactionsThisis documented by the presence of pyridine as a final productof the reaction and complete oxidation of the nitroso groupin the case of the nitrosoaryl 14-dihydropyridine derivatives(Valenzuela et al [104]) Tested compounds reacted fastertoward alkylperoxyl radicals and ABTS radical cation thanalkyl ones (Lopez-Alarcon et al [103])
Nitrosonifedipine a photodegradation product of nifedi-pine significantly recovers cellular damage induced by tumornecrosis factor-alpha It also prevents toxic effects of cumeneperoxide which hampers integrity of cell membranes throughoxidative stress Its positive effects are equal to Trolox-C
Oxidative Medicine and Cellular Longevity 19
As a result nitrosonifedipine was already a long time agoclaimed as a candidate for a new class of antioxidative drugs(Kirule et al [195]) cellular protectors against oxidative stressin glomerular endothelial cells [174]
Moreover Misik et al [198] Ondrias et al [199] andStasko et al [200] studied AOA of nifedipine and its oxidizednitroso analogue NO-NIF prevents the progression of type2 diabetic nephropathy associated with endothelial dysfunc-tion through selective AO effects (Ishizawa et al [201]) NO-NIF administration reduces albuminuria and proteinuriaas well as glomerular expansion without affecting glucosemetabolism or systolic blood pressure NO-NIF also sup-presses renal and systemic OS and decreases the expressionof intercellular adhesion molecule-1 (ICAM-1) a marker ofendothelial cell injury in the glomeruli of the KKAy miceSimilar effects were achieved in endothelial nitric oxide syn-thase (eNOS) knockout mice Moreover NO-NIF suppressesurinary angiotensinogen (AGT) excretion and intrarenalAGT protein expression in proximal tubular cells in theKKAy mice On the other hand hyperglycemia-inducedmitochondrial superoxide production was not attenuated byNO-NIF in cultured endothelial cells
Fujii and Berliner found EPR evidence for free radicaladducts of nifedipine in vivo [202] The nature of these rad-icals was surmised by comparing the reaction of illuminatednitrosonifedipine with polyunsaturated fatty acids Surpris-ingly identical radical spectra were detected from excisedliver doped with nonilluminated nifedipine suggesting thatthis drug can be enzymatically converted in vivo to its nitrosoanalogue without the requirement for illumination This isone of the first reports of in vivo EPR evidence for a class ofunsaturated fatty acid radical conjugates resulting from thenormal metabolism of a common drug
Dıaz-Araya et al [173] studied some 4-nitrophenyl-DHPson Fe3+ initiated LP in rat brain slices LP as measuredby MDA formation was inhibited by all the tested nitro-aryl derivatives of 14-DHP over a wide range of concen-trations On the basis of both time course and IC
50experi-
ments the tentative order of AOA on rat brain slices wasnicardipine gt nisoldipine gt (RSSR)-furnidipine gt (RRSS)-furnidipine gt nitrendipine gt nimodipine gt nifedipine14-DHP derivatives that lack a nitro group in the mole-cule (isradipine and amlodipine) also inhibited LP in ratbrain slices but at higher concentrations than that of nitro-substituted derivatives All tested compounds reduced andoxidized nitrosoaryl derivatives (26-dimethyl-4-(2-nitro-sophenyl)-35-pyridinedicarboxylic acid dimethyl ester (pho-tooxidation product of nifedipine ndash NTP) ao) and weremore potent inhibitors of LP than their parent molecules(Valenzuela et al [104])
The electrooxidation process of 4-nitrosoaromatic DHPsis a strongly pH-dependent (two-electron two-proton mech-anism) ECEC type of mechanism that is the sequenceeminusH+eminusH+ at pH gt 85 ECCE mechanism (eminusH+H+eminus)at pH lt 85 dominates Reduction reaction of nitroso groupis as follows R-NO + 2eminus + 2H+ rarr RNHOH (Bollo et al[203])
352 Lacidipine It is a generic DHP type antihypertensiveCA 35-diethyl 4-2-[(1E)-3-(tert-butoxy)-3-oxoprop-1-en-1-yl]phenyl-26-dimethyl-14-dihydropyridine-35-dicarboxy-late
Ursini [204] described redox behaviour of lacidipine andshowed its tissue protective features Cristofori et al studiedantiatherosclerotic activity in addition to lacidipinersquos CAand AO properties [205] Lacidipine reduced the extent ofatherosclerotic area in hypercholesterolemic apoE-deficientmice (these mice show widespread vascular lesions whichclosely resemble the inflammatory fibrous plaques seen inhumans in atherosclerosis) The reduction may be associatedwith the capacity of the drug to maintain endothelial NOlevels at concentrations useful to protect against vasculardamage This work suggested that DHPs modulate vascularrelaxation via increased release of NO
Herbette et al [178] remarked optimal hydrophobicity oflacidipine due to cinnamic acid substituent so membraneinteractions and facilitation of the treatment of atherosclero-sis could proceed (see also Section 331 (2)-(a))
353 Amlodipine Amlodipine (Norvasc) (RS)-3-ethyl5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-14-dihydropyridine-35-dicarboxylate (AML) hasan antioxidant effect on vessels in vitro and is a 3rd genera-tion of charged dihydropyridine CCB that is widely used forthe treatment of hypertensive patients
Amlodipine was shown to have the highest affinity(amlodipine gt verapamil ≫ diltiazem) for the membranebilayer (119870
119901= 104) It produced the significant changes in
membrane thermodynamic properties including a reductionin the thermal phase transition temperature (minus11) enthalpy(minus14) and cooperative unit size (minus59) relative to thecontrol phosphatidylcholine liposomes (Mason et al [49])
Amlodipine AOA is related to its reductant nature orhydrogen donor properties respectively Its ability for donat-ing protons and electrons to the lipid peroxide moleculesblocks the LP process
Amlodipine and even its enantiomers (Zhang et al [206])act as ROS andNOS effectors in several model systems of OSAntioxidant properties of amlodipine were recently reviewedby Vitolina et al [32] Both in vitro and in vivo studiesof amlodipine AO properties revealed inhibition of lipidsoxidative damage primarily those associated with cellularmembranes and lipoprotein particles (LDL) (Mason et al[50])
Under controlled experimental conditions in vitro amlo-dipine showed AOA and ARA by inhibition of lipid peroxideformation and trapping ROS Its scavenging activity forhydroxyl and peroxyl radicals at concentrations as low as100 nmolL (which is remarkably less compared to the classi-cal antioxidants GSH uric acid and Trolox) was shown to beindependent of the calcium channel modulation (Franzoni etal [207])
AML showed efficiency as scavenger of peroxyl radicals(TOSC assay 5945 plusmn 544 unitsmg) significantly stronger(gt50 119875 lt 0001) than GSH (2733plusmn 636 unitsmg) and 70weaker (119875 lt 00001) than uric acid (18144 plusmn 696 unitsmg)and Trolox (17522 plusmn 734 unitsmg)
20 Oxidative Medicine and Cellular Longevity
Of interest the scavenging capacity of AML towardshydroxyl radicals (1455 plusmn 154 unitsmg) was 320 higher(119875 lt 000001) than that of GSH (358 plusmn 112 unitsmg) 20higher than that of uric acid (1198plusmn121 unitsmg) and 100higher than that of Trolox (759 plusmn 143 unitsmg)
Amlodipine was shown to increase enzyme activity ofparaoxonase (PON) and glutathione peroxidase (GSH-Px)However it also decreases glutathione reductase (GSSG-R)activity and diminishes the concentration of the endogenousantioxidant 120572-tocopherol (vitamin E) Moreover AML in aconcentration of 2 ngmL decreased the content of malonicdialdehyde and activity of superoxide dismutase in the blood(Gatsura [208])
Verapamil and amlodipine produced a potent anti-ischemic effect and reduced area of myocardial infarction inrats The observed changes were accompanied by inhibitionof LP In contrast to verapamil in vitro application of AML ina dose of 50 ngmL decreased hemoglobin affinity for oxygenWhen present in a concentration of 2 ngmLAMDdecreasedthe content of MDA and activity of SOD in the blood
On the other hand amlodipine shows no activity relatedto inhibition of macrophage superoxide release and cellmigration which occurs as a consequence of decreasedTNF120572induced O
2
∙ releaseAmlodipine-induced reduction of OS in the brain is
associated with sympathoinhibitory effects in stroke-pronespontaneously hypertensive rats (SHRSP) (Hirooka et al[209]) Antihypertensive treatment with amlodipine reducedOS in all examined areas of the brain and decreased bloodpressure without a reflex increase in sympathetic nerveactivity Nicardipine another CA DHP surprisingly wassignificantly less active than amlodipine
354 Lercanidipine Tomlinson and Benzie reported AOeffect of lercanidipine [210] which is well known as anti-hypertensive drug Zanidip 2[(33-diphenylpropyl)(methyl)-amino]-11-dimethylethyl methyl 26-dimethyl-4-(3-nitro-phenyl)-14-dihydropyridine-35-dicarboxylate Compara-tive data about this drug AOA were presented in parts of thispaper about other individual CA DHPs and in the part aboutthe ex vivo DHPs effects on LDL
355 Nimodipine Nimodipine (ND) commercially knownas Nimotop is 3-(2-methoxyethyl) 5-propan-2-yl 26-dim-ethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxy-late It is centrally active CA
Treatment with glutathione blocked andwith nimodipineattenuated neuronal cell death caused by prolonged exposureof cell culture to 4-HNE (Faraqui [211])
Nascimento et al [212] found AO effect of nimodipine inyoung rats after pilocarpine- (PIL-) induced (in 400mgkg)seizures The PIL administration increased the striatal cata-lase (CAT) activity The administration of ND 30mgkg30min before PIL preserved normal value of CAT activityOn the other hand no difference was detected in the animalstreated with lower dose 10mgkg These results confirmthe neuroprotectiveantiepileptic effect of ND in young ratssuggesting that this drug acts positively on lipid peroxidation
(in both doses) Nimodipine cannot induce these effects viablockade of Ca2+ channel
Ismailoglu et al [213] studied the therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjury These beneficial effects in rats after cerebral corticalinjury seemed to be related to AOA of nimodipine
356 Benidipine Licensed in Japan and South Asia as CA(CCB) benidipine possesses AO properties Chemically it is5-methyl 3-[(3R)-1-(phenylmethyl)piperidin-3-yl] 26-dim-ethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxy-late (or its hydrochloride (4R)-rel-35-pyridinedicarboxylicacid 14-dihydro-26-dimethyl-4-(3-nitrophenyl)- 3-methyl5-[(3R)-1-(phenylmethyl)-3-piperidinyl] ester hydrochloride(1 1))
Benidipine influences processes connected with OS inseveral ways It prevents lysophosphatidylcholine- (lysoPC)-induced injury and ROS production in human aorticendothelial cells (HAECs) (Matsubara and Hasegawa [214])Matsubara et al [215] explained this effect based on stimula-tion of nitric oxide release
LysoPC is a component of oxidized low-density lipopro-teins (oxLDLs) which plays an important role in the patho-genesis of atherosclerosis Pretreatmentwith benidipine (03ndash3 120583molL) for 24 h protected against lysoPC-induced cyto-toxicity in the HAECs through inhibition of both lysoPC-stimulated ROS production and caspase-37-like activationwith a similar potency Since caspase-37 is involved inexecuting the apoptotic process the reduction of the activityof this enzyme by benidipine may explain the antiapoptoticeffect of the drug However benidipine did not suppresslysoPC-induced phosphorylation of mitogen-activated pro-tein kinases and Ca2+ influx in HAECs These results suggestthat the antioxidant properties of benidipine may be respon-sible for its ability to inhibit ROS production a possiblereason for reduced activation of caspase-37 In conclusionbenidipine suppresses lysoPC-induced endothelial dysfunc-tion through inhibition of ROS production which is due atleast in part to its antioxidant effect and not through theinhibition of L-type voltage-dependent calcium channels
Matsubara and Hasegawa [216] examined the effectsof benidipine on cytokine-induced expression of adhesionmolecules and chemokines (chemoattractants) which areimportant for the adhesion of monocytes to endotheliumPretreatment of HAECs with benidipine (03ndash10 120583molL)for 24 h significantly suppressed cytokine-induced vascularcell adhesion molecule-1 (VCAM-1) and intracellular celladhesion molecule-1 (ICAM-1) mRNA and protein expres-sion resulting in reduced adhesion of THP-1 monocytesBenidipine also suppressed induction of monocyte chemoat-tractant protein-1 (MCP-1) and interleukin-8 Benidipinealso inhibited redox-sensitive transcriptional nuclear factor-120581B (NF-120581B) pathway as determined by Western blotting ofinhibitory 120581B (I120581B) phosphorylation and luciferase reporterassay Results of analysis using optical isomers of benidip-ine and antioxidants suggest that these inhibitory effectswere dependent on pharmacological effects other than Ca2+antagonism Benidipine may thus have anti-inflammatoryproperties and benefits for the treatment of atherosclerosis
Oxidative Medicine and Cellular Longevity 21
Benidipine was also shown to inhibit ROS production inpolymorphonuclear leukocytes and oxidative stress in salt-loaded stroke-prone spontaneously hypertensive rats (Mat-subara et al [217])
It should be mentioned that other DHPs also haveendothelial AO actions [218]
357 Azelnidipine (AZL) Azelnidipine 3-[1-[di(phen-yl)methyl]azetidin-3-yl] 5-propan-2-yl 2-amino-6-methyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate(AZL) CAS number 123524-52-7 is commercially available4-nitroaryl-DHP type calcium antagonist with long-actingantihypertensive action (long-acting CA (CCB)) and a lowreported incidence of tachycardia It additionally possessesbeneficial effects in OS and diabetic conditions
Azelnidipine prevents cardiac dysfunction in strepto-zotocin-diabetic rats by reducing intracellular calcium accu-mulation (altering intracellular Ca2+ handling proteins) OSand apoptosis (Kain et al [219]) AZL can reduce the superox-ide production It exerts its protective effects by targeting theNADPH oxidase and mitochondrial redox enzymes AZL-treated diabetic rats express enhanced level of bcl-2 in thelysates of heart muscle indicating that AZL plays protectiverole in cardiac apoptosis
It has been previously observed that azelnidipine inhibitstumor necrosis factor-alpha-induced endothelial cell (EC)oxidative stress through its AO properties (Nakamura etal [220]) Azelnidipine but not nitrendipine completelyinhibits the Ang II-induced ROS generation in ECs (Matsuiet al [221])
Furthermore azelnidipine but not nitrendipine wasfound to partially restore decreased pigment epithelium-derived factor (PEDF) mRNA levels in Ang II-exposed ECsThis study suggests that AZL influence depends on its antiox-idative properties Authors concluded that upregulation ofPEDF by azelnidipine may become a therapeutic targetfor the treatment of diabetic retinopathy associated withhypertension
Antihypertensive agents with AO effects are potentiallyuseful for diabetic patients with hypertension While DHPtypeCAare among themost frequently used antihypertensivedrugs azelnidipine has been reported to have a unique AOeffect in vitro and in vivo in experimental animals (Ohmuraet al [222]) In hypertensive diabetic patients azelnidipinetreatment for 12 weeks induced a more significant decreasein erythrocyte LOOH level than amlodipine although thevalues related to blood pressure during each treatmentremained comparable These data confirm the usefulness ofLOOH level in erythrocyte membrane as a marker of OS invivo and indicate that azelnidipine has a unique antioxidativeproperty in humans
Daikuhara et al [223] reported the results of the OLCAstudy based on combination of (1) olmesartan and a calciumchannel blocker (azelnidipine) or (2) candesartan and a CCBamlodipine in two groups of diabetic hypertensive patientsPatients treated with the first combination presented highlypersistent early morning antihypertensive effect and strongerdecrease in heart rate fasting blood glucose andHbA1c levels
and microalbuminuria when compared to patients treatedwith the combination (2) Because diabetes is associated withsevere chronic OS the observed results might be at least in apart due to the AOA of azelnidipine
In favor of this are findings of Abe et al [224] who foundadditive antioxidative effects of azelnidipine on angiotensinreceptor blocker olmesartan treatment for type 2 diabeticpatients with albuminuria
Similarly the AOA of thiazolidinediones (insulin sensi-tizer) and their effect on cardiovascular function in type 2diabetic model rats and also those of some DHPs (nifedipineamlodipine or AZL commonly used antianginal and anti-hypertensive agents) in cultured human endothelial cells LPwere examined (Mizushige [225]) The AOA was evaluatedby measuring 8-iso-prostaglandine F
2120572concentration and
azelnidipine exhibited potent AOAInsulin (INS) resistance combined with hyperinsuline-
mia is involved in the generation of OS A relation-ship exists between increased production of ROS and thediverse pathogenic mechanisms involved in diabetic vascularcomplications including nephropathy Manabe et al [226]revealed that high doses of INS augmented mesangial cellproliferation through generation of intracellular ROS andactivation of redox signaling pathways Cell proliferation wasincreased in a dose-dependent manner by high doses of INS(01ndash10 120583M) but was inhibited by 01120583M AZL Namely theINS-increased phosphorylation of mitogen activated proteinkinaseextracellular signal-regulated kinase 12 (MAPKERK12) was inhibited by 01 120583MAZL The same AZL concen-tration blocked intracellular ROS production more effec-tively than 01 120583M nifedipine The NADPH oxidase inhibitorapocynin (001ndash01120583M) prevented INS-induced mesangialcell proliferation So azelnidipine inhibits insulin-inducedmesangial cell proliferation by inhibiting the productionof ROS Therefore azelnidipine may have the potential toprotect against the onset of diabetic nephropathy and slowits progression
Azelnidipine inhibited H2O2-induced cell death in
neonatal rat cardiomyocytes (Koyama et al [227]) Azelnidip-ine and nifedipine did not affect theH
2O2-induced activation
of extracellular signal-regulated protein kinases (ERK) andp38 MAPK (mitogen-activated protein kinase) In contrastazelnidipine but not nifedipine inhibited H
2O2-induced c-
Jun NH2-terminal kinases (JNK) activation Authors con-
cluded that azelnidipine has inhibited theH2O2-induced JNK
activation and cardiac cell death Therefore azelnidipine mayhave cardioprotective effects against OS
A specific atheroprotection activity of azelnidipine relatesto inhibition of TNF-120572-induced activator protein-1 activa-tion and interleukin-8 expression in human umbilical veinendothelial cells (HUVEC) through suppression of NADPHoxidase-mediated reactive oxygen species generation (Naka-mura et al [220]) TNF-120572 could play a central role in patho-genesis of insulin resistance and accelerated atherosclerosis inthe metabolic syndrome The concentration of AZL found tobe effective in these in vitro experiments is within therapeuticrange As EC do not possess voltage-operated L-type calciumchannels it is suggested that the beneficial effects of azelni-dipine are not likely due to CA property but to its unique AO
22 Oxidative Medicine and Cellular Longevity
ability Furthermore it has been recently found that serumlevels of monocyte chemoattractant protein-1 a biomarkerfor subclinical atherosclerosis were significantly decreased bythe AZL treatment in patients with essential hypertension Inthis paper [220] authors hypothesize that due to its uniqueTNF-120572 signalmodulatory activity and antioxidative propertyazelnidipine may be a promising DHP for targeting diabetesand cardiovascular diseases in hypertensive patients withmetabolic syndrome
Shinomiya et al [228] evaluated its AOA in culturedhuman arterial EC under OS Azelnidipine has shown apotent antioxidative effect that could be of significant clinicalbenefit when combined with its long-lasting antihypertensiveaction and low incidence of tachycardia
Azelnidipine inhibited TGF-1205731 and angiotensin II- (AngII-) activated 1205721(I) collagen mRNA expression in hepaticstellate cells (HSCs) (Ohyama et al [229]) FurthermoreTGF-1205731- and Ang II-induced OS and TGF-1205731-induced p38and JNK phosphorylation were reduced inHSCs treated withAZL Azelnidipine significantly decreased inflammatory cellinfiltration profibrotic genes expression HSC activation LPoxidative DNA damage and fibrosis in liver of CCl
4- or
TAA-treated mice Finally AZL prevented decrease of theexpression of some AO enzymes and accelerated regressionof liver fibrosis in CCl
4-treated mice Hence the antifibrotic
mechanism of AZL against CCl4-induced liver fibrosis in
mice may have been due to an increased level of AO defenseAs azelnidipine is widely used in clinical practice withoutserious adverse effects it may provide an effective newstrategy for antifibrotic therapy
358 Manidipine Manidipine (2-[4-(diphenylmethyl)pip-erazin-1-yl]ethyl methyl 26-dimethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate) is a DHP CCB withreported nephroprotective properties Calo et al [230] stud-ied effect of manidipine on gene expression and proteinlevel of OS related proteins p22(phox) (human neutrophilcytochrome b light chain (CYBA)) and heme oxygenase-1HO-1 Relevance for antihypertensive effects was revealedThe study assessed the effect of manidipine on normalsubjectsrsquo monocyte gene and protein expression of OS relatedproteins such as p22phox a NADPH oxidase system subunitcritical in generating O
2
∙minus and HO-1 induced by and pro-tective against OS Manidipine was compared with the ACEinhibitor captopril and the CCB nifedipine in the presenceand in the absence of sodiumarsenite (NaAsO
2) as an inducer
of OS Monocyte p22phox (CYBA) mRNA production wasreduced by both manidipine and captopril while no changeswere induced by nifedipine Manidipine increased monocyteHO-1 mRNA production while nifedipine and captoprilshowed no effect The effects of manidipine on p22phoxand HO-1 gene expression in the presence of OS were alsoconfirmed at the protein level Thus manidipine seems tosuppress p22phox and to increase the HO-1 mRNA produc-tion and protein level The manidipine-induced increase ofHO-1 gene and protein expression seems to be a peculiareffect of this drug since it is not observed with captopriland nifedipine This effect together with the reduction of
p22phoxmRNAproduction could play a role in its protectivemechanism against OS
359 Mebudipine The protective effect of mebudipine (14-dihydro-26-dimethyl-4-(3-nitrophenyl)-35-pyridinedicar-boxylic acid 3-methyl-5-tert-butyl ester BAY-n-6391) wasrevealed on OS and LP (MDA decrease SOD GPX andcatalase increase) in myocardial ischemic-reperfusion injuryin male rats (Ghyasi et al [231])
There are articles about other commercial and experi-mental DHPs on OS but we have reviewed only the mostcommonly studied compounds Effects of other commercialCA DHPs on OS are also mentioned in several parts of thisreview
36 14-DHPs Ca Agonists andTheir AOA and ARA For themost popular calcium agonist DHP Bay K 8644 no reactionwith peroxyl radicals was registered (Toniolo et al [114])However interactionwith other compounds possessing AOAand ARA (quercetin) was found
Opposite to that AON-acetylcysteine (NAC) diminishedincrease in Ca2+ transient amplitude and cell shorteninginduced by ISO and forskolin whereas NAC had no effecton the (S)-(minus)-methyl-14-dihydro-26-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylatemdash(minus)-BayK 8644-induced increases (Andersson et al [232])
Increased vasoconstriction responses to Bay K 8644 (3 times10minus7ndash3times 10minus5M)were significantly decreased by pyridoindoleantioxidant stobadine treatment in diabetes (Ceylan-Isik etal [233])
The functional interaction between two L-type Ca2+channel activators quercetin and Bay K 8644 has beeninvestigated in vascular smooth muscle cells Biological ARAcompound quercetin at nutritionally meaningful concen-trations limited the responsiveness of vascular L-type Ca2+channels to the pharmacological stimulation operated by BayK 8644 These data contribute to a better understanding ofquercetin effects on experimental in vivo cardioprotection(Saponara et al [234]) Thus these findings indicated thatalthough Bay K 8644 does not exert potent and direct AOAyet acting as calcium agonist it may affect efficiency of AOsubstances and vice versa
Interaction of grapefruit juice (containing quercetin andits analogues) with DHPs CA diminished effectiveness of CAaction of DHPs (Sica [235])
37 Interpretations of the Mechanism(s) of RadicalScavenging and AOA by DHPs
371 Molecular Mechanism(s) of Radical Scavenging andAOA of DHPs in the Model Systems 35-Dicarbonyl-14-di-hydropyridine derivatives possess powerful bis-120573-carbony-lvinyl-amino conjugation and for that reason cannot be con-sidered as ordinary amino antioxidants The electron andorH donation from DHPs ensures their reductant role andresults in AOA and ARA Oxidation reaction from DHPsresults in production of corresponding heteroaromatic pyri-dine derivatives
Oxidative Medicine and Cellular Longevity 23
Detailed studies were made about substituent in DHPring positions 14- namely 4-unsubstituted- 4-substituted4-alkyl- 4-aryl- 4-alkylaryl- ao 26- 35- (diacetyl ordialkoxycarbonyl chain ao) electronic and steric effects onAOA and ARA of DHPs [44 45 51] see Sections 331and 35 The bell-shaped dependence of DHPs AOA onthe 35-dialkoxycarbonyl- chain length was observed [4445 107 109 112] with the maximum activity at C
2H5ndash
C4H9 Decrease of AOA and incorporation into liposomes for
DHPs with alkyl chains longer than R gt C4H9further were
clarified as probable tendency to self-aggregation of thesecompounds ([51] and citation number 245 therein) Electronacceptorelectron donor properties are relevant for expres-sion of AOA or ARA of 35-disubstituted DHPs 35-Diacyl-substituted and 35-dicarbanilido- and 35-dipyridylamido-substituted DHPs are more active as AOs as their 35-dicyano-substituted analogues which have electron acceptorproperties [186]
Dubur et al [89] observed overwhelming steric influenceof substituents in position 4 of the DHP ring Gaviraghiet al [163 164] proposed that AO activity of DHPs ispartly dependent on capacity of the 14-DHP ring to donateelectrons to the propagating radical (ROO∙ or RO∙) and toreduce it to a less reactive form The abstraction (donation)of electron andor H in the oxidation and LP reactionstakes place from all 35-dicarbonyl-14-DHP systems andresults in the formation of corresponding pyridine derivatives(Augustyniak et al [51]) The physicochemical mechanism ofARA and AOA of 14-DHP has been extensively studied anddiscussed (Mulder et al [236]) but precise mechanisms oftheir activity need further clarification
The reactivity of C-4 substituted 14-DHPs possessingeither secondary or tertiary nitrogen atom in the DHP ringtoward alkyl alkylperoxyl radicals and ABTS radical cationwas determined in aqueous media at pH 74 [103] Thesecompounds reacted faster toward alkylperoxyl radicals andABTS radical cation than alkyl ones N-Ethyl-substitutedDHPs showed the lowest reactivity
The 4-methyl substituted DHP was the most reac-tive compound in previously mentioned reactions (Lopez-Alarcon et al [103]) However it was less active (068versus 10) than Trolox-C DHPs having electron-donatingsubstituents (4-Me-DHP and p-MeO-Phe-DHP) showed thehighest kinetic rate constants toward ABTS radical cation p-nitro-Phe-DHP a compound with an electron-withdrawingsubstituent showed a lower kinetic rate constant and N-alkyl-DHP compounds show kinetic rate constants lowerthan the -NH-DHP
Hydrogen at the 1-position of the DHP ring was revealedaccording to the deuteriumkinetic isotope effect studies to beinvolved in the proposedARAmechanismThis fact ismostlynoticeable in the case of alkyl radicals N-Ethyl-substitutedDHPs show the lowest reactivity when compared to Troloxor nisoldipine In all cases the respective pyridine derivativewas detected as the main product of the reaction (Lopez-Alarcon et al [103]) Authors indicate that the kinetic rateconstants toward alkyl alkylperoxyl andABTS radical cationdepend on the nature of the substituents in the C-4 positionof DHP and the presence of the secondary amine group in the
dihydropyridine ring that is the presence of the hydrogen in1-position
Yanez et al [197] have studied the reactivity of 11derivatives of 14-DHPs (including commercial CA) withalkylperoxyl radicals and ABTS radical cation The tested14-DHPs were 83-fold more reactive towards alkylperoxylradicals than to the ABTS cation radical All commercial14-DHP type CCBs were weaker than Trolox-C The par-ticipation of the hydrogen atom in the 1-position appearsto be very relevant for exhibited reactivity Hantzsch ester(diludine)was again found to be themost active compound inthe reaction with alkylperoxyl radicals 23-fold more activethan Trolox The photodegradation product of nifedipine(nitrosophenyl derivative of pyridine) also showed a highactivity Kinetic rate constants for the reaction between 14-DHP compounds and alkylperoxyl radicals exhibited a fairlygood linear correlation with the oxidation peak potentialof DHP derivatives However the activity of tested 14-DHPs towards ABTS radical cation showed an independencebetween kinetic rate constants and oxidation peak potentials
Kirule et al [195] andTirzit et al [196] studiedmechanismof AOA of 4-nitrophenyl-14-DHPs nifedipine and its ana-logues involving formation of 4-(21015840-nitrosophenyl)-pyridinederivative (as active principle) as a result of intramolecularredox reaction using chemical electrochemical and bio-chemical approaches (see Sections 331 and 351)
Nunez-Vergara et al [237] reported the electrochemicaloxidation of C4-hydroxyphenyl-substituted 14-DHP deriva-tives The oxidation proceeds via formation of the unstabledihydropyridyl radical as confirmed by controlled-potentialelectrolysis (CPE) and ESR experiments This type of 14-DHPs has significant activity towards the radicals even whencompared with commercial 14-DHP drugs with well-knownantioxidant ability
It was observed that nicardipine preferentially targets RO∙radicals and is inactive against ROO∙ Lacidipine on theother hand is equally active towards both types of radicals(Gaviraghi et al [164]) The cytoprotective effect againstexposure to H
2O2was more significant for lacidipine (ID
50=
14 nM its log119875 = 54 membrane partition = 136000 assumesposition located 7 A near to the membrane center otherless lipophilic DHPs located 12ndash16 A far from the center)as compared to amlodipine nifedipine and nicardipine insmooth muscle cell culture (Gaviraghi et al [164]) Oxidativeeffect of H
2O2shifts the Ca channel toward an open state
Thus the redox property of CCBs DHPs may augment theirCCB properties
Oxidation of pharmacologically active Hantzsch 14-dihydropyridines was found by electrogenerated superoxideusing a voltammetric approach in DMSO solutions (Ortiz etal [238] and Ortiz et al [239]) Raghuvanshi and Singh [240]have also reported oxidative aromatization of these DHPsinduced by superoxide
Chemiluminescence (CL) was used in the studies ana-lyzing the antioxidant activity of 12 various 4-flavonil-14-dihydropyridine derivatives (Kruk et al [241]) on a chemicalsystem involving a superoxide radical anion These deriva-tives showed structural similarity to flavonoids with respectto the presence of rings A B and C The results obtained in
24 Oxidative Medicine and Cellular Longevity
this study indicate that the tested derivatives may catalyzeconversion of superoxide radicals through mimicking theactivity of superoxide dismutase by delivering H+ for reac-tion
O2
minus∙+O2
minus∙+ 2H+ 997888rarr H
2O2+1O2
(3)
The enhanced emission of the light in the presence oftested compounds was significant and related to stimulatedproduction ofH
2O2and 1O
2fromO
2
∙The latter specieswereremoved from the reactionmixture by the following sequenceof reactions
H+
O2
minus∙997888rarr HO
2
∙
HO2
∙+O2
∙minus997888rarr HO
2
minus+1O2
2HO2
∙997888rarr H
2O2+1O2
2 (1O2) 997888rarr (O
2)2+ h]lowast
(4)
or to take part in spontaneous dismutation of H2O2
2H2O2997888rarr 2H
2O + 1O
2(5)
The authors have offered an original concept of action for 4-flavonil-14-dihydropyridine derivatives unrelated to that ofO2
∙ radical-trapping chain-breaking antioxidants Insteadthey showed that these compounds act similar to superoxidedismutases converting O
2
∙ to H2O2 Hydrogen peroxide
is less toxic for cells than O2
∙ because it is predominantlyremoved by peroxidases and catalases Finally AO effect ofthese DHPs differed from those mediated by flavonoids witha catechol structure of ring B which are well-known 1O
2
quenchersMulder and collaborators came to similar conclusions
especially related to molecular mechanisms of antioxidativeactivity of DHPs [236]TheAOproperties of Hantzsch 14-di-hydropyridine esters and two dibenzo-14-dihydropyridines910-dihydroacridine (DHAC) and N-methyl-910-dihydro-acridine (N-Me-DHAC) have been explored by determin-ing the autoxidation of styrene or cumene at 30∘C Theseexperiments showed that Hantzsch esters are virtually inac-tive as chain-breaking antioxidants (CB-AOs) contrary tothe findings observed by Lopez-Alarcon et al [103] whoused CB-AOA in aqueous media at pH 74 Their reactivitytoward peroxyl radicals was shown to be some 5 orders ofmagnitude lower than that of the excellent CB-AO 22578-pentamethyl-6-hydroxy-chroman (PMHC)
DHAC was found to be sim10 times less reactive thanPMHC kinetic measurements using DHAC N-deuterio-DHAC and N-Me-DHAC pointing out the abstraction ofN-H hydrogen in DHAC by peroxyl radicals despite the factthat the calculated C-H bond dissociation enthalpy (BDE) inDHAC is about 11 kcalmol lower than the N-H BDE Therates of hydrogen atom abstraction by the 22-diphenyl-1-picrylhydrazyl radical (DPPH∙) have also been determined
for the same series of compounds The trends in the peroxyl∙and DPPH∙ rate constants were found to be similar [236]
Tirzit et al [242] have observed quenching of singletoxygen by DHPs This observation paved the ground forfurther research related to reactions of DHPs with hydroxylradicals (Tirzit et al [243]) singlet oxygen (Kazush etal [94]) and mechanisms of action A series of 14-DHPderivatives in NAD-H-Cu2+-H
2O2system inhibited forming
of the hydroxyl radical (HO∙) while 14-DHP derivativeswith electron donor substituents in the molecule were shownto be capable themselves of generating HO∙ in the presenceof Cu2+ and H
2O2 Rubene et al [186] also described
interaction of 14-DHP derivatives with Fentonrsquos reagentwhich produces hydroxyl radical (HO∙) Rate constants ofthe DHPs reaction (1st order) with HO∙ radical were highin the range 109 L times mol times secminus1 close to that of NADHcysteine and thiourea 35-Diacetyl- derivatives reacted fastercompared to 35-dialkoxycarbonyl- ones The reaction ratedecrease was observed in the case of substitution at position4 as compared to 4-unsubstituted DHPs Some DHPs havingelectron donor -COOminus groups in the 35- or 26- positionsof DHP ring reacted immediately (having rate constantshigher as 109 L times mol times secminus1) Rate constants with HO
2
∙
and O2
∙minus radicals were of lower degree Thus DHPs actingas oxygen radical scavengers could effectively inhibit ROSrelated reactions of LP initiation stage
Nifedipine and nitrendipine reactivity toward singletoxygen was also studied [244] Nifedipine was shown tobe a good scavenger of excited oxygen mainly via physicaldeactivation with values of the total rate constant rangingfrom 208 times 105Mminus1 sminus1 (in dioxane) to 930 times 105Mminus1 sminus1(in propylene carbonate)The less reactive pathway generateda photooxidation product For that reason a mechanisminvolving a perepoxide-like encounter complex in the firststep of the reaction path was proposed (see [244] Figures8 and 9 therein) The dependence was observed on solventmicroscopic parameters of the total rate constant for the reac-tion between singlet oxygen and 14-DHPs These findingsshow that nifedipine possesses stronger protective activity inbiological systems than nitrendipine
Density-functional-theory (DFT) calculations made byWang et al [245] confirmed the former experimental obser-vations that Hantzsch ester diludine is potent antioxi-dant with high H atom-donating ability and relatively lowprooxidant activity Possible reaction pathways for radicalsderived from 14-dihydropyridine and the resonance modesfor radical species were given [245]
Moreover two ethoxycarbonyl (EtOCO) substituentsat C(2) and C(6) should further enhance Hantzsch esterdiludine H-atom-donating ability due to resonance effectsHowever DHPs should be used in nonpolar rather than inpolar solvents since in the latter not H-atom but electrontransfer is preferred in the radical scavenging process [245]
Mulder et al [246] proposed that quantum-thermochem-ical calculations must be used with caution to indicate ldquoapromising lead antioxidantrdquo as they criticized the density-functional-theory (DFT) calculations made by Wang et al[245]
Oxidative Medicine and Cellular Longevity 25
372 Possible Mechanisms of DHPs ARA and AOA in the Bio-logical Systems Interaction with Other OSModifiers Some ofthese mechanisms were already described (Sections 331 (2)-(b) 331 (2)-(c) 331 (3)-(b) 35)
Enzymatic sources of ROSwith confirmed functional rolein hypertension are NADPH oxidase NO synthase (NOS)xanthine oxidase and cyclooxygenase Godfraind [3] hasreviewed AO effects and protective action of calcium channelblockers (CCBs) Yao et al [247] observed antioxidant effects(as inhibition of LP) for cardio- and neuroprotective CCBs(3ndash300 120583molL) including 7 DHPs in homogenates of ratbrain IC
50values (120583M) were as follows nifedipine (515) gt
barnidipine (586) gt benidipine (712) gt nicardipine (1293)gt amlodipine (1355) gt nilvadipine (1673) gt nitrendipine(2521) gt diltiazem (gt300) = verapamil (gt300) There arealso research articles describing the AO properties of CCBsthrough direct scavenging effect or through preservationof the endogenous SOD activity These findings indicatethat CCBs may also act by reducing the production ofvasoconstrictors angiotensin and endothelin
When present in concentrations that can be achievedin plasma CCBs may inhibit LP formation [3] This AOactivity seems to be typical for high lipophilic CCBs becausetheir chemical structure facilitates proton-donating andresonance-stabilization mechanisms that quench the freeradical reaction Their insertion in the membrane nearpolyunsaturated fatty acids at relatively high concentrationspotentiates proton donation (or atomary H) to lipid peroxidemolecules thereby blocking the peroxidation process Theremaining unpaired free electron associated with the CCBmolecule can be stabilized in well-defined resonance struc-tures associated with the DHP ring (Mason et al [48])
The radical reaction (according to Godfraind [3]) thatdescribes the AO effects of a DHP CCBs is LOOlowast + DHPrarr LOOH + DHPlowast (where LOOlowast is lipid peroxide radical)which in general is reaction (7) of the LP reaction cascadeconsisting of sim10 reactions (Scheme 2) [89]
As the rate constants of in vitro interaction of 4-substituted DHPs with peroxyl radicals are three ordersof magnitude lower than that of the vitamin E derivativethese DHPs must be considered as weak AO (Ursini [204])However due to partition coefficient of DHPs in membranesand in case of specific binding high local concentration ofDHPs may be obtained
DHPs without CCB properties for instance Bay w 9798although structurally related to nifedipine inhibit TNF-120572-induced vascular cell adhesion molecule-1 expression inendothelial cells by suppressing reactive oxygen speciesgeneration [248]
Mitrega et al [249] have discovered that antiarrhythmicand hemodynamic effects of oxidized heteroaromatic DHPsoxy nifedipine oxy nimodipine oxy nitrendipine and oxynisoldipine suggest that CCB DHPs and their metabolitescould act at least in two ways targeting OS related eventsas reductants (see Section 351 (1)) andor bypassing OSrelatedmetabolic routes Authors postulated that contrary tocurrent belief NIF metabolites are pharmacologically activeATP sensitive potassium channels were mentioned as a tar-get
38 DHPs Anti- or Prooxidants Several substances (ascorbicacid being the most commonly studied) can serve either asantioxidants or as prooxidants depending on given condi-tions (Herbert [250]) Therefore Halliwell [251] has reporteddilemma related to polyphenols as possible antioxidantsand prooxidants causing experimental artifacts (about 25)by oxidation of antioxidant compounds in the cell culturemedia Nevertheless it is generally accepted opinion thatpolyphenols act as antioxidants in vivo Studies on DHPs alsoface such a dilemmaThe exact roles (anti- or prooxidative) ofany specific DHP depend on its structure appliedachievedconcentration and specificity of the targetexperimentaltesting system
This situation resembles the case of antioxidative effectsof tocopherol which depends on the fate of the secondaryradical as proposed by Winterbourn [252] The question wasldquoVitamin E - Pro- or Antioxidantrdquo
997888rarr chain termination of lipid peroxidation
(6)
Prooxidant
Toc∙ + Lipid-H 997888rarr Lipid∙ (in LDL particles) (7)
This example shows that generally speaking any AO mustfulfil several criteria to be considered as an effective com-pound physiologically
(i) It must be able to functionally interact with endoge-nous scavengers even at low concentrations
(ii) It must affect endogenous pathways of OS(iii) It should not have undesirable adverse effect(iv) It should manifest the antioxidant efficacy dependent
on the oxidant(v) It must discriminate among different strategies
needed for 1-electron and 2-electron processes(vi) Radical scavengers can be prooxidant unless linked to
a radical sink (Winterbourn [252])
According to these statements DHPs could be effective asAO under physiological conditions in vivo (Godfraind [3]and others [30 31 38]) and in vitro in various experimentalsystems (cell and tissue) (see Sections 33 34 35)
Hence calcium antagonists appeared to disrupt thefine balance between the production and scavenging ofROS Nifedipine verapamil and diltiazem were shown toinduce significant oxidative stress in the epididymal sperm(increased MDA and decreased catalase and superoxidedismutase activity) This may be the reason for the inductionof male infertility [253]
The dualism of 14-DHP effects has been recorded asinhibition or promotion of LP as quenching or initiating
26 Oxidative Medicine and Cellular Longevity
oxygen and nitrogen free radical chain reactions radiopro-tecting or radiosensitizing antagonizing or synergizing Ca2+in electromechanical coupling as well as in the membranestabilization or labilization
39 Could DHPs Be Involved in Antioxidative Stress Beforebeing applied in vivo the optimal dose and optimal timeintervals forDHPs applicationmust be knownNamely whileROS have been traditionally considered as toxic byproductsof aerobic metabolism we know nowadays that ROS may actas essential signaling molecules needed for the control ofmany different physiological processes Whether the role ofROS will be damaging protective or signaling depends onthe delicate equilibrium between time- and location-specificROS production and scavenging Accordingly the imbalanceof the increased AO potential so-called antioxidative stresscould be dangerous similar to chronic OS in particular incase of extended exposure Inappropriate interventions inthe oxidative homeostasis by excessive antioxidants especiallyin case of chronic exposure to antioxidants might havevery negative effects as was published in the ATBC studyshowing an increased cancer incidence in smokers treatedby excessive beta-carotene [254] Therefore overconsump-tion of any natural or synthetic AO including DHPs asdietary supplements or drugs must be avoided in order tosuppress oxidative damage and must not disrupt the well-integrated antioxidant defense network (Poljsak [255] andPoljsak and Milisav [256]) This is especially important whenadministrating lipid-soluble antioxidants that can be storedin biomembranes thus not only attenuating or preventing LPbut also affecting physiological effects of the natural antiox-idants in particular tocopherol The interrelationship withthe status of endogenous antioxidantsprooxidants should befollowed
DHPs primarily suppress the initiation stages of LPprocessThey do not entirely stop the LP propagation Actingsynergistically with tocopherol diludine may prevent patho-logical excess of ROS production within the lipid moiety ofthe cellular membranes and LDL However due to its lowsolubility and fast metabolism its concentration in the cellsis low For that reason it cannot cause antioxidative stresseven if used for an extended period of time Thus diludine(diethone) could be only a mild antioxidant it has potentialfor restoring the pool of natural antioxidants (as synergist of120572-tocopherol and polyphenols) in the cells
Moreover DHPs CA used for cardioprotection andvasodilatation as commercial drugs in low concentrationsare fast metabolized via CYP3A4 and for that reason theirapplication does not induce cellular AO stress [53 160]However Godfraind and Salomone [257] have postulated noevidence that allows recommending dietary supplementationwith antioxidants for the primary or secondary prevention ofcardiovascular disease
So far there are no reports on antioxidative stress causedby some DHPs diludine and its analogues Diludine andits analogues therefore could act as adaptogens supportinghormetic effects of mild oxidative stress These compoundsmay act as potential multisided modulators of Yin-Yang
cycles of redox and cell functions (the electroplasmic cycle)(Wagner et al [258])
4 Conclusions
14-Dihydropyridines (14-DHPs) have broad spectrum ofOS modulating activities DHPs have reducing and lipidperoxidation inhibitor properties act as reductants in simplechemical systems and stabilize various biological systems(LDL mitochondria microsomes cells and tissues) againstOS Examples and peculiarities and mechanisms of antiox-idant activity (AOA) and antiradical activity (ARA) as wellas stress-protective effect of DHPs including commercialcalcium antagonists (CA) were highlighted These activitiesdepend on various structural parameters related to DHPs(presence and character of substituents) lipophilicity anddepth of the incorporation in the biologicalmembranesTheyalso depend on the experimental model system for exploringthe lipid peroxidation or oxidative stress Stress-protectiveeffect of some metabolites of CA (nifedipine) is reviewedAlthough some DHPs including CA have prooxidant prop-erties (on epididymal sperm cells) they can generally beconsidered as potent antioxidants Therefore comparisonof the AOA and ARA of different DHPs (mutually andwith other AOs) was described in detail According to thedata presented the DHPs might be considered as bellwetheramong synthetic compounds targeting OS and as a kind ofpharmacological measure for respective field of organic andmedicinal chemistry
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
Authors from Latvian IOS acknowledge ESF 201300021DP1112013APIAVIAA011 and National Research Pro-gramme PUBLIC HEALTHBiomedicine of the Republicof Latvia for financial support administration of the Insti-tute for technical support and Rufus Smits PhD for con-sultations in English The support of Cooperation in Euro-pean System of Science and Technology (COST) Domain ofChemistry Molecular Sciences and Technologies (CMST)was of highest importance for preparation of this paper
[2] D J Triggle ldquo14-Dihydropyridines as calcium channel ligandsand privileged structuresrdquoCellular andMolecular Neurobiologyvol 23 no 3 pp 293ndash303 2003
[3] T Godfraind ldquoAntioxidant effects and the therapeutic modeof action of calcium channel blockers in hypertension andatherosclerosisrdquo Philosophical Transactions of the Royal SocietyB Biological Sciences vol 360 no 1464 pp 2259ndash2272 2005
[4] E Cadenas ldquoMitochondrial free radical production and cellsignalingrdquoMolecular Aspects of Medicine vol 25 no 1-2 pp 17ndash26 2004
[5] E Cadenas ldquoFree radicals oxidative stress and diseasesrdquo inLecture PSC 616 p 38 Missouri University of Science andTechnology Rolla Mo USA httpwwwcarnicominstituteorgarticlesenrique cadenaspdf
[6] K Rahman ldquoStudies on free radicals antioxidants and co-fac-torsrdquo Clinical Interventions in Aging vol 2 no 2 pp 219ndash2362007
[7] V Bocci and G Valacchi ldquoFree radicals and antioxidants howto reestablish redox homeostasis in chronic diseasesrdquo CurrentMedicinal Chemistry vol 20 no 27 pp 3397ndash3415 2013
[8] M Valko C J Rhodes J Moncol M Izakovic and M MazurldquoFree radicals metals and antioxidants in oxidative stress-induced cancerrdquo Chemico-Biological Interactions vol 160 no 1pp 1ndash40 2006
[9] G Bartosz ldquoReactive oxygen species destroyers or messen-gersrdquo Biochemical Pharmacology vol 77 no 8 pp 1303ndash13152009
[10] R Visconti and D Grieco ldquoNew insights on oxidative stress incancerrdquo Current Opinion in Drug Discovery and Developmentvol 12 no 2 pp 240ndash245 2009
[11] R N Kujundzic N Zarkovic and K G Troselj ldquoPyridinenucleotides in regulation of cell death and survival by redoxand non-redox reactionsrdquo Critical Reviews in Eukaryotic GeneExpression vol 24 no 4 pp 287ndash309 2014
[12] B Halliwell and J M C Gutteridge ldquoThe definition and mea-surement of antioxidants in biological systemsrdquo Free RadicalBiology and Medicine vol 18 no 1 pp 125ndash126 1995
[13] V D Kancheva and O T Kasaikina ldquoBio-antioxidantsmdashachemical base of their antioxidant activity and beneficial effect
on human healthrdquo Current Medicinal Chemistry vol 20 no 37pp 4784ndash4805 2013
[14] H V Panglossi Ed Frontiers in Antioxidants Research NovaScience Publishers New York NY USA 2006
[15] E B Burlakova E M Molochkina and G A NikiforovldquoHybrid antioxidantsrdquo Oxidation Communications vol 31 no4 pp 739ndash757 2008 httpmembraneustceducnpaperpdfHybrid20Antioxidantspdf
[16] A Bast and G R M M Haenen ldquoTen misconceptions aboutantioxidantsrdquo Trends in Pharmacological Sciences vol 34 no 8pp 430ndash436 2013
[17] E B Burlakova A V 0lesenko E M Molochkina N PPalmina and N G Khrapova Bioantioxidants for RadiationDamage and Malignant Growth Nauka Moscow Russia 1975(Russian)
[18] J Fang T Seki and H Maeda ldquoTherapeutic strategies by mod-ulating oxygen stress in cancer and inflammationrdquo AdvancedDrug Delivery Reviews vol 61 no 4 pp 290ndash302 2009
[19] M Valko D Leibfritz J Moncol M T D Cronin M Mazurand J Telser ldquoFree radicals and antioxidants in normal physi-ological functions and human diseaserdquo International Journal ofBiochemistry and Cell Biology vol 39 no 1 pp 44ndash84 2007
[20] M Jimenez-Del-Rio and C Velez-Pardo ldquoThe bad the goodand the ugly about oxidative stressrdquo Oxidative Medicine andCellular Longevity vol 2012 Article ID 163913 13 pages 2012
[21] C D Kamat S Gadal M Mhatre K S Williamson Q N Pyeand K Hensley ldquoAntioxidants in central nervous system dis-eases preclinical promise and translational challengesrdquo Journalof Alzheimerrsquos Disease vol 15 no 3 pp 473ndash493 2008
[22] A Pompella H Sies R Wacker et al ldquoThe use of totalantioxidant capacity as surrogate marker for food quality andits effect on health is to be discouragedrdquo Nutrition vol 30 no7-8 pp 791ndash793 2014
[23] Z Ye and H Song ldquoAntioxidant vitamins intake and the risk ofcoronary heart disease meta-analysis of cohort studiesrdquo Euro-pean Journal of Cardiovascular Prevention and Rehabilitationvol 15 no 1 pp 26ndash34 2008
[24] P Knekt J Ritz M A Pereira et al ldquoAntioxidant vitamins andcoronary heart disease risk a pooled analysis of 9 cohortsrdquoTheAmerican Journal of Clinical Nutrition vol 80 no 6 pp 1508ndash1520 2004
[25] A C Carr and M C M Vissers ldquoSynthetic or food-derivedvitamin Cmdashare they equally bioavailablerdquo Nutrients vol 5 no11 pp 4284ndash4304 2013
[26] R Tabrizchi ldquoEdaravoneMitsubishi-TokyordquoCurrentOpinion inInvestigational Drugs vol 1 no 3 pp 347ndash354 2000
[27] K Kikuchi S Tancharoen N Takeshige et al ldquoThe efficacy ofedaravone (radicut) a free radical scavenger for cardiovasculardiseaserdquo International Journal of Molecular Sciences vol 14 no7 pp 13909ndash13930 2013
[28] D Mauzerall and F H Westheimer ldquo1-Benzyldihydronicoti-namidemdasha model for reduced DPNrdquo Journal of the AmericanChemical Society vol 77 no 8 pp 2261ndash2264 1955 ChemicalAbstracts vol 50 Article ID 2588i 1956
[29] F Bossert and W Vater ldquo14-Dihydropyridinesmdasha basis fordeveloping new drugsrdquo Medicinal Research Reviews vol 9 no3 pp 291ndash324 1989
[30] G Swarnalatha G Prasanthi N Sirisha and CMadhusudhanaChetty ldquo14-Dihydropyridines a multtifunctional moleculemdash areviewrdquo International Journal of ChemTech Research vol 3 no1 pp 75ndash89 2011
28 Oxidative Medicine and Cellular Longevity
[31] M Cataldi and F Bruno ldquo14-Dihydropyridines the multiplepersonalities of a blockbuster drug familyrdquo Translational Medi-cine UniSa vol 4 no 2 pp 12ndash26 2012 httpwwwncbinlmnihgovpmcarticlesPMC3728803
[32] R Vitolina A Krauze G Duburs and A Velena ldquoAspects ofthe amlodipine pleiotropy in biochemistry pharmacology andclinicsrdquo International Journal of Pharmaceutical Sciences andResearch vol 3 no 5 pp 1215ndash1232 2012
[33] D Grover S N Mokale and M T Shete ldquoDihydropyridinea novel pharmacophorerdquo International Journal of Pharmaceu-tical Erudition vol 1 no 2 pp 16ndash29 2011 httppharmaeru-ditionorgContentPaper20111-RV-320Final2016-29pdf
[34] A M Vijesh A M Isloor S K Peethambar K N ShivanandaT Arulmoli and N A Isloor ldquoHantzsch reaction synthesis andcharacterization of somenew 14-dihydropyridine derivatives aspotent antimicrobial and antioxidant agentsrdquo European Journalof Medicinal Chemistry vol 46 no 11 pp 5591ndash5597 2011
[35] P Mehta and P Verma ldquoAntimicrobial activity of some deriva-tives of 14-dihydropyridinesrdquo Journal of Chemistry vol 2013Article ID 865128 4 pages 2013
[36] P Olejnıkova L Svorc D Olsovska et al ldquoAntimicrobialactivity of novel C2-substituted 14-dihydropyridine analoguesrdquoScientia Pharmaceutica vol 82 no 2 pp 221ndash232 2014
[37] S Sepehri H Perez Sanchez and A Fassihi ldquoHantzsch-typedihydropyridines and biginelli-type tetra-hydropyrimidinesa review of their chemotherapeutic activitiesrdquo Journal of Phar-macy amp Pharmaceutical Sciences vol 18 no 1 pp 1ndash52 2015httpsejournalslibraryualbertacaindexphpJPPSarticleview2383617863
[38] S A Khedkar and P B Auti ldquo14-Dihydropyridines a classof pharmacologically important moleculesrdquo Mini-Reviews inMedicinal Chemistry vol 14 no 3 pp 282ndash290 2014
[39] G D Tirzit and G Ya Duburs ldquo14-dihydropyridines as inhi-bitors of free-radical reactionsrdquo Chemistry of Heterocyclic Com-pounds vol 8 no 1 pp 126ndash127 1972 Translated from KhimiyaGeterotsiklicheskikh Soedinenii no1 pp 133ndash134 1972 (Rus-sian)
[40] I Bogeski R Kappl C Kummerow R Gulaboski M Hothand B A Niemeyer ldquoRedox regulation of calcium ion channelschemical and physiological aspectsrdquoCell Calcium vol 50 no 5pp 407ndash423 2011
[41] S A Giller G Y Dubur Y R Uldrikis et al ldquoDiludine [Themethod to obtain 35-dicarbonylderivatives of 26-dimethyl-14-dihydropyridines]rdquo Authors certificate of USSR no 3004651971 [Byull Izobret no13 p 95 1971] and following patentsPatent of England no 1294650 1973 Patent of France no2055458 1971 Patent of Japan no 702883 1973 Patent ofHolland no 149787 1976 Patent of Italy no 969022 1974 Patentof FRG no 2036403 1978 US Patent no 3883673 1975 USPatent no 3948924 1976
[42] S A Giller G Y Dubur Y R Uldrikis et al ldquoImprovementsin or relating to the stabilization of carotenerdquo GB Patent no1294650 1972
[43] S A Giller G Y Dubur Y R Uldrikis et al ldquoStabilization ofcarotenerdquo US Patent no 3883673 1975 Chemical Abstracts vol83 Article ID 95193 1975
[44] Yu A Zilber G Ya Dubur K K Kumsar and A Kh VelenaldquoThe effect of antioxidants on the peroxidation of bimole-cular phospholipid membranesrdquo Latvijas PSR ZA Vestis Izves-tia Akademii Nauk Latviyskoy SSR vol 6 pp 80ndash82 1971(Russian) translated from the original Russian Doc Accesion
No AD0771751 distributed by NTIS US Department of Com-merce httpwwwdticmildtictrfulltextu2771751pdf
[45] G Ya Dubur Yu A Zilbers A Kh Velena A O Kumerovaand G D Tirzitis ldquoMultistage study of regulation of peroxida-tion processes in biological membranes by antioxidants of 14-dihydropyridine grouprdquo Izvestiya Akademii Nauk LatviyskoySSR vol 336 no 7 pp 65ndash68 1975 (Russian)
[46] R P Mason and M W Trumbore ldquoDifferential membraneinteractions of calcium channel blockers Implications forantioxidant activityrdquo Biochemical Pharmacology vol 51 no 5pp 653ndash660 1996
[47] R P Mason M F Walter M W Trumbore E G Olmstead Jrand P E Mason ldquoMembrane antioxidant effects of the chargeddihydropyridine calcium antagonist amlodipinerdquo Journal ofMolecular and Cellular Cardiology vol 31 no 1 pp 275ndash2811999
[48] R PMason I T MakMW Trumbore and P EMason ldquoAnti-oxidant properties of calcium antagonists related to membranebiophysical interactionsrdquo American Journal of Cardiology vol84 no 4 pp 16ndash22 1999
[49] R PMasonMW Trumbore and P EMason ldquoMembrane bio-physical interaction of amlodipine and antioxidant propertiesrdquoDrugs vol 59 no 2 pp 9ndash16 2000 (French)
[50] R P Mason P Marche and T H Hintze ldquoNovel vascularbiology of third-generation L-type calcium channel antagonistsAncillary actions of amlodipinerdquo Arteriosclerosis Thrombosisand Vascular Biology vol 23 no 12 pp 2155ndash2163 2003
[51] A Augustyniak G Bartosz A Cipak et al ldquoNatural andsynthetic antioxidants an updated overviewrdquo Free RadicalResearch vol 44 no 10 pp 1216ndash1262 2010
[52] T Grune N Zarkovic and K Kostelidou ldquoLipid peroxidationresearch in Europe and the COST B35 action lsquoLipid Peroxida-tion Associated Disordersrsquordquo Free Radical Research vol 44 no10 pp 1095ndash1097 2010
[53] E Carosati P Ioan M Micucci et al ldquo14-Dihydropyridinescaffold in medicinal chemistry the story so far and perspec-tives (part 2) action in other targets and antitargetsrdquo CurrentMedicinal Chemistry vol 19 no 25 pp 4306ndash4323 2012
[54] U Eisner and J Kuthan ldquoThe chemistry of dihydropyridinesrdquoChemical Reviews vol 72 no 1 pp 1ndash42 1972 httpwwwsci-encemadnessorgtalkfilesphppid=138742ampaid=6475
[55] J Kuthan and A Kurfurst ldquoDevelopment in dihydropyri-dine chemistryrdquo Industrial amp Engineering Chemistry ProductResearch and Development vol 21 no 2 pp 191ndash261 1982
[56] A Sausins and G Duburs ldquoSynthesis of 14-dihydropyridinesby cyclocondensation reactionsrdquo Heterocycles vol 27 no 1 pp269ndash289 1988
[57] A E Sausins and G Y Duburs ldquoSynthesis of 14-dihydro-pyridines in cyclocondensation reactions (review)rdquo Chemistryof Heterocyclic Compounds vol 28 no 4 pp 363ndash391 1992Translated from Khimiya Geterotsiklicheskikh Soedinenii no 4pp 435ndash467 1992 (Russian)
[58] S Kazda ldquoTwenty years of dihydropyridinesrdquo in Dihydropy-ridines Progress in Pharmacology and Therapy W-D Busse BGarthoff and F Seuter Eds pp 1ndash12 Springer Verlag BerlinGermany 1993
[59] J-P Wan and Y Liu ldquoRecent advances in new multicomponentsynthesis of structurally diversified 14-dihydropyridinesrdquo RSCAdvances vol 2 no 26 pp 9763ndash9777 2012
[61] Reaxys Database[62] J Tuttle ldquoStructure mechanism and reactivity of hantzsch
estersrdquo in MacMillan Lab Group Meeting (082504) p 332004 httpwwwprincetoneduchemistrymacmillangroup-meetingsJBT20Hantzschpdf
[63] A Saini S Kumar and J S Sandhu ldquoHantzsch reaction recentadvances in Hantzsch 14-dihydropyridinesrdquo Journal of Sci-entific amp Industrial Research vol 67 pp 95ndash111 2008
[64] L LW Cheung S A Styler and A P Dicks ldquoRapid and conve-nient synthesis of the 14-dihydropyridine privileged structurerdquoJournal of Chemical Education vol 87 no 6 pp 628ndash630 2010
[65] A Kumar R A Maurya S Sharma M Kumar and G BhatialdquoSynthesis and biological evaluation of N-aryl-14-dihydro-pyridines as novel antidyslipidemic and antioxidant agentsrdquoEuropean Journal of Medicinal Chemistry vol 45 no 2 pp 501ndash509 2010
[66] R S Kumar A Idhayadhulla A J Abdul Nasser and J SelvinldquoSynthesis and anticoagulant activity of a new series of 14-dihydropyridine derivativesrdquo European Journal of MedicinalChemistry vol 46 no 2 pp 804ndash810 2011
[67] H A Stefani C B Oliveira R B Almeida et al ldquoDihydro-pyrimidin-(2H)-ones obtained by ultrasound irradiation anew class of potential antioxidant agentsrdquo European Journal ofMedicinal Chemistry vol 41 no 4 pp 513ndash518 2006
[68] H Sun C Shang L Jin and J Zhang ldquoSynthesis and antiox-idant activity of a series of novel 3-chalcone-substituted 14-dihydropyridine derivativesrdquoHeterocyclic Communications vol18 no 5-6 pp 239ndash243 2012
[69] D B Tikhonov and B S Zhorov ldquoStructural model for dihy-dropyridine binding to L-type calcium channelsrdquo The Journalof Biological Chemistry vol 284 no 28 pp 19006ndash19017 2009
[70] G Y Dubur and Y R Uldrikis ldquoThe oxidation of 14-dihydro-pyridinesrdquo Chemistry of Heterocyclic Compounds vol 6 no 1pp 80ndash84 1970 Translated from Khimiya GeterotsiklicheskikhSoedinenii no 1 pp 83ndash88 1970 (Russian)
[71] G Ya Duburs A O Kumerova and Ya R Uldrikis ldquoEnzymicoxidation of hydrogenated pyridines with peroxidase-hydrogenperoxide systemrdquoLatvijas PSRZAVestis vol 73 no 7 pp 73ndash771970 (Russian) Chemical Abstracts vol 73 Article ID 94913g1970
[72] K Xie Y-C Liu Y Cui J-GWang Y Fu andT CWMak ldquoN-methyl-(R)-3-(tert-butyl)-sulfinyl-14-dihydropyridine a novelNADHmodel compoundrdquoMolecules vol 12 no 3 pp 415ndash4222007
[73] S Tamagaki T Mimura and W Tagaki ldquoMetal-ion-facilitatedoxidations of dihydropyridines with molecular oxygen andhydrogen peroxiderdquo Journal of the Chemical Society PerkinTransactions 2 no 10 pp 1645ndash1650 1990
[74] D Tirzite G Tirzitis andD Antipova ldquoReductive ability of 14-dihydropyridine derivatives in relation to ions of trivalent ironrdquoChemistry of Heterocyclic Compounds vol 35 no 5 pp 592ndash594 1999
[76] J Ogle J Stradins and L Baumane ldquoFormation and decay offree cation-radicals in the course of electro-oxidation of 12- and14-dihydropyridines (Hantzsch esters)rdquo Electrochimica Actavol 39 no 1 pp 73ndash79 1994
[77] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for the
synthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts C Wittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Berlin Germany 2010
[78] WDu and Zh Yu ldquoBiomimetic in situ regeneration of cofactorsNAD(P)+ and NAD(P)H models hantzsch esters and dihy-drophenanthridinerdquo Synlett vol 23 no 9 pp 1300ndash1304 2012
[79] H K Chenault and G M Whitesides ldquoRegeneration ofnicotinamide cofactors for use in organic synthesisrdquo AppliedBiochemistry and Biotechnology vol 14 no 2 pp 147ndash197 1987
[80] Y R Uldrikis A A Zidermane E A Biseniex I E Preisa GY Dubur and G D Tirzit ldquoEsters of 26-dimethyl-14-dihydro-pyridine-35-dicarboxylic acid and method of obtainingthereofrdquo WO 8000345 A1 1978 httpworldwideespacenetcompublicationDetailsbiblioDB=EPODOCampII=1ampND=3ampadjacent=trueamplocale=en EPampFT=Dampdate=19800306ampCC=WOampNR=8000345A1ampKC=A1
[81] Y Sambongi H Nitta K Ichihashi M Futai and I Ueda ldquoAnovel water-soluble Hantzsch 14-dihydropyridine compoundthat functions in biological processes through NADH regener-ationrdquo Journal of Organic Chemistry vol 67 no 10 pp 3499ndash3501 2002
[82] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for thesynthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts ChWittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Verlag Berlin Germany 2010
[83] T Okamura T Kikuchi A Nagamine et al ldquoAn approach formeasuring in vivo cerebral redox states using the oxidative con-version of dihydropyridine to pyridinium ion and themetabolictrapping principlerdquo Free Radical Biology and Medicine vol 38no 9 pp 1197ndash1205 2005
[84] K A Schellenberg and F H Westheimer ldquoA free-radicaloxidation of a dihydropyridine1ardquo The Journal of OrganicChemistry vol 30 no 6 pp 1859ndash1862 1965
[85] K A Schellenberg ldquoReaction of hydroxyl radical with thymi-dine Scavenging by a dihydropyridinerdquo Federation Proceedingsvol 38 no 3 I p 1433 1979
[86] E S Huyser J A K Harmony and F L McMillian ldquoPeroxideoxidations of dihydropyridine derivativesrdquo Journal of the Amer-ican Chemical Society vol 94 no 9 pp 3176ndash3180 1972
[87] A Sakamoto S T Ohnishi and R Ogawa ldquoInhibition of lipidperoxidation by some dihydropyridine derivativesrdquo Journal ofAnesthesia vol 7 no 2 pp 193ndash197 1993
[88] R Hardeland ldquoReview Neuroprotection by radical avoidancesearch for suitable agentsrdquo Molecules vol 14 no 12 pp 5054ndash5102 2009
[89] G Ya Dubur A Kh Velena V M Gukasov and Yu AVladimirov ldquoRegulation of peroxidation of mitochondrialmembrane lipids initiated by Fe2+ ions by antoxidants of the14-dihydropyridine series in experiments in vitrordquo Biomed-itsinskaya Khimiya vol 22 no 5 pp 665ndash673 1976 (Russian)Chemical Abstracts vol 88 Article ID 2640 1977
[90] G RMMHaenenM J T J Arts A Bast andMD ColemanldquoStructure and activity in assessing antioxidant activity in vitroand in vivo a critical appraisal illustrated with the flavonoidsrdquoEnvironmental Toxicology and Pharmacology vol 21 no 2 pp191ndash198 2006
[91] G Tirzitis and G Bartosz ldquoDetermination of antiradical andantioxidant activity basic principles and new insightsrdquo ActaBiochimica Polonica vol 57 no 2 pp 139ndash142 2010
30 Oxidative Medicine and Cellular Longevity
[92] G R Buettner and R P Mason ldquoSpin-trapping methods fordetecting superoxide and hydroxyl free radicals in vitro and invivordquo inCritical Reviews of Oxidative Stress and Aging Advancesin Basic Science Diagnostics and Intervention R G Cutler andH Rodriguez Eds vol 1 chapter 2 pp 27ndash38World ScientificLondon UK 2003
[93] M M Tarpey and I Fridovich ldquoMethods of detection ofvascular reactive species Nitric oxide superoxide hydrogenperoxide and peroxynitriterdquo Circulation Research vol 89 no3 pp 224ndash236 2001
[94] E Y Kazush E I Sagun G D Tirzit and G Y DaburldquoQuenching of singlet oxygen by electron donating derivativesof 14-dihydropyridinerdquo Chemistry of Heterocyclic Compoundsvol 30 no 5 pp 562ndash563 1994
[95] G Tirzitis E Kazush and G Duburs ldquoReaction of 14-dihydropyridine derivatives with peroxynitrite anionrdquo Chem-istry of Heterocyclic Compounds vol 34 no 3 pp 321ndash3231998 (Russian) Translated from Khimiya GeterotsiklicheskikhSoedinenii no 3 pp 355ndash357 1998
[96] L J Nunez-Vergara C Lopez-Alarcon P A Navarrete-EncinaA M Atria C Camargo and J A Squella ldquoElectrochemicaland EPR characterization of 14-dihydropyridines Reactivitytowards alkyl radicalsrdquo Free Radical Research vol 37 no 1 pp109ndash120 2003
[97] D Tirzite A Krauze A Zubareva G Tirzitis and G DubursldquoSynthesis and antiradical activity of 5-acetyl-2-alkylthio-4-aryl-6-methyl-14-dihydropyridine-3-carboxylic acid nitrilesrdquoChemistry of Heterocyclic Compounds vol 38 no 7 pp 795ndash800 2002
[98] H Ohkawa N Ohishi and K Yagi ldquoAssay for lipid peroxidesin animal tissues by thiobarbituric acid reactionrdquo AnalyticalBiochemistry vol 95 no 2 pp 351ndash358 1979
[99] N Zarkovic ldquo4-Hydroxynonenal as a bioactive marker ofpathophysiological processesrdquo Molecular Aspects of Medicinevol 24 no 4-5 pp 281ndash291 2003
[100] M Parola G Bellomo G Robino G Barrera and M UDianzani ldquo4-Hydroxynonenal as a biological signal molecularbasis and pathophysiological implicationsrdquo Antioxidants andRedox Signaling vol 1 no 3 pp 255ndash284 1999
[101] T Lovakovic M Poljak-Blazi G Duburs et al ldquoGrowthmodulation of human cells in vitro by mild oxidative stressand 14-dihydropyridine derivative antioxidantsrdquo CollegiumAntropologicum vol 35 no 1 pp 137ndash141 2011
[102] R van den Berg G R M M Haenen H van den Bergand A Bast ldquoApplicability of an improved Trolox equivalentantioxidant capacity (TEAC) assay for evaluation of antioxidantcapacity measurements of mixturesrdquo Food Chemistry vol 66no 4 pp 511ndash517 1999
[103] C Lopez-Alarcon P Navarrete C Camargo J A Squella andL J Nunez-Vergara ldquoReactivity of 14-dihydropyridines towardalkyl alkylperoxyl radicals and ABTS radical cationrdquo ChemicalResearch in Toxicology vol 16 no 2 pp 208ndash215 2003
[104] V Valenzuela P Santander C Camargo J A Squella C Lopez-Alarcon and L J Nunez-Vergara ldquo14-Dihydropyridines reac-tivity of nitrosoaryl and nitroaryl derivatives with alkylperoxylradicals andABTS radical cationrdquo Free Radical Research vol 38no 7 pp 715ndash727 2004
[105] L G Tsetlin N A Chebotareva B I Kurganov A K VelenaG Y Dubur and V Z Lankin ldquoStudy of 14-dihydropyridinesas lipoxygenase inhibitors with the use of hydrated reversedmicellesrdquo Pharmaceutical Chemistry Journal vol 22 no 6 pp425ndash428 1988 (Russian)
[106] J Panek Z Reblova L Kocirkova et al ldquoAntioxidant activityof dihydropyridine derivativesrdquo Czech Journal of Food Sciencesvol 18 pp 144ndash145 2000
[107] G Tirzitis I Kirule and G Duburs ldquoAntioxidationsaktivitatder 35-dicarbonylderivate des 26-demethyl-14-dihydropyri-dinsrdquo Fett Wissenschaft TechnologieFat Science Technology vol90 no 10 pp 411ndash413 1988
[108] M Plotniece G Tirzitis Y Uldrikis et al ldquoSynthesis of 14-dihydropyridine derivatives having an oxy- alkoxy- or dimeth-ylaminophenyl substituent in the 4 position their antioxidantactivity and their binding to phospholipid membranesrdquo Chem-istry of Heterocyclic Compounds vol 32 no 10 pp 1166ndash11721996 Translated from Khimiya Geterotsiklicheskikh Soedineniino 10(352) pp 1358ndash1365 1996 (Russian)
[109] D Y Rubene V S Sharov V I Olenev G D Tirzit G Y Duburand Y A Vladimirov ldquoUse of chemiluminescent method forthe evaluation of antioxidant activity of some derivatives of 14-dihydropyridinerdquo Russian Journal of Physical Chemistry A vol55 no 2 pp 511ndash512 1981 (Russian)
[110] M C R Symons and JM C Gutteridge Free Radicals and IronChemistry Biology and Medicine Oxford Science PublicationsOxford University Press Oxford UK 1998
[111] M Repetto J Semprine and A Boveris ldquoLipid peroxidationchemical mechanism biological implications and analyticaldeterminationrdquo in Lipid Peroxidation A Catala Ed Section ILipid Peroxidation Chemical Mechanisms Antioxidants Bio-logical Implications of Biochemistry Genetics and MolecularBiology chapter 1 pp 3ndash30 InTech Rijeka Croatia 2012
[112] A Velena J Zilbers and G Duburs ldquoDerivatives of 14-dihydropyridines asmodulators of ascorbate-induced lipid per-oxidation and high-amplitude swelling ofmitochondria causedby ascorbate sodium linoleate and sodiumpyrophosphaterdquoCellBiochemistry and Function vol 17 no 4 pp 237ndash252 1999
[113] M V Bilenko L N Shelenkova G Y Dubur and A K VelenaldquoUse of antioxidants to prevent renal damage during acuteischemia and reperfusionrdquo Bulletin of Experimental Biology andMedicine vol 96 no 3 pp 1195ndash1198 1983 Translated fromByulletenrsquo Eksperimentalrsquonoi Biologii i Meditsiny vol 96 no 9pp 8ndash11 1983 (Russian)
[114] R Toniolo F Tubaro F Ursini and G Bontempelli ldquoAn elec-troanalytical investigation on the redox properties of calciumantagonist dihydropyridinesrdquo Electroanalysis vol 15 no 10 pp855ndash861 2003
[115] L Kourimska J Pokorny and G Tirzitis ldquoThe antioxidant aci-tivity of 26-dimethyl-35-diethoxycarbonyl-14-dihydropyri-dine in edible oilsrdquo Nahrung vol 37 no 1 pp 91ndash93 1993
[116] C Lopez-Alarcon H Speisky J A Squella C Olea-Azar CCamargo and L J Nunez-Vergara ldquoReactivity of 14-dihydro-pyridines toward SIN-1-derived peroxynitriterdquo PharmaceuticalResearch vol 21 no 10 pp 1750ndash1757 2004
[117] R A Olek W Ziolkowski J J Kaczor L Greci J Popinigisand J Antosiewicz ldquoAntioxidant activity of NADH and its ana-loguemdashan in vitro studyrdquo Journal of Biochemistry andMolecularBiology vol 37 no 4 pp 416ndash421 2004
[118] E Niki N Noguchi and N Gotoh ldquoInhibition of oxidativemodification of low density lipoprotein by antioxidantsrdquo Jour-nal of Nutritional Science andVitaminology vol 39 supplementpp S1ndashS8 1993
[119] N Rojstaczer and D J Triggle ldquoStructure-function relation-ships of calcium antagonists effect on oxidative modificationof low density lipoproteinrdquo Biochemical Pharmacology vol 51no 2 pp 141ndash150 1996
Oxidative Medicine and Cellular Longevity 31
[120] A Sevanian L Shen and FUrsini ldquoInhibition of LDLoxidationand oxidized LDL-induced cytotoxicity by dihydropyridinecalcium antagonistsrdquo Pharmaceutical Research vol 17 no 8 pp999ndash1006 2000
[121] A Negre-Salvayre and R Salvayre ldquoProtection by Ca2+ channelblockers (nifedipine diltiazem and verapamil) against the tox-icity of oxidized low density lipoprotein to cultured lymphoidcellsrdquo British Journal of Pharmacology vol 107 no 3 pp 738ndash744 1992
[122] A Negre-Salvayre G FitoussiM Troly and R Salvayre ldquoCom-parative cytoprotective effect of dihydropyridine calcium chan-nel blockers against the toxicity of oxidized low density lipopro-tein for cultured lymphoid cellsrdquo Biochemical Pharmacologyvol 44 no 12 pp 2379ndash2386 1992
[123] L Cominacini A F Pasini U Garbin et al ldquoAntioxidant activ-ity of different dihydropyridinesrdquo Biochemical and BiophysicalResearch Communications vol 302 no 4 pp 679ndash684 2003
[124] L Cominacini U Garbin A Fratta Pasini et al ldquoOxidized low-density lipoprotein increases the production of intracellularreactive oxygen species in endothelial cells inhibitory effect oflacidipinerdquo Journal of Hypertension vol 16 no 12 part 2 pp1913ndash1919 1998
[125] H M Lander ldquoAn essential role for free radicals and derivedspecies in signal transductionrdquo The FASEB Journal vol 11 no2 pp 118ndash124 1997
[126] M L L Martinez E Rizzi M M Castro et al ldquoLercanidipinedecreases vascular matrix metalloproteinase-2 activity andprotects against vascular dysfunction in diabetic ratsrdquo EuropeanJournal of Pharmacology vol 599 no 1ndash3 pp 110ndash116 2008
[127] P Lesnik C Dachet L Petit et al ldquoImpact of a combinationof a calcium antagonist and a 120573-blocker on cell- and copper-mediated oxidation of LDL and on the accumulation and effluxof cholesterol in human macrophages and murine J774 cellsrdquoArteriosclerosis Thrombosis and Vascular Biology vol 17 no 5pp 979ndash988 1997
[128] G Sobal E J Menzel and H Sinzinger ldquoCalcium antagonistsas inhibitors of in vitro low density lipoprotein oxidation andglycationrdquoBiochemical Pharmacology vol 61 no 3 pp 373ndash3792001
[129] E Lupo R Locher B Weisser and W Vetter ldquoIn vitro antiox-idant activity of calcium antagonists against LDL oxidationcompared with 120572-tocopherolrdquo Biochemical and BiophysicalResearch Communications vol 203 no 3 pp 1803ndash1808 1994
[130] J Zou Y Li H-Q Fan and J-G Wang ldquoEffects of dihydropy-ridine calcium channel blockers on oxidized low-density lipo-protein induced proliferation and oxidative stress of vascularsmooth muscle cellsrdquo BMC Research Notes vol 5 article 1682012
[131] C Napoli S Salomone T Godfraind et al ldquo14-Dihydro-pyridine calcium channel blockers inhibit plasma and LDL oxi-dation and formation of oxidation-specific epitopes in the arte-rial wall and prolong survival in stroke-prone spontaneouslyhypertensive ratsrdquo Stroke vol 30 no 9 pp 1907ndash1915 1999
[132] G Zernig I Graziadei T Moshammer C Zech N Reider andH Glossmann ldquoMitochondrial Ca2+ antagonist binding sitesare associated with an inner mitochondrial membrane anionchannelrdquo Molecular Pharmacology vol 38 no 3 pp 362ndash3691990
[133] F E Hunter Jr A Scott P E Hochstein et al ldquoStudies of themechanism of ascorbate-induced swelling and lysis of isolatedliver mitochondriardquo The Journal of Biological Chemistry vol239 pp 604ndash613 1964
[134] D R Janero B Burghardt and R Lopez ldquoProtection of cardiacmembrane phospholipid against oxidative injury by calciumantagonistsrdquoBiochemical Pharmacology vol 37 no 21 pp 4197ndash4203 1988
[135] A Karadag B Ozcelik and S S Saner ldquoReview of methods todetermine antioxidant capacitiesrdquo FoodAnalyticalMethods vol2 no 1 pp 41ndash60 2009
[136] Y I Gubskiı N V Litvinova and E V Shnurko-TabakovaldquoAntioxidant and antiradical activity of various classes of antiox-idantsrdquo Ukrainskiı Biokhimicheskiı Zhurnal vol 66 no 4 pp114ndash116 1994 (Russian)
[137] M Takei M Hiramatsu and A Mori ldquoInhibitory effects ofcalcium antagonists onmitochondrial swelling induced by lipidperoxidation or arachidonic acid in the rat brain in vitrordquoNeurochemical Research vol 19 no 9 pp 1199ndash1206 1994
[138] M Takei M Hiramatsu R Edamatsu and A Mori ldquoFreeradical scavenging by calcium antagonistsrdquo Neurosciences vol20 no 2 pp 75ndash82 1994
[139] Ya P Stradin G Ya Dubur Yu A Beilis Ya R Uldrikis andA F Korotkova ldquoVoltammetry of 14-dihydropyridine deriva-tives I Potentials of electrochemical oxidation of 35-diacyl-and 35-di(alkoxycarbonyl)-14-dihydropyridines in acetoni-trilerdquo Chemistry of Heterocyclic Compounds no 1 pp 84ndash871972 (Russian)
[140] E V Ivanov T V Ponomarjova G N Merkusev et al ldquoEinneuer Haut-Radioprotektor Diethon (experimentelle Unter-suchung)rdquo Radiobiologia Radiotherapia vol 31 no 1 pp 69ndash78 1990
[141] E V Ivanov T V Ponomareva G N Merkushev et al ldquoRadia-tion modulating properties of derivates of 14-dihydropyridineand 12345678910-decahydroacridine-18 dionerdquo Radiat-sionnaia Biologiia Radioecologiia vol 44 no 5 pp 550ndash5592004 (Russian)
[142] R O Vitolinia D A Berzinia A K Velena I A Vutsina A AKimenis and G Y Duburs ldquoThe protective effects of the cal-cium antagonist foridon in acute myocardial ischaemiardquo Kardi-ologiya vol 27 no 3 pp 90ndash93 1987 (Russian)
[143] A H Velena G Ya Duburs R O Vitolina et al ldquoEffect ofryodipine on electromechanical parameters of heart and vesselscAMP phosphodiesterase activity and swelling-contractioncycle of mitochondriardquo Arzneimittelforschung vol 35 no 6 pp907ndash914 1985
[144] L I Utno Z E Lipsberga A A Silova M I Girgensone EA Bisenieks and G I Ia ldquoCardioprotective properties of a 14-dihydropyridine derivative glutapyrone in deep hypothermiardquoBiulletenrsquo Eksperimentalrsquonoı Biologii i Meditsiny vol 108 no 11pp 558ndash561 1989 (Russian)
[145] M A S FernandesM S Santos J A F Vicente et al ldquoEffects of14-dihydropyridine derivatives (cerebrocrast gammapyroneglutapyrone and diethone) onmitochondrial bioenergetics andoxidative stress a comparative studyrdquoMitochondrion vol 3 no1 pp 47ndash59 2003
[146] M A S Fernandes M S Santos A J M Moreno et al ldquoEffectsof 5-acetyl(carbamoyl)-6-methylsulfanyl-14-dihydropyridine-5-carbonitriles on rat liver mitochondrial functionrdquo Toxicologyin Vitro vol 23 no 7 pp 1333ndash1341 2009
[147] L Klimaviciusa A Kalda A Kaasik et al ldquoNeuroprotectiveactivity of 14-dihydropyridine derivatives structure determi-nantsrdquo Proceedings of the Latvian Academy of Sciences BNatural Exact and Applied Sciences vol 61 no 1-2 pp 33ndash372007
32 Oxidative Medicine and Cellular Longevity
[148] L Klimaviciusa M A S Fernandes N Lencberga et alldquoTargeting the mitochondria by novel adamantane-containing14-dihydropyridine compoundsrdquo in Bioenergetics K B ClarkEd pp 257ndash272 InTech 2012
[149] V Klusa L Klimaviciusa G Duburs J Poikans and AZharkovsky ldquoAnti-neurotoxic effects of tauropyrone a taurineanaloguerdquo Advances in Experimental Medicine and Biology vol583 pp 499ndash508 2006
[150] N Sampson P Berger and Ch Zenzmaier ldquoRedox signalingas a therapeutic target to inhibit myofibroblast activation indegenerative fibrotic diseaserdquo BioMed Research Internationalvol 2014 Article ID 131737 14 pages 2014
[151] T L Leto and M Geiszt ldquoRole of Nox family NADPH oxidasesin host defenserdquoAntioxidantsampRedox Signaling vol 8 no 9-10pp 1549ndash1561 2006
[152] K K Griendling D Sorescu and M Ushio-Fukai ldquoNAD(P)Hoxidase role in cardiovascular biology and diseaserdquo CirculationResearch vol 86 no 5 pp 494ndash501 2000
[153] H Chen Y S Song and P H Chan ldquoInhibition of NADPHoxi-dase is neuroprotective after ischemia-reperfusionrdquo Journal ofCerebral Blood Flow and Metabolism vol 29 no 7 pp 1262ndash1272 2009
[154] P Hochstein and L Ernster ldquoADP-activated lipid peroxidationcoupled to the TPNH oxidase system of microsomesrdquo Biochem-ical and Biophysical Research Communications vol 12 no 5 pp388ndash394 1963
[155] I I Gubskiı AGGoriushkoNV Litvinova et al ldquoAntioxidantproperties and membranotropic effect of certain derivatives of14-dihydropyridinerdquo Ukrainskiı Biokhimicheskiı Zhurnal vol71 no 4 pp 35ndash39 1999 (Russian)
[156] F Engineer and R Sridhar ldquoInhibition of rat heart andliver microsomal lipid peroxidation by nifedipinerdquo BiochemicalPharmacology vol 38 no 8 pp 1279ndash1285 1989
[157] T Goncalves A P Carvalho and C R Oliveira ldquoAntioxidanteffect of calcium antagonists on microsomai membranes iso-lated from different brain areasrdquo European Journal of Pharma-cology vol 204 no 3 pp 315ndash322 1991
[158] M E Letelier P Izquierdo L Godoy A M Lepe and MFaundez ldquoLiver microsomal biotransformation of nitro-aryldrugs mechanism for potential oxidative stress inductionrdquoJournal of Applied Toxicology vol 24 no 6 pp 519ndash525 2004
[159] M E Letelier P Entrala C Lopez-Alarcon et al ldquoNitroaryl-14-dihydropyridines as antioxidants against rat liver microsomesoxidation induced by ironascorbate Nitrofurantoin and naph-thalenerdquo Toxicology in Vitro vol 21 no 8 pp 1610ndash1618 2007
[160] F P Guengerich W R Brian M Iwasaki M-A Sari CBaarnhielm and P Berntsson ldquoOxidation of dihydropyridinecalcium channel blockers and analogues by human liver cyto-chrome P-450 IIIA4rdquo Journal of Medicinal Chemistry vol 34no 6 pp 1838ndash1844 1991
[161] S H Park S-W RhaW-Y Shin et al ldquoAS-160 Calcium channelblockers of dihydropyridine class reduce the antiplatelet effectof Clopidogrel what is clinical impactrdquo The American Journalof Cardiology vol 107 no 8 supplement p 47A 2011
[162] C Asma and D M Reda ldquoEvaluation of dihydropyridinecalcium antagonist effects on the stress bioindicator orga-nism Saccharomyces cerevisiaerdquo Annals of Biological Researchvol 4 no 10 pp 40ndash46 2013 httpscholarsresearchlibrarycomABR-vol4-iss10ABR-2013-4-10-40-46pdf
[163] G Gaviraghi A M Pastorino E Ratti and D G TristldquoCalcium channel blockers with antioxidant activityrdquo in Free
Radicals Lipoprotein Oxidation andAtherosclerosis G BellomoG Finardi E Maggi and E Rice-Evans Eds pp 431ndash456Richelieu Press London UK 1995
[164] G Gaviraghi AM Pastorino E Ratti and D G Trist ldquoAntiox-idant dihydropyridines a new and comprehensive therapy forfree radical-induced cardiovascular diseasesrdquo in Free Radicalsin Biology and Environment F Minisci Ed vol 27 of NATOASI Series pp 193ndash221 Springer Dordrecht The Netherlands1997
[165] P D Henry ldquoAntiperoxidative actions of calcium antagonistsand atherogenesisrdquo Journal of Cardiovascular Pharmacologyvol 18 supplement 1 pp S6ndashS10 1991
[166] F Kouoh B Gressier T Dine et al ldquoAntioxidant effects andanti-elastase activity of the calcium antagonist nicardipine onactivated human and rabbit neutrophilsmdasha potential antiath-erosclerotic property of calcium antagonistsrdquo CardiovascularDrugs andTherapy vol 16 no 6 pp 515ndash520 2002
[167] S Parthasarathy D Litvinov K Selvarajan and M GarelnabildquoLipid peroxidation and decompositionmdashconflicting roles inplaque vulnerability and stabilityrdquo Biochimica et BiophysicaActa vol 1781 no 5 pp 221ndash231 2008
[168] D-Q Liu Z-Q Pang D-H Zhao and B-H Sheng ldquoEffects offuryl-dihydropyridines I on lipid peroxides of ischemic myo-cardium and ATPases activity of erythrocyte membranes inratsrdquo Acta Pharmacologica Sinica vol 12 no 3 pp 253ndash2561991
[169] V Lukic-Panin T Kamiya H Zhang et al ldquoPrevention of neu-ronal damage by calcium channel blockers with antioxidativeeffects after transient focal ischemia in ratsrdquo Brain Research vol1176 no 1 pp 143ndash150 2007
[170] Y Allanore D Borderie H Lemarechal O G Ekindjian andA Kahan ldquoAcute and sustained effects of dihydropyridine-typecalcium channel antagonists on oxidative stress in systemicsclerosisrdquo American Journal of Medicine vol 116 no 9 pp 595ndash600 2004
[171] I Casetta V Govoni and E Granieri ldquoOxidative stress antioxi-dants and neurodegenerative diseasesrdquo Current PharmaceuticalDesign vol 11 no 16 pp 2033ndash2052 2005
[172] M J T J Arts Assessing antioxidant activity [PhD the-sis] Maastricht University Maastricht The Netherlands 2007httparnounimaasnlshowcgifid=8676
[173] G Dıaz-Araya L Godoy L Naranjo A Squella M E Letelierand L J Nunez-Vergara ldquoAntioxidant effects of 14-dihydro-pyridine and nitroso aryl derivatives on the Fe+3ascorbate-stimulated lipid peroxidation in rat brain slicesrdquo General Phar-macology The Vascular System vol 31 no 3 pp 385ndash391 1998
[174] Y Fukuhara K Tsuchiya Y Horinouchi et al ldquoProtectiveeffect of photodegradation product of nifedipine against tumornecrosis factor 120572-induced oxidative stress in human glomerularendothelial cellsrdquo Journal of Medical Investigation vol 58 no1-2 pp 118ndash126 2011
[175] W Stengel M Jainz and K Andreas ldquoDifferent potencies ofdihydropyridine derivatives in blocking T-type but not L-typeCa2+ channels in neuroblastoma-glioma hybrid cellsrdquo EuropeanJournal of Pharmacology vol 342 no 2-3 pp 339ndash345 1998
[176] O M Panasenko D J Tirzite G D Tirzitis and G J DubursldquoEffect of some 14-dihydropyridine derivatives on structuralorganization of erythrocyte membranesrdquo Biologicheskie Mem-brany (Biochemistry (Moscow) Series A Membrane and CellBiology) vol 1 pp 919ndash925 1984 (Russian)
[177] L G Herbette Y M H Vant Erve and D G Rhodes ldquoInter-action of 14 dihydropyridine calcium channel antagonists with
Oxidative Medicine and Cellular Longevity 33
biological membranes lipid bilayer partitioning could occurbefore drug binding to receptorsrdquo Journal of Molecular andCellular Cardiology vol 21 no 2 pp 187ndash201 1989
[178] L G Herbette P E Mason G Gaviraghi T N Tulenko andR P Mason ldquoThe molecular basis for lacidipinersquos unique phar-macokinetics optimal hydrophobicity results in membraneinteractions that may facilitate the treatment of atherosclerosisrdquoJournal of Cardiovascular Pharmacology vol 23 supplement 5pp S16ndashS25 1994
[179] G V Belevitch G Y Dubur G E Dobretsov N K Kurek andM M Spirin ldquoCalcium antagonists riodipine nifedipine andverapamil binding to model and biological membranes fluore-scence analysisrdquo Biologicheskie Membrany (Biochemistry(Moscow) Series A Membrane and Cell Biology) vol 5 pp768ndash776 1988 (Russian)
[180] R P Mason G E Gonye D W Chester and L G HerbetteldquoPartitioning and location of Bay K 8644 14-dihydropyridinecalcium channel agonist in model and biological membranesrdquoBiophysical Journal vol 55 no 4 pp 769ndash778 1989
[181] M Cindric A Cipak J Serly et al ldquoReversal of multidrugresistance inmurine lymphoma cells by amphiphilic dihydropy-ridine antioxidant derivativerdquo Anticancer Research vol 30 no10 pp 4063ndash4070 2010
[182] F Shekari H Sadeghpour K Javidnia et al ldquoCytotoxic andmultidrug resistance reversal activities of novel 14-dihydro-pyridines against human cancer cellsrdquo European Journal ofPharmacology vol 746 no 1 pp 233ndash244 2015
[183] X-F Zhou Q Shao R A Coburn and M E Morris ldquoQuanti-tative structure-activity relationship and quantitative structure-pharmacokinetics relationship of 14-dihydropyridines andpyridines as multidrug resistance modulatorsrdquo PharmaceuticalResearch vol 22 no 12 pp 1989ndash1996 2005
[184] R Berkels T Breitenbach H Bartels et al ldquoDifferent antioxida-tive potencies of dihydropyridine calcium channel modulatorsin various modelsrdquo Vascular Pharmacology vol 42 no 4 pp145ndash152 2005
[185] S Borovic G Tirzitis D Tirzite et al ldquoBioactive 14-dihydro-isonicotinic acid derivatives prevent oxidative damage of livercellsrdquo European Journal of Pharmacology vol 537 no 1ndash3 pp12ndash19 2006
[186] D Ya Rubene G D Tirzitis and G Ya Duburs ldquoInteractionof some 14-dihydropyridine derivatives with Fentonrsquos reagentrdquoLatvijas PSRZinatnuAkademijas Vestis Kimijas Serija Proceed-ings of the Latvian SSR Academy of Sciences Chemistry Seriespp 212ndash216 1982 (Russian)
[187] K Ondrias V Misık D Gergel and A Stasko ldquoLipid per-oxidation of phosphatidylcholine liposomes depressed by thecalcium channel blockers nifedipine and verapamil and bythe antiarrhythmic-antihypoxic drug stobadinerdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1003 no 3pp 238ndash245 1989
[188] I T Mak and W B Weglicki ldquoComparative antioxidant acti-vities of propranolol nifedipine verapamil and diltiazemagainst sarcolemmal membrane lipid peroxidationrdquoCirculationResearch vol 66 no 5 pp 1449ndash1452 1990
[189] I T Mak P Boehme and W B Weglicki ldquoProtective effects ofcalcium channel blockers against free radical-impaired endo-thelial cell proliferationrdquo Biochemical Pharmacology vol 50 no9 pp 1531ndash1534 1995
[190] S Ray S Mondal and N Dana ldquoEvaluation of protective roleof nifedipine on lipid peroxidation using reduced glutathione as
model markerrdquo Oxidants and Antioxidants in Medical Sciencevol 1 no 2 pp 97ndash100 2012
[191] M Yamato T Shiba T Ide Y Honda K-I Yamada andH Tsutsui ldquoNifedipine treatment reduces brain damage aftertransient focal ischemia possibly through its antioxidativeeffectsrdquoHypertension Research vol 34 no 7 pp 840ndash845 2011
[192] V Chander and K Chopra ldquoNifedipine attenuates changes innitric oxide levels renal oxidative stress and nephrotoxicityinduced by cyclosporinerdquo Renal Failure vol 27 no 4 pp 441ndash450 2005
[193] K M Gaafa M M Badawy and A A Hamza ldquoThe protectiveeffects of ascorbic acid cimetidine and nifedipine on diethyl-dithiocarbamate-induced hepatic toxicity in albino ratsrdquo Drugand Chemical Toxicology vol 34 no 4 pp 405ndash419 2011
[194] H Sugawara K Tobise and S Onodera ldquoAbsence of antiox-idant effects of nifedipine and diltiazem on myocardial mem-brane lipid peroxidation in contrast with those of nisoldipineand propranololrdquo Biochemical Pharmacology vol 47 no 5 pp887ndash892 1994
[195] I E Kirule D Y Rubene E A Bisenieks G D Tirzit and GY Dubur ldquo4-Nitrophenyl-14-dihydropyridinesmdasha new groupof inhibitors of peroxide oxidationrdquo Chemistry of HeterocyclicCompounds vol 18 no 3 p 316 1982
[196] G D Tirzit I E Kirule L K Baumane R A Gavar Y PStradynrsquo andG YDubur ldquoMechanism of the antioxidant actionof 26-dimethyl-35-dimethoxy-carbonyl-4-(2-nitrophenyl)14-dihydropyridinerdquoChemistry ofHeterocyclic Compounds vol 20no 8 pp 915ndash918 1984
[197] C Yanez C Lopez-Alarcon C Camargo V Valenzuela J ASquella and L J Nunez-Vergara ldquoStructural effects on thereactivity 14-dihydropyridines with alkylperoxyl radicals andABTS radical cationrdquo Bioorganic and Medicinal Chemistry vol12 no 9 pp 2459ndash2468 2004
[198] VMisik A J Stasko D Gergel and K Ondrias ldquoSpin-trappingand antioxidant properties of illuminated and nonilluminatednifedipine and nimodipine in heart homogenate and modelsystemrdquo Molecular Pharmacology vol 40 no 3 pp 435ndash4391991
[199] K Ondrias V Misık A Stasko D Gergelrsquo and M HromadovaldquoComparison of antioxidant properties of nifedipine and illu-minated nifedipine with nitroso spin traps in low densitylipoproteins and phosphatidylcholine liposomesrdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1211 no 1pp 114ndash119 1994
[200] A Stasko V Brezova S Biskupic K Ondrias and V MisıkldquoReactive radical intermediates formed from illuminated nife-dipinerdquoFree Radical Biology andMedicine vol 17 no 6 pp 545ndash556 1994
[201] K Ishizawa Y Izawa-Ishizawa N Yamano et al ldquoNitrosoni-fedipine ameliorates the progression of type 2 diabetic nephro-pathy by exerting antioxidative effectsrdquo PLoS ONE vol 9 no 1Article ID e86335 2014
[202] H Fujii and L J Berliner ldquoIn vivo EPR evidence for free radicaladducts of nifedipinerdquoMagnetic Resonance in Medicine vol 42no 4 pp 691ndash694 1999
[203] S Bollo S Finger J C Sturm L J Nunez-Vergara and JA Squella ldquoCyclic voltammetry and scanning electrochemicalmicroscopy studies of the heterogeneous electron transferreaction of some nitrosoaromatic compoundsrdquo ElectrochimicaActa vol 52 no 15 pp 4892ndash4898 2007
34 Oxidative Medicine and Cellular Longevity
[204] F Ursini ldquoTissue protection by lacidipine insight from redoxbehaviorrdquo Journal of Cardiovascular Pharmacology vol 30supplement 2 pp S28ndashS30 1997
[205] P G Cristofori F A Crivellente I Faustinelli et al ldquoInvolve-ment of the nitric oxide system in the anti-atheroscleroticpotential of lacidipine in the apoE-deficient mouse a mor-phological functional and electrochemical studyrdquo ToxicologicPathology vol 32 no 4 pp 493ndash499 2004
[206] X-P Zhang E L Kit S Mital S Chahwala and T HHintze ldquoParadoxical release of nitric oxide by an L-type calciumchannel antagonist the R+ enantiomer of amlodipinerdquo Journalof Cardiovascular Pharmacology vol 39 no 2 pp 208ndash2142002
[207] F Franzoni G Santoro F Regoli et al ldquoAn in vitro study of theperoxyl and hydroxyl radical scavenging capacity of the calciumantagonist amlodipinerdquo Biomedicine and Pharmacotherapy vol58 no 8 pp 423ndash426 2004
[208] S V Gatsura ldquoOxygen-dependent mechanisms underlying theantiischemic effect of verapamil and amlodipinerdquo Bulletin ofExperimental Biology and Medicine vol 137 no 1 pp 40ndash422004
[209] Y Hirooka Y Kimura M Nozoe Y Sagara K Ito and KSunagawa ldquoAmlodipine-induced reduction of oxidative stressin the brain is associated with sympatho-inhibitory effects instroke-prone spontaneously hypertensive ratsrdquo HypertensionResearch vol 29 no 1 pp 49ndash56 2006
[210] B Tomlinson and I F F Benzie ldquoAntioxidant effect of lercani-dipine (note)rdquo Hypertension vol 42 no 4 pp e10ndashe11 2003
[211] A A Faraqui ldquoNeurochemical aspects of 4-hydroxynonenalrdquoin Lipid Mediators and Their Metabolism in the Brain A AFaraqui Ed chapter 6 pp 159ndash191 Springer New York NYUSA 2011
[212] V S NascimentoM S DrsquoAlva A AOliveira et al ldquoAntioxidanteffect of nimodipine in young rats after pilocarpine-inducedseizuresrdquo Pharmacology Biochemistry and Behavior vol 82 no1 pp 11ndash16 2005
[213] O Ismailoglu P Atilla S Palaoglu et al ldquoThe therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjuryrdquo Turkish Neurosurgery vol 22 no 6 pp 740ndash746 2012
[214] M Matsubara and K Hasegawa ldquoBenidipine a dihydropy-ridine-calcium channel blocker prevents lysophosphatidyl-choline-induced injury and reactive oxygen species productionin human aortic endothelial cellsrdquo Atherosclerosis vol 178 no1 pp 57ndash66 2005
[215] M Matsubara K Yao and K Hasegawa ldquoBenidipine adihydropyridine-calcium channel blocker inhibits lysophos-phatidylcholine-induced endothelial injury via stimulation ofnitric oxide releaserdquo Pharmacological Research vol 53 no 1 pp35ndash43 2006
[216] MMatsubara and K Hasegawa ldquoEffects of benidipine a dihyd-ropyridine-Ca2+ channel blocker on expression of cytokine-induced adhesion molecules and chemoattractants in humanaortic endothelial cellsrdquo European Journal of Pharmacology vol498 no 1ndash3 pp 303ndash314 2004
[217] M Matsubara O Akizuki J-I Ikeda K Saeki K Yao and KSasaki ldquoBenidipine an anti-hypertensive drug inhibits reactiveoxygen species production in polymorphonuclear leukocytesand oxidative stress in salt-loaded stroke-prone spontaneouslyhypertensive ratsrdquo European Journal of Pharmacology vol 580no 1-2 pp 201ndash213 2008
[218] A C Rosenkranz H Lob T Breitenbach R Berkels and RRoesen ldquoEndothelial antioxidant actions of dihydropyridines
and angiotensin converting enzyme inhibitorsrdquo European Jour-nal of Pharmacology vol 529 no 1ndash3 pp 55ndash62 2006
[219] V Kain S Kumar and S L Sitasawad ldquoAzelnidipine preventscardiac dysfunction in streptozotocin-diabetic rats by reducingintracellular calcium accumulation oxidative stress and apop-tosisrdquo Cardiovascular Diabetology vol 10 article 97 2011
[220] K Nakamura S Yamagishi and H Inoue ldquoUnique atheropro-tective property of azelnidipine a dihydropyridine-based cal-cium antagonistrdquoMedical Hypotheses vol 65 no 1 pp 155ndash1572005
[221] TMatsui S Yamagishi K Nakamura S Kikuchi andH InoueldquoAzelnidipine a dihydropyridine-based calcium antagonistinhibits angiotensin II-induced oxidative stress generation anddownregulation of pigment epithelium-derived factor mRNAlevels in microvascular endothelial cellsrdquo Drugs under Experi-mental and Clinical Research vol 31 no 5-6 pp 215ndash219 2005
[222] C Ohmura H Watada T Shimizu et al ldquoCalcium channelblocker azelnidipine reduces lipid hydroperoxides in patientswith type 2 diabetes independent of blood pressurerdquo EndocrineJournal vol 54 no 5 pp 805ndash811 2007
[223] H Daikuhara F Kikuchi and T Ishida ldquoThe combination ofOLmesartan and a CAlcium channel blocker (azelnidipine) orcandesartan and a calcium channel blocker (amlodipine) intype 2 diabetic hypertensive patients theOLCA studyrdquoDiabetesand Vascular Disease Research vol 9 no 4 pp 280ndash286 2012
[224] MAbe NMaruyama KOkada SMatsumoto KMatsumotoand M Soma ldquoAdditive antioxidative effects of azelnidipine onangiotensin receptor blocker olmesartan treatment for type 2diabetic patients with albuminuriardquoHypertension Research vol34 no 8 pp 935ndash941 2011
[225] K Mizushige ldquoAntioxidative activities of thiazolidinedionesand dihydropyridine-type calcium antagonistsrdquo IRYOmdashJapa-nese Journal of National Medical Services vol 59 no 11 pp 581ndash592 2005
[226] S Manabe T Okura T Fukuoka and J Higaki ldquoAntioxidativeeffects of azelnidipine on mesangial cell proliferation inducedby highly concentrated insulinrdquo European Journal of Pharma-cology vol 567 no 3 pp 252ndash257 2007
[227] Y Koyama Y Takeishi H Takahashi et al ldquoAzelnidipine inhi-bits H
2O2-induced cell death in neonatal rat cardiomyocytesrdquo
CardiovascularDrugs andTherapy vol 21 no 1 pp 69ndash72 2007[228] K Shinomiya K Mizushige M Fukunaga et al ldquoAntioxidant
effect of a new calcium antagonist azelnipidine in culturedhuman arterial endothelial cellsrdquo Journal of International Med-ical Research vol 32 no 2 pp 170ndash175 2004
[229] T Ohyama K Sato K Kishimoto et al ldquoAzelnidipine is acalcium blocker that attenuates liver fibrosis and may increaseantioxidant defencerdquo British Journal of Pharmacology vol 165no 4 pp 1173ndash1187 2012
[230] L A Calo F Zaghetto E Pagnin P A Davis A Sempliciniand A C Pessina ldquoEffect of manidipine on gene expressionand protein level of oxidative stress-related proteins p22phoxand HO-1 Relevance for antihypertensive and anti-remodelingeffectsrdquo Journal of Cardiovascular Pharmacology vol 43 no 4pp 531ndash538 2004
[231] R Ghyasi G Sepehri M Mohammadi R Badalzadeh and AGhyasi ldquoEffect of mebudipine on oxidative stress and lipid per-oxidation in myocardial ischemic-reperfusion injury in maleratrdquo Journal of Research in Medical Sciences vol 17 no 12 pp1150ndash1155 2012
Oxidative Medicine and Cellular Longevity 35
[232] DCAndersson J Fauconnier T Yamada et al ldquoMitochondrialproduction of reactive oxygen species contributes to the 120573-adrenergic stimulation of mouse cardiomycytesrdquoThe Journal ofPhysiology vol 589 no 7 pp 1791ndash1801 2011
[233] A F Ceylan-Isik N Ari M Stefek et al ldquoEffects of a long-term treatment with an antioxidant pyridoindole on vascularresponsiveness in diabetes-induced aging ratsrdquo Current AgingScience vol 4 no 2 pp 150ndash157 2011
[234] S Saponara G Sgaragli and F Fusi ldquoQuercetin antagonismof Bay K 8644 effects on rat tail artery L-type Ca2+ channelsrdquoEuropean Journal of Pharmacology vol 598 no 1ndash3 pp 75ndash802008
[235] D A Sica ldquoInteraction of grapefruit juice and calcium channelblockersrdquo American Journal of Hypertension vol 19 no 7 pp768ndash773 2006
[236] P Mulder G Litwinienko S Lin P D MacLean L R CBarclay and K U Ingold ldquoThe L-type calcium channel block-ers Hantzsch 14-dihydropyridines are not peroxyl radical-trapping chain-breaking antioxidantsrdquo Chemical Research inToxicology vol 19 no 1 pp 79ndash85 2006
[237] L J Nunez-Vergara R Salazar C Camargo et al ldquoOxidation ofC4-hydroxyphenyl 14-dihydropyridines in dimethylsulfoxideand its reactivity towards alkylperoxyl radicals in aqueousmediumrdquo Bioorganic and Medicinal Chemistry vol 15 no 12pp 4318ndash4326 2007
[238] M E Ortiz L J Nunez-Vergara and J A Squella ldquoRelativereactivity of dihydropyridine derivatives to electrogeneratedsuperoxide ion in DMSO solutions a voltammetric approachrdquoPharmaceutical Research vol 20 no 2 pp 292ndash296 2003
[239] M E Ortiz L J Nunez-Vergara C Camargo and J A SquellaldquoOxidation of Hantzsch 14-dihydropyridines of pharmacolog-ical significance by electrogenerated superoxiderdquo Pharmaceuti-cal Research vol 21 no 3 pp 428ndash435 2004
[240] R S Raghuvanshi and K N Singh ldquoSuperoxide induced oxida-tive aromatization of Hantzsch 14-dihydropyridinesrdquo IndianJournal of Chemistry Section B Organic and Medicinal Chem-istry vol 47 no 11 pp 1735ndash1738 2008
[241] I Kruk A Kladna K Lichszteld et al ldquoAntioxidant activityof 4-flavonil-14-dihydropyridine derivativesrdquo Biopolymers vol62 no 3 pp 163ndash167 2001
[242] G D Tirzit I M Byteva K I Salokhiddinov G P Gurinovichand G Y Dubur ldquo14-Dihydropyridine derivatives as deactiva-tors of singlet oxygenrdquo Chemistry of Heterocyclic Compoundsvol 17 no 7 pp 682ndash684 1981
[243] G D Tirzit E Y Kazush and G Y Dubur ldquoInfluence of14-dihydropyridine derivatives on the generation of hydroxylradicalsrdquo Chemistry of Heterocyclic Compounds vol 28 no 4pp 435ndash437 1992
[244] N A Pizarro-Urzua and L J Nunez-Vergara ldquoNifedipine andnitrendipine reactivity toward singlet oxygenrdquo Journal of Photo-chemistry and Photobiology A Chemistry vol 175 no 2-3 pp129ndash137 2005
[245] L-F Wang H-Y Zhang L Konga Z-W Chena and J-G ShildquoDFT calculations indicate that 14-dihydropyridine is a promis-ing lead antioxidantrdquo Helvetica Chimica Acta vol 87 no 6 pp1515ndash1521 2004
[246] P Mulder H-G Korth and K U Ingold ldquoWhy quantum-thermochemical calculations must be used with caution toindicate lsquoa promising lead antioxidantrsquordquoHelvetica Chimica Actavol 88 no 2 pp 370ndash374 2005
[247] K Yao Y Ina K Nagashima K Ohmori and T Ohno ldquoAntiox-idant effects of calcium antagonists in rat brain homogenatesrdquo
Biological and Pharmaceutical Bulletin vol 23 no 6 pp 766ndash769 2000
[248] T Matsui S-I Yamagishi K Nakamura and H Inoue ldquoBayw 9798 a dihydropyridine structurally related to nifedipinewith no calcium channel-blocking properties inhibits tumournecrosis factor-120572-induced vascular cell adhesion molecule-1expression in endothelial cells by suppressing reactive oxygenspecies generationrdquo Journal of International Medical Researchvol 35 no 6 pp 886ndash891 2007
[249] K AMitrega B VargheseM Porc and T F Krzeminski ldquoAnti-arrhythmic and hemodynamic effects of oxy nifedipine oxynimodipine oxy nitrendipine and oxy nisoldipinerdquo Pharmaco-logical Research vol 66 no 4 pp 300ndash308 2012
[250] V Herbert ldquoSymposium prooxidant effects of antioxidantvitamins Introductionrdquo The Journal of Nutrition vol 126 no4 supplement pp 1197Sndash1200S 1996 httpjnnutritionorgcontent1264 Suppl1197Sfullpdf
[251] B Halliwell ldquoAre polyphenols antioxidants or pro-oxidantsWhat do we learn from cell culture and in vivo studiesrdquoArchives of Biochemistry and Biophysics vol 476 no 2 pp 107ndash112 2008
[252] C Winterbourn Pro-Oxidants or Antioxidants ChristchurchSchool of Medicine Depatment of Pathology Free RadicalSchool SFRBMUniversity of Otago San Francisco Calif USA2009 httpwwwsfrbmorgfrsWinterbournpdf
[253] A Morakinyo B Iranloye and O Adegoke ldquoCalcium antag-onists modulate oxidative stress and acrosomal reaction in ratspermatozoardquo Archives of Medical Science vol 7 no 4 pp 613ndash618 2011
[254] The Alpha-Tocopherol Beta Carotene Cancer Prevention StudyGroup ldquoThe effect of vitamin E and beta carotene on theincidence of lung cancer and other cancers in male smokersrdquoTheNew England Journal of Medicine vol 330 no 15 pp 1029ndash1035 1994
[255] B Poljsak ldquoStrategies for reducing or preventing the generationof oxidative stressrdquo Oxidative Medicine and Cellular Longevityvol 2011 Article ID 194586 15 pages 2011
[256] B Poljsak and I Milisav ldquoThe neglected significance of lsquoanti-oxidative stressrsquordquoOxidativeMedicine and Cellular Longevity vol2012 Article ID 480895 12 pages 2012
[257] T Godfraind and S Salomone ldquoAmbiguities in dietary antiox-idant supplementation compared to calcium channel blockerstherapyrdquo Frontiers in Pharmacology vol 6 article 10 2015
[258] H Wagner H Norr and H Winterhoff ldquoDrugs with adap-togenic effects for strengthening the powers of resistancerdquoZeitschrift fur Phytotherapie vol 13 no 2 pp 42ndash54 1992
Oxidative Medicine and Cellular Longevity 11
cells against toxicity of previously oxidized LDL The IC50
values were 6 plusmn 2 and 80 plusmn 20 120583M respectively [122] Theinhibition of the cytotoxic effect of LDL oxidized in thepresence of DHP type Ca2+ channel blockers correlated wellwith protection from oxidation by these compounds Com-plete protection cannot be obtained because the DHPs arecytotoxic themselves The potential relevance to the preven-tion of atherogenesis is envisaged
DHP typeCCBnifedipinewas themost effective inhibitorof oxidation promoted either by UV radiation or by copperions in experiments with cultured lymphoid cells LDL (2mgapoBmL) CCBs from other two CCB classes diltiazem andverapamil were only poorly active or completely ineffective[121] The protective effect of nifedipine occurs at two levelsbesides its direct antioxidant effect by inhibition of LDLoxidation it also exhibits a direct cytoprotective effect againstcytotoxicity of oxidized LDL by yet unknown mechanismsThe protective effect of CCBs was not due to an inhibitionof LDL uptake This effect seems to be independent of theinhibition of LDL oxidation per se since LDL was oxidizedin the absence of the drug before the incubation withcells Moreover this direct protective effect was observedat lower concentrations (IC
50of 1 plusmn 02 120583M) compared to
the antioxidant effect (IC50
of TBARS inhibition is around10 plusmn 2 120583M at UV promoted and 4 plusmn 05 120583M by Cu2+ ionsinitiated) The AO effect of nifedipine is also correlated withthe protection of endogenous tocopherols (IC
50= 50 120583M)
It was suggested that the AO effect of CCBs protected cellsindirectly from the cytotoxic effect of oxidized LDL [121]
A recent study has reported that beneficial vascular effectsof lercanidipine in diabetic rats depend on its antioxidantactivity related to attenuating the increase in oxidativestress and in vascular matrix metalloproteinase-2 (MMP-2) (Martinez et al [126]) Lesnik et al [127] studied theimpact of a combination of this calcium antagonist and a120573-blocker atenolol on cell- and copper-mediated oxidationof LDL and on the accumulation and efflux of cholesterolin human macrophages and murine J774 cells They realizedthat lercanidipine reduced the oxidative modification of LDLrather than diminished cholesterol accumulation in humanfoam cells
Comparing the antioxidative action of CA (DHPs amlo-dipine lacidipine nifedipine and isradipine as well as diltia-zem and semotiadil) in the copper-catalyzed oxidation oflow-density lipoprotein (LDL) with that of glycated (g)gly-coxidated (go) LDL demonstrated that the strongest AOeffects during long-term LDL glycation are seen for isradip-ine lacidipine nifedipine and semotiadil [128] Inhibitoryeffects were in the range 10minus5ndash10minus3MAuthors suggested thatdue to the increased generation of ROS by glucose-modifiedLDL the chain-breaking capacity of CA may be overriddenThe AOA of CA depends on their lipophilicity and theirability to incorporate into the LDL particle that is to reachthe site of peroxidation CA like other AOs significantlyretards advanced glycation end products (AGE) formationwhereas initial glycation reactions such as Amadori productformation are only weakly inhibited The observation thatboth oxidative changes and at least long-termglycation effectsare indeed drastically reduced by CA is corroborated by
fluorescence analysis AGE-ELISA quantitation of lipid per-oxidation and TBARS measurement of long-term ggo LDL
The effects of lipophilic DHP calcium channel blockerson oxidized LDL-induced proliferation and oxidative stressof vascular smooth muscle cells were also studied [130] (seeTable 5)
Lacidipine and amlodipine reduced carotid intima-media thickness by decreasing proliferative effect of oxLDLwhereas (S-)-amlodipine had no antiproliferative effect ROS-MAPKs (mitogen-activated protein kinases) pathway mightbe involved in the mechanism
Both 14-DHP CCBs lacidipine and nifedipine reduceplasma and LDL oxidation and formation of oxidation-specific epitopes Their application may also relate to pro-longed survival of rats independently of blood pressuremod-ifications (in the SPSHR model 1mgkg per day lacidipineand 80mgkg per day nifedipine) These results suggestedthat the protective effect of these two 14-DHP drugs invivo as shown in cerebral ischemia and stroke may in partresult from inhibition of LDL oxidative process althoughthese two drugs possess different lipophilic properties [131]Both lacidipine (03 and 10mgkg) andnifedipine (80mgkg)prolonged lag time of the conjugated diene formation inLDL isolated from arterial wall and 119905max These drugssignificantly reduced electrophoreticmobility of oxLDL fromSPSHR subjected to XXO oxidation system 14-DHP CCBsalso protected apolipoprotein B which is important for thebinding with macrophage LDL receptor lysine residues Thedoses used (gt10minus6molL for SPSHR and normotensive WKYrats) however are 2 to 3 orders of magnitude higher thanthose inhibiting vascular smooth muscle contraction in vitroand in vivo They also exceed values that are commonlyused in clinical practice The daily dose of lacidipine forhypertensive patients is 007mgkg asymp4- to 14-fold lower thanthe 2 doses used in SPSHR The maximum daily dose ofnifedipine given to hypertensive patients is 20mgkg asymp40-fold lower thanwhatwere used [131]These discrepanciesmaybe related to differences in bioavailability of CA between ratsand humans [131]
Accordingly in routine clinical use 14-DHPCCBs donotreach the concentrations required for antioxidant activity invitro [131]
Another data concerning the effect of CA DHPs on OSrelated to LDL is presented under Section 35
(b) Effect of DHPs on Isolated Rat Liver and Heart Mitochon-dria As a major cellular source of oxygen radicals (Cadenas[4 5]) mitochondria are promising targets for pharmaco-logical and toxicological actions of various membrane-activecompounds including several 14-DHP derivatives Zernig etal [132] have discovered CA binding sites associated with aninner mitochondrial membrane anion channel
More than 40-year long research onmitochondrial effectsof the DHPs (on their bioenergetics chemiosmotic proper-ties and ion fluxes) clearly points them out as mitochondri-otropic compounds
The activity of the first 35 synthesized compounds(derivatives of 14-DHP their heteroaromatic analogues
12 Oxidative Medicine and Cellular Longevity
NAD-H+ and butylated hydroxytoluene (BHT BOT)) orig-inally was examined in rat liver mitochondrial LP system inthe presence of Fe2+ ions and using the ultraweak chemilu-minescence method (Dubur et al [89])
Several 14-DHP derivatives Hantzsch ester diludine andits analogues were found to be effective antioxidants in thisexperimental system changing the kinetics of LP lengtheningthe time of the appearance of the maximum of the slowburst of the chemiluminescence (latency latent period) anddiminishing the reaction rate (the tangent of the slope angleduring the time in which the amplitude of the slow burstcharacterizing LP rate increases) and its peak value Theirpresence has influenced the reaction constant 119870
6 in relation
to a very significant reduction of lipid hydroperoxides andorinactivation of free radicals as follows
ROO∙ + ROO∙ 997888rarr P + h]lowast termination (1)
(P = molecular products) or
ROO∙ + ROO∙ +H2O 997888rarr ROH + RO∙ + 1O
2
lowast (2)
In this study diludine was one of themost active compoundsDHPs had activity similar to the standard synthetic AO-BHT(ionol) However when plotted against applied concentrationand time window diludinersquos activity profile differed from thatof BHT
There were also similar studies (using different LP rateexperimental detection system and method Hunter et al[133]) based on exploring a group of 26 26-dimethyl-35-disubstituted- and 26-dimethyl-345-trisubstituted-14-dihydropyridines (14-H
2Py=14-DHPs) and five related pyri-
dines as inhibitors of rat liver Mit swelling (Δ119860520119905) and O
2
uptake by ascorbic acid- (AsA-) dependent lipid peroxidationand as modulators of Mit swelling induced by Na+-linoleateor Na+-pyrophosphate (Velena et al [112])
Some of tested 4-DHPs (4-unsubstituted 35-dialkoxy-carbonyl-26-dimethyl-14-DHPs and 35-diamido-26-dim-ethyl-14-DHPs both 4-unsubstituted or those possessinglipophilic 4-aryl- groups) have shown significant AO andmembrane stabilizing activity These studies further revealedthat 14-DHPs preferably act as AO during the stages ofinitiation and prolongation of LP chain reactions at lowconcentrations The studied 14-DHPs had IC
50(when 119881
0119881
or 1205911205910= 2) 01 120583M to 100 120583M and the minimal activity was
scored for oxidized (heteroaromatized) derivativesAt the concentration of 100120583M 35-di-n-butyloxycarbo-
nyl-26-dimethyl-14-DHP entirely stops mitochondrialswelling in the presence of 08mM Na+-pyrophosphateAt the same concentration the following compoundsalter the mitochondrial swelling rate in the presence ofnatural protonophore Na+-linoleate 35-di-p-hydroxyphen-oxycarbonyl- and 35-di-p-tolyloxycarbonyl-26-dimethyl-14-DHPs 35-diethoxycarbonyl-26-dimethyl-pyridine (oxi-dized form of Hantzsch ester) and more lipophilic 35-diamyloxycarbonyl-26-dimethyl-pyridine The alteration ofswelling may be scored as prolonged promoted acceleratedor inhibited The type of alteration depends on the structureand concentration of 14-DHPs the type of initiators of theswelling process and the medium composition
In accord with previously published Janerorsquos results (lackof AO for Ca2+ antagonists nifedipine and nicardipine evenat 500120583M concentration in LP tests performed on heartmembrane [134]) no antioxidative activity for 4-phenyl sub-stituted derivatives of 35-dialkoxycarbonyl 14-DHP (closeanalogues of Ca2+ antagonists) was found contrary to various4-nitrophenyl 14-DHP derivatives calcium antagonists forwhich the significant antioxidant activity was reported [3146ndash53]
Studies made on phosphatidylcholine liposomes (ourunpublished data) suggest approximately three and twotimes more antioxidative activity for 100 120583M 4-unsubstitutedDHP compound diludine when compared to 4-substitutedDHPs riodipinenifedipine and nicardipine respectively atmethemoglobin-induced LP (oxygraphy)
Inhibition of mitochondrial AsA-dependent LP and sta-bilization ofmitochondriawere shown to be characteristic fora large group of 14-DHP compounds [112] showing to pos-sess the AOA in simplest in vitro systems (Tirzit andDuburs [39] Zilber et al [44] and Dubur et al [45])based on reactions with the stable free radical 11-diphenyl-2-picrylhydrazyl (DPPH) LP of fatty acid ester (linethole andmethyloleate) emulsions and phospholipid (phosphatidyl-choline) liposomes Generally these properties did not coin-cide with Ca2+ antagonism Depending on DHP structure itseems that AOA properties are less specific than Ca2+ antago-nist properties Both properties may be interrelated but notinterdependent
These data show that the presence and the nature ofa substituent in position 4 as well as 35-substituentsare important factors for 14-DHP antioxidant effects invarious systems that is AsA-dependent nonenzymatic aswell as enzymatic NADPH-dependent lipid peroxidationSometimes the efficacy of inhibition of nonenzymatic LPby 14-DHPs is higher than the inhibition of the enzymaticLP However the action may be opposite stimulation of theLP Hantzsch ester (HEH diludine) and its close analoguesexhibited significant AOA and membrane stabilizing prop-erties in both AsA-dependent nonenzymatic peroxidationof mitochondria and NADPH-dependent enzymatic LP ofmicrosomes usually at similar 10 to 100120583M concentrations[112]
The order of AOpotency (IC50
values) in vitro depends ondrug structure as well as on the experimental conditions andspecificity of the biological system Eachmethod for determi-nation of AOA and ARA has advantages and disadvantages(Karadag et al [135])
Accordingly as reported by Gubskiı et al [136] IC50
forthe AsA-dependent LP was 025 120583M and 20 120583M for 14-DHPCa2+ antagonists nitrepine (nitrendipine) and nifedipinerespectively Takei et alrsquos [137 138] studies on mitochondrialswelling induced by LP or arachidonic acid in the rat braindetermined the IC
50values of 127 105 1568 and 384 120583Mfor
efonidipine nicardipine nifedipine and nimodipine respec-tively For LDL in the copper-induced oxidation system theorder of potencywas vitamin Egt felodipinegt 2-chlorophenylanalogue of nifedipine gt nifedipine gt amlodipine nitrendip-ine verapamil and diltiazem (Rojstaczer and Triggle [119])
Oxidative Medicine and Cellular Longevity 13
It was interesting to compare the AOAofDHPswith theirsusceptibility to oxidation that is electron and hydrogendonating properties
It has been estimated that electron donor substituentsin positions 2 and 6 of 14-DHP cycle usually promoteoxidation while electron acceptor substituents promotequench oxidation Stronger electron acceptors in positions 3and 5 also significantly quench oxidation These estimationsare based on studies including chemical enzymatic andelectrochemical oxidation of 14-DHPderivatives (Dubur andUldrikis [70] Duburs et al [71] and Stradin et al [139])
On the other hand diminished AOA of 14-DHP relatesto presence of substituents in position 4 (both electron donorand electron acceptor) (Velena et al [112])
35-Dicarbamoyl substituents possess minimal quench-ing feature and are followed by benzoyl- acetyl- andalkoxycarbonyl- groups Maximal decrease was obtainedwith condensed substituents (ie oxoindeno- or oxocyclo-hexeno- groups) and a CN-group 4-Unsubstituted 35-dicar-bamoyl derivatives can be easily oxidized and consequen-tially inactivated whereas 4-substituted 35-dicarbamoyl-14-DHPs possess an oxidation potential analogous to the 4-unsubstituted 35-COOR derivatives Therefore they haveadequate electron donor properties and are considerablystableThismay be the reason for significantmembrane stabi-lization upon exposure to 4-substituted derivatives Ofimportance their AOA was usually more pronounced incomparison to 4-unsubstituted derivatives
Among them 26-dimethyl-35-difurfuryloxycarbonyl-14-DHP showed the highest antioxidative activity In thegroup of 35-dialkoxycarbonyl derivatives the strongestactivity was attributed to compounds with medium lengthalkyl chains (i-butyl- t-butyl- and i-amyl- substituents) highlevel of lipophilicity minimal electron acceptor propertiesand moderate steric hindrance as contrasted to short or longalkyl chain ester derivatives (35-dimethoxycarbonyl- 35-diethoxycarbonyl derivatives and 35-didodecyloxycarbonylderivative) These data demonstrate the bell-shaped depen-dence of AOA on alkyl chain length [112] and are in accordwith results obtained in liposomes However these datadiffer from those obtained in emulsions where diludine wasthe most active compound Finally oxidized heteroaromaticderivatives showed only minimal activity
In both LP systems studied (AsA-dependent in mito-chondria and NADPH-dependent in microsomes) some of14-DHPs showed activity similar to classical antioxidantbutylated hydroxytoluene (ionol BHT) (Velena et al [112])However there was a significant difference related to con-centration and incubation time It allowed us to postu-late that 14-dihydropyridines (InH) acting as antioxidants-reductants and scavengers of reactive oxygen species and lipidfree radicals preferably influence initiation and propagation(prolongation) of lipid peroxidation chain reactions (1)ndash(5) according to Scheme 2 The phenomenon is particularlyprominent in the presence of Fe2+ and other ions of variablevalency
Chain break and termination reactions (6)ndash(10) of theLP reaction cascade [89] were influenced by 14-DHPs in alesser degree than were initiation and propagation steps This
may be important for their therapeutic effects even in theadvanced stages of LP
Scheme 2 (stages of initiation propagation and terminationof lipid peroxidation chain reactions (1ndash10)) Initiation andpropagation reactions are as follows
(8) RO∙ + In∙minus rarr Y (Y = molecular products)(9) ROO∙ + Fe2+ rarr Fe3+ + X (X = molecular products)(10) RO∙ + RO∙minus rarr Y (Y = molecular products)
In the reversible swelling of mitochondria accompanyingLP (initiated by mixture of 5mM GSSG1mM GSH) several14-DHPs showed low or no activity manifested only as adecrease of the swelling amplitude without a rate decreaseAn addition of GSH (4mM) or ATP to swollenmitochondriacaused their contraction in both control and tested systemIt may be suggested that 14-DHPs acting as antioxidantsin mitochondria preferably influence LP reactions initiatedby ions with variable valency or their complexes with hemetype compounds methemoglobin hemin hematin and soforth (Velena et al [112]) If the peroxidation process has amaximal velocity and 50 percent of initial O
2were consumed
14-DHPs cannot completely break the chain reactions andprevent subsequent membrane damage by addition of DHPsubstance at 10 120583M concentration at the moment of 50percent oxygen consumption the subsequent oxygen uptakeproceeded unchanged This observation is important for theapplication of DHPs as inhibitors of initiation and to a lesserdegree propagation stages of LP chain reactions
The influence of 14-DHPs on Mit swelling is not strictlyassociated with their own oxidation There is the possibilitythat the labilizing (or stabilizing) effect relates to surfaceactivity (connected with substituent lipophilicity) or may bethe consequence of complexation with some -OH (or -CH
3)
group sensitive receptors at the mitochondrial membraneNamely a bathochromic shift of the absorption band maxi-mum (about 10 nm) was observed in the visible region beforeswelling However after swelling in the presence of Na+linoleate the spectrum returns to its initial value [112]
Some 14-DHPs not only protect mitochondria againstswelling caused by AsA-dependent LP salts of fatty acids
14 Oxidative Medicine and Cellular Longevity
in vitro [112] but also have beneficial effects on repairingtheir integrity in vivo after exposure to irradiation hepato-toxins ischemia hypoxia or hypothermia Some of themwere shown to normalize the process of intracellular repara-tion and physiological regeneration of ultrastructures Theywere also shown to stimulate reparative processes If pre-treated with 14-DHPs irradiatedmitochondria will not swell(Ivanov et al [140 141])
Diludine ionol and some other AOs mitochondria pro-tectors act as anti-ischemic agents If applied prophylacticallyin vivo they may prevent ischemic and reperfusion lesionsin heart kidney and other organs (Bilenko et al [113]) Theeffect is dependent on applied dose timing and way ofapplicationWhen added onto the cryoconservationmediumfor mitochondria preservation 14-DHPs prevented decreaseof membrane potential normalized facilitated respirationand prevented loss of mitochondrial Na+ and Ca2+ ionsafter thawing ([112] see citation number 36 (Subbota et alKharkov 1984) therein) Diludine was stronger protectorwhen compared to ionol
CA drug foridone (riodipine) was shown to possesscardioprotective features primarily due to is protective effecton mitochondria exposed to OS [142 143]
Similarly the DHP water-soluble antiarrhythmic com-pound glutapyrone inhibits initiation of LP by free radicalsin erythrocytes and heart mitochondria Its cardioprotectiveeffect has been experimentally shown in heart mitochondrialmembranes especially during deep hypothermia (Utno et al[144])
Cerebrocrast was effective in several translation modelsmimicking pathological situations known to be associatedwith cellular OS The potential protective action of 14-DHP derivatives (4-substituted compounds cerebrocrastgammapyrone glutapyrone and 4-unsubstituted drug dieth-one) has been studied in rat liver in experimental modelsrelevant for oxidative stress and mitochondrial bioenergetics(Fernandes et al [145]) When succinate was used as therespiratory substrate higher concentrations (gt25 120583M) ofcerebrocrast depressed respiratory control ratio (RCR) ADPto oxygen ratio (ADPO) state 3 and uncoupled respirationrates transmembrane potential (deltapsi) and the phosphatecarrier rate At the same time state 4 respiration rate wasthree times increased At concentrations lower than 25120583Mcerebrocrast inhibited mitochondrial IMAC and partiallyprevented Ca2+-induced opening of the mitochondrial PTPGammapyrone glutapyrone and diethone did not inducethese phenomena When applied at concentrations up to100 120583M cerebrocrast gammapyrone and glutapyrone didnot affect ADPFe2+-induced LP of mitochondria in rat liver(as measured by oxygen consumption and TBARS forma-tion) On the other hand low diethone concentrations (upto 5 120583M) inhibited it in a dose-dependent manner Diethonealso prevented against deltapsi dissipation induced by LPinitiated by ADPFe2+ Based on these data it may bespeculated that cerebrocrast (inhibition of the IMAC) anddiethone (acting as an AO) may provide effective protectionof mitochondria during OS Cerebrocrast has shown sometherapeutic potential for treatment of several pathologicalconditions related to cellular OS [145]
5-Acetyl(carbamoyl)-6-methylsulfanyl-14-DHP-carbo-nitriles (Figure 3) with minor differences in their molecularstructure displaying antioxidant and antiradical activitiesin vitro show different biological activities Namely 4-p-chlorophenyl derivative OSI-1146 displays AO and anti-radical activities in cardiovascular OS models whereasOSI-3701 and OSI-3761 display hepatoprotective activityThus these compounds may be potentially useful for treat-ing several pathological processes including those associatedwith OS (Fernandes et al [146]) However besides mito-chondria the cellular targets for their pharmacologicalactions have not been fully investigated [146] All these com-pounds increase the susceptibility of Mit to MPT The mostpotent is OSI-3701 although it does not affect bioenergeticparameters
Although all these compounds protected mitochondriaagainst LP induced by the oxidant pair ADPFe2+ OSI-1146was shown to be the most potent Current data point outmitochondria as potential targets for protective and toxicactions of DHPs suggesting that the potential for their use astherapeutic agents should also take into consideration theirtoxic effects on mitochondria (Fernandes et al [146])
Several structurally different DHP derivatives (antioxi-dant diludine (diethone) as a 4-unsubstituted DHP 4-substi-tuted DHPs CA foridone (bicyclic compound) and the 4-phenyldiethone compound where phenyl group is joined tothe DHP in position 4) inhibited the 1-methyl-4-phenyl-pyridinium iodide (MPP+) induced ROS production incerebellar granule cells (CGC) with a distinct potency orderforidone (26-dimethyl-35-dimethoxycarbonyl-4-(o-difluo-romethoxyphenyl)-14-dihydropyridine) gt 26-dimethyl-35-diethoxycarbonyl-4-phenyl-14-dihydropyridine gt diludineThey also reversed the MPP+-induced decrease of the mito-chondrial membrane potential in the same order (Klimavi-ciusa et al [147]) Accordingly it was postulated that theclassical two-ring (bicyclic) structure of DHP derivativesrepresents an advantage in relation to neuroprotection andROS defense and is independent on compoundrsquos propertiesrelated to calcium ions
Novel adamantane-containing 14-DHP compounds (Kli-maviciusa et al [148]) were also found to improve mitochon-drial functions (MPP+ model) (Klimaviciusa et al [148])Klusa et al [149] have discovered antineurotoxic effects of14-DHP taurine derivative tauropyrone recorded as Mitfunction improvement
Many 14-DHPs including Ca2+ antagonists and AOmodify LP processes and influencemitochondrial function invarious organs (liver heart kidney and brain) in a differentway and degree Their beneficial action oxygen or lipidfree radical scavenging antioxidative effects binding withor intercalating into phospholipid bilayer regulation of iongating and regulation of mitochondrial permeability transi-tion pores (Tirzit and Duburs [39] Zilber et al [44] andDubur et al [45]) separately or in combination with eachother depends on two strong elements (1) their individ-ual structure including nature of substituents and theirpositions and (2) the nature of the biological system Forexample the direction of LP (inhibition of promotion) wasshown to depend on structure and concentration of applied
Oxidative Medicine and Cellular Longevity 15
14-DHPs as well as stages of chain reactions Accordinglymitochondrial swelling may be prolonged (retarded) accel-erated (promoted) or inhibited (Velena et al [112])
Therefore there is a ground for 14-dihydropyridineseither Ca2+ antagonists or antioxidants to be nominated asuseful tools in development of ldquomitochondrial drugsrdquo relatedto the control of OS
(c) DHPs as AOs in Endoplasmic Reticulum (Inhibition ofNADPH-Dependent LP System) Inhibition of NADPH Oxi-dase by DHPs Elevated level of NADPH oxidase 4- (NOX4-)derived hydrogen peroxide (H
2O2) joined with concomitant
decrease of nitric oxide (NO) mediated signaling and reac-tive oxygen species scavengers are considered to be centralfactor in molecular pathogenesis of fibrosis (Sampson etal [150]) Inhibition of microsomal NADPH-dependent LPwith particular focus on NADPH oxidases (NOX1ndash5 andDUOX1) may be very important for neuro- cardio- andhepatoprotection (Velena et al [112] Leto and Geiszt [151]Griendling et al [152] and Chen et al [153]) Endoplasmicreticulum may be an important target as this is where 14-DHPs could display their antioxidative properties (Velena etal [112] Leto and Geiszt [151] Griendling et al [152] andChen et al [153])
However the initiation of LP in the NADPH-dependentmicrosomal system does not appear to involve either super-oxide or hydrogen peroxide since neither SOD nor cata-lase can inhibit it On the other hand reduced iron playsan important role in both the initiation and propaga-tion of NADPH-dependent microsomal lipid peroxidation(Hochstein and Ernster [154] and Repetto et al [111])
Many DHPs possess inhibitory activity not only towardsAsA-dependent LP in mitochondria but also towardsNADPH-dependent LP as shown in isolated rat liver micro-somes (Velena et al [112]) This means that these compoundsinteract with the shared parts (nonenzymatic and enzymatic)of LP pathways
Microcalorimetry and fluorescent probes procedureswere used for studying the interaction of alpha-tocopheroland 14-DHPs with endoplasmic reticulum membranes andmodel systems human serum albumin and phospholipidbilayers [155] Modification of microviscosity of the endo-plasmatic reticular membranes depends on localization ofantioxidants within the protein structures or phospholipidphase Increase of membrane structuralization under theinfluence of 14-DHPs blocked their antioxidant action inspontaneous and induced lipid peroxidation
Inhibition of rat heart and liver microsomal lipid perox-idation by nifedipine was observed [156] while Goncalves etal [157] found antioxidant effect of calcium antagonists onmicrosomal membranes isolated from different brain areas
Nitroaryl-14-DHPs are both calcium channel antagonistsand antioxidant agents (Letelier et al [158 159]) commonlyused for treatment of cardiovascular diseases These drugsmust be metabolized through cytochrome P450 oxidativesystem (NADPH-cytochrome P450 reductase) mainly local-ized in the hepatic endoplasmic reticulum Several lipophilicdrugs generate OS while being metabolized by this cellularsystem Thus DHP antioxidant properties may prevent the
OS associated with hepatic biotransformation of drugs Var-ious commercial and new nitro-phenyl-DHPs were studiedagainst LP using rat liver microsomes under oxidative stress[159]
Incubation of rat liver microsomes with the 41015840-nitro-4-phenyl-14-DHP compounds (26-dimethyl-4-(41015840-nitro-phenyl)-14-dihydropyridin-35-diethyl-dicarboxylate andN-ethyl-26-dimethyl-4-(41015840-nitrophenyl)-14-dihydropyri-din-35-dimethyl-dicarboxylate) results in an inhibitionof LP the UDPGT (UDP-glucuronyltransferase) oxidativeactivation and the microsomal thiol oxidation induced byFe3+ascorbate a generator system of ROS This effect wasalso produced by nitrofurantoin and naphthalene in thepresence of NADPH
Interestingly IC50
ofDHPs obtained frommicrosomal LPassays decreased to the same extent as the microsomal thiolsoxidation provoked by Fe3+ascorbate [159] Neverthelessthe AO effects of a nitrophenyl-DHP compound in whichhydrogen at position one of the DHP ring was replaced bythe ethyl groupwere significantlyweaker Authors speculatedthat DHPs can resemble NADH transferring one hydrogenatom of 4-position (Hminus) to anion superoxide and another ofthe 1-position (H+) by way of a cationic radical intermediateto generate pyridine derivatives and water [159]
The AO effects of various tested DHP derivatives (m- andp-NO
2phenyl as well as methyl or ethyl and isopropyl-DHP
35-dicarboxylate derivatives) were not significantly differentThe authors assumed that the -NH- group of the dihydropy-ridine ring could contribute both to the development ofthe calcium channel antagonism and to the antioxidativeproperties of DHPs [159]
Prevention of the membrane LP seemingly depends onthe concentration of potential antioxidants such as vitaminE or even 14-DHP in lipids However only the differencesin synthetic DHPs lipophilicity cannot explain significantvariations of DHPs concentration in microsomal membraneand cannot clarify the strength of their antioxidative activityThis work [159] has further demonstrated that 14-DHPsmay prevent the OS induced by biotransformation of somedrugs for example antibiotic nitrofurantoin Simultaneousadministration of DHPs and nitrofurantoinmay be beneficialin reducing nitrofurantoin side effects
While most of Ca antagonist 14-DHPs are metabolizedby CYP3A4 (Guengerich et al [160]) not all of them are goodinhibitors of its activity Thus nicardipine but not nifedipineand nitrendipine inhibits CYP3A4 in vitro [53] Interactionof different DHPs with various types of cytochrome P450 wasdescribed by Carosati et al [53] It was also reported thatDHP class calcium channel blockers reduce the antiplateleteffect of clopidogrel (Park et al [161])This implies themutualinteractions of both drugs with CYP3A4
(3) In Vivo Evaluation of nifedipine effects on Saccharomycescerevisiaewas recently published (Asma andReda [162]) Sur-prisingly nifedipine exercised a toxic effect on Saccharomycescerevisiae shown through measuring cellular proliferationrespiratory activity and the level of some biomarkers (CATand MDA)
16 Oxidative Medicine and Cellular Longevity
However majority of data obtained on various animalcells and tissues by other authors show the protective role ofDHPs against both LP and oxidative stress [113 163 164]
The AOA attributed to many 14-DHPs Ca2+ antag-onists and other compounds reflecting on catalytic LDLperoxidation (see Section 331 (2) and Section 35) shouldencourage their testing for treating cardiovascular diseasesandor alterations of lipid metabolism
The possibility that 14-DHP-based calcium antagonistsexert an antiatherosclerotic action (via inhibition of LDLoxidation and other mechanisms) has been proved by manyexperimental data [165] and several clinical trials Besidesantihypertensive effect nicardipine was shown to possessantioxidative and antielastase activity [165 166] These prop-erties may be useful for prevention of inflammatory reactionwhich is relevant for hypertension pathogenesis
14-DHPs administration inhibits LDL oxidation medi-ated by oxygen radicals leading to decreased carotid inti-mal media thickness and reduced progression of coronaryatherosclerosis [130] It additionally preserves Apo B-100integrity against ROS Of importance antiatherogenic mech-anisms differ between animals and humans (primarily inthe stage of conversion of aldehydes to carboxylic acids)(Parthasarathy et al [167])
For example furyl-DHP compound (FDP-1 diethyl 26-dimethyl-4-(furyl)-14-dihydropyridine-35-dicarboxylate)was shown to act as an antioxidant (decreasing MDA GOTand FFA release of ischemic myocardium and inhibiting Ca-ATPase of erythrocyte membranes) preventing against heartmyocardium ischemia-reperfusion injury and arrhythmiawhen applied (in rats) at 10mgkg (Liu et al [168])
Similarly antioxidative effects of azelnidipine andamlodipine prevented neuronal damage by CCBs aftertransient focal ischemia in rats (Lukic-Panin et al [169])
Allanore et al [170] found that both nifedipine andnicardipine significantly decrease the mean level of plasmamarkers for oxidative stress in patients suffering from sys-temic sclerosis
Antioxidants may be considered as promising neuropro-tective compounds Still while experimental data demon-strate neuroprotective effect in vitro and in animal mod-els clinical evidence is still unsatisfactory and insufficient[171]
(a) Role of Metabolism of DHPs in Their AOA Metabolicpathways and ldquobioavailabilityrdquo of the probable AOA com-pound determine antioxidant activity in vivo Antioxidantmetabolites may vary in stability and activity leading to twoopposite scenarios lack or presence of activity substantiallycontributing to the overall AOA [172] Metabolic biotransfor-mation of DHPs includes oxidation (heteroaromatization)side chain ester group cleavage (deesterification) and 4-substituent abstraction ao [160] None of the DHPs metabo-lites was shown to be more toxic than original reduced formof the compound The commonly detected metabolites ofthe DHPs do not seem to possess the AO activity (withsome exceptions as in the case of metabolites of nifedipineand its analogues including nitrosonifedipine [173 174]) (seefurther in Section 35) Due to DHPs intrinsic instability
achieving andmaintaining an adequate concentrationmay beproblematic both in vitro and in vivo
(b) Role of Concentration and Lipophilicity (MembraneWateror LipidWater Partition Coefficients) of DHPs inTheir Actionas AOs and Antiradical Compounds Antioxidative effects ofany antioxidant depend on its concentration at the site ofaction This parameter is hardly measurable especially intwo-phase systems representing one of obstacles in com-parison to AOA upon applying various compounds [172]It is often incorrectly assumed that the concentrations inthe aqueous solution and at the site of action are the sameHowever even when the concentration in the aqueous phasemay be well controlled the concentration at the site ofaction in the lipid matrix of the membranes might fluctuatebetween different test compounds depending on a differencein lipophilicity [175] The prevention of the membrane LPalso seems to be dependent on the DHP concentration in thelipidmatrix (Mason andTrumbore [46]) and its amphiphilic-ity For example AOA of diludine is associated with itslipophilicity and consequential ability to be incorporatedinto liposomes (Panasenko et al [176]) It was also foundthat diludine easily incorporates into the outer monolayer oferythrocyte membranes [176]
Membranebuffer partition coefficients (lambda) weredirectly measured in the sarcolemma and sarcoplasmicreticulum membranes for three CA DHPs The obtainedvalues were in a broad range between 5000 and 150000(Herbette et al [177])These drugs interact primarily with themembrane bilayer component but may also bind to proteinsboth nonreceptors and receptors The intrinsic forward rateconstants for DHP binding to sarcolemmal calcium channelreceptors were apparently not strongly dependent on theirmembrane partition coefficients For example nimodipine(lambda = 6300) had a forward rate constant of 68 plusmn 06 times106Ms whereas the forward rate constant for Bay P 8857
(lambda = 149000) was 14plusmn08times107Ms Since these DHPsare highly liposoluble model calculations for this bindingreaction demonstrated that these rates on lipid solubilitywould probably not be reflected in the experimental forwardrate constants In addition the intrinsic forward rate constantfor nimodipine binding to sarcolemmal calcium channelreceptors was found not to be linearly dependent on theviscosity of the buffer medium over a fivefold range The rateof drug nonspecific binding to nonreceptor protein present inhighly purified sarcoplasmic reticulum membranes appearsto be extremely fast at least 103 times faster than specificdrug binding to the receptor in the sarcolemma Authorsconcluded that partitioning into the lipid bilayer matrix ofthe sarcolemma could be a general property of CA DHPsand may be a prerequisite for their binding to sarcolemmalmembrane receptors (Herbette et al [177])
The binding of DHP calcium channel agonists and antag-onists (including those with AO properties) to receptors incardiac sarcolemmal membranes is a complex reaction thatmay involve an interaction with the lipid bilayer matrix ofthe sarcolemma (Herbette et al [178]) Belevitch et al [179]studied the binding of DHP CCBs (riodipine and nifedip-ine) and verapamil to model and biological membranes by
Oxidative Medicine and Cellular Longevity 17
fluorescence analysis The consistent location of Ca agonistBay K 8644 was determined to be within the region ofthe first few methylene segments of the fatty acyl chains ofthe membranes (Mason et al [180]) This position is nearto that observed for the DHP calcium channel antagonistsnimodipine and Bay P 8857
Themajority of studies onOSwere performedwithDHPswith various lipophilicity but only a few studies reportedamphiphilicity ofDHPderivatives AmphiphilicDHPderiva-tive K-2-11 reduced the cellular generation of ROS It alsorevealed complete reversal of multidrug resistance (MDR) ofthe resistant cells K-2-11 was more efficient than well-knownMDR inhibitor verapamil Cytotoxic effects of anticancerdrug doxorubicin were enhanced by K-2-11 in bothMDR andparental nonresistant cell line (Cindric et al [181]) K-2-11suppresses increase of ROS and consequentially prevents NF-120581B activation leading to decreased expression of MDR1 andincreased expression of antiapoptotic genes This signalingswitch is necessary for restoring the chemosensitivity ofcancer cells This phenomenon is characteristic both for14-DHPs [182] (18 novel asymmetrical DHPs bearing 3-pyridyl methyl carboxylate and alkyl carboxylate moietiesat C3 and C5 positions resp as well as nitrophenyl orheteroaromatic rings at C4) and for their oxidized formspyridine compounds (Zhou et al [183])
34 Dependence of AOA of DHPs on the Experimental SystemAO effect of DHPs depends on their structure and theexperimental system used (in vitromodel system subcellularorganelle and cells ex vivo and in vivo) Ideally for theevaluation of the profile and value of DHPs AO propertieseach compound should be tested in as many systems aspossible (Dubur et al [45])
Lipidomics studies have been traditionally explored forstudying AOA of DHPs Proteomics methods are less rep-resented and are mostly focused on the properties of DHPsrelated to scavenging of protein free radicals So far there areno studies on the role of DHPs in scavenging nitrosoperoxy-carbonate the reactive species formed out of peroxynitrite inthe presence of carbon dioxide Although it was shown thatalbumin binds diludine no studies revealed the relevance ofthis effect for the AOA of diludine
There are findings showing that dihydropyridine calciumantagonists (DHPs CA) could indirectly play a beneficialprotective role during development of atherosclerosisNamely Berkels et al [184] have studied antioxidativeproperties of four substances the DHP prototype CAnifedipine the long-acting CA lacidipine the DHP calciumchannel agonist BayK8644 and the bulkyDHPderivate BayO 5572 in three different models (1) in an in vitro superoxideanion generating system (hypoxanthinexanthine oxidase)for testing the ldquopurerdquo antioxidative effect (2) in an artificialmembrane preparation (dimyristoylphosphatidylcholine) formimicking a more physiological environment and (3) underconditions of stimulated ROS release (hyperglycemia) fromnative endothelial cells derived from porcine coronary arter-ies
The study also revealed the potential correlation betweenlipophilic and AO properties of DHPs In the first model
Bay K 8644 was significantly more effective in scavengingsuperoxide anions than lacidipine Bay O 5572 or nifedipine(micro- to millimolar concentration range) Addition of anartificial membrane preparation resulted in an enhancedAO effect with lacidipine being the most effective DHP inquenching radicals (low micromolar concentration range)In the third model mimicking hyperglycemia (30mmolL)nifedipine was significantly more potent antioxidant (ther-apeutical nanomolar concentration range) than the otherDHPs Calculated lipophilicity of these four substances(lacidipine gt Bay O 5572 gt Bay K 8644 gt nifedipine) waspositively correlated with antioxidative potential only in thesecond experimental model It has been concluded that AOproperties of DHP substances need to be tested in variousmodels for demonstrating that nifedipine exhibits ROS-quenching properties in a therapeutic concentration range[184]
341 AOA of DHPs in Isolated Cells and Cell Cultures(Comparison with Other Simplest Systems) Although DHPspossess neuromodulatory andor antimutagenic propertiesthe mechanisms of action related to these phenomena arenot entirely elucidated Borovic et al [185] have studied 14-dihydroisonicotinic acid (14-DHINA) derivatives of 14-DHP water-soluble analogues of a well-known AO diludine(diethone) 26-dimethyl-35-diethoxycarbonyl-14-dihydro-isonicotinic acid sodium 2-(26-dimethyl-35-diethoxycar-bonyl-14-dihydropyridine-4-carboxamido)glutamate gluta-pyrone and sodium 2-(26-dimethyl-35-diethoxycarbonyl-14-dihydropyridine-4-carboxamido)ethane-sulphate tauro-pyrone as AO and bioprotectors (Figure 4)
14-DHINArsquos activities were studied in comparison toTrolox by NN-diphenyl-N1015840-picrylhydrazyl (DPPH∙) deoxy-ribose degradation ABTS∙ radical scavenging and AOA(antioxidative capacity method) assays copper-induced LPof cultured rat liver cells (MDA determination by HPLCand 4-hydroxynonenal-protein conjugates by dot-blot) 3H-thymidine incorporation and trypan blue assay for liver cellsgrowth and viability Ic decreased the amount of 4-HNE-protein adducts In all assays Ia was the most potent AOable to completely abolish copper induced LP of liver cellswhile Ic only slightly decreased it Thus AOA is importantactivity principle of Ia which was even superior to Trolox intreated cell cultures Ia (and its analogues) are easily oxidizedin the Fenton system (Rubene et al [186]) exerting ARA too
35 Peculiarities Related to Antioxidative and AntiradicalActivity of Some 14-DHPs Ca Antagonists Nine commer-cialized structurally and functionally different DHPs CAwill be discussed further Their common feature is ability toprevent OS This also counts for some of their metabolitesas already discussed The comparative effects of some DHPsCA on oxidative stress-induced modification of LDL werealready reviewed in Section 331 (2)-(a) AOA of CA DHPswas discussed in Sections 331 (2)-(b) and 331 (2)-(c)
351 Nifedipine and Its Close Analogues Nifedipine vera-pamil and antiarrhythmic-antihypoxic drug stobadin wereshown to depress lipid peroxidation of phosphatidylcholine
18 Oxidative Medicine and Cellular Longevity
NH
COOH
NH
COONa
Glutapyrone
NH
Gammapyrone
NH
C 2H5OOC COOC2H5
Tauropyrone
14-DHINA
H3C H3C
H3C
H3CCH3 CH3
CH3
CH3
COOC2H5COOC2H5
COOC2H5 C2H5OOCC2H5OOCC2H5OOC
CONHCH(CH2)2COONa CONH(CH2)3COONa
CONH(CH2)2SO3Na
Figure 4 Derivatives of 14-dihydroisonicotinic acid (14-DHINA)
liposomes (Ondrias et al [187]) However data obtained insome other experimental systems are conflicting
In an in vitromodel of sarcolemmal membrane lipid per-oxidation three calcium blockers (nifedipine verapamil anddiltiazem) exhibited concentration-dependent (10ndash400 120583M)inhibitory effects [188 189] Nifedipine the most effectivecalcium blocker was more than two-fold potent compared topropranolol achieving significant effect at 10 120583M Nifedipineprotective role on LP using reduced glutathione as modelmarker was recently described (Ray et al [190]) Antiper-oxidative properties of CA nifedipine and its analogueswere explored in different systemspathogenic processesatherogenesis (Henry [165]) brain focal ischemia (Yamatoet al [191]) nephroprotection related to cyclosporine intake(Chander and Chopra [192]) and hepatoprotection relatedto intake of diethyldithiocarbamate (Gaafa et al [193])Recent data suggest that nifedipine action as protector forendothelial cells proceeds independently from its CA proper-ties
The absence of antioxidant effects of nifedipine anddiltiazemonmyocardialmembrane lipid peroxidation oppo-site to nisoldipine and propranolol was also described[194] Nisoldipine and propranolol were shown to havea concentration-dependent antiperoxidant effect with IC
50
values of 282 and 501 120583M respectively Finally nisol-dipine appeared to possess dual antiperoxidant mecha-nisms involving both preventive and chain-breaking proper-ties
These findings were confirmed in some other studiesincluding reports on the lack of antioxidative activity ofnifedipine and nicardipine even at 500120583M concentrationin heart membrane lipid peroxidation tests [134] SimilarlyROS formation in bovine aorta smooth muscle cells was notaffected by addition of amlodipine nimodipine and nife-dipine [123]
(1) Metabolites of Nifedipine and Its Analogues as Antioxidantsand Regulators of OS Antioxidant activity of nifedipine35-dimethoxycarbonyl-26-dimethyl-4-(2-nitrophenyl)-14-dihydropyridine was originally studied in vitro by Kirule etal [195] and Tirzit et al [196] According to the kinetic dataof peroxide accumulation and the ESR spectra (inhibition ofthe autoxidation of methyl oleate in presence of nifedipine)AO action was exerted by the formation of nitroso analogueof the oxidized nifedipine nitroso nifedipine 26-dimethyl-4-(2-nitrosophenyl)-35-pyridine dicarboxylate (NO-NIF)This nitroso aromatic derivative can form nitroxyl radicalsexhibiting remarkable AOA in the presence of unsaturatedfatty acids and lipids [196]
The primary species of free radicals that have beenobtained and identified were ion radicals of the nitrophenyltype (Ogle et al [76]) Such a mechanism coincides withmechanisms proposed afterwards by Nunez-Vergara et al[96] Lopez-Alarcon et al [103] Valenzuela et al [104]Fukuhara et al [174] and Yanez et al [197]
There are also data showing that nitroso compounds mayinhibit LP by direct radical trapping and subsequent forma-tion of stable nitroxide radicals It was further found that thereactivity between the synthesized 14-DHP derivatives withalkylperoxyl radicals involves electron transfer reactionsThisis documented by the presence of pyridine as a final productof the reaction and complete oxidation of the nitroso groupin the case of the nitrosoaryl 14-dihydropyridine derivatives(Valenzuela et al [104]) Tested compounds reacted fastertoward alkylperoxyl radicals and ABTS radical cation thanalkyl ones (Lopez-Alarcon et al [103])
Nitrosonifedipine a photodegradation product of nifedi-pine significantly recovers cellular damage induced by tumornecrosis factor-alpha It also prevents toxic effects of cumeneperoxide which hampers integrity of cell membranes throughoxidative stress Its positive effects are equal to Trolox-C
Oxidative Medicine and Cellular Longevity 19
As a result nitrosonifedipine was already a long time agoclaimed as a candidate for a new class of antioxidative drugs(Kirule et al [195]) cellular protectors against oxidative stressin glomerular endothelial cells [174]
Moreover Misik et al [198] Ondrias et al [199] andStasko et al [200] studied AOA of nifedipine and its oxidizednitroso analogue NO-NIF prevents the progression of type2 diabetic nephropathy associated with endothelial dysfunc-tion through selective AO effects (Ishizawa et al [201]) NO-NIF administration reduces albuminuria and proteinuriaas well as glomerular expansion without affecting glucosemetabolism or systolic blood pressure NO-NIF also sup-presses renal and systemic OS and decreases the expressionof intercellular adhesion molecule-1 (ICAM-1) a marker ofendothelial cell injury in the glomeruli of the KKAy miceSimilar effects were achieved in endothelial nitric oxide syn-thase (eNOS) knockout mice Moreover NO-NIF suppressesurinary angiotensinogen (AGT) excretion and intrarenalAGT protein expression in proximal tubular cells in theKKAy mice On the other hand hyperglycemia-inducedmitochondrial superoxide production was not attenuated byNO-NIF in cultured endothelial cells
Fujii and Berliner found EPR evidence for free radicaladducts of nifedipine in vivo [202] The nature of these rad-icals was surmised by comparing the reaction of illuminatednitrosonifedipine with polyunsaturated fatty acids Surpris-ingly identical radical spectra were detected from excisedliver doped with nonilluminated nifedipine suggesting thatthis drug can be enzymatically converted in vivo to its nitrosoanalogue without the requirement for illumination This isone of the first reports of in vivo EPR evidence for a class ofunsaturated fatty acid radical conjugates resulting from thenormal metabolism of a common drug
Dıaz-Araya et al [173] studied some 4-nitrophenyl-DHPson Fe3+ initiated LP in rat brain slices LP as measuredby MDA formation was inhibited by all the tested nitro-aryl derivatives of 14-DHP over a wide range of concen-trations On the basis of both time course and IC
50experi-
ments the tentative order of AOA on rat brain slices wasnicardipine gt nisoldipine gt (RSSR)-furnidipine gt (RRSS)-furnidipine gt nitrendipine gt nimodipine gt nifedipine14-DHP derivatives that lack a nitro group in the mole-cule (isradipine and amlodipine) also inhibited LP in ratbrain slices but at higher concentrations than that of nitro-substituted derivatives All tested compounds reduced andoxidized nitrosoaryl derivatives (26-dimethyl-4-(2-nitro-sophenyl)-35-pyridinedicarboxylic acid dimethyl ester (pho-tooxidation product of nifedipine ndash NTP) ao) and weremore potent inhibitors of LP than their parent molecules(Valenzuela et al [104])
The electrooxidation process of 4-nitrosoaromatic DHPsis a strongly pH-dependent (two-electron two-proton mech-anism) ECEC type of mechanism that is the sequenceeminusH+eminusH+ at pH gt 85 ECCE mechanism (eminusH+H+eminus)at pH lt 85 dominates Reduction reaction of nitroso groupis as follows R-NO + 2eminus + 2H+ rarr RNHOH (Bollo et al[203])
352 Lacidipine It is a generic DHP type antihypertensiveCA 35-diethyl 4-2-[(1E)-3-(tert-butoxy)-3-oxoprop-1-en-1-yl]phenyl-26-dimethyl-14-dihydropyridine-35-dicarboxy-late
Ursini [204] described redox behaviour of lacidipine andshowed its tissue protective features Cristofori et al studiedantiatherosclerotic activity in addition to lacidipinersquos CAand AO properties [205] Lacidipine reduced the extent ofatherosclerotic area in hypercholesterolemic apoE-deficientmice (these mice show widespread vascular lesions whichclosely resemble the inflammatory fibrous plaques seen inhumans in atherosclerosis) The reduction may be associatedwith the capacity of the drug to maintain endothelial NOlevels at concentrations useful to protect against vasculardamage This work suggested that DHPs modulate vascularrelaxation via increased release of NO
Herbette et al [178] remarked optimal hydrophobicity oflacidipine due to cinnamic acid substituent so membraneinteractions and facilitation of the treatment of atherosclero-sis could proceed (see also Section 331 (2)-(a))
353 Amlodipine Amlodipine (Norvasc) (RS)-3-ethyl5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-14-dihydropyridine-35-dicarboxylate (AML) hasan antioxidant effect on vessels in vitro and is a 3rd genera-tion of charged dihydropyridine CCB that is widely used forthe treatment of hypertensive patients
Amlodipine was shown to have the highest affinity(amlodipine gt verapamil ≫ diltiazem) for the membranebilayer (119870
119901= 104) It produced the significant changes in
membrane thermodynamic properties including a reductionin the thermal phase transition temperature (minus11) enthalpy(minus14) and cooperative unit size (minus59) relative to thecontrol phosphatidylcholine liposomes (Mason et al [49])
Amlodipine AOA is related to its reductant nature orhydrogen donor properties respectively Its ability for donat-ing protons and electrons to the lipid peroxide moleculesblocks the LP process
Amlodipine and even its enantiomers (Zhang et al [206])act as ROS andNOS effectors in several model systems of OSAntioxidant properties of amlodipine were recently reviewedby Vitolina et al [32] Both in vitro and in vivo studiesof amlodipine AO properties revealed inhibition of lipidsoxidative damage primarily those associated with cellularmembranes and lipoprotein particles (LDL) (Mason et al[50])
Under controlled experimental conditions in vitro amlo-dipine showed AOA and ARA by inhibition of lipid peroxideformation and trapping ROS Its scavenging activity forhydroxyl and peroxyl radicals at concentrations as low as100 nmolL (which is remarkably less compared to the classi-cal antioxidants GSH uric acid and Trolox) was shown to beindependent of the calcium channel modulation (Franzoni etal [207])
AML showed efficiency as scavenger of peroxyl radicals(TOSC assay 5945 plusmn 544 unitsmg) significantly stronger(gt50 119875 lt 0001) than GSH (2733plusmn 636 unitsmg) and 70weaker (119875 lt 00001) than uric acid (18144 plusmn 696 unitsmg)and Trolox (17522 plusmn 734 unitsmg)
20 Oxidative Medicine and Cellular Longevity
Of interest the scavenging capacity of AML towardshydroxyl radicals (1455 plusmn 154 unitsmg) was 320 higher(119875 lt 000001) than that of GSH (358 plusmn 112 unitsmg) 20higher than that of uric acid (1198plusmn121 unitsmg) and 100higher than that of Trolox (759 plusmn 143 unitsmg)
Amlodipine was shown to increase enzyme activity ofparaoxonase (PON) and glutathione peroxidase (GSH-Px)However it also decreases glutathione reductase (GSSG-R)activity and diminishes the concentration of the endogenousantioxidant 120572-tocopherol (vitamin E) Moreover AML in aconcentration of 2 ngmL decreased the content of malonicdialdehyde and activity of superoxide dismutase in the blood(Gatsura [208])
Verapamil and amlodipine produced a potent anti-ischemic effect and reduced area of myocardial infarction inrats The observed changes were accompanied by inhibitionof LP In contrast to verapamil in vitro application of AML ina dose of 50 ngmL decreased hemoglobin affinity for oxygenWhen present in a concentration of 2 ngmLAMDdecreasedthe content of MDA and activity of SOD in the blood
On the other hand amlodipine shows no activity relatedto inhibition of macrophage superoxide release and cellmigration which occurs as a consequence of decreasedTNF120572induced O
2
∙ releaseAmlodipine-induced reduction of OS in the brain is
associated with sympathoinhibitory effects in stroke-pronespontaneously hypertensive rats (SHRSP) (Hirooka et al[209]) Antihypertensive treatment with amlodipine reducedOS in all examined areas of the brain and decreased bloodpressure without a reflex increase in sympathetic nerveactivity Nicardipine another CA DHP surprisingly wassignificantly less active than amlodipine
354 Lercanidipine Tomlinson and Benzie reported AOeffect of lercanidipine [210] which is well known as anti-hypertensive drug Zanidip 2[(33-diphenylpropyl)(methyl)-amino]-11-dimethylethyl methyl 26-dimethyl-4-(3-nitro-phenyl)-14-dihydropyridine-35-dicarboxylate Compara-tive data about this drug AOA were presented in parts of thispaper about other individual CA DHPs and in the part aboutthe ex vivo DHPs effects on LDL
355 Nimodipine Nimodipine (ND) commercially knownas Nimotop is 3-(2-methoxyethyl) 5-propan-2-yl 26-dim-ethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxy-late It is centrally active CA
Treatment with glutathione blocked andwith nimodipineattenuated neuronal cell death caused by prolonged exposureof cell culture to 4-HNE (Faraqui [211])
Nascimento et al [212] found AO effect of nimodipine inyoung rats after pilocarpine- (PIL-) induced (in 400mgkg)seizures The PIL administration increased the striatal cata-lase (CAT) activity The administration of ND 30mgkg30min before PIL preserved normal value of CAT activityOn the other hand no difference was detected in the animalstreated with lower dose 10mgkg These results confirmthe neuroprotectiveantiepileptic effect of ND in young ratssuggesting that this drug acts positively on lipid peroxidation
(in both doses) Nimodipine cannot induce these effects viablockade of Ca2+ channel
Ismailoglu et al [213] studied the therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjury These beneficial effects in rats after cerebral corticalinjury seemed to be related to AOA of nimodipine
356 Benidipine Licensed in Japan and South Asia as CA(CCB) benidipine possesses AO properties Chemically it is5-methyl 3-[(3R)-1-(phenylmethyl)piperidin-3-yl] 26-dim-ethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxy-late (or its hydrochloride (4R)-rel-35-pyridinedicarboxylicacid 14-dihydro-26-dimethyl-4-(3-nitrophenyl)- 3-methyl5-[(3R)-1-(phenylmethyl)-3-piperidinyl] ester hydrochloride(1 1))
Benidipine influences processes connected with OS inseveral ways It prevents lysophosphatidylcholine- (lysoPC)-induced injury and ROS production in human aorticendothelial cells (HAECs) (Matsubara and Hasegawa [214])Matsubara et al [215] explained this effect based on stimula-tion of nitric oxide release
LysoPC is a component of oxidized low-density lipopro-teins (oxLDLs) which plays an important role in the patho-genesis of atherosclerosis Pretreatmentwith benidipine (03ndash3 120583molL) for 24 h protected against lysoPC-induced cyto-toxicity in the HAECs through inhibition of both lysoPC-stimulated ROS production and caspase-37-like activationwith a similar potency Since caspase-37 is involved inexecuting the apoptotic process the reduction of the activityof this enzyme by benidipine may explain the antiapoptoticeffect of the drug However benidipine did not suppresslysoPC-induced phosphorylation of mitogen-activated pro-tein kinases and Ca2+ influx in HAECs These results suggestthat the antioxidant properties of benidipine may be respon-sible for its ability to inhibit ROS production a possiblereason for reduced activation of caspase-37 In conclusionbenidipine suppresses lysoPC-induced endothelial dysfunc-tion through inhibition of ROS production which is due atleast in part to its antioxidant effect and not through theinhibition of L-type voltage-dependent calcium channels
Matsubara and Hasegawa [216] examined the effectsof benidipine on cytokine-induced expression of adhesionmolecules and chemokines (chemoattractants) which areimportant for the adhesion of monocytes to endotheliumPretreatment of HAECs with benidipine (03ndash10 120583molL)for 24 h significantly suppressed cytokine-induced vascularcell adhesion molecule-1 (VCAM-1) and intracellular celladhesion molecule-1 (ICAM-1) mRNA and protein expres-sion resulting in reduced adhesion of THP-1 monocytesBenidipine also suppressed induction of monocyte chemoat-tractant protein-1 (MCP-1) and interleukin-8 Benidipinealso inhibited redox-sensitive transcriptional nuclear factor-120581B (NF-120581B) pathway as determined by Western blotting ofinhibitory 120581B (I120581B) phosphorylation and luciferase reporterassay Results of analysis using optical isomers of benidip-ine and antioxidants suggest that these inhibitory effectswere dependent on pharmacological effects other than Ca2+antagonism Benidipine may thus have anti-inflammatoryproperties and benefits for the treatment of atherosclerosis
Oxidative Medicine and Cellular Longevity 21
Benidipine was also shown to inhibit ROS production inpolymorphonuclear leukocytes and oxidative stress in salt-loaded stroke-prone spontaneously hypertensive rats (Mat-subara et al [217])
It should be mentioned that other DHPs also haveendothelial AO actions [218]
357 Azelnidipine (AZL) Azelnidipine 3-[1-[di(phen-yl)methyl]azetidin-3-yl] 5-propan-2-yl 2-amino-6-methyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate(AZL) CAS number 123524-52-7 is commercially available4-nitroaryl-DHP type calcium antagonist with long-actingantihypertensive action (long-acting CA (CCB)) and a lowreported incidence of tachycardia It additionally possessesbeneficial effects in OS and diabetic conditions
Azelnidipine prevents cardiac dysfunction in strepto-zotocin-diabetic rats by reducing intracellular calcium accu-mulation (altering intracellular Ca2+ handling proteins) OSand apoptosis (Kain et al [219]) AZL can reduce the superox-ide production It exerts its protective effects by targeting theNADPH oxidase and mitochondrial redox enzymes AZL-treated diabetic rats express enhanced level of bcl-2 in thelysates of heart muscle indicating that AZL plays protectiverole in cardiac apoptosis
It has been previously observed that azelnidipine inhibitstumor necrosis factor-alpha-induced endothelial cell (EC)oxidative stress through its AO properties (Nakamura etal [220]) Azelnidipine but not nitrendipine completelyinhibits the Ang II-induced ROS generation in ECs (Matsuiet al [221])
Furthermore azelnidipine but not nitrendipine wasfound to partially restore decreased pigment epithelium-derived factor (PEDF) mRNA levels in Ang II-exposed ECsThis study suggests that AZL influence depends on its antiox-idative properties Authors concluded that upregulation ofPEDF by azelnidipine may become a therapeutic targetfor the treatment of diabetic retinopathy associated withhypertension
Antihypertensive agents with AO effects are potentiallyuseful for diabetic patients with hypertension While DHPtypeCAare among themost frequently used antihypertensivedrugs azelnidipine has been reported to have a unique AOeffect in vitro and in vivo in experimental animals (Ohmuraet al [222]) In hypertensive diabetic patients azelnidipinetreatment for 12 weeks induced a more significant decreasein erythrocyte LOOH level than amlodipine although thevalues related to blood pressure during each treatmentremained comparable These data confirm the usefulness ofLOOH level in erythrocyte membrane as a marker of OS invivo and indicate that azelnidipine has a unique antioxidativeproperty in humans
Daikuhara et al [223] reported the results of the OLCAstudy based on combination of (1) olmesartan and a calciumchannel blocker (azelnidipine) or (2) candesartan and a CCBamlodipine in two groups of diabetic hypertensive patientsPatients treated with the first combination presented highlypersistent early morning antihypertensive effect and strongerdecrease in heart rate fasting blood glucose andHbA1c levels
and microalbuminuria when compared to patients treatedwith the combination (2) Because diabetes is associated withsevere chronic OS the observed results might be at least in apart due to the AOA of azelnidipine
In favor of this are findings of Abe et al [224] who foundadditive antioxidative effects of azelnidipine on angiotensinreceptor blocker olmesartan treatment for type 2 diabeticpatients with albuminuria
Similarly the AOA of thiazolidinediones (insulin sensi-tizer) and their effect on cardiovascular function in type 2diabetic model rats and also those of some DHPs (nifedipineamlodipine or AZL commonly used antianginal and anti-hypertensive agents) in cultured human endothelial cells LPwere examined (Mizushige [225]) The AOA was evaluatedby measuring 8-iso-prostaglandine F
2120572concentration and
azelnidipine exhibited potent AOAInsulin (INS) resistance combined with hyperinsuline-
mia is involved in the generation of OS A relation-ship exists between increased production of ROS and thediverse pathogenic mechanisms involved in diabetic vascularcomplications including nephropathy Manabe et al [226]revealed that high doses of INS augmented mesangial cellproliferation through generation of intracellular ROS andactivation of redox signaling pathways Cell proliferation wasincreased in a dose-dependent manner by high doses of INS(01ndash10 120583M) but was inhibited by 01120583M AZL Namely theINS-increased phosphorylation of mitogen activated proteinkinaseextracellular signal-regulated kinase 12 (MAPKERK12) was inhibited by 01 120583MAZL The same AZL concen-tration blocked intracellular ROS production more effec-tively than 01 120583M nifedipine The NADPH oxidase inhibitorapocynin (001ndash01120583M) prevented INS-induced mesangialcell proliferation So azelnidipine inhibits insulin-inducedmesangial cell proliferation by inhibiting the productionof ROS Therefore azelnidipine may have the potential toprotect against the onset of diabetic nephropathy and slowits progression
Azelnidipine inhibited H2O2-induced cell death in
neonatal rat cardiomyocytes (Koyama et al [227]) Azelnidip-ine and nifedipine did not affect theH
2O2-induced activation
of extracellular signal-regulated protein kinases (ERK) andp38 MAPK (mitogen-activated protein kinase) In contrastazelnidipine but not nifedipine inhibited H
2O2-induced c-
Jun NH2-terminal kinases (JNK) activation Authors con-
cluded that azelnidipine has inhibited theH2O2-induced JNK
activation and cardiac cell death Therefore azelnidipine mayhave cardioprotective effects against OS
A specific atheroprotection activity of azelnidipine relatesto inhibition of TNF-120572-induced activator protein-1 activa-tion and interleukin-8 expression in human umbilical veinendothelial cells (HUVEC) through suppression of NADPHoxidase-mediated reactive oxygen species generation (Naka-mura et al [220]) TNF-120572 could play a central role in patho-genesis of insulin resistance and accelerated atherosclerosis inthe metabolic syndrome The concentration of AZL found tobe effective in these in vitro experiments is within therapeuticrange As EC do not possess voltage-operated L-type calciumchannels it is suggested that the beneficial effects of azelni-dipine are not likely due to CA property but to its unique AO
22 Oxidative Medicine and Cellular Longevity
ability Furthermore it has been recently found that serumlevels of monocyte chemoattractant protein-1 a biomarkerfor subclinical atherosclerosis were significantly decreased bythe AZL treatment in patients with essential hypertension Inthis paper [220] authors hypothesize that due to its uniqueTNF-120572 signalmodulatory activity and antioxidative propertyazelnidipine may be a promising DHP for targeting diabetesand cardiovascular diseases in hypertensive patients withmetabolic syndrome
Shinomiya et al [228] evaluated its AOA in culturedhuman arterial EC under OS Azelnidipine has shown apotent antioxidative effect that could be of significant clinicalbenefit when combined with its long-lasting antihypertensiveaction and low incidence of tachycardia
Azelnidipine inhibited TGF-1205731 and angiotensin II- (AngII-) activated 1205721(I) collagen mRNA expression in hepaticstellate cells (HSCs) (Ohyama et al [229]) FurthermoreTGF-1205731- and Ang II-induced OS and TGF-1205731-induced p38and JNK phosphorylation were reduced inHSCs treated withAZL Azelnidipine significantly decreased inflammatory cellinfiltration profibrotic genes expression HSC activation LPoxidative DNA damage and fibrosis in liver of CCl
4- or
TAA-treated mice Finally AZL prevented decrease of theexpression of some AO enzymes and accelerated regressionof liver fibrosis in CCl
4-treated mice Hence the antifibrotic
mechanism of AZL against CCl4-induced liver fibrosis in
mice may have been due to an increased level of AO defenseAs azelnidipine is widely used in clinical practice withoutserious adverse effects it may provide an effective newstrategy for antifibrotic therapy
358 Manidipine Manidipine (2-[4-(diphenylmethyl)pip-erazin-1-yl]ethyl methyl 26-dimethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate) is a DHP CCB withreported nephroprotective properties Calo et al [230] stud-ied effect of manidipine on gene expression and proteinlevel of OS related proteins p22(phox) (human neutrophilcytochrome b light chain (CYBA)) and heme oxygenase-1HO-1 Relevance for antihypertensive effects was revealedThe study assessed the effect of manidipine on normalsubjectsrsquo monocyte gene and protein expression of OS relatedproteins such as p22phox a NADPH oxidase system subunitcritical in generating O
2
∙minus and HO-1 induced by and pro-tective against OS Manidipine was compared with the ACEinhibitor captopril and the CCB nifedipine in the presenceand in the absence of sodiumarsenite (NaAsO
2) as an inducer
of OS Monocyte p22phox (CYBA) mRNA production wasreduced by both manidipine and captopril while no changeswere induced by nifedipine Manidipine increased monocyteHO-1 mRNA production while nifedipine and captoprilshowed no effect The effects of manidipine on p22phoxand HO-1 gene expression in the presence of OS were alsoconfirmed at the protein level Thus manidipine seems tosuppress p22phox and to increase the HO-1 mRNA produc-tion and protein level The manidipine-induced increase ofHO-1 gene and protein expression seems to be a peculiareffect of this drug since it is not observed with captopriland nifedipine This effect together with the reduction of
p22phoxmRNAproduction could play a role in its protectivemechanism against OS
359 Mebudipine The protective effect of mebudipine (14-dihydro-26-dimethyl-4-(3-nitrophenyl)-35-pyridinedicar-boxylic acid 3-methyl-5-tert-butyl ester BAY-n-6391) wasrevealed on OS and LP (MDA decrease SOD GPX andcatalase increase) in myocardial ischemic-reperfusion injuryin male rats (Ghyasi et al [231])
There are articles about other commercial and experi-mental DHPs on OS but we have reviewed only the mostcommonly studied compounds Effects of other commercialCA DHPs on OS are also mentioned in several parts of thisreview
36 14-DHPs Ca Agonists andTheir AOA and ARA For themost popular calcium agonist DHP Bay K 8644 no reactionwith peroxyl radicals was registered (Toniolo et al [114])However interactionwith other compounds possessing AOAand ARA (quercetin) was found
Opposite to that AON-acetylcysteine (NAC) diminishedincrease in Ca2+ transient amplitude and cell shorteninginduced by ISO and forskolin whereas NAC had no effecton the (S)-(minus)-methyl-14-dihydro-26-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylatemdash(minus)-BayK 8644-induced increases (Andersson et al [232])
Increased vasoconstriction responses to Bay K 8644 (3 times10minus7ndash3times 10minus5M)were significantly decreased by pyridoindoleantioxidant stobadine treatment in diabetes (Ceylan-Isik etal [233])
The functional interaction between two L-type Ca2+channel activators quercetin and Bay K 8644 has beeninvestigated in vascular smooth muscle cells Biological ARAcompound quercetin at nutritionally meaningful concen-trations limited the responsiveness of vascular L-type Ca2+channels to the pharmacological stimulation operated by BayK 8644 These data contribute to a better understanding ofquercetin effects on experimental in vivo cardioprotection(Saponara et al [234]) Thus these findings indicated thatalthough Bay K 8644 does not exert potent and direct AOAyet acting as calcium agonist it may affect efficiency of AOsubstances and vice versa
Interaction of grapefruit juice (containing quercetin andits analogues) with DHPs CA diminished effectiveness of CAaction of DHPs (Sica [235])
37 Interpretations of the Mechanism(s) of RadicalScavenging and AOA by DHPs
371 Molecular Mechanism(s) of Radical Scavenging andAOA of DHPs in the Model Systems 35-Dicarbonyl-14-di-hydropyridine derivatives possess powerful bis-120573-carbony-lvinyl-amino conjugation and for that reason cannot be con-sidered as ordinary amino antioxidants The electron andorH donation from DHPs ensures their reductant role andresults in AOA and ARA Oxidation reaction from DHPsresults in production of corresponding heteroaromatic pyri-dine derivatives
Oxidative Medicine and Cellular Longevity 23
Detailed studies were made about substituent in DHPring positions 14- namely 4-unsubstituted- 4-substituted4-alkyl- 4-aryl- 4-alkylaryl- ao 26- 35- (diacetyl ordialkoxycarbonyl chain ao) electronic and steric effects onAOA and ARA of DHPs [44 45 51] see Sections 331and 35 The bell-shaped dependence of DHPs AOA onthe 35-dialkoxycarbonyl- chain length was observed [4445 107 109 112] with the maximum activity at C
2H5ndash
C4H9 Decrease of AOA and incorporation into liposomes for
DHPs with alkyl chains longer than R gt C4H9further were
clarified as probable tendency to self-aggregation of thesecompounds ([51] and citation number 245 therein) Electronacceptorelectron donor properties are relevant for expres-sion of AOA or ARA of 35-disubstituted DHPs 35-Diacyl-substituted and 35-dicarbanilido- and 35-dipyridylamido-substituted DHPs are more active as AOs as their 35-dicyano-substituted analogues which have electron acceptorproperties [186]
Dubur et al [89] observed overwhelming steric influenceof substituents in position 4 of the DHP ring Gaviraghiet al [163 164] proposed that AO activity of DHPs ispartly dependent on capacity of the 14-DHP ring to donateelectrons to the propagating radical (ROO∙ or RO∙) and toreduce it to a less reactive form The abstraction (donation)of electron andor H in the oxidation and LP reactionstakes place from all 35-dicarbonyl-14-DHP systems andresults in the formation of corresponding pyridine derivatives(Augustyniak et al [51]) The physicochemical mechanism ofARA and AOA of 14-DHP has been extensively studied anddiscussed (Mulder et al [236]) but precise mechanisms oftheir activity need further clarification
The reactivity of C-4 substituted 14-DHPs possessingeither secondary or tertiary nitrogen atom in the DHP ringtoward alkyl alkylperoxyl radicals and ABTS radical cationwas determined in aqueous media at pH 74 [103] Thesecompounds reacted faster toward alkylperoxyl radicals andABTS radical cation than alkyl ones N-Ethyl-substitutedDHPs showed the lowest reactivity
The 4-methyl substituted DHP was the most reac-tive compound in previously mentioned reactions (Lopez-Alarcon et al [103]) However it was less active (068versus 10) than Trolox-C DHPs having electron-donatingsubstituents (4-Me-DHP and p-MeO-Phe-DHP) showed thehighest kinetic rate constants toward ABTS radical cation p-nitro-Phe-DHP a compound with an electron-withdrawingsubstituent showed a lower kinetic rate constant and N-alkyl-DHP compounds show kinetic rate constants lowerthan the -NH-DHP
Hydrogen at the 1-position of the DHP ring was revealedaccording to the deuteriumkinetic isotope effect studies to beinvolved in the proposedARAmechanismThis fact ismostlynoticeable in the case of alkyl radicals N-Ethyl-substitutedDHPs show the lowest reactivity when compared to Troloxor nisoldipine In all cases the respective pyridine derivativewas detected as the main product of the reaction (Lopez-Alarcon et al [103]) Authors indicate that the kinetic rateconstants toward alkyl alkylperoxyl andABTS radical cationdepend on the nature of the substituents in the C-4 positionof DHP and the presence of the secondary amine group in the
dihydropyridine ring that is the presence of the hydrogen in1-position
Yanez et al [197] have studied the reactivity of 11derivatives of 14-DHPs (including commercial CA) withalkylperoxyl radicals and ABTS radical cation The tested14-DHPs were 83-fold more reactive towards alkylperoxylradicals than to the ABTS cation radical All commercial14-DHP type CCBs were weaker than Trolox-C The par-ticipation of the hydrogen atom in the 1-position appearsto be very relevant for exhibited reactivity Hantzsch ester(diludine)was again found to be themost active compound inthe reaction with alkylperoxyl radicals 23-fold more activethan Trolox The photodegradation product of nifedipine(nitrosophenyl derivative of pyridine) also showed a highactivity Kinetic rate constants for the reaction between 14-DHP compounds and alkylperoxyl radicals exhibited a fairlygood linear correlation with the oxidation peak potentialof DHP derivatives However the activity of tested 14-DHPs towards ABTS radical cation showed an independencebetween kinetic rate constants and oxidation peak potentials
Kirule et al [195] andTirzit et al [196] studiedmechanismof AOA of 4-nitrophenyl-14-DHPs nifedipine and its ana-logues involving formation of 4-(21015840-nitrosophenyl)-pyridinederivative (as active principle) as a result of intramolecularredox reaction using chemical electrochemical and bio-chemical approaches (see Sections 331 and 351)
Nunez-Vergara et al [237] reported the electrochemicaloxidation of C4-hydroxyphenyl-substituted 14-DHP deriva-tives The oxidation proceeds via formation of the unstabledihydropyridyl radical as confirmed by controlled-potentialelectrolysis (CPE) and ESR experiments This type of 14-DHPs has significant activity towards the radicals even whencompared with commercial 14-DHP drugs with well-knownantioxidant ability
It was observed that nicardipine preferentially targets RO∙radicals and is inactive against ROO∙ Lacidipine on theother hand is equally active towards both types of radicals(Gaviraghi et al [164]) The cytoprotective effect againstexposure to H
2O2was more significant for lacidipine (ID
50=
14 nM its log119875 = 54 membrane partition = 136000 assumesposition located 7 A near to the membrane center otherless lipophilic DHPs located 12ndash16 A far from the center)as compared to amlodipine nifedipine and nicardipine insmooth muscle cell culture (Gaviraghi et al [164]) Oxidativeeffect of H
2O2shifts the Ca channel toward an open state
Thus the redox property of CCBs DHPs may augment theirCCB properties
Oxidation of pharmacologically active Hantzsch 14-dihydropyridines was found by electrogenerated superoxideusing a voltammetric approach in DMSO solutions (Ortiz etal [238] and Ortiz et al [239]) Raghuvanshi and Singh [240]have also reported oxidative aromatization of these DHPsinduced by superoxide
Chemiluminescence (CL) was used in the studies ana-lyzing the antioxidant activity of 12 various 4-flavonil-14-dihydropyridine derivatives (Kruk et al [241]) on a chemicalsystem involving a superoxide radical anion These deriva-tives showed structural similarity to flavonoids with respectto the presence of rings A B and C The results obtained in
24 Oxidative Medicine and Cellular Longevity
this study indicate that the tested derivatives may catalyzeconversion of superoxide radicals through mimicking theactivity of superoxide dismutase by delivering H+ for reac-tion
O2
minus∙+O2
minus∙+ 2H+ 997888rarr H
2O2+1O2
(3)
The enhanced emission of the light in the presence oftested compounds was significant and related to stimulatedproduction ofH
2O2and 1O
2fromO
2
∙The latter specieswereremoved from the reactionmixture by the following sequenceof reactions
H+
O2
minus∙997888rarr HO
2
∙
HO2
∙+O2
∙minus997888rarr HO
2
minus+1O2
2HO2
∙997888rarr H
2O2+1O2
2 (1O2) 997888rarr (O
2)2+ h]lowast
(4)
or to take part in spontaneous dismutation of H2O2
2H2O2997888rarr 2H
2O + 1O
2(5)
The authors have offered an original concept of action for 4-flavonil-14-dihydropyridine derivatives unrelated to that ofO2
∙ radical-trapping chain-breaking antioxidants Insteadthey showed that these compounds act similar to superoxidedismutases converting O
2
∙ to H2O2 Hydrogen peroxide
is less toxic for cells than O2
∙ because it is predominantlyremoved by peroxidases and catalases Finally AO effect ofthese DHPs differed from those mediated by flavonoids witha catechol structure of ring B which are well-known 1O
2
quenchersMulder and collaborators came to similar conclusions
especially related to molecular mechanisms of antioxidativeactivity of DHPs [236]TheAOproperties of Hantzsch 14-di-hydropyridine esters and two dibenzo-14-dihydropyridines910-dihydroacridine (DHAC) and N-methyl-910-dihydro-acridine (N-Me-DHAC) have been explored by determin-ing the autoxidation of styrene or cumene at 30∘C Theseexperiments showed that Hantzsch esters are virtually inac-tive as chain-breaking antioxidants (CB-AOs) contrary tothe findings observed by Lopez-Alarcon et al [103] whoused CB-AOA in aqueous media at pH 74 Their reactivitytoward peroxyl radicals was shown to be some 5 orders ofmagnitude lower than that of the excellent CB-AO 22578-pentamethyl-6-hydroxy-chroman (PMHC)
DHAC was found to be sim10 times less reactive thanPMHC kinetic measurements using DHAC N-deuterio-DHAC and N-Me-DHAC pointing out the abstraction ofN-H hydrogen in DHAC by peroxyl radicals despite the factthat the calculated C-H bond dissociation enthalpy (BDE) inDHAC is about 11 kcalmol lower than the N-H BDE Therates of hydrogen atom abstraction by the 22-diphenyl-1-picrylhydrazyl radical (DPPH∙) have also been determined
for the same series of compounds The trends in the peroxyl∙and DPPH∙ rate constants were found to be similar [236]
Tirzit et al [242] have observed quenching of singletoxygen by DHPs This observation paved the ground forfurther research related to reactions of DHPs with hydroxylradicals (Tirzit et al [243]) singlet oxygen (Kazush etal [94]) and mechanisms of action A series of 14-DHPderivatives in NAD-H-Cu2+-H
2O2system inhibited forming
of the hydroxyl radical (HO∙) while 14-DHP derivativeswith electron donor substituents in the molecule were shownto be capable themselves of generating HO∙ in the presenceof Cu2+ and H
2O2 Rubene et al [186] also described
interaction of 14-DHP derivatives with Fentonrsquos reagentwhich produces hydroxyl radical (HO∙) Rate constants ofthe DHPs reaction (1st order) with HO∙ radical were highin the range 109 L times mol times secminus1 close to that of NADHcysteine and thiourea 35-Diacetyl- derivatives reacted fastercompared to 35-dialkoxycarbonyl- ones The reaction ratedecrease was observed in the case of substitution at position4 as compared to 4-unsubstituted DHPs Some DHPs havingelectron donor -COOminus groups in the 35- or 26- positionsof DHP ring reacted immediately (having rate constantshigher as 109 L times mol times secminus1) Rate constants with HO
2
∙
and O2
∙minus radicals were of lower degree Thus DHPs actingas oxygen radical scavengers could effectively inhibit ROSrelated reactions of LP initiation stage
Nifedipine and nitrendipine reactivity toward singletoxygen was also studied [244] Nifedipine was shown tobe a good scavenger of excited oxygen mainly via physicaldeactivation with values of the total rate constant rangingfrom 208 times 105Mminus1 sminus1 (in dioxane) to 930 times 105Mminus1 sminus1(in propylene carbonate)The less reactive pathway generateda photooxidation product For that reason a mechanisminvolving a perepoxide-like encounter complex in the firststep of the reaction path was proposed (see [244] Figures8 and 9 therein) The dependence was observed on solventmicroscopic parameters of the total rate constant for the reac-tion between singlet oxygen and 14-DHPs These findingsshow that nifedipine possesses stronger protective activity inbiological systems than nitrendipine
Density-functional-theory (DFT) calculations made byWang et al [245] confirmed the former experimental obser-vations that Hantzsch ester diludine is potent antioxi-dant with high H atom-donating ability and relatively lowprooxidant activity Possible reaction pathways for radicalsderived from 14-dihydropyridine and the resonance modesfor radical species were given [245]
Moreover two ethoxycarbonyl (EtOCO) substituentsat C(2) and C(6) should further enhance Hantzsch esterdiludine H-atom-donating ability due to resonance effectsHowever DHPs should be used in nonpolar rather than inpolar solvents since in the latter not H-atom but electrontransfer is preferred in the radical scavenging process [245]
Mulder et al [246] proposed that quantum-thermochem-ical calculations must be used with caution to indicate ldquoapromising lead antioxidantrdquo as they criticized the density-functional-theory (DFT) calculations made by Wang et al[245]
Oxidative Medicine and Cellular Longevity 25
372 Possible Mechanisms of DHPs ARA and AOA in the Bio-logical Systems Interaction with Other OSModifiers Some ofthese mechanisms were already described (Sections 331 (2)-(b) 331 (2)-(c) 331 (3)-(b) 35)
Enzymatic sources of ROSwith confirmed functional rolein hypertension are NADPH oxidase NO synthase (NOS)xanthine oxidase and cyclooxygenase Godfraind [3] hasreviewed AO effects and protective action of calcium channelblockers (CCBs) Yao et al [247] observed antioxidant effects(as inhibition of LP) for cardio- and neuroprotective CCBs(3ndash300 120583molL) including 7 DHPs in homogenates of ratbrain IC
50values (120583M) were as follows nifedipine (515) gt
barnidipine (586) gt benidipine (712) gt nicardipine (1293)gt amlodipine (1355) gt nilvadipine (1673) gt nitrendipine(2521) gt diltiazem (gt300) = verapamil (gt300) There arealso research articles describing the AO properties of CCBsthrough direct scavenging effect or through preservationof the endogenous SOD activity These findings indicatethat CCBs may also act by reducing the production ofvasoconstrictors angiotensin and endothelin
When present in concentrations that can be achievedin plasma CCBs may inhibit LP formation [3] This AOactivity seems to be typical for high lipophilic CCBs becausetheir chemical structure facilitates proton-donating andresonance-stabilization mechanisms that quench the freeradical reaction Their insertion in the membrane nearpolyunsaturated fatty acids at relatively high concentrationspotentiates proton donation (or atomary H) to lipid peroxidemolecules thereby blocking the peroxidation process Theremaining unpaired free electron associated with the CCBmolecule can be stabilized in well-defined resonance struc-tures associated with the DHP ring (Mason et al [48])
The radical reaction (according to Godfraind [3]) thatdescribes the AO effects of a DHP CCBs is LOOlowast + DHPrarr LOOH + DHPlowast (where LOOlowast is lipid peroxide radical)which in general is reaction (7) of the LP reaction cascadeconsisting of sim10 reactions (Scheme 2) [89]
As the rate constants of in vitro interaction of 4-substituted DHPs with peroxyl radicals are three ordersof magnitude lower than that of the vitamin E derivativethese DHPs must be considered as weak AO (Ursini [204])However due to partition coefficient of DHPs in membranesand in case of specific binding high local concentration ofDHPs may be obtained
DHPs without CCB properties for instance Bay w 9798although structurally related to nifedipine inhibit TNF-120572-induced vascular cell adhesion molecule-1 expression inendothelial cells by suppressing reactive oxygen speciesgeneration [248]
Mitrega et al [249] have discovered that antiarrhythmicand hemodynamic effects of oxidized heteroaromatic DHPsoxy nifedipine oxy nimodipine oxy nitrendipine and oxynisoldipine suggest that CCB DHPs and their metabolitescould act at least in two ways targeting OS related eventsas reductants (see Section 351 (1)) andor bypassing OSrelatedmetabolic routes Authors postulated that contrary tocurrent belief NIF metabolites are pharmacologically activeATP sensitive potassium channels were mentioned as a tar-get
38 DHPs Anti- or Prooxidants Several substances (ascorbicacid being the most commonly studied) can serve either asantioxidants or as prooxidants depending on given condi-tions (Herbert [250]) Therefore Halliwell [251] has reporteddilemma related to polyphenols as possible antioxidantsand prooxidants causing experimental artifacts (about 25)by oxidation of antioxidant compounds in the cell culturemedia Nevertheless it is generally accepted opinion thatpolyphenols act as antioxidants in vivo Studies on DHPs alsoface such a dilemmaThe exact roles (anti- or prooxidative) ofany specific DHP depend on its structure appliedachievedconcentration and specificity of the targetexperimentaltesting system
This situation resembles the case of antioxidative effectsof tocopherol which depends on the fate of the secondaryradical as proposed by Winterbourn [252] The question wasldquoVitamin E - Pro- or Antioxidantrdquo
997888rarr chain termination of lipid peroxidation
(6)
Prooxidant
Toc∙ + Lipid-H 997888rarr Lipid∙ (in LDL particles) (7)
This example shows that generally speaking any AO mustfulfil several criteria to be considered as an effective com-pound physiologically
(i) It must be able to functionally interact with endoge-nous scavengers even at low concentrations
(ii) It must affect endogenous pathways of OS(iii) It should not have undesirable adverse effect(iv) It should manifest the antioxidant efficacy dependent
on the oxidant(v) It must discriminate among different strategies
needed for 1-electron and 2-electron processes(vi) Radical scavengers can be prooxidant unless linked to
a radical sink (Winterbourn [252])
According to these statements DHPs could be effective asAO under physiological conditions in vivo (Godfraind [3]and others [30 31 38]) and in vitro in various experimentalsystems (cell and tissue) (see Sections 33 34 35)
Hence calcium antagonists appeared to disrupt thefine balance between the production and scavenging ofROS Nifedipine verapamil and diltiazem were shown toinduce significant oxidative stress in the epididymal sperm(increased MDA and decreased catalase and superoxidedismutase activity) This may be the reason for the inductionof male infertility [253]
The dualism of 14-DHP effects has been recorded asinhibition or promotion of LP as quenching or initiating
26 Oxidative Medicine and Cellular Longevity
oxygen and nitrogen free radical chain reactions radiopro-tecting or radiosensitizing antagonizing or synergizing Ca2+in electromechanical coupling as well as in the membranestabilization or labilization
39 Could DHPs Be Involved in Antioxidative Stress Beforebeing applied in vivo the optimal dose and optimal timeintervals forDHPs applicationmust be knownNamely whileROS have been traditionally considered as toxic byproductsof aerobic metabolism we know nowadays that ROS may actas essential signaling molecules needed for the control ofmany different physiological processes Whether the role ofROS will be damaging protective or signaling depends onthe delicate equilibrium between time- and location-specificROS production and scavenging Accordingly the imbalanceof the increased AO potential so-called antioxidative stresscould be dangerous similar to chronic OS in particular incase of extended exposure Inappropriate interventions inthe oxidative homeostasis by excessive antioxidants especiallyin case of chronic exposure to antioxidants might havevery negative effects as was published in the ATBC studyshowing an increased cancer incidence in smokers treatedby excessive beta-carotene [254] Therefore overconsump-tion of any natural or synthetic AO including DHPs asdietary supplements or drugs must be avoided in order tosuppress oxidative damage and must not disrupt the well-integrated antioxidant defense network (Poljsak [255] andPoljsak and Milisav [256]) This is especially important whenadministrating lipid-soluble antioxidants that can be storedin biomembranes thus not only attenuating or preventing LPbut also affecting physiological effects of the natural antiox-idants in particular tocopherol The interrelationship withthe status of endogenous antioxidantsprooxidants should befollowed
DHPs primarily suppress the initiation stages of LPprocessThey do not entirely stop the LP propagation Actingsynergistically with tocopherol diludine may prevent patho-logical excess of ROS production within the lipid moiety ofthe cellular membranes and LDL However due to its lowsolubility and fast metabolism its concentration in the cellsis low For that reason it cannot cause antioxidative stresseven if used for an extended period of time Thus diludine(diethone) could be only a mild antioxidant it has potentialfor restoring the pool of natural antioxidants (as synergist of120572-tocopherol and polyphenols) in the cells
Moreover DHPs CA used for cardioprotection andvasodilatation as commercial drugs in low concentrationsare fast metabolized via CYP3A4 and for that reason theirapplication does not induce cellular AO stress [53 160]However Godfraind and Salomone [257] have postulated noevidence that allows recommending dietary supplementationwith antioxidants for the primary or secondary prevention ofcardiovascular disease
So far there are no reports on antioxidative stress causedby some DHPs diludine and its analogues Diludine andits analogues therefore could act as adaptogens supportinghormetic effects of mild oxidative stress These compoundsmay act as potential multisided modulators of Yin-Yang
cycles of redox and cell functions (the electroplasmic cycle)(Wagner et al [258])
4 Conclusions
14-Dihydropyridines (14-DHPs) have broad spectrum ofOS modulating activities DHPs have reducing and lipidperoxidation inhibitor properties act as reductants in simplechemical systems and stabilize various biological systems(LDL mitochondria microsomes cells and tissues) againstOS Examples and peculiarities and mechanisms of antiox-idant activity (AOA) and antiradical activity (ARA) as wellas stress-protective effect of DHPs including commercialcalcium antagonists (CA) were highlighted These activitiesdepend on various structural parameters related to DHPs(presence and character of substituents) lipophilicity anddepth of the incorporation in the biologicalmembranesTheyalso depend on the experimental model system for exploringthe lipid peroxidation or oxidative stress Stress-protectiveeffect of some metabolites of CA (nifedipine) is reviewedAlthough some DHPs including CA have prooxidant prop-erties (on epididymal sperm cells) they can generally beconsidered as potent antioxidants Therefore comparisonof the AOA and ARA of different DHPs (mutually andwith other AOs) was described in detail According to thedata presented the DHPs might be considered as bellwetheramong synthetic compounds targeting OS and as a kind ofpharmacological measure for respective field of organic andmedicinal chemistry
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
Authors from Latvian IOS acknowledge ESF 201300021DP1112013APIAVIAA011 and National Research Pro-gramme PUBLIC HEALTHBiomedicine of the Republicof Latvia for financial support administration of the Insti-tute for technical support and Rufus Smits PhD for con-sultations in English The support of Cooperation in Euro-pean System of Science and Technology (COST) Domain ofChemistry Molecular Sciences and Technologies (CMST)was of highest importance for preparation of this paper
[2] D J Triggle ldquo14-Dihydropyridines as calcium channel ligandsand privileged structuresrdquoCellular andMolecular Neurobiologyvol 23 no 3 pp 293ndash303 2003
[3] T Godfraind ldquoAntioxidant effects and the therapeutic modeof action of calcium channel blockers in hypertension andatherosclerosisrdquo Philosophical Transactions of the Royal SocietyB Biological Sciences vol 360 no 1464 pp 2259ndash2272 2005
[4] E Cadenas ldquoMitochondrial free radical production and cellsignalingrdquoMolecular Aspects of Medicine vol 25 no 1-2 pp 17ndash26 2004
[5] E Cadenas ldquoFree radicals oxidative stress and diseasesrdquo inLecture PSC 616 p 38 Missouri University of Science andTechnology Rolla Mo USA httpwwwcarnicominstituteorgarticlesenrique cadenaspdf
[6] K Rahman ldquoStudies on free radicals antioxidants and co-fac-torsrdquo Clinical Interventions in Aging vol 2 no 2 pp 219ndash2362007
[7] V Bocci and G Valacchi ldquoFree radicals and antioxidants howto reestablish redox homeostasis in chronic diseasesrdquo CurrentMedicinal Chemistry vol 20 no 27 pp 3397ndash3415 2013
[8] M Valko C J Rhodes J Moncol M Izakovic and M MazurldquoFree radicals metals and antioxidants in oxidative stress-induced cancerrdquo Chemico-Biological Interactions vol 160 no 1pp 1ndash40 2006
[9] G Bartosz ldquoReactive oxygen species destroyers or messen-gersrdquo Biochemical Pharmacology vol 77 no 8 pp 1303ndash13152009
[10] R Visconti and D Grieco ldquoNew insights on oxidative stress incancerrdquo Current Opinion in Drug Discovery and Developmentvol 12 no 2 pp 240ndash245 2009
[11] R N Kujundzic N Zarkovic and K G Troselj ldquoPyridinenucleotides in regulation of cell death and survival by redoxand non-redox reactionsrdquo Critical Reviews in Eukaryotic GeneExpression vol 24 no 4 pp 287ndash309 2014
[12] B Halliwell and J M C Gutteridge ldquoThe definition and mea-surement of antioxidants in biological systemsrdquo Free RadicalBiology and Medicine vol 18 no 1 pp 125ndash126 1995
[13] V D Kancheva and O T Kasaikina ldquoBio-antioxidantsmdashachemical base of their antioxidant activity and beneficial effect
on human healthrdquo Current Medicinal Chemistry vol 20 no 37pp 4784ndash4805 2013
[14] H V Panglossi Ed Frontiers in Antioxidants Research NovaScience Publishers New York NY USA 2006
[15] E B Burlakova E M Molochkina and G A NikiforovldquoHybrid antioxidantsrdquo Oxidation Communications vol 31 no4 pp 739ndash757 2008 httpmembraneustceducnpaperpdfHybrid20Antioxidantspdf
[16] A Bast and G R M M Haenen ldquoTen misconceptions aboutantioxidantsrdquo Trends in Pharmacological Sciences vol 34 no 8pp 430ndash436 2013
[17] E B Burlakova A V 0lesenko E M Molochkina N PPalmina and N G Khrapova Bioantioxidants for RadiationDamage and Malignant Growth Nauka Moscow Russia 1975(Russian)
[18] J Fang T Seki and H Maeda ldquoTherapeutic strategies by mod-ulating oxygen stress in cancer and inflammationrdquo AdvancedDrug Delivery Reviews vol 61 no 4 pp 290ndash302 2009
[19] M Valko D Leibfritz J Moncol M T D Cronin M Mazurand J Telser ldquoFree radicals and antioxidants in normal physi-ological functions and human diseaserdquo International Journal ofBiochemistry and Cell Biology vol 39 no 1 pp 44ndash84 2007
[20] M Jimenez-Del-Rio and C Velez-Pardo ldquoThe bad the goodand the ugly about oxidative stressrdquo Oxidative Medicine andCellular Longevity vol 2012 Article ID 163913 13 pages 2012
[21] C D Kamat S Gadal M Mhatre K S Williamson Q N Pyeand K Hensley ldquoAntioxidants in central nervous system dis-eases preclinical promise and translational challengesrdquo Journalof Alzheimerrsquos Disease vol 15 no 3 pp 473ndash493 2008
[22] A Pompella H Sies R Wacker et al ldquoThe use of totalantioxidant capacity as surrogate marker for food quality andits effect on health is to be discouragedrdquo Nutrition vol 30 no7-8 pp 791ndash793 2014
[23] Z Ye and H Song ldquoAntioxidant vitamins intake and the risk ofcoronary heart disease meta-analysis of cohort studiesrdquo Euro-pean Journal of Cardiovascular Prevention and Rehabilitationvol 15 no 1 pp 26ndash34 2008
[24] P Knekt J Ritz M A Pereira et al ldquoAntioxidant vitamins andcoronary heart disease risk a pooled analysis of 9 cohortsrdquoTheAmerican Journal of Clinical Nutrition vol 80 no 6 pp 1508ndash1520 2004
[25] A C Carr and M C M Vissers ldquoSynthetic or food-derivedvitamin Cmdashare they equally bioavailablerdquo Nutrients vol 5 no11 pp 4284ndash4304 2013
[26] R Tabrizchi ldquoEdaravoneMitsubishi-TokyordquoCurrentOpinion inInvestigational Drugs vol 1 no 3 pp 347ndash354 2000
[27] K Kikuchi S Tancharoen N Takeshige et al ldquoThe efficacy ofedaravone (radicut) a free radical scavenger for cardiovasculardiseaserdquo International Journal of Molecular Sciences vol 14 no7 pp 13909ndash13930 2013
[28] D Mauzerall and F H Westheimer ldquo1-Benzyldihydronicoti-namidemdasha model for reduced DPNrdquo Journal of the AmericanChemical Society vol 77 no 8 pp 2261ndash2264 1955 ChemicalAbstracts vol 50 Article ID 2588i 1956
[29] F Bossert and W Vater ldquo14-Dihydropyridinesmdasha basis fordeveloping new drugsrdquo Medicinal Research Reviews vol 9 no3 pp 291ndash324 1989
[30] G Swarnalatha G Prasanthi N Sirisha and CMadhusudhanaChetty ldquo14-Dihydropyridines a multtifunctional moleculemdash areviewrdquo International Journal of ChemTech Research vol 3 no1 pp 75ndash89 2011
28 Oxidative Medicine and Cellular Longevity
[31] M Cataldi and F Bruno ldquo14-Dihydropyridines the multiplepersonalities of a blockbuster drug familyrdquo Translational Medi-cine UniSa vol 4 no 2 pp 12ndash26 2012 httpwwwncbinlmnihgovpmcarticlesPMC3728803
[32] R Vitolina A Krauze G Duburs and A Velena ldquoAspects ofthe amlodipine pleiotropy in biochemistry pharmacology andclinicsrdquo International Journal of Pharmaceutical Sciences andResearch vol 3 no 5 pp 1215ndash1232 2012
[33] D Grover S N Mokale and M T Shete ldquoDihydropyridinea novel pharmacophorerdquo International Journal of Pharmaceu-tical Erudition vol 1 no 2 pp 16ndash29 2011 httppharmaeru-ditionorgContentPaper20111-RV-320Final2016-29pdf
[34] A M Vijesh A M Isloor S K Peethambar K N ShivanandaT Arulmoli and N A Isloor ldquoHantzsch reaction synthesis andcharacterization of somenew 14-dihydropyridine derivatives aspotent antimicrobial and antioxidant agentsrdquo European Journalof Medicinal Chemistry vol 46 no 11 pp 5591ndash5597 2011
[35] P Mehta and P Verma ldquoAntimicrobial activity of some deriva-tives of 14-dihydropyridinesrdquo Journal of Chemistry vol 2013Article ID 865128 4 pages 2013
[36] P Olejnıkova L Svorc D Olsovska et al ldquoAntimicrobialactivity of novel C2-substituted 14-dihydropyridine analoguesrdquoScientia Pharmaceutica vol 82 no 2 pp 221ndash232 2014
[37] S Sepehri H Perez Sanchez and A Fassihi ldquoHantzsch-typedihydropyridines and biginelli-type tetra-hydropyrimidinesa review of their chemotherapeutic activitiesrdquo Journal of Phar-macy amp Pharmaceutical Sciences vol 18 no 1 pp 1ndash52 2015httpsejournalslibraryualbertacaindexphpJPPSarticleview2383617863
[38] S A Khedkar and P B Auti ldquo14-Dihydropyridines a classof pharmacologically important moleculesrdquo Mini-Reviews inMedicinal Chemistry vol 14 no 3 pp 282ndash290 2014
[39] G D Tirzit and G Ya Duburs ldquo14-dihydropyridines as inhi-bitors of free-radical reactionsrdquo Chemistry of Heterocyclic Com-pounds vol 8 no 1 pp 126ndash127 1972 Translated from KhimiyaGeterotsiklicheskikh Soedinenii no1 pp 133ndash134 1972 (Rus-sian)
[40] I Bogeski R Kappl C Kummerow R Gulaboski M Hothand B A Niemeyer ldquoRedox regulation of calcium ion channelschemical and physiological aspectsrdquoCell Calcium vol 50 no 5pp 407ndash423 2011
[41] S A Giller G Y Dubur Y R Uldrikis et al ldquoDiludine [Themethod to obtain 35-dicarbonylderivatives of 26-dimethyl-14-dihydropyridines]rdquo Authors certificate of USSR no 3004651971 [Byull Izobret no13 p 95 1971] and following patentsPatent of England no 1294650 1973 Patent of France no2055458 1971 Patent of Japan no 702883 1973 Patent ofHolland no 149787 1976 Patent of Italy no 969022 1974 Patentof FRG no 2036403 1978 US Patent no 3883673 1975 USPatent no 3948924 1976
[42] S A Giller G Y Dubur Y R Uldrikis et al ldquoImprovementsin or relating to the stabilization of carotenerdquo GB Patent no1294650 1972
[43] S A Giller G Y Dubur Y R Uldrikis et al ldquoStabilization ofcarotenerdquo US Patent no 3883673 1975 Chemical Abstracts vol83 Article ID 95193 1975
[44] Yu A Zilber G Ya Dubur K K Kumsar and A Kh VelenaldquoThe effect of antioxidants on the peroxidation of bimole-cular phospholipid membranesrdquo Latvijas PSR ZA Vestis Izves-tia Akademii Nauk Latviyskoy SSR vol 6 pp 80ndash82 1971(Russian) translated from the original Russian Doc Accesion
No AD0771751 distributed by NTIS US Department of Com-merce httpwwwdticmildtictrfulltextu2771751pdf
[45] G Ya Dubur Yu A Zilbers A Kh Velena A O Kumerovaand G D Tirzitis ldquoMultistage study of regulation of peroxida-tion processes in biological membranes by antioxidants of 14-dihydropyridine grouprdquo Izvestiya Akademii Nauk LatviyskoySSR vol 336 no 7 pp 65ndash68 1975 (Russian)
[46] R P Mason and M W Trumbore ldquoDifferential membraneinteractions of calcium channel blockers Implications forantioxidant activityrdquo Biochemical Pharmacology vol 51 no 5pp 653ndash660 1996
[47] R P Mason M F Walter M W Trumbore E G Olmstead Jrand P E Mason ldquoMembrane antioxidant effects of the chargeddihydropyridine calcium antagonist amlodipinerdquo Journal ofMolecular and Cellular Cardiology vol 31 no 1 pp 275ndash2811999
[48] R PMason I T MakMW Trumbore and P EMason ldquoAnti-oxidant properties of calcium antagonists related to membranebiophysical interactionsrdquo American Journal of Cardiology vol84 no 4 pp 16ndash22 1999
[49] R PMasonMW Trumbore and P EMason ldquoMembrane bio-physical interaction of amlodipine and antioxidant propertiesrdquoDrugs vol 59 no 2 pp 9ndash16 2000 (French)
[50] R P Mason P Marche and T H Hintze ldquoNovel vascularbiology of third-generation L-type calcium channel antagonistsAncillary actions of amlodipinerdquo Arteriosclerosis Thrombosisand Vascular Biology vol 23 no 12 pp 2155ndash2163 2003
[51] A Augustyniak G Bartosz A Cipak et al ldquoNatural andsynthetic antioxidants an updated overviewrdquo Free RadicalResearch vol 44 no 10 pp 1216ndash1262 2010
[52] T Grune N Zarkovic and K Kostelidou ldquoLipid peroxidationresearch in Europe and the COST B35 action lsquoLipid Peroxida-tion Associated Disordersrsquordquo Free Radical Research vol 44 no10 pp 1095ndash1097 2010
[53] E Carosati P Ioan M Micucci et al ldquo14-Dihydropyridinescaffold in medicinal chemistry the story so far and perspec-tives (part 2) action in other targets and antitargetsrdquo CurrentMedicinal Chemistry vol 19 no 25 pp 4306ndash4323 2012
[54] U Eisner and J Kuthan ldquoThe chemistry of dihydropyridinesrdquoChemical Reviews vol 72 no 1 pp 1ndash42 1972 httpwwwsci-encemadnessorgtalkfilesphppid=138742ampaid=6475
[55] J Kuthan and A Kurfurst ldquoDevelopment in dihydropyri-dine chemistryrdquo Industrial amp Engineering Chemistry ProductResearch and Development vol 21 no 2 pp 191ndash261 1982
[56] A Sausins and G Duburs ldquoSynthesis of 14-dihydropyridinesby cyclocondensation reactionsrdquo Heterocycles vol 27 no 1 pp269ndash289 1988
[57] A E Sausins and G Y Duburs ldquoSynthesis of 14-dihydro-pyridines in cyclocondensation reactions (review)rdquo Chemistryof Heterocyclic Compounds vol 28 no 4 pp 363ndash391 1992Translated from Khimiya Geterotsiklicheskikh Soedinenii no 4pp 435ndash467 1992 (Russian)
[58] S Kazda ldquoTwenty years of dihydropyridinesrdquo in Dihydropy-ridines Progress in Pharmacology and Therapy W-D Busse BGarthoff and F Seuter Eds pp 1ndash12 Springer Verlag BerlinGermany 1993
[59] J-P Wan and Y Liu ldquoRecent advances in new multicomponentsynthesis of structurally diversified 14-dihydropyridinesrdquo RSCAdvances vol 2 no 26 pp 9763ndash9777 2012
[61] Reaxys Database[62] J Tuttle ldquoStructure mechanism and reactivity of hantzsch
estersrdquo in MacMillan Lab Group Meeting (082504) p 332004 httpwwwprincetoneduchemistrymacmillangroup-meetingsJBT20Hantzschpdf
[63] A Saini S Kumar and J S Sandhu ldquoHantzsch reaction recentadvances in Hantzsch 14-dihydropyridinesrdquo Journal of Sci-entific amp Industrial Research vol 67 pp 95ndash111 2008
[64] L LW Cheung S A Styler and A P Dicks ldquoRapid and conve-nient synthesis of the 14-dihydropyridine privileged structurerdquoJournal of Chemical Education vol 87 no 6 pp 628ndash630 2010
[65] A Kumar R A Maurya S Sharma M Kumar and G BhatialdquoSynthesis and biological evaluation of N-aryl-14-dihydro-pyridines as novel antidyslipidemic and antioxidant agentsrdquoEuropean Journal of Medicinal Chemistry vol 45 no 2 pp 501ndash509 2010
[66] R S Kumar A Idhayadhulla A J Abdul Nasser and J SelvinldquoSynthesis and anticoagulant activity of a new series of 14-dihydropyridine derivativesrdquo European Journal of MedicinalChemistry vol 46 no 2 pp 804ndash810 2011
[67] H A Stefani C B Oliveira R B Almeida et al ldquoDihydro-pyrimidin-(2H)-ones obtained by ultrasound irradiation anew class of potential antioxidant agentsrdquo European Journal ofMedicinal Chemistry vol 41 no 4 pp 513ndash518 2006
[68] H Sun C Shang L Jin and J Zhang ldquoSynthesis and antiox-idant activity of a series of novel 3-chalcone-substituted 14-dihydropyridine derivativesrdquoHeterocyclic Communications vol18 no 5-6 pp 239ndash243 2012
[69] D B Tikhonov and B S Zhorov ldquoStructural model for dihy-dropyridine binding to L-type calcium channelsrdquo The Journalof Biological Chemistry vol 284 no 28 pp 19006ndash19017 2009
[70] G Y Dubur and Y R Uldrikis ldquoThe oxidation of 14-dihydro-pyridinesrdquo Chemistry of Heterocyclic Compounds vol 6 no 1pp 80ndash84 1970 Translated from Khimiya GeterotsiklicheskikhSoedinenii no 1 pp 83ndash88 1970 (Russian)
[71] G Ya Duburs A O Kumerova and Ya R Uldrikis ldquoEnzymicoxidation of hydrogenated pyridines with peroxidase-hydrogenperoxide systemrdquoLatvijas PSRZAVestis vol 73 no 7 pp 73ndash771970 (Russian) Chemical Abstracts vol 73 Article ID 94913g1970
[72] K Xie Y-C Liu Y Cui J-GWang Y Fu andT CWMak ldquoN-methyl-(R)-3-(tert-butyl)-sulfinyl-14-dihydropyridine a novelNADHmodel compoundrdquoMolecules vol 12 no 3 pp 415ndash4222007
[73] S Tamagaki T Mimura and W Tagaki ldquoMetal-ion-facilitatedoxidations of dihydropyridines with molecular oxygen andhydrogen peroxiderdquo Journal of the Chemical Society PerkinTransactions 2 no 10 pp 1645ndash1650 1990
[74] D Tirzite G Tirzitis andD Antipova ldquoReductive ability of 14-dihydropyridine derivatives in relation to ions of trivalent ironrdquoChemistry of Heterocyclic Compounds vol 35 no 5 pp 592ndash594 1999
[76] J Ogle J Stradins and L Baumane ldquoFormation and decay offree cation-radicals in the course of electro-oxidation of 12- and14-dihydropyridines (Hantzsch esters)rdquo Electrochimica Actavol 39 no 1 pp 73ndash79 1994
[77] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for the
synthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts C Wittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Berlin Germany 2010
[78] WDu and Zh Yu ldquoBiomimetic in situ regeneration of cofactorsNAD(P)+ and NAD(P)H models hantzsch esters and dihy-drophenanthridinerdquo Synlett vol 23 no 9 pp 1300ndash1304 2012
[79] H K Chenault and G M Whitesides ldquoRegeneration ofnicotinamide cofactors for use in organic synthesisrdquo AppliedBiochemistry and Biotechnology vol 14 no 2 pp 147ndash197 1987
[80] Y R Uldrikis A A Zidermane E A Biseniex I E Preisa GY Dubur and G D Tirzit ldquoEsters of 26-dimethyl-14-dihydro-pyridine-35-dicarboxylic acid and method of obtainingthereofrdquo WO 8000345 A1 1978 httpworldwideespacenetcompublicationDetailsbiblioDB=EPODOCampII=1ampND=3ampadjacent=trueamplocale=en EPampFT=Dampdate=19800306ampCC=WOampNR=8000345A1ampKC=A1
[81] Y Sambongi H Nitta K Ichihashi M Futai and I Ueda ldquoAnovel water-soluble Hantzsch 14-dihydropyridine compoundthat functions in biological processes through NADH regener-ationrdquo Journal of Organic Chemistry vol 67 no 10 pp 3499ndash3501 2002
[82] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for thesynthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts ChWittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Verlag Berlin Germany 2010
[83] T Okamura T Kikuchi A Nagamine et al ldquoAn approach formeasuring in vivo cerebral redox states using the oxidative con-version of dihydropyridine to pyridinium ion and themetabolictrapping principlerdquo Free Radical Biology and Medicine vol 38no 9 pp 1197ndash1205 2005
[84] K A Schellenberg and F H Westheimer ldquoA free-radicaloxidation of a dihydropyridine1ardquo The Journal of OrganicChemistry vol 30 no 6 pp 1859ndash1862 1965
[85] K A Schellenberg ldquoReaction of hydroxyl radical with thymi-dine Scavenging by a dihydropyridinerdquo Federation Proceedingsvol 38 no 3 I p 1433 1979
[86] E S Huyser J A K Harmony and F L McMillian ldquoPeroxideoxidations of dihydropyridine derivativesrdquo Journal of the Amer-ican Chemical Society vol 94 no 9 pp 3176ndash3180 1972
[87] A Sakamoto S T Ohnishi and R Ogawa ldquoInhibition of lipidperoxidation by some dihydropyridine derivativesrdquo Journal ofAnesthesia vol 7 no 2 pp 193ndash197 1993
[88] R Hardeland ldquoReview Neuroprotection by radical avoidancesearch for suitable agentsrdquo Molecules vol 14 no 12 pp 5054ndash5102 2009
[89] G Ya Dubur A Kh Velena V M Gukasov and Yu AVladimirov ldquoRegulation of peroxidation of mitochondrialmembrane lipids initiated by Fe2+ ions by antoxidants of the14-dihydropyridine series in experiments in vitrordquo Biomed-itsinskaya Khimiya vol 22 no 5 pp 665ndash673 1976 (Russian)Chemical Abstracts vol 88 Article ID 2640 1977
[90] G RMMHaenenM J T J Arts A Bast andMD ColemanldquoStructure and activity in assessing antioxidant activity in vitroand in vivo a critical appraisal illustrated with the flavonoidsrdquoEnvironmental Toxicology and Pharmacology vol 21 no 2 pp191ndash198 2006
[91] G Tirzitis and G Bartosz ldquoDetermination of antiradical andantioxidant activity basic principles and new insightsrdquo ActaBiochimica Polonica vol 57 no 2 pp 139ndash142 2010
30 Oxidative Medicine and Cellular Longevity
[92] G R Buettner and R P Mason ldquoSpin-trapping methods fordetecting superoxide and hydroxyl free radicals in vitro and invivordquo inCritical Reviews of Oxidative Stress and Aging Advancesin Basic Science Diagnostics and Intervention R G Cutler andH Rodriguez Eds vol 1 chapter 2 pp 27ndash38World ScientificLondon UK 2003
[93] M M Tarpey and I Fridovich ldquoMethods of detection ofvascular reactive species Nitric oxide superoxide hydrogenperoxide and peroxynitriterdquo Circulation Research vol 89 no3 pp 224ndash236 2001
[94] E Y Kazush E I Sagun G D Tirzit and G Y DaburldquoQuenching of singlet oxygen by electron donating derivativesof 14-dihydropyridinerdquo Chemistry of Heterocyclic Compoundsvol 30 no 5 pp 562ndash563 1994
[95] G Tirzitis E Kazush and G Duburs ldquoReaction of 14-dihydropyridine derivatives with peroxynitrite anionrdquo Chem-istry of Heterocyclic Compounds vol 34 no 3 pp 321ndash3231998 (Russian) Translated from Khimiya GeterotsiklicheskikhSoedinenii no 3 pp 355ndash357 1998
[96] L J Nunez-Vergara C Lopez-Alarcon P A Navarrete-EncinaA M Atria C Camargo and J A Squella ldquoElectrochemicaland EPR characterization of 14-dihydropyridines Reactivitytowards alkyl radicalsrdquo Free Radical Research vol 37 no 1 pp109ndash120 2003
[97] D Tirzite A Krauze A Zubareva G Tirzitis and G DubursldquoSynthesis and antiradical activity of 5-acetyl-2-alkylthio-4-aryl-6-methyl-14-dihydropyridine-3-carboxylic acid nitrilesrdquoChemistry of Heterocyclic Compounds vol 38 no 7 pp 795ndash800 2002
[98] H Ohkawa N Ohishi and K Yagi ldquoAssay for lipid peroxidesin animal tissues by thiobarbituric acid reactionrdquo AnalyticalBiochemistry vol 95 no 2 pp 351ndash358 1979
[99] N Zarkovic ldquo4-Hydroxynonenal as a bioactive marker ofpathophysiological processesrdquo Molecular Aspects of Medicinevol 24 no 4-5 pp 281ndash291 2003
[100] M Parola G Bellomo G Robino G Barrera and M UDianzani ldquo4-Hydroxynonenal as a biological signal molecularbasis and pathophysiological implicationsrdquo Antioxidants andRedox Signaling vol 1 no 3 pp 255ndash284 1999
[101] T Lovakovic M Poljak-Blazi G Duburs et al ldquoGrowthmodulation of human cells in vitro by mild oxidative stressand 14-dihydropyridine derivative antioxidantsrdquo CollegiumAntropologicum vol 35 no 1 pp 137ndash141 2011
[102] R van den Berg G R M M Haenen H van den Bergand A Bast ldquoApplicability of an improved Trolox equivalentantioxidant capacity (TEAC) assay for evaluation of antioxidantcapacity measurements of mixturesrdquo Food Chemistry vol 66no 4 pp 511ndash517 1999
[103] C Lopez-Alarcon P Navarrete C Camargo J A Squella andL J Nunez-Vergara ldquoReactivity of 14-dihydropyridines towardalkyl alkylperoxyl radicals and ABTS radical cationrdquo ChemicalResearch in Toxicology vol 16 no 2 pp 208ndash215 2003
[104] V Valenzuela P Santander C Camargo J A Squella C Lopez-Alarcon and L J Nunez-Vergara ldquo14-Dihydropyridines reac-tivity of nitrosoaryl and nitroaryl derivatives with alkylperoxylradicals andABTS radical cationrdquo Free Radical Research vol 38no 7 pp 715ndash727 2004
[105] L G Tsetlin N A Chebotareva B I Kurganov A K VelenaG Y Dubur and V Z Lankin ldquoStudy of 14-dihydropyridinesas lipoxygenase inhibitors with the use of hydrated reversedmicellesrdquo Pharmaceutical Chemistry Journal vol 22 no 6 pp425ndash428 1988 (Russian)
[106] J Panek Z Reblova L Kocirkova et al ldquoAntioxidant activityof dihydropyridine derivativesrdquo Czech Journal of Food Sciencesvol 18 pp 144ndash145 2000
[107] G Tirzitis I Kirule and G Duburs ldquoAntioxidationsaktivitatder 35-dicarbonylderivate des 26-demethyl-14-dihydropyri-dinsrdquo Fett Wissenschaft TechnologieFat Science Technology vol90 no 10 pp 411ndash413 1988
[108] M Plotniece G Tirzitis Y Uldrikis et al ldquoSynthesis of 14-dihydropyridine derivatives having an oxy- alkoxy- or dimeth-ylaminophenyl substituent in the 4 position their antioxidantactivity and their binding to phospholipid membranesrdquo Chem-istry of Heterocyclic Compounds vol 32 no 10 pp 1166ndash11721996 Translated from Khimiya Geterotsiklicheskikh Soedineniino 10(352) pp 1358ndash1365 1996 (Russian)
[109] D Y Rubene V S Sharov V I Olenev G D Tirzit G Y Duburand Y A Vladimirov ldquoUse of chemiluminescent method forthe evaluation of antioxidant activity of some derivatives of 14-dihydropyridinerdquo Russian Journal of Physical Chemistry A vol55 no 2 pp 511ndash512 1981 (Russian)
[110] M C R Symons and JM C Gutteridge Free Radicals and IronChemistry Biology and Medicine Oxford Science PublicationsOxford University Press Oxford UK 1998
[111] M Repetto J Semprine and A Boveris ldquoLipid peroxidationchemical mechanism biological implications and analyticaldeterminationrdquo in Lipid Peroxidation A Catala Ed Section ILipid Peroxidation Chemical Mechanisms Antioxidants Bio-logical Implications of Biochemistry Genetics and MolecularBiology chapter 1 pp 3ndash30 InTech Rijeka Croatia 2012
[112] A Velena J Zilbers and G Duburs ldquoDerivatives of 14-dihydropyridines asmodulators of ascorbate-induced lipid per-oxidation and high-amplitude swelling ofmitochondria causedby ascorbate sodium linoleate and sodiumpyrophosphaterdquoCellBiochemistry and Function vol 17 no 4 pp 237ndash252 1999
[113] M V Bilenko L N Shelenkova G Y Dubur and A K VelenaldquoUse of antioxidants to prevent renal damage during acuteischemia and reperfusionrdquo Bulletin of Experimental Biology andMedicine vol 96 no 3 pp 1195ndash1198 1983 Translated fromByulletenrsquo Eksperimentalrsquonoi Biologii i Meditsiny vol 96 no 9pp 8ndash11 1983 (Russian)
[114] R Toniolo F Tubaro F Ursini and G Bontempelli ldquoAn elec-troanalytical investigation on the redox properties of calciumantagonist dihydropyridinesrdquo Electroanalysis vol 15 no 10 pp855ndash861 2003
[115] L Kourimska J Pokorny and G Tirzitis ldquoThe antioxidant aci-tivity of 26-dimethyl-35-diethoxycarbonyl-14-dihydropyri-dine in edible oilsrdquo Nahrung vol 37 no 1 pp 91ndash93 1993
[116] C Lopez-Alarcon H Speisky J A Squella C Olea-Azar CCamargo and L J Nunez-Vergara ldquoReactivity of 14-dihydro-pyridines toward SIN-1-derived peroxynitriterdquo PharmaceuticalResearch vol 21 no 10 pp 1750ndash1757 2004
[117] R A Olek W Ziolkowski J J Kaczor L Greci J Popinigisand J Antosiewicz ldquoAntioxidant activity of NADH and its ana-loguemdashan in vitro studyrdquo Journal of Biochemistry andMolecularBiology vol 37 no 4 pp 416ndash421 2004
[118] E Niki N Noguchi and N Gotoh ldquoInhibition of oxidativemodification of low density lipoprotein by antioxidantsrdquo Jour-nal of Nutritional Science andVitaminology vol 39 supplementpp S1ndashS8 1993
[119] N Rojstaczer and D J Triggle ldquoStructure-function relation-ships of calcium antagonists effect on oxidative modificationof low density lipoproteinrdquo Biochemical Pharmacology vol 51no 2 pp 141ndash150 1996
Oxidative Medicine and Cellular Longevity 31
[120] A Sevanian L Shen and FUrsini ldquoInhibition of LDLoxidationand oxidized LDL-induced cytotoxicity by dihydropyridinecalcium antagonistsrdquo Pharmaceutical Research vol 17 no 8 pp999ndash1006 2000
[121] A Negre-Salvayre and R Salvayre ldquoProtection by Ca2+ channelblockers (nifedipine diltiazem and verapamil) against the tox-icity of oxidized low density lipoprotein to cultured lymphoidcellsrdquo British Journal of Pharmacology vol 107 no 3 pp 738ndash744 1992
[122] A Negre-Salvayre G FitoussiM Troly and R Salvayre ldquoCom-parative cytoprotective effect of dihydropyridine calcium chan-nel blockers against the toxicity of oxidized low density lipopro-tein for cultured lymphoid cellsrdquo Biochemical Pharmacologyvol 44 no 12 pp 2379ndash2386 1992
[123] L Cominacini A F Pasini U Garbin et al ldquoAntioxidant activ-ity of different dihydropyridinesrdquo Biochemical and BiophysicalResearch Communications vol 302 no 4 pp 679ndash684 2003
[124] L Cominacini U Garbin A Fratta Pasini et al ldquoOxidized low-density lipoprotein increases the production of intracellularreactive oxygen species in endothelial cells inhibitory effect oflacidipinerdquo Journal of Hypertension vol 16 no 12 part 2 pp1913ndash1919 1998
[125] H M Lander ldquoAn essential role for free radicals and derivedspecies in signal transductionrdquo The FASEB Journal vol 11 no2 pp 118ndash124 1997
[126] M L L Martinez E Rizzi M M Castro et al ldquoLercanidipinedecreases vascular matrix metalloproteinase-2 activity andprotects against vascular dysfunction in diabetic ratsrdquo EuropeanJournal of Pharmacology vol 599 no 1ndash3 pp 110ndash116 2008
[127] P Lesnik C Dachet L Petit et al ldquoImpact of a combinationof a calcium antagonist and a 120573-blocker on cell- and copper-mediated oxidation of LDL and on the accumulation and effluxof cholesterol in human macrophages and murine J774 cellsrdquoArteriosclerosis Thrombosis and Vascular Biology vol 17 no 5pp 979ndash988 1997
[128] G Sobal E J Menzel and H Sinzinger ldquoCalcium antagonistsas inhibitors of in vitro low density lipoprotein oxidation andglycationrdquoBiochemical Pharmacology vol 61 no 3 pp 373ndash3792001
[129] E Lupo R Locher B Weisser and W Vetter ldquoIn vitro antiox-idant activity of calcium antagonists against LDL oxidationcompared with 120572-tocopherolrdquo Biochemical and BiophysicalResearch Communications vol 203 no 3 pp 1803ndash1808 1994
[130] J Zou Y Li H-Q Fan and J-G Wang ldquoEffects of dihydropy-ridine calcium channel blockers on oxidized low-density lipo-protein induced proliferation and oxidative stress of vascularsmooth muscle cellsrdquo BMC Research Notes vol 5 article 1682012
[131] C Napoli S Salomone T Godfraind et al ldquo14-Dihydro-pyridine calcium channel blockers inhibit plasma and LDL oxi-dation and formation of oxidation-specific epitopes in the arte-rial wall and prolong survival in stroke-prone spontaneouslyhypertensive ratsrdquo Stroke vol 30 no 9 pp 1907ndash1915 1999
[132] G Zernig I Graziadei T Moshammer C Zech N Reider andH Glossmann ldquoMitochondrial Ca2+ antagonist binding sitesare associated with an inner mitochondrial membrane anionchannelrdquo Molecular Pharmacology vol 38 no 3 pp 362ndash3691990
[133] F E Hunter Jr A Scott P E Hochstein et al ldquoStudies of themechanism of ascorbate-induced swelling and lysis of isolatedliver mitochondriardquo The Journal of Biological Chemistry vol239 pp 604ndash613 1964
[134] D R Janero B Burghardt and R Lopez ldquoProtection of cardiacmembrane phospholipid against oxidative injury by calciumantagonistsrdquoBiochemical Pharmacology vol 37 no 21 pp 4197ndash4203 1988
[135] A Karadag B Ozcelik and S S Saner ldquoReview of methods todetermine antioxidant capacitiesrdquo FoodAnalyticalMethods vol2 no 1 pp 41ndash60 2009
[136] Y I Gubskiı N V Litvinova and E V Shnurko-TabakovaldquoAntioxidant and antiradical activity of various classes of antiox-idantsrdquo Ukrainskiı Biokhimicheskiı Zhurnal vol 66 no 4 pp114ndash116 1994 (Russian)
[137] M Takei M Hiramatsu and A Mori ldquoInhibitory effects ofcalcium antagonists onmitochondrial swelling induced by lipidperoxidation or arachidonic acid in the rat brain in vitrordquoNeurochemical Research vol 19 no 9 pp 1199ndash1206 1994
[138] M Takei M Hiramatsu R Edamatsu and A Mori ldquoFreeradical scavenging by calcium antagonistsrdquo Neurosciences vol20 no 2 pp 75ndash82 1994
[139] Ya P Stradin G Ya Dubur Yu A Beilis Ya R Uldrikis andA F Korotkova ldquoVoltammetry of 14-dihydropyridine deriva-tives I Potentials of electrochemical oxidation of 35-diacyl-and 35-di(alkoxycarbonyl)-14-dihydropyridines in acetoni-trilerdquo Chemistry of Heterocyclic Compounds no 1 pp 84ndash871972 (Russian)
[140] E V Ivanov T V Ponomarjova G N Merkusev et al ldquoEinneuer Haut-Radioprotektor Diethon (experimentelle Unter-suchung)rdquo Radiobiologia Radiotherapia vol 31 no 1 pp 69ndash78 1990
[141] E V Ivanov T V Ponomareva G N Merkushev et al ldquoRadia-tion modulating properties of derivates of 14-dihydropyridineand 12345678910-decahydroacridine-18 dionerdquo Radiat-sionnaia Biologiia Radioecologiia vol 44 no 5 pp 550ndash5592004 (Russian)
[142] R O Vitolinia D A Berzinia A K Velena I A Vutsina A AKimenis and G Y Duburs ldquoThe protective effects of the cal-cium antagonist foridon in acute myocardial ischaemiardquo Kardi-ologiya vol 27 no 3 pp 90ndash93 1987 (Russian)
[143] A H Velena G Ya Duburs R O Vitolina et al ldquoEffect ofryodipine on electromechanical parameters of heart and vesselscAMP phosphodiesterase activity and swelling-contractioncycle of mitochondriardquo Arzneimittelforschung vol 35 no 6 pp907ndash914 1985
[144] L I Utno Z E Lipsberga A A Silova M I Girgensone EA Bisenieks and G I Ia ldquoCardioprotective properties of a 14-dihydropyridine derivative glutapyrone in deep hypothermiardquoBiulletenrsquo Eksperimentalrsquonoı Biologii i Meditsiny vol 108 no 11pp 558ndash561 1989 (Russian)
[145] M A S FernandesM S Santos J A F Vicente et al ldquoEffects of14-dihydropyridine derivatives (cerebrocrast gammapyroneglutapyrone and diethone) onmitochondrial bioenergetics andoxidative stress a comparative studyrdquoMitochondrion vol 3 no1 pp 47ndash59 2003
[146] M A S Fernandes M S Santos A J M Moreno et al ldquoEffectsof 5-acetyl(carbamoyl)-6-methylsulfanyl-14-dihydropyridine-5-carbonitriles on rat liver mitochondrial functionrdquo Toxicologyin Vitro vol 23 no 7 pp 1333ndash1341 2009
[147] L Klimaviciusa A Kalda A Kaasik et al ldquoNeuroprotectiveactivity of 14-dihydropyridine derivatives structure determi-nantsrdquo Proceedings of the Latvian Academy of Sciences BNatural Exact and Applied Sciences vol 61 no 1-2 pp 33ndash372007
32 Oxidative Medicine and Cellular Longevity
[148] L Klimaviciusa M A S Fernandes N Lencberga et alldquoTargeting the mitochondria by novel adamantane-containing14-dihydropyridine compoundsrdquo in Bioenergetics K B ClarkEd pp 257ndash272 InTech 2012
[149] V Klusa L Klimaviciusa G Duburs J Poikans and AZharkovsky ldquoAnti-neurotoxic effects of tauropyrone a taurineanaloguerdquo Advances in Experimental Medicine and Biology vol583 pp 499ndash508 2006
[150] N Sampson P Berger and Ch Zenzmaier ldquoRedox signalingas a therapeutic target to inhibit myofibroblast activation indegenerative fibrotic diseaserdquo BioMed Research Internationalvol 2014 Article ID 131737 14 pages 2014
[151] T L Leto and M Geiszt ldquoRole of Nox family NADPH oxidasesin host defenserdquoAntioxidantsampRedox Signaling vol 8 no 9-10pp 1549ndash1561 2006
[152] K K Griendling D Sorescu and M Ushio-Fukai ldquoNAD(P)Hoxidase role in cardiovascular biology and diseaserdquo CirculationResearch vol 86 no 5 pp 494ndash501 2000
[153] H Chen Y S Song and P H Chan ldquoInhibition of NADPHoxi-dase is neuroprotective after ischemia-reperfusionrdquo Journal ofCerebral Blood Flow and Metabolism vol 29 no 7 pp 1262ndash1272 2009
[154] P Hochstein and L Ernster ldquoADP-activated lipid peroxidationcoupled to the TPNH oxidase system of microsomesrdquo Biochem-ical and Biophysical Research Communications vol 12 no 5 pp388ndash394 1963
[155] I I Gubskiı AGGoriushkoNV Litvinova et al ldquoAntioxidantproperties and membranotropic effect of certain derivatives of14-dihydropyridinerdquo Ukrainskiı Biokhimicheskiı Zhurnal vol71 no 4 pp 35ndash39 1999 (Russian)
[156] F Engineer and R Sridhar ldquoInhibition of rat heart andliver microsomal lipid peroxidation by nifedipinerdquo BiochemicalPharmacology vol 38 no 8 pp 1279ndash1285 1989
[157] T Goncalves A P Carvalho and C R Oliveira ldquoAntioxidanteffect of calcium antagonists on microsomai membranes iso-lated from different brain areasrdquo European Journal of Pharma-cology vol 204 no 3 pp 315ndash322 1991
[158] M E Letelier P Izquierdo L Godoy A M Lepe and MFaundez ldquoLiver microsomal biotransformation of nitro-aryldrugs mechanism for potential oxidative stress inductionrdquoJournal of Applied Toxicology vol 24 no 6 pp 519ndash525 2004
[159] M E Letelier P Entrala C Lopez-Alarcon et al ldquoNitroaryl-14-dihydropyridines as antioxidants against rat liver microsomesoxidation induced by ironascorbate Nitrofurantoin and naph-thalenerdquo Toxicology in Vitro vol 21 no 8 pp 1610ndash1618 2007
[160] F P Guengerich W R Brian M Iwasaki M-A Sari CBaarnhielm and P Berntsson ldquoOxidation of dihydropyridinecalcium channel blockers and analogues by human liver cyto-chrome P-450 IIIA4rdquo Journal of Medicinal Chemistry vol 34no 6 pp 1838ndash1844 1991
[161] S H Park S-W RhaW-Y Shin et al ldquoAS-160 Calcium channelblockers of dihydropyridine class reduce the antiplatelet effectof Clopidogrel what is clinical impactrdquo The American Journalof Cardiology vol 107 no 8 supplement p 47A 2011
[162] C Asma and D M Reda ldquoEvaluation of dihydropyridinecalcium antagonist effects on the stress bioindicator orga-nism Saccharomyces cerevisiaerdquo Annals of Biological Researchvol 4 no 10 pp 40ndash46 2013 httpscholarsresearchlibrarycomABR-vol4-iss10ABR-2013-4-10-40-46pdf
[163] G Gaviraghi A M Pastorino E Ratti and D G TristldquoCalcium channel blockers with antioxidant activityrdquo in Free
Radicals Lipoprotein Oxidation andAtherosclerosis G BellomoG Finardi E Maggi and E Rice-Evans Eds pp 431ndash456Richelieu Press London UK 1995
[164] G Gaviraghi AM Pastorino E Ratti and D G Trist ldquoAntiox-idant dihydropyridines a new and comprehensive therapy forfree radical-induced cardiovascular diseasesrdquo in Free Radicalsin Biology and Environment F Minisci Ed vol 27 of NATOASI Series pp 193ndash221 Springer Dordrecht The Netherlands1997
[165] P D Henry ldquoAntiperoxidative actions of calcium antagonistsand atherogenesisrdquo Journal of Cardiovascular Pharmacologyvol 18 supplement 1 pp S6ndashS10 1991
[166] F Kouoh B Gressier T Dine et al ldquoAntioxidant effects andanti-elastase activity of the calcium antagonist nicardipine onactivated human and rabbit neutrophilsmdasha potential antiath-erosclerotic property of calcium antagonistsrdquo CardiovascularDrugs andTherapy vol 16 no 6 pp 515ndash520 2002
[167] S Parthasarathy D Litvinov K Selvarajan and M GarelnabildquoLipid peroxidation and decompositionmdashconflicting roles inplaque vulnerability and stabilityrdquo Biochimica et BiophysicaActa vol 1781 no 5 pp 221ndash231 2008
[168] D-Q Liu Z-Q Pang D-H Zhao and B-H Sheng ldquoEffects offuryl-dihydropyridines I on lipid peroxides of ischemic myo-cardium and ATPases activity of erythrocyte membranes inratsrdquo Acta Pharmacologica Sinica vol 12 no 3 pp 253ndash2561991
[169] V Lukic-Panin T Kamiya H Zhang et al ldquoPrevention of neu-ronal damage by calcium channel blockers with antioxidativeeffects after transient focal ischemia in ratsrdquo Brain Research vol1176 no 1 pp 143ndash150 2007
[170] Y Allanore D Borderie H Lemarechal O G Ekindjian andA Kahan ldquoAcute and sustained effects of dihydropyridine-typecalcium channel antagonists on oxidative stress in systemicsclerosisrdquo American Journal of Medicine vol 116 no 9 pp 595ndash600 2004
[171] I Casetta V Govoni and E Granieri ldquoOxidative stress antioxi-dants and neurodegenerative diseasesrdquo Current PharmaceuticalDesign vol 11 no 16 pp 2033ndash2052 2005
[172] M J T J Arts Assessing antioxidant activity [PhD the-sis] Maastricht University Maastricht The Netherlands 2007httparnounimaasnlshowcgifid=8676
[173] G Dıaz-Araya L Godoy L Naranjo A Squella M E Letelierand L J Nunez-Vergara ldquoAntioxidant effects of 14-dihydro-pyridine and nitroso aryl derivatives on the Fe+3ascorbate-stimulated lipid peroxidation in rat brain slicesrdquo General Phar-macology The Vascular System vol 31 no 3 pp 385ndash391 1998
[174] Y Fukuhara K Tsuchiya Y Horinouchi et al ldquoProtectiveeffect of photodegradation product of nifedipine against tumornecrosis factor 120572-induced oxidative stress in human glomerularendothelial cellsrdquo Journal of Medical Investigation vol 58 no1-2 pp 118ndash126 2011
[175] W Stengel M Jainz and K Andreas ldquoDifferent potencies ofdihydropyridine derivatives in blocking T-type but not L-typeCa2+ channels in neuroblastoma-glioma hybrid cellsrdquo EuropeanJournal of Pharmacology vol 342 no 2-3 pp 339ndash345 1998
[176] O M Panasenko D J Tirzite G D Tirzitis and G J DubursldquoEffect of some 14-dihydropyridine derivatives on structuralorganization of erythrocyte membranesrdquo Biologicheskie Mem-brany (Biochemistry (Moscow) Series A Membrane and CellBiology) vol 1 pp 919ndash925 1984 (Russian)
[177] L G Herbette Y M H Vant Erve and D G Rhodes ldquoInter-action of 14 dihydropyridine calcium channel antagonists with
Oxidative Medicine and Cellular Longevity 33
biological membranes lipid bilayer partitioning could occurbefore drug binding to receptorsrdquo Journal of Molecular andCellular Cardiology vol 21 no 2 pp 187ndash201 1989
[178] L G Herbette P E Mason G Gaviraghi T N Tulenko andR P Mason ldquoThe molecular basis for lacidipinersquos unique phar-macokinetics optimal hydrophobicity results in membraneinteractions that may facilitate the treatment of atherosclerosisrdquoJournal of Cardiovascular Pharmacology vol 23 supplement 5pp S16ndashS25 1994
[179] G V Belevitch G Y Dubur G E Dobretsov N K Kurek andM M Spirin ldquoCalcium antagonists riodipine nifedipine andverapamil binding to model and biological membranes fluore-scence analysisrdquo Biologicheskie Membrany (Biochemistry(Moscow) Series A Membrane and Cell Biology) vol 5 pp768ndash776 1988 (Russian)
[180] R P Mason G E Gonye D W Chester and L G HerbetteldquoPartitioning and location of Bay K 8644 14-dihydropyridinecalcium channel agonist in model and biological membranesrdquoBiophysical Journal vol 55 no 4 pp 769ndash778 1989
[181] M Cindric A Cipak J Serly et al ldquoReversal of multidrugresistance inmurine lymphoma cells by amphiphilic dihydropy-ridine antioxidant derivativerdquo Anticancer Research vol 30 no10 pp 4063ndash4070 2010
[182] F Shekari H Sadeghpour K Javidnia et al ldquoCytotoxic andmultidrug resistance reversal activities of novel 14-dihydro-pyridines against human cancer cellsrdquo European Journal ofPharmacology vol 746 no 1 pp 233ndash244 2015
[183] X-F Zhou Q Shao R A Coburn and M E Morris ldquoQuanti-tative structure-activity relationship and quantitative structure-pharmacokinetics relationship of 14-dihydropyridines andpyridines as multidrug resistance modulatorsrdquo PharmaceuticalResearch vol 22 no 12 pp 1989ndash1996 2005
[184] R Berkels T Breitenbach H Bartels et al ldquoDifferent antioxida-tive potencies of dihydropyridine calcium channel modulatorsin various modelsrdquo Vascular Pharmacology vol 42 no 4 pp145ndash152 2005
[185] S Borovic G Tirzitis D Tirzite et al ldquoBioactive 14-dihydro-isonicotinic acid derivatives prevent oxidative damage of livercellsrdquo European Journal of Pharmacology vol 537 no 1ndash3 pp12ndash19 2006
[186] D Ya Rubene G D Tirzitis and G Ya Duburs ldquoInteractionof some 14-dihydropyridine derivatives with Fentonrsquos reagentrdquoLatvijas PSRZinatnuAkademijas Vestis Kimijas Serija Proceed-ings of the Latvian SSR Academy of Sciences Chemistry Seriespp 212ndash216 1982 (Russian)
[187] K Ondrias V Misık D Gergel and A Stasko ldquoLipid per-oxidation of phosphatidylcholine liposomes depressed by thecalcium channel blockers nifedipine and verapamil and bythe antiarrhythmic-antihypoxic drug stobadinerdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1003 no 3pp 238ndash245 1989
[188] I T Mak and W B Weglicki ldquoComparative antioxidant acti-vities of propranolol nifedipine verapamil and diltiazemagainst sarcolemmal membrane lipid peroxidationrdquoCirculationResearch vol 66 no 5 pp 1449ndash1452 1990
[189] I T Mak P Boehme and W B Weglicki ldquoProtective effects ofcalcium channel blockers against free radical-impaired endo-thelial cell proliferationrdquo Biochemical Pharmacology vol 50 no9 pp 1531ndash1534 1995
[190] S Ray S Mondal and N Dana ldquoEvaluation of protective roleof nifedipine on lipid peroxidation using reduced glutathione as
model markerrdquo Oxidants and Antioxidants in Medical Sciencevol 1 no 2 pp 97ndash100 2012
[191] M Yamato T Shiba T Ide Y Honda K-I Yamada andH Tsutsui ldquoNifedipine treatment reduces brain damage aftertransient focal ischemia possibly through its antioxidativeeffectsrdquoHypertension Research vol 34 no 7 pp 840ndash845 2011
[192] V Chander and K Chopra ldquoNifedipine attenuates changes innitric oxide levels renal oxidative stress and nephrotoxicityinduced by cyclosporinerdquo Renal Failure vol 27 no 4 pp 441ndash450 2005
[193] K M Gaafa M M Badawy and A A Hamza ldquoThe protectiveeffects of ascorbic acid cimetidine and nifedipine on diethyl-dithiocarbamate-induced hepatic toxicity in albino ratsrdquo Drugand Chemical Toxicology vol 34 no 4 pp 405ndash419 2011
[194] H Sugawara K Tobise and S Onodera ldquoAbsence of antiox-idant effects of nifedipine and diltiazem on myocardial mem-brane lipid peroxidation in contrast with those of nisoldipineand propranololrdquo Biochemical Pharmacology vol 47 no 5 pp887ndash892 1994
[195] I E Kirule D Y Rubene E A Bisenieks G D Tirzit and GY Dubur ldquo4-Nitrophenyl-14-dihydropyridinesmdasha new groupof inhibitors of peroxide oxidationrdquo Chemistry of HeterocyclicCompounds vol 18 no 3 p 316 1982
[196] G D Tirzit I E Kirule L K Baumane R A Gavar Y PStradynrsquo andG YDubur ldquoMechanism of the antioxidant actionof 26-dimethyl-35-dimethoxy-carbonyl-4-(2-nitrophenyl)14-dihydropyridinerdquoChemistry ofHeterocyclic Compounds vol 20no 8 pp 915ndash918 1984
[197] C Yanez C Lopez-Alarcon C Camargo V Valenzuela J ASquella and L J Nunez-Vergara ldquoStructural effects on thereactivity 14-dihydropyridines with alkylperoxyl radicals andABTS radical cationrdquo Bioorganic and Medicinal Chemistry vol12 no 9 pp 2459ndash2468 2004
[198] VMisik A J Stasko D Gergel and K Ondrias ldquoSpin-trappingand antioxidant properties of illuminated and nonilluminatednifedipine and nimodipine in heart homogenate and modelsystemrdquo Molecular Pharmacology vol 40 no 3 pp 435ndash4391991
[199] K Ondrias V Misık A Stasko D Gergelrsquo and M HromadovaldquoComparison of antioxidant properties of nifedipine and illu-minated nifedipine with nitroso spin traps in low densitylipoproteins and phosphatidylcholine liposomesrdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1211 no 1pp 114ndash119 1994
[200] A Stasko V Brezova S Biskupic K Ondrias and V MisıkldquoReactive radical intermediates formed from illuminated nife-dipinerdquoFree Radical Biology andMedicine vol 17 no 6 pp 545ndash556 1994
[201] K Ishizawa Y Izawa-Ishizawa N Yamano et al ldquoNitrosoni-fedipine ameliorates the progression of type 2 diabetic nephro-pathy by exerting antioxidative effectsrdquo PLoS ONE vol 9 no 1Article ID e86335 2014
[202] H Fujii and L J Berliner ldquoIn vivo EPR evidence for free radicaladducts of nifedipinerdquoMagnetic Resonance in Medicine vol 42no 4 pp 691ndash694 1999
[203] S Bollo S Finger J C Sturm L J Nunez-Vergara and JA Squella ldquoCyclic voltammetry and scanning electrochemicalmicroscopy studies of the heterogeneous electron transferreaction of some nitrosoaromatic compoundsrdquo ElectrochimicaActa vol 52 no 15 pp 4892ndash4898 2007
34 Oxidative Medicine and Cellular Longevity
[204] F Ursini ldquoTissue protection by lacidipine insight from redoxbehaviorrdquo Journal of Cardiovascular Pharmacology vol 30supplement 2 pp S28ndashS30 1997
[205] P G Cristofori F A Crivellente I Faustinelli et al ldquoInvolve-ment of the nitric oxide system in the anti-atheroscleroticpotential of lacidipine in the apoE-deficient mouse a mor-phological functional and electrochemical studyrdquo ToxicologicPathology vol 32 no 4 pp 493ndash499 2004
[206] X-P Zhang E L Kit S Mital S Chahwala and T HHintze ldquoParadoxical release of nitric oxide by an L-type calciumchannel antagonist the R+ enantiomer of amlodipinerdquo Journalof Cardiovascular Pharmacology vol 39 no 2 pp 208ndash2142002
[207] F Franzoni G Santoro F Regoli et al ldquoAn in vitro study of theperoxyl and hydroxyl radical scavenging capacity of the calciumantagonist amlodipinerdquo Biomedicine and Pharmacotherapy vol58 no 8 pp 423ndash426 2004
[208] S V Gatsura ldquoOxygen-dependent mechanisms underlying theantiischemic effect of verapamil and amlodipinerdquo Bulletin ofExperimental Biology and Medicine vol 137 no 1 pp 40ndash422004
[209] Y Hirooka Y Kimura M Nozoe Y Sagara K Ito and KSunagawa ldquoAmlodipine-induced reduction of oxidative stressin the brain is associated with sympatho-inhibitory effects instroke-prone spontaneously hypertensive ratsrdquo HypertensionResearch vol 29 no 1 pp 49ndash56 2006
[210] B Tomlinson and I F F Benzie ldquoAntioxidant effect of lercani-dipine (note)rdquo Hypertension vol 42 no 4 pp e10ndashe11 2003
[211] A A Faraqui ldquoNeurochemical aspects of 4-hydroxynonenalrdquoin Lipid Mediators and Their Metabolism in the Brain A AFaraqui Ed chapter 6 pp 159ndash191 Springer New York NYUSA 2011
[212] V S NascimentoM S DrsquoAlva A AOliveira et al ldquoAntioxidanteffect of nimodipine in young rats after pilocarpine-inducedseizuresrdquo Pharmacology Biochemistry and Behavior vol 82 no1 pp 11ndash16 2005
[213] O Ismailoglu P Atilla S Palaoglu et al ldquoThe therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjuryrdquo Turkish Neurosurgery vol 22 no 6 pp 740ndash746 2012
[214] M Matsubara and K Hasegawa ldquoBenidipine a dihydropy-ridine-calcium channel blocker prevents lysophosphatidyl-choline-induced injury and reactive oxygen species productionin human aortic endothelial cellsrdquo Atherosclerosis vol 178 no1 pp 57ndash66 2005
[215] M Matsubara K Yao and K Hasegawa ldquoBenidipine adihydropyridine-calcium channel blocker inhibits lysophos-phatidylcholine-induced endothelial injury via stimulation ofnitric oxide releaserdquo Pharmacological Research vol 53 no 1 pp35ndash43 2006
[216] MMatsubara and K Hasegawa ldquoEffects of benidipine a dihyd-ropyridine-Ca2+ channel blocker on expression of cytokine-induced adhesion molecules and chemoattractants in humanaortic endothelial cellsrdquo European Journal of Pharmacology vol498 no 1ndash3 pp 303ndash314 2004
[217] M Matsubara O Akizuki J-I Ikeda K Saeki K Yao and KSasaki ldquoBenidipine an anti-hypertensive drug inhibits reactiveoxygen species production in polymorphonuclear leukocytesand oxidative stress in salt-loaded stroke-prone spontaneouslyhypertensive ratsrdquo European Journal of Pharmacology vol 580no 1-2 pp 201ndash213 2008
[218] A C Rosenkranz H Lob T Breitenbach R Berkels and RRoesen ldquoEndothelial antioxidant actions of dihydropyridines
and angiotensin converting enzyme inhibitorsrdquo European Jour-nal of Pharmacology vol 529 no 1ndash3 pp 55ndash62 2006
[219] V Kain S Kumar and S L Sitasawad ldquoAzelnidipine preventscardiac dysfunction in streptozotocin-diabetic rats by reducingintracellular calcium accumulation oxidative stress and apop-tosisrdquo Cardiovascular Diabetology vol 10 article 97 2011
[220] K Nakamura S Yamagishi and H Inoue ldquoUnique atheropro-tective property of azelnidipine a dihydropyridine-based cal-cium antagonistrdquoMedical Hypotheses vol 65 no 1 pp 155ndash1572005
[221] TMatsui S Yamagishi K Nakamura S Kikuchi andH InoueldquoAzelnidipine a dihydropyridine-based calcium antagonistinhibits angiotensin II-induced oxidative stress generation anddownregulation of pigment epithelium-derived factor mRNAlevels in microvascular endothelial cellsrdquo Drugs under Experi-mental and Clinical Research vol 31 no 5-6 pp 215ndash219 2005
[222] C Ohmura H Watada T Shimizu et al ldquoCalcium channelblocker azelnidipine reduces lipid hydroperoxides in patientswith type 2 diabetes independent of blood pressurerdquo EndocrineJournal vol 54 no 5 pp 805ndash811 2007
[223] H Daikuhara F Kikuchi and T Ishida ldquoThe combination ofOLmesartan and a CAlcium channel blocker (azelnidipine) orcandesartan and a calcium channel blocker (amlodipine) intype 2 diabetic hypertensive patients theOLCA studyrdquoDiabetesand Vascular Disease Research vol 9 no 4 pp 280ndash286 2012
[224] MAbe NMaruyama KOkada SMatsumoto KMatsumotoand M Soma ldquoAdditive antioxidative effects of azelnidipine onangiotensin receptor blocker olmesartan treatment for type 2diabetic patients with albuminuriardquoHypertension Research vol34 no 8 pp 935ndash941 2011
[225] K Mizushige ldquoAntioxidative activities of thiazolidinedionesand dihydropyridine-type calcium antagonistsrdquo IRYOmdashJapa-nese Journal of National Medical Services vol 59 no 11 pp 581ndash592 2005
[226] S Manabe T Okura T Fukuoka and J Higaki ldquoAntioxidativeeffects of azelnidipine on mesangial cell proliferation inducedby highly concentrated insulinrdquo European Journal of Pharma-cology vol 567 no 3 pp 252ndash257 2007
[227] Y Koyama Y Takeishi H Takahashi et al ldquoAzelnidipine inhi-bits H
2O2-induced cell death in neonatal rat cardiomyocytesrdquo
CardiovascularDrugs andTherapy vol 21 no 1 pp 69ndash72 2007[228] K Shinomiya K Mizushige M Fukunaga et al ldquoAntioxidant
effect of a new calcium antagonist azelnipidine in culturedhuman arterial endothelial cellsrdquo Journal of International Med-ical Research vol 32 no 2 pp 170ndash175 2004
[229] T Ohyama K Sato K Kishimoto et al ldquoAzelnidipine is acalcium blocker that attenuates liver fibrosis and may increaseantioxidant defencerdquo British Journal of Pharmacology vol 165no 4 pp 1173ndash1187 2012
[230] L A Calo F Zaghetto E Pagnin P A Davis A Sempliciniand A C Pessina ldquoEffect of manidipine on gene expressionand protein level of oxidative stress-related proteins p22phoxand HO-1 Relevance for antihypertensive and anti-remodelingeffectsrdquo Journal of Cardiovascular Pharmacology vol 43 no 4pp 531ndash538 2004
[231] R Ghyasi G Sepehri M Mohammadi R Badalzadeh and AGhyasi ldquoEffect of mebudipine on oxidative stress and lipid per-oxidation in myocardial ischemic-reperfusion injury in maleratrdquo Journal of Research in Medical Sciences vol 17 no 12 pp1150ndash1155 2012
Oxidative Medicine and Cellular Longevity 35
[232] DCAndersson J Fauconnier T Yamada et al ldquoMitochondrialproduction of reactive oxygen species contributes to the 120573-adrenergic stimulation of mouse cardiomycytesrdquoThe Journal ofPhysiology vol 589 no 7 pp 1791ndash1801 2011
[233] A F Ceylan-Isik N Ari M Stefek et al ldquoEffects of a long-term treatment with an antioxidant pyridoindole on vascularresponsiveness in diabetes-induced aging ratsrdquo Current AgingScience vol 4 no 2 pp 150ndash157 2011
[234] S Saponara G Sgaragli and F Fusi ldquoQuercetin antagonismof Bay K 8644 effects on rat tail artery L-type Ca2+ channelsrdquoEuropean Journal of Pharmacology vol 598 no 1ndash3 pp 75ndash802008
[235] D A Sica ldquoInteraction of grapefruit juice and calcium channelblockersrdquo American Journal of Hypertension vol 19 no 7 pp768ndash773 2006
[236] P Mulder G Litwinienko S Lin P D MacLean L R CBarclay and K U Ingold ldquoThe L-type calcium channel block-ers Hantzsch 14-dihydropyridines are not peroxyl radical-trapping chain-breaking antioxidantsrdquo Chemical Research inToxicology vol 19 no 1 pp 79ndash85 2006
[237] L J Nunez-Vergara R Salazar C Camargo et al ldquoOxidation ofC4-hydroxyphenyl 14-dihydropyridines in dimethylsulfoxideand its reactivity towards alkylperoxyl radicals in aqueousmediumrdquo Bioorganic and Medicinal Chemistry vol 15 no 12pp 4318ndash4326 2007
[238] M E Ortiz L J Nunez-Vergara and J A Squella ldquoRelativereactivity of dihydropyridine derivatives to electrogeneratedsuperoxide ion in DMSO solutions a voltammetric approachrdquoPharmaceutical Research vol 20 no 2 pp 292ndash296 2003
[239] M E Ortiz L J Nunez-Vergara C Camargo and J A SquellaldquoOxidation of Hantzsch 14-dihydropyridines of pharmacolog-ical significance by electrogenerated superoxiderdquo Pharmaceuti-cal Research vol 21 no 3 pp 428ndash435 2004
[240] R S Raghuvanshi and K N Singh ldquoSuperoxide induced oxida-tive aromatization of Hantzsch 14-dihydropyridinesrdquo IndianJournal of Chemistry Section B Organic and Medicinal Chem-istry vol 47 no 11 pp 1735ndash1738 2008
[241] I Kruk A Kladna K Lichszteld et al ldquoAntioxidant activityof 4-flavonil-14-dihydropyridine derivativesrdquo Biopolymers vol62 no 3 pp 163ndash167 2001
[242] G D Tirzit I M Byteva K I Salokhiddinov G P Gurinovichand G Y Dubur ldquo14-Dihydropyridine derivatives as deactiva-tors of singlet oxygenrdquo Chemistry of Heterocyclic Compoundsvol 17 no 7 pp 682ndash684 1981
[243] G D Tirzit E Y Kazush and G Y Dubur ldquoInfluence of14-dihydropyridine derivatives on the generation of hydroxylradicalsrdquo Chemistry of Heterocyclic Compounds vol 28 no 4pp 435ndash437 1992
[244] N A Pizarro-Urzua and L J Nunez-Vergara ldquoNifedipine andnitrendipine reactivity toward singlet oxygenrdquo Journal of Photo-chemistry and Photobiology A Chemistry vol 175 no 2-3 pp129ndash137 2005
[245] L-F Wang H-Y Zhang L Konga Z-W Chena and J-G ShildquoDFT calculations indicate that 14-dihydropyridine is a promis-ing lead antioxidantrdquo Helvetica Chimica Acta vol 87 no 6 pp1515ndash1521 2004
[246] P Mulder H-G Korth and K U Ingold ldquoWhy quantum-thermochemical calculations must be used with caution toindicate lsquoa promising lead antioxidantrsquordquoHelvetica Chimica Actavol 88 no 2 pp 370ndash374 2005
[247] K Yao Y Ina K Nagashima K Ohmori and T Ohno ldquoAntiox-idant effects of calcium antagonists in rat brain homogenatesrdquo
Biological and Pharmaceutical Bulletin vol 23 no 6 pp 766ndash769 2000
[248] T Matsui S-I Yamagishi K Nakamura and H Inoue ldquoBayw 9798 a dihydropyridine structurally related to nifedipinewith no calcium channel-blocking properties inhibits tumournecrosis factor-120572-induced vascular cell adhesion molecule-1expression in endothelial cells by suppressing reactive oxygenspecies generationrdquo Journal of International Medical Researchvol 35 no 6 pp 886ndash891 2007
[249] K AMitrega B VargheseM Porc and T F Krzeminski ldquoAnti-arrhythmic and hemodynamic effects of oxy nifedipine oxynimodipine oxy nitrendipine and oxy nisoldipinerdquo Pharmaco-logical Research vol 66 no 4 pp 300ndash308 2012
[250] V Herbert ldquoSymposium prooxidant effects of antioxidantvitamins Introductionrdquo The Journal of Nutrition vol 126 no4 supplement pp 1197Sndash1200S 1996 httpjnnutritionorgcontent1264 Suppl1197Sfullpdf
[251] B Halliwell ldquoAre polyphenols antioxidants or pro-oxidantsWhat do we learn from cell culture and in vivo studiesrdquoArchives of Biochemistry and Biophysics vol 476 no 2 pp 107ndash112 2008
[252] C Winterbourn Pro-Oxidants or Antioxidants ChristchurchSchool of Medicine Depatment of Pathology Free RadicalSchool SFRBMUniversity of Otago San Francisco Calif USA2009 httpwwwsfrbmorgfrsWinterbournpdf
[253] A Morakinyo B Iranloye and O Adegoke ldquoCalcium antag-onists modulate oxidative stress and acrosomal reaction in ratspermatozoardquo Archives of Medical Science vol 7 no 4 pp 613ndash618 2011
[254] The Alpha-Tocopherol Beta Carotene Cancer Prevention StudyGroup ldquoThe effect of vitamin E and beta carotene on theincidence of lung cancer and other cancers in male smokersrdquoTheNew England Journal of Medicine vol 330 no 15 pp 1029ndash1035 1994
[255] B Poljsak ldquoStrategies for reducing or preventing the generationof oxidative stressrdquo Oxidative Medicine and Cellular Longevityvol 2011 Article ID 194586 15 pages 2011
[256] B Poljsak and I Milisav ldquoThe neglected significance of lsquoanti-oxidative stressrsquordquoOxidativeMedicine and Cellular Longevity vol2012 Article ID 480895 12 pages 2012
[257] T Godfraind and S Salomone ldquoAmbiguities in dietary antiox-idant supplementation compared to calcium channel blockerstherapyrdquo Frontiers in Pharmacology vol 6 article 10 2015
[258] H Wagner H Norr and H Winterhoff ldquoDrugs with adap-togenic effects for strengthening the powers of resistancerdquoZeitschrift fur Phytotherapie vol 13 no 2 pp 42ndash54 1992
12 Oxidative Medicine and Cellular Longevity
NAD-H+ and butylated hydroxytoluene (BHT BOT)) orig-inally was examined in rat liver mitochondrial LP system inthe presence of Fe2+ ions and using the ultraweak chemilu-minescence method (Dubur et al [89])
Several 14-DHP derivatives Hantzsch ester diludine andits analogues were found to be effective antioxidants in thisexperimental system changing the kinetics of LP lengtheningthe time of the appearance of the maximum of the slowburst of the chemiluminescence (latency latent period) anddiminishing the reaction rate (the tangent of the slope angleduring the time in which the amplitude of the slow burstcharacterizing LP rate increases) and its peak value Theirpresence has influenced the reaction constant 119870
6 in relation
to a very significant reduction of lipid hydroperoxides andorinactivation of free radicals as follows
ROO∙ + ROO∙ 997888rarr P + h]lowast termination (1)
(P = molecular products) or
ROO∙ + ROO∙ +H2O 997888rarr ROH + RO∙ + 1O
2
lowast (2)
In this study diludine was one of themost active compoundsDHPs had activity similar to the standard synthetic AO-BHT(ionol) However when plotted against applied concentrationand time window diludinersquos activity profile differed from thatof BHT
There were also similar studies (using different LP rateexperimental detection system and method Hunter et al[133]) based on exploring a group of 26 26-dimethyl-35-disubstituted- and 26-dimethyl-345-trisubstituted-14-dihydropyridines (14-H
2Py=14-DHPs) and five related pyri-
dines as inhibitors of rat liver Mit swelling (Δ119860520119905) and O
2
uptake by ascorbic acid- (AsA-) dependent lipid peroxidationand as modulators of Mit swelling induced by Na+-linoleateor Na+-pyrophosphate (Velena et al [112])
Some of tested 4-DHPs (4-unsubstituted 35-dialkoxy-carbonyl-26-dimethyl-14-DHPs and 35-diamido-26-dim-ethyl-14-DHPs both 4-unsubstituted or those possessinglipophilic 4-aryl- groups) have shown significant AO andmembrane stabilizing activity These studies further revealedthat 14-DHPs preferably act as AO during the stages ofinitiation and prolongation of LP chain reactions at lowconcentrations The studied 14-DHPs had IC
50(when 119881
0119881
or 1205911205910= 2) 01 120583M to 100 120583M and the minimal activity was
scored for oxidized (heteroaromatized) derivativesAt the concentration of 100120583M 35-di-n-butyloxycarbo-
nyl-26-dimethyl-14-DHP entirely stops mitochondrialswelling in the presence of 08mM Na+-pyrophosphateAt the same concentration the following compoundsalter the mitochondrial swelling rate in the presence ofnatural protonophore Na+-linoleate 35-di-p-hydroxyphen-oxycarbonyl- and 35-di-p-tolyloxycarbonyl-26-dimethyl-14-DHPs 35-diethoxycarbonyl-26-dimethyl-pyridine (oxi-dized form of Hantzsch ester) and more lipophilic 35-diamyloxycarbonyl-26-dimethyl-pyridine The alteration ofswelling may be scored as prolonged promoted acceleratedor inhibited The type of alteration depends on the structureand concentration of 14-DHPs the type of initiators of theswelling process and the medium composition
In accord with previously published Janerorsquos results (lackof AO for Ca2+ antagonists nifedipine and nicardipine evenat 500120583M concentration in LP tests performed on heartmembrane [134]) no antioxidative activity for 4-phenyl sub-stituted derivatives of 35-dialkoxycarbonyl 14-DHP (closeanalogues of Ca2+ antagonists) was found contrary to various4-nitrophenyl 14-DHP derivatives calcium antagonists forwhich the significant antioxidant activity was reported [3146ndash53]
Studies made on phosphatidylcholine liposomes (ourunpublished data) suggest approximately three and twotimes more antioxidative activity for 100 120583M 4-unsubstitutedDHP compound diludine when compared to 4-substitutedDHPs riodipinenifedipine and nicardipine respectively atmethemoglobin-induced LP (oxygraphy)
Inhibition of mitochondrial AsA-dependent LP and sta-bilization ofmitochondriawere shown to be characteristic fora large group of 14-DHP compounds [112] showing to pos-sess the AOA in simplest in vitro systems (Tirzit andDuburs [39] Zilber et al [44] and Dubur et al [45])based on reactions with the stable free radical 11-diphenyl-2-picrylhydrazyl (DPPH) LP of fatty acid ester (linethole andmethyloleate) emulsions and phospholipid (phosphatidyl-choline) liposomes Generally these properties did not coin-cide with Ca2+ antagonism Depending on DHP structure itseems that AOA properties are less specific than Ca2+ antago-nist properties Both properties may be interrelated but notinterdependent
These data show that the presence and the nature ofa substituent in position 4 as well as 35-substituentsare important factors for 14-DHP antioxidant effects invarious systems that is AsA-dependent nonenzymatic aswell as enzymatic NADPH-dependent lipid peroxidationSometimes the efficacy of inhibition of nonenzymatic LPby 14-DHPs is higher than the inhibition of the enzymaticLP However the action may be opposite stimulation of theLP Hantzsch ester (HEH diludine) and its close analoguesexhibited significant AOA and membrane stabilizing prop-erties in both AsA-dependent nonenzymatic peroxidationof mitochondria and NADPH-dependent enzymatic LP ofmicrosomes usually at similar 10 to 100120583M concentrations[112]
The order of AOpotency (IC50
values) in vitro depends ondrug structure as well as on the experimental conditions andspecificity of the biological system Eachmethod for determi-nation of AOA and ARA has advantages and disadvantages(Karadag et al [135])
Accordingly as reported by Gubskiı et al [136] IC50
forthe AsA-dependent LP was 025 120583M and 20 120583M for 14-DHPCa2+ antagonists nitrepine (nitrendipine) and nifedipinerespectively Takei et alrsquos [137 138] studies on mitochondrialswelling induced by LP or arachidonic acid in the rat braindetermined the IC
50values of 127 105 1568 and 384 120583Mfor
efonidipine nicardipine nifedipine and nimodipine respec-tively For LDL in the copper-induced oxidation system theorder of potencywas vitamin Egt felodipinegt 2-chlorophenylanalogue of nifedipine gt nifedipine gt amlodipine nitrendip-ine verapamil and diltiazem (Rojstaczer and Triggle [119])
Oxidative Medicine and Cellular Longevity 13
It was interesting to compare the AOAofDHPswith theirsusceptibility to oxidation that is electron and hydrogendonating properties
It has been estimated that electron donor substituentsin positions 2 and 6 of 14-DHP cycle usually promoteoxidation while electron acceptor substituents promotequench oxidation Stronger electron acceptors in positions 3and 5 also significantly quench oxidation These estimationsare based on studies including chemical enzymatic andelectrochemical oxidation of 14-DHPderivatives (Dubur andUldrikis [70] Duburs et al [71] and Stradin et al [139])
On the other hand diminished AOA of 14-DHP relatesto presence of substituents in position 4 (both electron donorand electron acceptor) (Velena et al [112])
35-Dicarbamoyl substituents possess minimal quench-ing feature and are followed by benzoyl- acetyl- andalkoxycarbonyl- groups Maximal decrease was obtainedwith condensed substituents (ie oxoindeno- or oxocyclo-hexeno- groups) and a CN-group 4-Unsubstituted 35-dicar-bamoyl derivatives can be easily oxidized and consequen-tially inactivated whereas 4-substituted 35-dicarbamoyl-14-DHPs possess an oxidation potential analogous to the 4-unsubstituted 35-COOR derivatives Therefore they haveadequate electron donor properties and are considerablystableThismay be the reason for significantmembrane stabi-lization upon exposure to 4-substituted derivatives Ofimportance their AOA was usually more pronounced incomparison to 4-unsubstituted derivatives
Among them 26-dimethyl-35-difurfuryloxycarbonyl-14-DHP showed the highest antioxidative activity In thegroup of 35-dialkoxycarbonyl derivatives the strongestactivity was attributed to compounds with medium lengthalkyl chains (i-butyl- t-butyl- and i-amyl- substituents) highlevel of lipophilicity minimal electron acceptor propertiesand moderate steric hindrance as contrasted to short or longalkyl chain ester derivatives (35-dimethoxycarbonyl- 35-diethoxycarbonyl derivatives and 35-didodecyloxycarbonylderivative) These data demonstrate the bell-shaped depen-dence of AOA on alkyl chain length [112] and are in accordwith results obtained in liposomes However these datadiffer from those obtained in emulsions where diludine wasthe most active compound Finally oxidized heteroaromaticderivatives showed only minimal activity
In both LP systems studied (AsA-dependent in mito-chondria and NADPH-dependent in microsomes) some of14-DHPs showed activity similar to classical antioxidantbutylated hydroxytoluene (ionol BHT) (Velena et al [112])However there was a significant difference related to con-centration and incubation time It allowed us to postu-late that 14-dihydropyridines (InH) acting as antioxidants-reductants and scavengers of reactive oxygen species and lipidfree radicals preferably influence initiation and propagation(prolongation) of lipid peroxidation chain reactions (1)ndash(5) according to Scheme 2 The phenomenon is particularlyprominent in the presence of Fe2+ and other ions of variablevalency
Chain break and termination reactions (6)ndash(10) of theLP reaction cascade [89] were influenced by 14-DHPs in alesser degree than were initiation and propagation steps This
may be important for their therapeutic effects even in theadvanced stages of LP
Scheme 2 (stages of initiation propagation and terminationof lipid peroxidation chain reactions (1ndash10)) Initiation andpropagation reactions are as follows
(8) RO∙ + In∙minus rarr Y (Y = molecular products)(9) ROO∙ + Fe2+ rarr Fe3+ + X (X = molecular products)(10) RO∙ + RO∙minus rarr Y (Y = molecular products)
In the reversible swelling of mitochondria accompanyingLP (initiated by mixture of 5mM GSSG1mM GSH) several14-DHPs showed low or no activity manifested only as adecrease of the swelling amplitude without a rate decreaseAn addition of GSH (4mM) or ATP to swollenmitochondriacaused their contraction in both control and tested systemIt may be suggested that 14-DHPs acting as antioxidantsin mitochondria preferably influence LP reactions initiatedby ions with variable valency or their complexes with hemetype compounds methemoglobin hemin hematin and soforth (Velena et al [112]) If the peroxidation process has amaximal velocity and 50 percent of initial O
2were consumed
14-DHPs cannot completely break the chain reactions andprevent subsequent membrane damage by addition of DHPsubstance at 10 120583M concentration at the moment of 50percent oxygen consumption the subsequent oxygen uptakeproceeded unchanged This observation is important for theapplication of DHPs as inhibitors of initiation and to a lesserdegree propagation stages of LP chain reactions
The influence of 14-DHPs on Mit swelling is not strictlyassociated with their own oxidation There is the possibilitythat the labilizing (or stabilizing) effect relates to surfaceactivity (connected with substituent lipophilicity) or may bethe consequence of complexation with some -OH (or -CH
3)
group sensitive receptors at the mitochondrial membraneNamely a bathochromic shift of the absorption band maxi-mum (about 10 nm) was observed in the visible region beforeswelling However after swelling in the presence of Na+linoleate the spectrum returns to its initial value [112]
Some 14-DHPs not only protect mitochondria againstswelling caused by AsA-dependent LP salts of fatty acids
14 Oxidative Medicine and Cellular Longevity
in vitro [112] but also have beneficial effects on repairingtheir integrity in vivo after exposure to irradiation hepato-toxins ischemia hypoxia or hypothermia Some of themwere shown to normalize the process of intracellular repara-tion and physiological regeneration of ultrastructures Theywere also shown to stimulate reparative processes If pre-treated with 14-DHPs irradiatedmitochondria will not swell(Ivanov et al [140 141])
Diludine ionol and some other AOs mitochondria pro-tectors act as anti-ischemic agents If applied prophylacticallyin vivo they may prevent ischemic and reperfusion lesionsin heart kidney and other organs (Bilenko et al [113]) Theeffect is dependent on applied dose timing and way ofapplicationWhen added onto the cryoconservationmediumfor mitochondria preservation 14-DHPs prevented decreaseof membrane potential normalized facilitated respirationand prevented loss of mitochondrial Na+ and Ca2+ ionsafter thawing ([112] see citation number 36 (Subbota et alKharkov 1984) therein) Diludine was stronger protectorwhen compared to ionol
CA drug foridone (riodipine) was shown to possesscardioprotective features primarily due to is protective effecton mitochondria exposed to OS [142 143]
Similarly the DHP water-soluble antiarrhythmic com-pound glutapyrone inhibits initiation of LP by free radicalsin erythrocytes and heart mitochondria Its cardioprotectiveeffect has been experimentally shown in heart mitochondrialmembranes especially during deep hypothermia (Utno et al[144])
Cerebrocrast was effective in several translation modelsmimicking pathological situations known to be associatedwith cellular OS The potential protective action of 14-DHP derivatives (4-substituted compounds cerebrocrastgammapyrone glutapyrone and 4-unsubstituted drug dieth-one) has been studied in rat liver in experimental modelsrelevant for oxidative stress and mitochondrial bioenergetics(Fernandes et al [145]) When succinate was used as therespiratory substrate higher concentrations (gt25 120583M) ofcerebrocrast depressed respiratory control ratio (RCR) ADPto oxygen ratio (ADPO) state 3 and uncoupled respirationrates transmembrane potential (deltapsi) and the phosphatecarrier rate At the same time state 4 respiration rate wasthree times increased At concentrations lower than 25120583Mcerebrocrast inhibited mitochondrial IMAC and partiallyprevented Ca2+-induced opening of the mitochondrial PTPGammapyrone glutapyrone and diethone did not inducethese phenomena When applied at concentrations up to100 120583M cerebrocrast gammapyrone and glutapyrone didnot affect ADPFe2+-induced LP of mitochondria in rat liver(as measured by oxygen consumption and TBARS forma-tion) On the other hand low diethone concentrations (upto 5 120583M) inhibited it in a dose-dependent manner Diethonealso prevented against deltapsi dissipation induced by LPinitiated by ADPFe2+ Based on these data it may bespeculated that cerebrocrast (inhibition of the IMAC) anddiethone (acting as an AO) may provide effective protectionof mitochondria during OS Cerebrocrast has shown sometherapeutic potential for treatment of several pathologicalconditions related to cellular OS [145]
5-Acetyl(carbamoyl)-6-methylsulfanyl-14-DHP-carbo-nitriles (Figure 3) with minor differences in their molecularstructure displaying antioxidant and antiradical activitiesin vitro show different biological activities Namely 4-p-chlorophenyl derivative OSI-1146 displays AO and anti-radical activities in cardiovascular OS models whereasOSI-3701 and OSI-3761 display hepatoprotective activityThus these compounds may be potentially useful for treat-ing several pathological processes including those associatedwith OS (Fernandes et al [146]) However besides mito-chondria the cellular targets for their pharmacologicalactions have not been fully investigated [146] All these com-pounds increase the susceptibility of Mit to MPT The mostpotent is OSI-3701 although it does not affect bioenergeticparameters
Although all these compounds protected mitochondriaagainst LP induced by the oxidant pair ADPFe2+ OSI-1146was shown to be the most potent Current data point outmitochondria as potential targets for protective and toxicactions of DHPs suggesting that the potential for their use astherapeutic agents should also take into consideration theirtoxic effects on mitochondria (Fernandes et al [146])
Several structurally different DHP derivatives (antioxi-dant diludine (diethone) as a 4-unsubstituted DHP 4-substi-tuted DHPs CA foridone (bicyclic compound) and the 4-phenyldiethone compound where phenyl group is joined tothe DHP in position 4) inhibited the 1-methyl-4-phenyl-pyridinium iodide (MPP+) induced ROS production incerebellar granule cells (CGC) with a distinct potency orderforidone (26-dimethyl-35-dimethoxycarbonyl-4-(o-difluo-romethoxyphenyl)-14-dihydropyridine) gt 26-dimethyl-35-diethoxycarbonyl-4-phenyl-14-dihydropyridine gt diludineThey also reversed the MPP+-induced decrease of the mito-chondrial membrane potential in the same order (Klimavi-ciusa et al [147]) Accordingly it was postulated that theclassical two-ring (bicyclic) structure of DHP derivativesrepresents an advantage in relation to neuroprotection andROS defense and is independent on compoundrsquos propertiesrelated to calcium ions
Novel adamantane-containing 14-DHP compounds (Kli-maviciusa et al [148]) were also found to improve mitochon-drial functions (MPP+ model) (Klimaviciusa et al [148])Klusa et al [149] have discovered antineurotoxic effects of14-DHP taurine derivative tauropyrone recorded as Mitfunction improvement
Many 14-DHPs including Ca2+ antagonists and AOmodify LP processes and influencemitochondrial function invarious organs (liver heart kidney and brain) in a differentway and degree Their beneficial action oxygen or lipidfree radical scavenging antioxidative effects binding withor intercalating into phospholipid bilayer regulation of iongating and regulation of mitochondrial permeability transi-tion pores (Tirzit and Duburs [39] Zilber et al [44] andDubur et al [45]) separately or in combination with eachother depends on two strong elements (1) their individ-ual structure including nature of substituents and theirpositions and (2) the nature of the biological system Forexample the direction of LP (inhibition of promotion) wasshown to depend on structure and concentration of applied
Oxidative Medicine and Cellular Longevity 15
14-DHPs as well as stages of chain reactions Accordinglymitochondrial swelling may be prolonged (retarded) accel-erated (promoted) or inhibited (Velena et al [112])
Therefore there is a ground for 14-dihydropyridineseither Ca2+ antagonists or antioxidants to be nominated asuseful tools in development of ldquomitochondrial drugsrdquo relatedto the control of OS
(c) DHPs as AOs in Endoplasmic Reticulum (Inhibition ofNADPH-Dependent LP System) Inhibition of NADPH Oxi-dase by DHPs Elevated level of NADPH oxidase 4- (NOX4-)derived hydrogen peroxide (H
2O2) joined with concomitant
decrease of nitric oxide (NO) mediated signaling and reac-tive oxygen species scavengers are considered to be centralfactor in molecular pathogenesis of fibrosis (Sampson etal [150]) Inhibition of microsomal NADPH-dependent LPwith particular focus on NADPH oxidases (NOX1ndash5 andDUOX1) may be very important for neuro- cardio- andhepatoprotection (Velena et al [112] Leto and Geiszt [151]Griendling et al [152] and Chen et al [153]) Endoplasmicreticulum may be an important target as this is where 14-DHPs could display their antioxidative properties (Velena etal [112] Leto and Geiszt [151] Griendling et al [152] andChen et al [153])
However the initiation of LP in the NADPH-dependentmicrosomal system does not appear to involve either super-oxide or hydrogen peroxide since neither SOD nor cata-lase can inhibit it On the other hand reduced iron playsan important role in both the initiation and propaga-tion of NADPH-dependent microsomal lipid peroxidation(Hochstein and Ernster [154] and Repetto et al [111])
Many DHPs possess inhibitory activity not only towardsAsA-dependent LP in mitochondria but also towardsNADPH-dependent LP as shown in isolated rat liver micro-somes (Velena et al [112]) This means that these compoundsinteract with the shared parts (nonenzymatic and enzymatic)of LP pathways
Microcalorimetry and fluorescent probes procedureswere used for studying the interaction of alpha-tocopheroland 14-DHPs with endoplasmic reticulum membranes andmodel systems human serum albumin and phospholipidbilayers [155] Modification of microviscosity of the endo-plasmatic reticular membranes depends on localization ofantioxidants within the protein structures or phospholipidphase Increase of membrane structuralization under theinfluence of 14-DHPs blocked their antioxidant action inspontaneous and induced lipid peroxidation
Inhibition of rat heart and liver microsomal lipid perox-idation by nifedipine was observed [156] while Goncalves etal [157] found antioxidant effect of calcium antagonists onmicrosomal membranes isolated from different brain areas
Nitroaryl-14-DHPs are both calcium channel antagonistsand antioxidant agents (Letelier et al [158 159]) commonlyused for treatment of cardiovascular diseases These drugsmust be metabolized through cytochrome P450 oxidativesystem (NADPH-cytochrome P450 reductase) mainly local-ized in the hepatic endoplasmic reticulum Several lipophilicdrugs generate OS while being metabolized by this cellularsystem Thus DHP antioxidant properties may prevent the
OS associated with hepatic biotransformation of drugs Var-ious commercial and new nitro-phenyl-DHPs were studiedagainst LP using rat liver microsomes under oxidative stress[159]
Incubation of rat liver microsomes with the 41015840-nitro-4-phenyl-14-DHP compounds (26-dimethyl-4-(41015840-nitro-phenyl)-14-dihydropyridin-35-diethyl-dicarboxylate andN-ethyl-26-dimethyl-4-(41015840-nitrophenyl)-14-dihydropyri-din-35-dimethyl-dicarboxylate) results in an inhibitionof LP the UDPGT (UDP-glucuronyltransferase) oxidativeactivation and the microsomal thiol oxidation induced byFe3+ascorbate a generator system of ROS This effect wasalso produced by nitrofurantoin and naphthalene in thepresence of NADPH
Interestingly IC50
ofDHPs obtained frommicrosomal LPassays decreased to the same extent as the microsomal thiolsoxidation provoked by Fe3+ascorbate [159] Neverthelessthe AO effects of a nitrophenyl-DHP compound in whichhydrogen at position one of the DHP ring was replaced bythe ethyl groupwere significantlyweaker Authors speculatedthat DHPs can resemble NADH transferring one hydrogenatom of 4-position (Hminus) to anion superoxide and another ofthe 1-position (H+) by way of a cationic radical intermediateto generate pyridine derivatives and water [159]
The AO effects of various tested DHP derivatives (m- andp-NO
2phenyl as well as methyl or ethyl and isopropyl-DHP
35-dicarboxylate derivatives) were not significantly differentThe authors assumed that the -NH- group of the dihydropy-ridine ring could contribute both to the development ofthe calcium channel antagonism and to the antioxidativeproperties of DHPs [159]
Prevention of the membrane LP seemingly depends onthe concentration of potential antioxidants such as vitaminE or even 14-DHP in lipids However only the differencesin synthetic DHPs lipophilicity cannot explain significantvariations of DHPs concentration in microsomal membraneand cannot clarify the strength of their antioxidative activityThis work [159] has further demonstrated that 14-DHPsmay prevent the OS induced by biotransformation of somedrugs for example antibiotic nitrofurantoin Simultaneousadministration of DHPs and nitrofurantoinmay be beneficialin reducing nitrofurantoin side effects
While most of Ca antagonist 14-DHPs are metabolizedby CYP3A4 (Guengerich et al [160]) not all of them are goodinhibitors of its activity Thus nicardipine but not nifedipineand nitrendipine inhibits CYP3A4 in vitro [53] Interactionof different DHPs with various types of cytochrome P450 wasdescribed by Carosati et al [53] It was also reported thatDHP class calcium channel blockers reduce the antiplateleteffect of clopidogrel (Park et al [161])This implies themutualinteractions of both drugs with CYP3A4
(3) In Vivo Evaluation of nifedipine effects on Saccharomycescerevisiaewas recently published (Asma andReda [162]) Sur-prisingly nifedipine exercised a toxic effect on Saccharomycescerevisiae shown through measuring cellular proliferationrespiratory activity and the level of some biomarkers (CATand MDA)
16 Oxidative Medicine and Cellular Longevity
However majority of data obtained on various animalcells and tissues by other authors show the protective role ofDHPs against both LP and oxidative stress [113 163 164]
The AOA attributed to many 14-DHPs Ca2+ antag-onists and other compounds reflecting on catalytic LDLperoxidation (see Section 331 (2) and Section 35) shouldencourage their testing for treating cardiovascular diseasesandor alterations of lipid metabolism
The possibility that 14-DHP-based calcium antagonistsexert an antiatherosclerotic action (via inhibition of LDLoxidation and other mechanisms) has been proved by manyexperimental data [165] and several clinical trials Besidesantihypertensive effect nicardipine was shown to possessantioxidative and antielastase activity [165 166] These prop-erties may be useful for prevention of inflammatory reactionwhich is relevant for hypertension pathogenesis
14-DHPs administration inhibits LDL oxidation medi-ated by oxygen radicals leading to decreased carotid inti-mal media thickness and reduced progression of coronaryatherosclerosis [130] It additionally preserves Apo B-100integrity against ROS Of importance antiatherogenic mech-anisms differ between animals and humans (primarily inthe stage of conversion of aldehydes to carboxylic acids)(Parthasarathy et al [167])
For example furyl-DHP compound (FDP-1 diethyl 26-dimethyl-4-(furyl)-14-dihydropyridine-35-dicarboxylate)was shown to act as an antioxidant (decreasing MDA GOTand FFA release of ischemic myocardium and inhibiting Ca-ATPase of erythrocyte membranes) preventing against heartmyocardium ischemia-reperfusion injury and arrhythmiawhen applied (in rats) at 10mgkg (Liu et al [168])
Similarly antioxidative effects of azelnidipine andamlodipine prevented neuronal damage by CCBs aftertransient focal ischemia in rats (Lukic-Panin et al [169])
Allanore et al [170] found that both nifedipine andnicardipine significantly decrease the mean level of plasmamarkers for oxidative stress in patients suffering from sys-temic sclerosis
Antioxidants may be considered as promising neuropro-tective compounds Still while experimental data demon-strate neuroprotective effect in vitro and in animal mod-els clinical evidence is still unsatisfactory and insufficient[171]
(a) Role of Metabolism of DHPs in Their AOA Metabolicpathways and ldquobioavailabilityrdquo of the probable AOA com-pound determine antioxidant activity in vivo Antioxidantmetabolites may vary in stability and activity leading to twoopposite scenarios lack or presence of activity substantiallycontributing to the overall AOA [172] Metabolic biotransfor-mation of DHPs includes oxidation (heteroaromatization)side chain ester group cleavage (deesterification) and 4-substituent abstraction ao [160] None of the DHPs metabo-lites was shown to be more toxic than original reduced formof the compound The commonly detected metabolites ofthe DHPs do not seem to possess the AO activity (withsome exceptions as in the case of metabolites of nifedipineand its analogues including nitrosonifedipine [173 174]) (seefurther in Section 35) Due to DHPs intrinsic instability
achieving andmaintaining an adequate concentrationmay beproblematic both in vitro and in vivo
(b) Role of Concentration and Lipophilicity (MembraneWateror LipidWater Partition Coefficients) of DHPs inTheir Actionas AOs and Antiradical Compounds Antioxidative effects ofany antioxidant depend on its concentration at the site ofaction This parameter is hardly measurable especially intwo-phase systems representing one of obstacles in com-parison to AOA upon applying various compounds [172]It is often incorrectly assumed that the concentrations inthe aqueous solution and at the site of action are the sameHowever even when the concentration in the aqueous phasemay be well controlled the concentration at the site ofaction in the lipid matrix of the membranes might fluctuatebetween different test compounds depending on a differencein lipophilicity [175] The prevention of the membrane LPalso seems to be dependent on the DHP concentration in thelipidmatrix (Mason andTrumbore [46]) and its amphiphilic-ity For example AOA of diludine is associated with itslipophilicity and consequential ability to be incorporatedinto liposomes (Panasenko et al [176]) It was also foundthat diludine easily incorporates into the outer monolayer oferythrocyte membranes [176]
Membranebuffer partition coefficients (lambda) weredirectly measured in the sarcolemma and sarcoplasmicreticulum membranes for three CA DHPs The obtainedvalues were in a broad range between 5000 and 150000(Herbette et al [177])These drugs interact primarily with themembrane bilayer component but may also bind to proteinsboth nonreceptors and receptors The intrinsic forward rateconstants for DHP binding to sarcolemmal calcium channelreceptors were apparently not strongly dependent on theirmembrane partition coefficients For example nimodipine(lambda = 6300) had a forward rate constant of 68 plusmn 06 times106Ms whereas the forward rate constant for Bay P 8857
(lambda = 149000) was 14plusmn08times107Ms Since these DHPsare highly liposoluble model calculations for this bindingreaction demonstrated that these rates on lipid solubilitywould probably not be reflected in the experimental forwardrate constants In addition the intrinsic forward rate constantfor nimodipine binding to sarcolemmal calcium channelreceptors was found not to be linearly dependent on theviscosity of the buffer medium over a fivefold range The rateof drug nonspecific binding to nonreceptor protein present inhighly purified sarcoplasmic reticulum membranes appearsto be extremely fast at least 103 times faster than specificdrug binding to the receptor in the sarcolemma Authorsconcluded that partitioning into the lipid bilayer matrix ofthe sarcolemma could be a general property of CA DHPsand may be a prerequisite for their binding to sarcolemmalmembrane receptors (Herbette et al [177])
The binding of DHP calcium channel agonists and antag-onists (including those with AO properties) to receptors incardiac sarcolemmal membranes is a complex reaction thatmay involve an interaction with the lipid bilayer matrix ofthe sarcolemma (Herbette et al [178]) Belevitch et al [179]studied the binding of DHP CCBs (riodipine and nifedip-ine) and verapamil to model and biological membranes by
Oxidative Medicine and Cellular Longevity 17
fluorescence analysis The consistent location of Ca agonistBay K 8644 was determined to be within the region ofthe first few methylene segments of the fatty acyl chains ofthe membranes (Mason et al [180]) This position is nearto that observed for the DHP calcium channel antagonistsnimodipine and Bay P 8857
Themajority of studies onOSwere performedwithDHPswith various lipophilicity but only a few studies reportedamphiphilicity ofDHPderivatives AmphiphilicDHPderiva-tive K-2-11 reduced the cellular generation of ROS It alsorevealed complete reversal of multidrug resistance (MDR) ofthe resistant cells K-2-11 was more efficient than well-knownMDR inhibitor verapamil Cytotoxic effects of anticancerdrug doxorubicin were enhanced by K-2-11 in bothMDR andparental nonresistant cell line (Cindric et al [181]) K-2-11suppresses increase of ROS and consequentially prevents NF-120581B activation leading to decreased expression of MDR1 andincreased expression of antiapoptotic genes This signalingswitch is necessary for restoring the chemosensitivity ofcancer cells This phenomenon is characteristic both for14-DHPs [182] (18 novel asymmetrical DHPs bearing 3-pyridyl methyl carboxylate and alkyl carboxylate moietiesat C3 and C5 positions resp as well as nitrophenyl orheteroaromatic rings at C4) and for their oxidized formspyridine compounds (Zhou et al [183])
34 Dependence of AOA of DHPs on the Experimental SystemAO effect of DHPs depends on their structure and theexperimental system used (in vitromodel system subcellularorganelle and cells ex vivo and in vivo) Ideally for theevaluation of the profile and value of DHPs AO propertieseach compound should be tested in as many systems aspossible (Dubur et al [45])
Lipidomics studies have been traditionally explored forstudying AOA of DHPs Proteomics methods are less rep-resented and are mostly focused on the properties of DHPsrelated to scavenging of protein free radicals So far there areno studies on the role of DHPs in scavenging nitrosoperoxy-carbonate the reactive species formed out of peroxynitrite inthe presence of carbon dioxide Although it was shown thatalbumin binds diludine no studies revealed the relevance ofthis effect for the AOA of diludine
There are findings showing that dihydropyridine calciumantagonists (DHPs CA) could indirectly play a beneficialprotective role during development of atherosclerosisNamely Berkels et al [184] have studied antioxidativeproperties of four substances the DHP prototype CAnifedipine the long-acting CA lacidipine the DHP calciumchannel agonist BayK8644 and the bulkyDHPderivate BayO 5572 in three different models (1) in an in vitro superoxideanion generating system (hypoxanthinexanthine oxidase)for testing the ldquopurerdquo antioxidative effect (2) in an artificialmembrane preparation (dimyristoylphosphatidylcholine) formimicking a more physiological environment and (3) underconditions of stimulated ROS release (hyperglycemia) fromnative endothelial cells derived from porcine coronary arter-ies
The study also revealed the potential correlation betweenlipophilic and AO properties of DHPs In the first model
Bay K 8644 was significantly more effective in scavengingsuperoxide anions than lacidipine Bay O 5572 or nifedipine(micro- to millimolar concentration range) Addition of anartificial membrane preparation resulted in an enhancedAO effect with lacidipine being the most effective DHP inquenching radicals (low micromolar concentration range)In the third model mimicking hyperglycemia (30mmolL)nifedipine was significantly more potent antioxidant (ther-apeutical nanomolar concentration range) than the otherDHPs Calculated lipophilicity of these four substances(lacidipine gt Bay O 5572 gt Bay K 8644 gt nifedipine) waspositively correlated with antioxidative potential only in thesecond experimental model It has been concluded that AOproperties of DHP substances need to be tested in variousmodels for demonstrating that nifedipine exhibits ROS-quenching properties in a therapeutic concentration range[184]
341 AOA of DHPs in Isolated Cells and Cell Cultures(Comparison with Other Simplest Systems) Although DHPspossess neuromodulatory andor antimutagenic propertiesthe mechanisms of action related to these phenomena arenot entirely elucidated Borovic et al [185] have studied 14-dihydroisonicotinic acid (14-DHINA) derivatives of 14-DHP water-soluble analogues of a well-known AO diludine(diethone) 26-dimethyl-35-diethoxycarbonyl-14-dihydro-isonicotinic acid sodium 2-(26-dimethyl-35-diethoxycar-bonyl-14-dihydropyridine-4-carboxamido)glutamate gluta-pyrone and sodium 2-(26-dimethyl-35-diethoxycarbonyl-14-dihydropyridine-4-carboxamido)ethane-sulphate tauro-pyrone as AO and bioprotectors (Figure 4)
14-DHINArsquos activities were studied in comparison toTrolox by NN-diphenyl-N1015840-picrylhydrazyl (DPPH∙) deoxy-ribose degradation ABTS∙ radical scavenging and AOA(antioxidative capacity method) assays copper-induced LPof cultured rat liver cells (MDA determination by HPLCand 4-hydroxynonenal-protein conjugates by dot-blot) 3H-thymidine incorporation and trypan blue assay for liver cellsgrowth and viability Ic decreased the amount of 4-HNE-protein adducts In all assays Ia was the most potent AOable to completely abolish copper induced LP of liver cellswhile Ic only slightly decreased it Thus AOA is importantactivity principle of Ia which was even superior to Trolox intreated cell cultures Ia (and its analogues) are easily oxidizedin the Fenton system (Rubene et al [186]) exerting ARA too
35 Peculiarities Related to Antioxidative and AntiradicalActivity of Some 14-DHPs Ca Antagonists Nine commer-cialized structurally and functionally different DHPs CAwill be discussed further Their common feature is ability toprevent OS This also counts for some of their metabolitesas already discussed The comparative effects of some DHPsCA on oxidative stress-induced modification of LDL werealready reviewed in Section 331 (2)-(a) AOA of CA DHPswas discussed in Sections 331 (2)-(b) and 331 (2)-(c)
351 Nifedipine and Its Close Analogues Nifedipine vera-pamil and antiarrhythmic-antihypoxic drug stobadin wereshown to depress lipid peroxidation of phosphatidylcholine
18 Oxidative Medicine and Cellular Longevity
NH
COOH
NH
COONa
Glutapyrone
NH
Gammapyrone
NH
C 2H5OOC COOC2H5
Tauropyrone
14-DHINA
H3C H3C
H3C
H3CCH3 CH3
CH3
CH3
COOC2H5COOC2H5
COOC2H5 C2H5OOCC2H5OOCC2H5OOC
CONHCH(CH2)2COONa CONH(CH2)3COONa
CONH(CH2)2SO3Na
Figure 4 Derivatives of 14-dihydroisonicotinic acid (14-DHINA)
liposomes (Ondrias et al [187]) However data obtained insome other experimental systems are conflicting
In an in vitromodel of sarcolemmal membrane lipid per-oxidation three calcium blockers (nifedipine verapamil anddiltiazem) exhibited concentration-dependent (10ndash400 120583M)inhibitory effects [188 189] Nifedipine the most effectivecalcium blocker was more than two-fold potent compared topropranolol achieving significant effect at 10 120583M Nifedipineprotective role on LP using reduced glutathione as modelmarker was recently described (Ray et al [190]) Antiper-oxidative properties of CA nifedipine and its analogueswere explored in different systemspathogenic processesatherogenesis (Henry [165]) brain focal ischemia (Yamatoet al [191]) nephroprotection related to cyclosporine intake(Chander and Chopra [192]) and hepatoprotection relatedto intake of diethyldithiocarbamate (Gaafa et al [193])Recent data suggest that nifedipine action as protector forendothelial cells proceeds independently from its CA proper-ties
The absence of antioxidant effects of nifedipine anddiltiazemonmyocardialmembrane lipid peroxidation oppo-site to nisoldipine and propranolol was also described[194] Nisoldipine and propranolol were shown to havea concentration-dependent antiperoxidant effect with IC
50
values of 282 and 501 120583M respectively Finally nisol-dipine appeared to possess dual antiperoxidant mecha-nisms involving both preventive and chain-breaking proper-ties
These findings were confirmed in some other studiesincluding reports on the lack of antioxidative activity ofnifedipine and nicardipine even at 500120583M concentrationin heart membrane lipid peroxidation tests [134] SimilarlyROS formation in bovine aorta smooth muscle cells was notaffected by addition of amlodipine nimodipine and nife-dipine [123]
(1) Metabolites of Nifedipine and Its Analogues as Antioxidantsand Regulators of OS Antioxidant activity of nifedipine35-dimethoxycarbonyl-26-dimethyl-4-(2-nitrophenyl)-14-dihydropyridine was originally studied in vitro by Kirule etal [195] and Tirzit et al [196] According to the kinetic dataof peroxide accumulation and the ESR spectra (inhibition ofthe autoxidation of methyl oleate in presence of nifedipine)AO action was exerted by the formation of nitroso analogueof the oxidized nifedipine nitroso nifedipine 26-dimethyl-4-(2-nitrosophenyl)-35-pyridine dicarboxylate (NO-NIF)This nitroso aromatic derivative can form nitroxyl radicalsexhibiting remarkable AOA in the presence of unsaturatedfatty acids and lipids [196]
The primary species of free radicals that have beenobtained and identified were ion radicals of the nitrophenyltype (Ogle et al [76]) Such a mechanism coincides withmechanisms proposed afterwards by Nunez-Vergara et al[96] Lopez-Alarcon et al [103] Valenzuela et al [104]Fukuhara et al [174] and Yanez et al [197]
There are also data showing that nitroso compounds mayinhibit LP by direct radical trapping and subsequent forma-tion of stable nitroxide radicals It was further found that thereactivity between the synthesized 14-DHP derivatives withalkylperoxyl radicals involves electron transfer reactionsThisis documented by the presence of pyridine as a final productof the reaction and complete oxidation of the nitroso groupin the case of the nitrosoaryl 14-dihydropyridine derivatives(Valenzuela et al [104]) Tested compounds reacted fastertoward alkylperoxyl radicals and ABTS radical cation thanalkyl ones (Lopez-Alarcon et al [103])
Nitrosonifedipine a photodegradation product of nifedi-pine significantly recovers cellular damage induced by tumornecrosis factor-alpha It also prevents toxic effects of cumeneperoxide which hampers integrity of cell membranes throughoxidative stress Its positive effects are equal to Trolox-C
Oxidative Medicine and Cellular Longevity 19
As a result nitrosonifedipine was already a long time agoclaimed as a candidate for a new class of antioxidative drugs(Kirule et al [195]) cellular protectors against oxidative stressin glomerular endothelial cells [174]
Moreover Misik et al [198] Ondrias et al [199] andStasko et al [200] studied AOA of nifedipine and its oxidizednitroso analogue NO-NIF prevents the progression of type2 diabetic nephropathy associated with endothelial dysfunc-tion through selective AO effects (Ishizawa et al [201]) NO-NIF administration reduces albuminuria and proteinuriaas well as glomerular expansion without affecting glucosemetabolism or systolic blood pressure NO-NIF also sup-presses renal and systemic OS and decreases the expressionof intercellular adhesion molecule-1 (ICAM-1) a marker ofendothelial cell injury in the glomeruli of the KKAy miceSimilar effects were achieved in endothelial nitric oxide syn-thase (eNOS) knockout mice Moreover NO-NIF suppressesurinary angiotensinogen (AGT) excretion and intrarenalAGT protein expression in proximal tubular cells in theKKAy mice On the other hand hyperglycemia-inducedmitochondrial superoxide production was not attenuated byNO-NIF in cultured endothelial cells
Fujii and Berliner found EPR evidence for free radicaladducts of nifedipine in vivo [202] The nature of these rad-icals was surmised by comparing the reaction of illuminatednitrosonifedipine with polyunsaturated fatty acids Surpris-ingly identical radical spectra were detected from excisedliver doped with nonilluminated nifedipine suggesting thatthis drug can be enzymatically converted in vivo to its nitrosoanalogue without the requirement for illumination This isone of the first reports of in vivo EPR evidence for a class ofunsaturated fatty acid radical conjugates resulting from thenormal metabolism of a common drug
Dıaz-Araya et al [173] studied some 4-nitrophenyl-DHPson Fe3+ initiated LP in rat brain slices LP as measuredby MDA formation was inhibited by all the tested nitro-aryl derivatives of 14-DHP over a wide range of concen-trations On the basis of both time course and IC
50experi-
ments the tentative order of AOA on rat brain slices wasnicardipine gt nisoldipine gt (RSSR)-furnidipine gt (RRSS)-furnidipine gt nitrendipine gt nimodipine gt nifedipine14-DHP derivatives that lack a nitro group in the mole-cule (isradipine and amlodipine) also inhibited LP in ratbrain slices but at higher concentrations than that of nitro-substituted derivatives All tested compounds reduced andoxidized nitrosoaryl derivatives (26-dimethyl-4-(2-nitro-sophenyl)-35-pyridinedicarboxylic acid dimethyl ester (pho-tooxidation product of nifedipine ndash NTP) ao) and weremore potent inhibitors of LP than their parent molecules(Valenzuela et al [104])
The electrooxidation process of 4-nitrosoaromatic DHPsis a strongly pH-dependent (two-electron two-proton mech-anism) ECEC type of mechanism that is the sequenceeminusH+eminusH+ at pH gt 85 ECCE mechanism (eminusH+H+eminus)at pH lt 85 dominates Reduction reaction of nitroso groupis as follows R-NO + 2eminus + 2H+ rarr RNHOH (Bollo et al[203])
352 Lacidipine It is a generic DHP type antihypertensiveCA 35-diethyl 4-2-[(1E)-3-(tert-butoxy)-3-oxoprop-1-en-1-yl]phenyl-26-dimethyl-14-dihydropyridine-35-dicarboxy-late
Ursini [204] described redox behaviour of lacidipine andshowed its tissue protective features Cristofori et al studiedantiatherosclerotic activity in addition to lacidipinersquos CAand AO properties [205] Lacidipine reduced the extent ofatherosclerotic area in hypercholesterolemic apoE-deficientmice (these mice show widespread vascular lesions whichclosely resemble the inflammatory fibrous plaques seen inhumans in atherosclerosis) The reduction may be associatedwith the capacity of the drug to maintain endothelial NOlevels at concentrations useful to protect against vasculardamage This work suggested that DHPs modulate vascularrelaxation via increased release of NO
Herbette et al [178] remarked optimal hydrophobicity oflacidipine due to cinnamic acid substituent so membraneinteractions and facilitation of the treatment of atherosclero-sis could proceed (see also Section 331 (2)-(a))
353 Amlodipine Amlodipine (Norvasc) (RS)-3-ethyl5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-14-dihydropyridine-35-dicarboxylate (AML) hasan antioxidant effect on vessels in vitro and is a 3rd genera-tion of charged dihydropyridine CCB that is widely used forthe treatment of hypertensive patients
Amlodipine was shown to have the highest affinity(amlodipine gt verapamil ≫ diltiazem) for the membranebilayer (119870
119901= 104) It produced the significant changes in
membrane thermodynamic properties including a reductionin the thermal phase transition temperature (minus11) enthalpy(minus14) and cooperative unit size (minus59) relative to thecontrol phosphatidylcholine liposomes (Mason et al [49])
Amlodipine AOA is related to its reductant nature orhydrogen donor properties respectively Its ability for donat-ing protons and electrons to the lipid peroxide moleculesblocks the LP process
Amlodipine and even its enantiomers (Zhang et al [206])act as ROS andNOS effectors in several model systems of OSAntioxidant properties of amlodipine were recently reviewedby Vitolina et al [32] Both in vitro and in vivo studiesof amlodipine AO properties revealed inhibition of lipidsoxidative damage primarily those associated with cellularmembranes and lipoprotein particles (LDL) (Mason et al[50])
Under controlled experimental conditions in vitro amlo-dipine showed AOA and ARA by inhibition of lipid peroxideformation and trapping ROS Its scavenging activity forhydroxyl and peroxyl radicals at concentrations as low as100 nmolL (which is remarkably less compared to the classi-cal antioxidants GSH uric acid and Trolox) was shown to beindependent of the calcium channel modulation (Franzoni etal [207])
AML showed efficiency as scavenger of peroxyl radicals(TOSC assay 5945 plusmn 544 unitsmg) significantly stronger(gt50 119875 lt 0001) than GSH (2733plusmn 636 unitsmg) and 70weaker (119875 lt 00001) than uric acid (18144 plusmn 696 unitsmg)and Trolox (17522 plusmn 734 unitsmg)
20 Oxidative Medicine and Cellular Longevity
Of interest the scavenging capacity of AML towardshydroxyl radicals (1455 plusmn 154 unitsmg) was 320 higher(119875 lt 000001) than that of GSH (358 plusmn 112 unitsmg) 20higher than that of uric acid (1198plusmn121 unitsmg) and 100higher than that of Trolox (759 plusmn 143 unitsmg)
Amlodipine was shown to increase enzyme activity ofparaoxonase (PON) and glutathione peroxidase (GSH-Px)However it also decreases glutathione reductase (GSSG-R)activity and diminishes the concentration of the endogenousantioxidant 120572-tocopherol (vitamin E) Moreover AML in aconcentration of 2 ngmL decreased the content of malonicdialdehyde and activity of superoxide dismutase in the blood(Gatsura [208])
Verapamil and amlodipine produced a potent anti-ischemic effect and reduced area of myocardial infarction inrats The observed changes were accompanied by inhibitionof LP In contrast to verapamil in vitro application of AML ina dose of 50 ngmL decreased hemoglobin affinity for oxygenWhen present in a concentration of 2 ngmLAMDdecreasedthe content of MDA and activity of SOD in the blood
On the other hand amlodipine shows no activity relatedto inhibition of macrophage superoxide release and cellmigration which occurs as a consequence of decreasedTNF120572induced O
2
∙ releaseAmlodipine-induced reduction of OS in the brain is
associated with sympathoinhibitory effects in stroke-pronespontaneously hypertensive rats (SHRSP) (Hirooka et al[209]) Antihypertensive treatment with amlodipine reducedOS in all examined areas of the brain and decreased bloodpressure without a reflex increase in sympathetic nerveactivity Nicardipine another CA DHP surprisingly wassignificantly less active than amlodipine
354 Lercanidipine Tomlinson and Benzie reported AOeffect of lercanidipine [210] which is well known as anti-hypertensive drug Zanidip 2[(33-diphenylpropyl)(methyl)-amino]-11-dimethylethyl methyl 26-dimethyl-4-(3-nitro-phenyl)-14-dihydropyridine-35-dicarboxylate Compara-tive data about this drug AOA were presented in parts of thispaper about other individual CA DHPs and in the part aboutthe ex vivo DHPs effects on LDL
355 Nimodipine Nimodipine (ND) commercially knownas Nimotop is 3-(2-methoxyethyl) 5-propan-2-yl 26-dim-ethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxy-late It is centrally active CA
Treatment with glutathione blocked andwith nimodipineattenuated neuronal cell death caused by prolonged exposureof cell culture to 4-HNE (Faraqui [211])
Nascimento et al [212] found AO effect of nimodipine inyoung rats after pilocarpine- (PIL-) induced (in 400mgkg)seizures The PIL administration increased the striatal cata-lase (CAT) activity The administration of ND 30mgkg30min before PIL preserved normal value of CAT activityOn the other hand no difference was detected in the animalstreated with lower dose 10mgkg These results confirmthe neuroprotectiveantiepileptic effect of ND in young ratssuggesting that this drug acts positively on lipid peroxidation
(in both doses) Nimodipine cannot induce these effects viablockade of Ca2+ channel
Ismailoglu et al [213] studied the therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjury These beneficial effects in rats after cerebral corticalinjury seemed to be related to AOA of nimodipine
356 Benidipine Licensed in Japan and South Asia as CA(CCB) benidipine possesses AO properties Chemically it is5-methyl 3-[(3R)-1-(phenylmethyl)piperidin-3-yl] 26-dim-ethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxy-late (or its hydrochloride (4R)-rel-35-pyridinedicarboxylicacid 14-dihydro-26-dimethyl-4-(3-nitrophenyl)- 3-methyl5-[(3R)-1-(phenylmethyl)-3-piperidinyl] ester hydrochloride(1 1))
Benidipine influences processes connected with OS inseveral ways It prevents lysophosphatidylcholine- (lysoPC)-induced injury and ROS production in human aorticendothelial cells (HAECs) (Matsubara and Hasegawa [214])Matsubara et al [215] explained this effect based on stimula-tion of nitric oxide release
LysoPC is a component of oxidized low-density lipopro-teins (oxLDLs) which plays an important role in the patho-genesis of atherosclerosis Pretreatmentwith benidipine (03ndash3 120583molL) for 24 h protected against lysoPC-induced cyto-toxicity in the HAECs through inhibition of both lysoPC-stimulated ROS production and caspase-37-like activationwith a similar potency Since caspase-37 is involved inexecuting the apoptotic process the reduction of the activityof this enzyme by benidipine may explain the antiapoptoticeffect of the drug However benidipine did not suppresslysoPC-induced phosphorylation of mitogen-activated pro-tein kinases and Ca2+ influx in HAECs These results suggestthat the antioxidant properties of benidipine may be respon-sible for its ability to inhibit ROS production a possiblereason for reduced activation of caspase-37 In conclusionbenidipine suppresses lysoPC-induced endothelial dysfunc-tion through inhibition of ROS production which is due atleast in part to its antioxidant effect and not through theinhibition of L-type voltage-dependent calcium channels
Matsubara and Hasegawa [216] examined the effectsof benidipine on cytokine-induced expression of adhesionmolecules and chemokines (chemoattractants) which areimportant for the adhesion of monocytes to endotheliumPretreatment of HAECs with benidipine (03ndash10 120583molL)for 24 h significantly suppressed cytokine-induced vascularcell adhesion molecule-1 (VCAM-1) and intracellular celladhesion molecule-1 (ICAM-1) mRNA and protein expres-sion resulting in reduced adhesion of THP-1 monocytesBenidipine also suppressed induction of monocyte chemoat-tractant protein-1 (MCP-1) and interleukin-8 Benidipinealso inhibited redox-sensitive transcriptional nuclear factor-120581B (NF-120581B) pathway as determined by Western blotting ofinhibitory 120581B (I120581B) phosphorylation and luciferase reporterassay Results of analysis using optical isomers of benidip-ine and antioxidants suggest that these inhibitory effectswere dependent on pharmacological effects other than Ca2+antagonism Benidipine may thus have anti-inflammatoryproperties and benefits for the treatment of atherosclerosis
Oxidative Medicine and Cellular Longevity 21
Benidipine was also shown to inhibit ROS production inpolymorphonuclear leukocytes and oxidative stress in salt-loaded stroke-prone spontaneously hypertensive rats (Mat-subara et al [217])
It should be mentioned that other DHPs also haveendothelial AO actions [218]
357 Azelnidipine (AZL) Azelnidipine 3-[1-[di(phen-yl)methyl]azetidin-3-yl] 5-propan-2-yl 2-amino-6-methyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate(AZL) CAS number 123524-52-7 is commercially available4-nitroaryl-DHP type calcium antagonist with long-actingantihypertensive action (long-acting CA (CCB)) and a lowreported incidence of tachycardia It additionally possessesbeneficial effects in OS and diabetic conditions
Azelnidipine prevents cardiac dysfunction in strepto-zotocin-diabetic rats by reducing intracellular calcium accu-mulation (altering intracellular Ca2+ handling proteins) OSand apoptosis (Kain et al [219]) AZL can reduce the superox-ide production It exerts its protective effects by targeting theNADPH oxidase and mitochondrial redox enzymes AZL-treated diabetic rats express enhanced level of bcl-2 in thelysates of heart muscle indicating that AZL plays protectiverole in cardiac apoptosis
It has been previously observed that azelnidipine inhibitstumor necrosis factor-alpha-induced endothelial cell (EC)oxidative stress through its AO properties (Nakamura etal [220]) Azelnidipine but not nitrendipine completelyinhibits the Ang II-induced ROS generation in ECs (Matsuiet al [221])
Furthermore azelnidipine but not nitrendipine wasfound to partially restore decreased pigment epithelium-derived factor (PEDF) mRNA levels in Ang II-exposed ECsThis study suggests that AZL influence depends on its antiox-idative properties Authors concluded that upregulation ofPEDF by azelnidipine may become a therapeutic targetfor the treatment of diabetic retinopathy associated withhypertension
Antihypertensive agents with AO effects are potentiallyuseful for diabetic patients with hypertension While DHPtypeCAare among themost frequently used antihypertensivedrugs azelnidipine has been reported to have a unique AOeffect in vitro and in vivo in experimental animals (Ohmuraet al [222]) In hypertensive diabetic patients azelnidipinetreatment for 12 weeks induced a more significant decreasein erythrocyte LOOH level than amlodipine although thevalues related to blood pressure during each treatmentremained comparable These data confirm the usefulness ofLOOH level in erythrocyte membrane as a marker of OS invivo and indicate that azelnidipine has a unique antioxidativeproperty in humans
Daikuhara et al [223] reported the results of the OLCAstudy based on combination of (1) olmesartan and a calciumchannel blocker (azelnidipine) or (2) candesartan and a CCBamlodipine in two groups of diabetic hypertensive patientsPatients treated with the first combination presented highlypersistent early morning antihypertensive effect and strongerdecrease in heart rate fasting blood glucose andHbA1c levels
and microalbuminuria when compared to patients treatedwith the combination (2) Because diabetes is associated withsevere chronic OS the observed results might be at least in apart due to the AOA of azelnidipine
In favor of this are findings of Abe et al [224] who foundadditive antioxidative effects of azelnidipine on angiotensinreceptor blocker olmesartan treatment for type 2 diabeticpatients with albuminuria
Similarly the AOA of thiazolidinediones (insulin sensi-tizer) and their effect on cardiovascular function in type 2diabetic model rats and also those of some DHPs (nifedipineamlodipine or AZL commonly used antianginal and anti-hypertensive agents) in cultured human endothelial cells LPwere examined (Mizushige [225]) The AOA was evaluatedby measuring 8-iso-prostaglandine F
2120572concentration and
azelnidipine exhibited potent AOAInsulin (INS) resistance combined with hyperinsuline-
mia is involved in the generation of OS A relation-ship exists between increased production of ROS and thediverse pathogenic mechanisms involved in diabetic vascularcomplications including nephropathy Manabe et al [226]revealed that high doses of INS augmented mesangial cellproliferation through generation of intracellular ROS andactivation of redox signaling pathways Cell proliferation wasincreased in a dose-dependent manner by high doses of INS(01ndash10 120583M) but was inhibited by 01120583M AZL Namely theINS-increased phosphorylation of mitogen activated proteinkinaseextracellular signal-regulated kinase 12 (MAPKERK12) was inhibited by 01 120583MAZL The same AZL concen-tration blocked intracellular ROS production more effec-tively than 01 120583M nifedipine The NADPH oxidase inhibitorapocynin (001ndash01120583M) prevented INS-induced mesangialcell proliferation So azelnidipine inhibits insulin-inducedmesangial cell proliferation by inhibiting the productionof ROS Therefore azelnidipine may have the potential toprotect against the onset of diabetic nephropathy and slowits progression
Azelnidipine inhibited H2O2-induced cell death in
neonatal rat cardiomyocytes (Koyama et al [227]) Azelnidip-ine and nifedipine did not affect theH
2O2-induced activation
of extracellular signal-regulated protein kinases (ERK) andp38 MAPK (mitogen-activated protein kinase) In contrastazelnidipine but not nifedipine inhibited H
2O2-induced c-
Jun NH2-terminal kinases (JNK) activation Authors con-
cluded that azelnidipine has inhibited theH2O2-induced JNK
activation and cardiac cell death Therefore azelnidipine mayhave cardioprotective effects against OS
A specific atheroprotection activity of azelnidipine relatesto inhibition of TNF-120572-induced activator protein-1 activa-tion and interleukin-8 expression in human umbilical veinendothelial cells (HUVEC) through suppression of NADPHoxidase-mediated reactive oxygen species generation (Naka-mura et al [220]) TNF-120572 could play a central role in patho-genesis of insulin resistance and accelerated atherosclerosis inthe metabolic syndrome The concentration of AZL found tobe effective in these in vitro experiments is within therapeuticrange As EC do not possess voltage-operated L-type calciumchannels it is suggested that the beneficial effects of azelni-dipine are not likely due to CA property but to its unique AO
22 Oxidative Medicine and Cellular Longevity
ability Furthermore it has been recently found that serumlevels of monocyte chemoattractant protein-1 a biomarkerfor subclinical atherosclerosis were significantly decreased bythe AZL treatment in patients with essential hypertension Inthis paper [220] authors hypothesize that due to its uniqueTNF-120572 signalmodulatory activity and antioxidative propertyazelnidipine may be a promising DHP for targeting diabetesand cardiovascular diseases in hypertensive patients withmetabolic syndrome
Shinomiya et al [228] evaluated its AOA in culturedhuman arterial EC under OS Azelnidipine has shown apotent antioxidative effect that could be of significant clinicalbenefit when combined with its long-lasting antihypertensiveaction and low incidence of tachycardia
Azelnidipine inhibited TGF-1205731 and angiotensin II- (AngII-) activated 1205721(I) collagen mRNA expression in hepaticstellate cells (HSCs) (Ohyama et al [229]) FurthermoreTGF-1205731- and Ang II-induced OS and TGF-1205731-induced p38and JNK phosphorylation were reduced inHSCs treated withAZL Azelnidipine significantly decreased inflammatory cellinfiltration profibrotic genes expression HSC activation LPoxidative DNA damage and fibrosis in liver of CCl
4- or
TAA-treated mice Finally AZL prevented decrease of theexpression of some AO enzymes and accelerated regressionof liver fibrosis in CCl
4-treated mice Hence the antifibrotic
mechanism of AZL against CCl4-induced liver fibrosis in
mice may have been due to an increased level of AO defenseAs azelnidipine is widely used in clinical practice withoutserious adverse effects it may provide an effective newstrategy for antifibrotic therapy
358 Manidipine Manidipine (2-[4-(diphenylmethyl)pip-erazin-1-yl]ethyl methyl 26-dimethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate) is a DHP CCB withreported nephroprotective properties Calo et al [230] stud-ied effect of manidipine on gene expression and proteinlevel of OS related proteins p22(phox) (human neutrophilcytochrome b light chain (CYBA)) and heme oxygenase-1HO-1 Relevance for antihypertensive effects was revealedThe study assessed the effect of manidipine on normalsubjectsrsquo monocyte gene and protein expression of OS relatedproteins such as p22phox a NADPH oxidase system subunitcritical in generating O
2
∙minus and HO-1 induced by and pro-tective against OS Manidipine was compared with the ACEinhibitor captopril and the CCB nifedipine in the presenceand in the absence of sodiumarsenite (NaAsO
2) as an inducer
of OS Monocyte p22phox (CYBA) mRNA production wasreduced by both manidipine and captopril while no changeswere induced by nifedipine Manidipine increased monocyteHO-1 mRNA production while nifedipine and captoprilshowed no effect The effects of manidipine on p22phoxand HO-1 gene expression in the presence of OS were alsoconfirmed at the protein level Thus manidipine seems tosuppress p22phox and to increase the HO-1 mRNA produc-tion and protein level The manidipine-induced increase ofHO-1 gene and protein expression seems to be a peculiareffect of this drug since it is not observed with captopriland nifedipine This effect together with the reduction of
p22phoxmRNAproduction could play a role in its protectivemechanism against OS
359 Mebudipine The protective effect of mebudipine (14-dihydro-26-dimethyl-4-(3-nitrophenyl)-35-pyridinedicar-boxylic acid 3-methyl-5-tert-butyl ester BAY-n-6391) wasrevealed on OS and LP (MDA decrease SOD GPX andcatalase increase) in myocardial ischemic-reperfusion injuryin male rats (Ghyasi et al [231])
There are articles about other commercial and experi-mental DHPs on OS but we have reviewed only the mostcommonly studied compounds Effects of other commercialCA DHPs on OS are also mentioned in several parts of thisreview
36 14-DHPs Ca Agonists andTheir AOA and ARA For themost popular calcium agonist DHP Bay K 8644 no reactionwith peroxyl radicals was registered (Toniolo et al [114])However interactionwith other compounds possessing AOAand ARA (quercetin) was found
Opposite to that AON-acetylcysteine (NAC) diminishedincrease in Ca2+ transient amplitude and cell shorteninginduced by ISO and forskolin whereas NAC had no effecton the (S)-(minus)-methyl-14-dihydro-26-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylatemdash(minus)-BayK 8644-induced increases (Andersson et al [232])
Increased vasoconstriction responses to Bay K 8644 (3 times10minus7ndash3times 10minus5M)were significantly decreased by pyridoindoleantioxidant stobadine treatment in diabetes (Ceylan-Isik etal [233])
The functional interaction between two L-type Ca2+channel activators quercetin and Bay K 8644 has beeninvestigated in vascular smooth muscle cells Biological ARAcompound quercetin at nutritionally meaningful concen-trations limited the responsiveness of vascular L-type Ca2+channels to the pharmacological stimulation operated by BayK 8644 These data contribute to a better understanding ofquercetin effects on experimental in vivo cardioprotection(Saponara et al [234]) Thus these findings indicated thatalthough Bay K 8644 does not exert potent and direct AOAyet acting as calcium agonist it may affect efficiency of AOsubstances and vice versa
Interaction of grapefruit juice (containing quercetin andits analogues) with DHPs CA diminished effectiveness of CAaction of DHPs (Sica [235])
37 Interpretations of the Mechanism(s) of RadicalScavenging and AOA by DHPs
371 Molecular Mechanism(s) of Radical Scavenging andAOA of DHPs in the Model Systems 35-Dicarbonyl-14-di-hydropyridine derivatives possess powerful bis-120573-carbony-lvinyl-amino conjugation and for that reason cannot be con-sidered as ordinary amino antioxidants The electron andorH donation from DHPs ensures their reductant role andresults in AOA and ARA Oxidation reaction from DHPsresults in production of corresponding heteroaromatic pyri-dine derivatives
Oxidative Medicine and Cellular Longevity 23
Detailed studies were made about substituent in DHPring positions 14- namely 4-unsubstituted- 4-substituted4-alkyl- 4-aryl- 4-alkylaryl- ao 26- 35- (diacetyl ordialkoxycarbonyl chain ao) electronic and steric effects onAOA and ARA of DHPs [44 45 51] see Sections 331and 35 The bell-shaped dependence of DHPs AOA onthe 35-dialkoxycarbonyl- chain length was observed [4445 107 109 112] with the maximum activity at C
2H5ndash
C4H9 Decrease of AOA and incorporation into liposomes for
DHPs with alkyl chains longer than R gt C4H9further were
clarified as probable tendency to self-aggregation of thesecompounds ([51] and citation number 245 therein) Electronacceptorelectron donor properties are relevant for expres-sion of AOA or ARA of 35-disubstituted DHPs 35-Diacyl-substituted and 35-dicarbanilido- and 35-dipyridylamido-substituted DHPs are more active as AOs as their 35-dicyano-substituted analogues which have electron acceptorproperties [186]
Dubur et al [89] observed overwhelming steric influenceof substituents in position 4 of the DHP ring Gaviraghiet al [163 164] proposed that AO activity of DHPs ispartly dependent on capacity of the 14-DHP ring to donateelectrons to the propagating radical (ROO∙ or RO∙) and toreduce it to a less reactive form The abstraction (donation)of electron andor H in the oxidation and LP reactionstakes place from all 35-dicarbonyl-14-DHP systems andresults in the formation of corresponding pyridine derivatives(Augustyniak et al [51]) The physicochemical mechanism ofARA and AOA of 14-DHP has been extensively studied anddiscussed (Mulder et al [236]) but precise mechanisms oftheir activity need further clarification
The reactivity of C-4 substituted 14-DHPs possessingeither secondary or tertiary nitrogen atom in the DHP ringtoward alkyl alkylperoxyl radicals and ABTS radical cationwas determined in aqueous media at pH 74 [103] Thesecompounds reacted faster toward alkylperoxyl radicals andABTS radical cation than alkyl ones N-Ethyl-substitutedDHPs showed the lowest reactivity
The 4-methyl substituted DHP was the most reac-tive compound in previously mentioned reactions (Lopez-Alarcon et al [103]) However it was less active (068versus 10) than Trolox-C DHPs having electron-donatingsubstituents (4-Me-DHP and p-MeO-Phe-DHP) showed thehighest kinetic rate constants toward ABTS radical cation p-nitro-Phe-DHP a compound with an electron-withdrawingsubstituent showed a lower kinetic rate constant and N-alkyl-DHP compounds show kinetic rate constants lowerthan the -NH-DHP
Hydrogen at the 1-position of the DHP ring was revealedaccording to the deuteriumkinetic isotope effect studies to beinvolved in the proposedARAmechanismThis fact ismostlynoticeable in the case of alkyl radicals N-Ethyl-substitutedDHPs show the lowest reactivity when compared to Troloxor nisoldipine In all cases the respective pyridine derivativewas detected as the main product of the reaction (Lopez-Alarcon et al [103]) Authors indicate that the kinetic rateconstants toward alkyl alkylperoxyl andABTS radical cationdepend on the nature of the substituents in the C-4 positionof DHP and the presence of the secondary amine group in the
dihydropyridine ring that is the presence of the hydrogen in1-position
Yanez et al [197] have studied the reactivity of 11derivatives of 14-DHPs (including commercial CA) withalkylperoxyl radicals and ABTS radical cation The tested14-DHPs were 83-fold more reactive towards alkylperoxylradicals than to the ABTS cation radical All commercial14-DHP type CCBs were weaker than Trolox-C The par-ticipation of the hydrogen atom in the 1-position appearsto be very relevant for exhibited reactivity Hantzsch ester(diludine)was again found to be themost active compound inthe reaction with alkylperoxyl radicals 23-fold more activethan Trolox The photodegradation product of nifedipine(nitrosophenyl derivative of pyridine) also showed a highactivity Kinetic rate constants for the reaction between 14-DHP compounds and alkylperoxyl radicals exhibited a fairlygood linear correlation with the oxidation peak potentialof DHP derivatives However the activity of tested 14-DHPs towards ABTS radical cation showed an independencebetween kinetic rate constants and oxidation peak potentials
Kirule et al [195] andTirzit et al [196] studiedmechanismof AOA of 4-nitrophenyl-14-DHPs nifedipine and its ana-logues involving formation of 4-(21015840-nitrosophenyl)-pyridinederivative (as active principle) as a result of intramolecularredox reaction using chemical electrochemical and bio-chemical approaches (see Sections 331 and 351)
Nunez-Vergara et al [237] reported the electrochemicaloxidation of C4-hydroxyphenyl-substituted 14-DHP deriva-tives The oxidation proceeds via formation of the unstabledihydropyridyl radical as confirmed by controlled-potentialelectrolysis (CPE) and ESR experiments This type of 14-DHPs has significant activity towards the radicals even whencompared with commercial 14-DHP drugs with well-knownantioxidant ability
It was observed that nicardipine preferentially targets RO∙radicals and is inactive against ROO∙ Lacidipine on theother hand is equally active towards both types of radicals(Gaviraghi et al [164]) The cytoprotective effect againstexposure to H
2O2was more significant for lacidipine (ID
50=
14 nM its log119875 = 54 membrane partition = 136000 assumesposition located 7 A near to the membrane center otherless lipophilic DHPs located 12ndash16 A far from the center)as compared to amlodipine nifedipine and nicardipine insmooth muscle cell culture (Gaviraghi et al [164]) Oxidativeeffect of H
2O2shifts the Ca channel toward an open state
Thus the redox property of CCBs DHPs may augment theirCCB properties
Oxidation of pharmacologically active Hantzsch 14-dihydropyridines was found by electrogenerated superoxideusing a voltammetric approach in DMSO solutions (Ortiz etal [238] and Ortiz et al [239]) Raghuvanshi and Singh [240]have also reported oxidative aromatization of these DHPsinduced by superoxide
Chemiluminescence (CL) was used in the studies ana-lyzing the antioxidant activity of 12 various 4-flavonil-14-dihydropyridine derivatives (Kruk et al [241]) on a chemicalsystem involving a superoxide radical anion These deriva-tives showed structural similarity to flavonoids with respectto the presence of rings A B and C The results obtained in
24 Oxidative Medicine and Cellular Longevity
this study indicate that the tested derivatives may catalyzeconversion of superoxide radicals through mimicking theactivity of superoxide dismutase by delivering H+ for reac-tion
O2
minus∙+O2
minus∙+ 2H+ 997888rarr H
2O2+1O2
(3)
The enhanced emission of the light in the presence oftested compounds was significant and related to stimulatedproduction ofH
2O2and 1O
2fromO
2
∙The latter specieswereremoved from the reactionmixture by the following sequenceof reactions
H+
O2
minus∙997888rarr HO
2
∙
HO2
∙+O2
∙minus997888rarr HO
2
minus+1O2
2HO2
∙997888rarr H
2O2+1O2
2 (1O2) 997888rarr (O
2)2+ h]lowast
(4)
or to take part in spontaneous dismutation of H2O2
2H2O2997888rarr 2H
2O + 1O
2(5)
The authors have offered an original concept of action for 4-flavonil-14-dihydropyridine derivatives unrelated to that ofO2
∙ radical-trapping chain-breaking antioxidants Insteadthey showed that these compounds act similar to superoxidedismutases converting O
2
∙ to H2O2 Hydrogen peroxide
is less toxic for cells than O2
∙ because it is predominantlyremoved by peroxidases and catalases Finally AO effect ofthese DHPs differed from those mediated by flavonoids witha catechol structure of ring B which are well-known 1O
2
quenchersMulder and collaborators came to similar conclusions
especially related to molecular mechanisms of antioxidativeactivity of DHPs [236]TheAOproperties of Hantzsch 14-di-hydropyridine esters and two dibenzo-14-dihydropyridines910-dihydroacridine (DHAC) and N-methyl-910-dihydro-acridine (N-Me-DHAC) have been explored by determin-ing the autoxidation of styrene or cumene at 30∘C Theseexperiments showed that Hantzsch esters are virtually inac-tive as chain-breaking antioxidants (CB-AOs) contrary tothe findings observed by Lopez-Alarcon et al [103] whoused CB-AOA in aqueous media at pH 74 Their reactivitytoward peroxyl radicals was shown to be some 5 orders ofmagnitude lower than that of the excellent CB-AO 22578-pentamethyl-6-hydroxy-chroman (PMHC)
DHAC was found to be sim10 times less reactive thanPMHC kinetic measurements using DHAC N-deuterio-DHAC and N-Me-DHAC pointing out the abstraction ofN-H hydrogen in DHAC by peroxyl radicals despite the factthat the calculated C-H bond dissociation enthalpy (BDE) inDHAC is about 11 kcalmol lower than the N-H BDE Therates of hydrogen atom abstraction by the 22-diphenyl-1-picrylhydrazyl radical (DPPH∙) have also been determined
for the same series of compounds The trends in the peroxyl∙and DPPH∙ rate constants were found to be similar [236]
Tirzit et al [242] have observed quenching of singletoxygen by DHPs This observation paved the ground forfurther research related to reactions of DHPs with hydroxylradicals (Tirzit et al [243]) singlet oxygen (Kazush etal [94]) and mechanisms of action A series of 14-DHPderivatives in NAD-H-Cu2+-H
2O2system inhibited forming
of the hydroxyl radical (HO∙) while 14-DHP derivativeswith electron donor substituents in the molecule were shownto be capable themselves of generating HO∙ in the presenceof Cu2+ and H
2O2 Rubene et al [186] also described
interaction of 14-DHP derivatives with Fentonrsquos reagentwhich produces hydroxyl radical (HO∙) Rate constants ofthe DHPs reaction (1st order) with HO∙ radical were highin the range 109 L times mol times secminus1 close to that of NADHcysteine and thiourea 35-Diacetyl- derivatives reacted fastercompared to 35-dialkoxycarbonyl- ones The reaction ratedecrease was observed in the case of substitution at position4 as compared to 4-unsubstituted DHPs Some DHPs havingelectron donor -COOminus groups in the 35- or 26- positionsof DHP ring reacted immediately (having rate constantshigher as 109 L times mol times secminus1) Rate constants with HO
2
∙
and O2
∙minus radicals were of lower degree Thus DHPs actingas oxygen radical scavengers could effectively inhibit ROSrelated reactions of LP initiation stage
Nifedipine and nitrendipine reactivity toward singletoxygen was also studied [244] Nifedipine was shown tobe a good scavenger of excited oxygen mainly via physicaldeactivation with values of the total rate constant rangingfrom 208 times 105Mminus1 sminus1 (in dioxane) to 930 times 105Mminus1 sminus1(in propylene carbonate)The less reactive pathway generateda photooxidation product For that reason a mechanisminvolving a perepoxide-like encounter complex in the firststep of the reaction path was proposed (see [244] Figures8 and 9 therein) The dependence was observed on solventmicroscopic parameters of the total rate constant for the reac-tion between singlet oxygen and 14-DHPs These findingsshow that nifedipine possesses stronger protective activity inbiological systems than nitrendipine
Density-functional-theory (DFT) calculations made byWang et al [245] confirmed the former experimental obser-vations that Hantzsch ester diludine is potent antioxi-dant with high H atom-donating ability and relatively lowprooxidant activity Possible reaction pathways for radicalsderived from 14-dihydropyridine and the resonance modesfor radical species were given [245]
Moreover two ethoxycarbonyl (EtOCO) substituentsat C(2) and C(6) should further enhance Hantzsch esterdiludine H-atom-donating ability due to resonance effectsHowever DHPs should be used in nonpolar rather than inpolar solvents since in the latter not H-atom but electrontransfer is preferred in the radical scavenging process [245]
Mulder et al [246] proposed that quantum-thermochem-ical calculations must be used with caution to indicate ldquoapromising lead antioxidantrdquo as they criticized the density-functional-theory (DFT) calculations made by Wang et al[245]
Oxidative Medicine and Cellular Longevity 25
372 Possible Mechanisms of DHPs ARA and AOA in the Bio-logical Systems Interaction with Other OSModifiers Some ofthese mechanisms were already described (Sections 331 (2)-(b) 331 (2)-(c) 331 (3)-(b) 35)
Enzymatic sources of ROSwith confirmed functional rolein hypertension are NADPH oxidase NO synthase (NOS)xanthine oxidase and cyclooxygenase Godfraind [3] hasreviewed AO effects and protective action of calcium channelblockers (CCBs) Yao et al [247] observed antioxidant effects(as inhibition of LP) for cardio- and neuroprotective CCBs(3ndash300 120583molL) including 7 DHPs in homogenates of ratbrain IC
50values (120583M) were as follows nifedipine (515) gt
barnidipine (586) gt benidipine (712) gt nicardipine (1293)gt amlodipine (1355) gt nilvadipine (1673) gt nitrendipine(2521) gt diltiazem (gt300) = verapamil (gt300) There arealso research articles describing the AO properties of CCBsthrough direct scavenging effect or through preservationof the endogenous SOD activity These findings indicatethat CCBs may also act by reducing the production ofvasoconstrictors angiotensin and endothelin
When present in concentrations that can be achievedin plasma CCBs may inhibit LP formation [3] This AOactivity seems to be typical for high lipophilic CCBs becausetheir chemical structure facilitates proton-donating andresonance-stabilization mechanisms that quench the freeradical reaction Their insertion in the membrane nearpolyunsaturated fatty acids at relatively high concentrationspotentiates proton donation (or atomary H) to lipid peroxidemolecules thereby blocking the peroxidation process Theremaining unpaired free electron associated with the CCBmolecule can be stabilized in well-defined resonance struc-tures associated with the DHP ring (Mason et al [48])
The radical reaction (according to Godfraind [3]) thatdescribes the AO effects of a DHP CCBs is LOOlowast + DHPrarr LOOH + DHPlowast (where LOOlowast is lipid peroxide radical)which in general is reaction (7) of the LP reaction cascadeconsisting of sim10 reactions (Scheme 2) [89]
As the rate constants of in vitro interaction of 4-substituted DHPs with peroxyl radicals are three ordersof magnitude lower than that of the vitamin E derivativethese DHPs must be considered as weak AO (Ursini [204])However due to partition coefficient of DHPs in membranesand in case of specific binding high local concentration ofDHPs may be obtained
DHPs without CCB properties for instance Bay w 9798although structurally related to nifedipine inhibit TNF-120572-induced vascular cell adhesion molecule-1 expression inendothelial cells by suppressing reactive oxygen speciesgeneration [248]
Mitrega et al [249] have discovered that antiarrhythmicand hemodynamic effects of oxidized heteroaromatic DHPsoxy nifedipine oxy nimodipine oxy nitrendipine and oxynisoldipine suggest that CCB DHPs and their metabolitescould act at least in two ways targeting OS related eventsas reductants (see Section 351 (1)) andor bypassing OSrelatedmetabolic routes Authors postulated that contrary tocurrent belief NIF metabolites are pharmacologically activeATP sensitive potassium channels were mentioned as a tar-get
38 DHPs Anti- or Prooxidants Several substances (ascorbicacid being the most commonly studied) can serve either asantioxidants or as prooxidants depending on given condi-tions (Herbert [250]) Therefore Halliwell [251] has reporteddilemma related to polyphenols as possible antioxidantsand prooxidants causing experimental artifacts (about 25)by oxidation of antioxidant compounds in the cell culturemedia Nevertheless it is generally accepted opinion thatpolyphenols act as antioxidants in vivo Studies on DHPs alsoface such a dilemmaThe exact roles (anti- or prooxidative) ofany specific DHP depend on its structure appliedachievedconcentration and specificity of the targetexperimentaltesting system
This situation resembles the case of antioxidative effectsof tocopherol which depends on the fate of the secondaryradical as proposed by Winterbourn [252] The question wasldquoVitamin E - Pro- or Antioxidantrdquo
997888rarr chain termination of lipid peroxidation
(6)
Prooxidant
Toc∙ + Lipid-H 997888rarr Lipid∙ (in LDL particles) (7)
This example shows that generally speaking any AO mustfulfil several criteria to be considered as an effective com-pound physiologically
(i) It must be able to functionally interact with endoge-nous scavengers even at low concentrations
(ii) It must affect endogenous pathways of OS(iii) It should not have undesirable adverse effect(iv) It should manifest the antioxidant efficacy dependent
on the oxidant(v) It must discriminate among different strategies
needed for 1-electron and 2-electron processes(vi) Radical scavengers can be prooxidant unless linked to
a radical sink (Winterbourn [252])
According to these statements DHPs could be effective asAO under physiological conditions in vivo (Godfraind [3]and others [30 31 38]) and in vitro in various experimentalsystems (cell and tissue) (see Sections 33 34 35)
Hence calcium antagonists appeared to disrupt thefine balance between the production and scavenging ofROS Nifedipine verapamil and diltiazem were shown toinduce significant oxidative stress in the epididymal sperm(increased MDA and decreased catalase and superoxidedismutase activity) This may be the reason for the inductionof male infertility [253]
The dualism of 14-DHP effects has been recorded asinhibition or promotion of LP as quenching or initiating
26 Oxidative Medicine and Cellular Longevity
oxygen and nitrogen free radical chain reactions radiopro-tecting or radiosensitizing antagonizing or synergizing Ca2+in electromechanical coupling as well as in the membranestabilization or labilization
39 Could DHPs Be Involved in Antioxidative Stress Beforebeing applied in vivo the optimal dose and optimal timeintervals forDHPs applicationmust be knownNamely whileROS have been traditionally considered as toxic byproductsof aerobic metabolism we know nowadays that ROS may actas essential signaling molecules needed for the control ofmany different physiological processes Whether the role ofROS will be damaging protective or signaling depends onthe delicate equilibrium between time- and location-specificROS production and scavenging Accordingly the imbalanceof the increased AO potential so-called antioxidative stresscould be dangerous similar to chronic OS in particular incase of extended exposure Inappropriate interventions inthe oxidative homeostasis by excessive antioxidants especiallyin case of chronic exposure to antioxidants might havevery negative effects as was published in the ATBC studyshowing an increased cancer incidence in smokers treatedby excessive beta-carotene [254] Therefore overconsump-tion of any natural or synthetic AO including DHPs asdietary supplements or drugs must be avoided in order tosuppress oxidative damage and must not disrupt the well-integrated antioxidant defense network (Poljsak [255] andPoljsak and Milisav [256]) This is especially important whenadministrating lipid-soluble antioxidants that can be storedin biomembranes thus not only attenuating or preventing LPbut also affecting physiological effects of the natural antiox-idants in particular tocopherol The interrelationship withthe status of endogenous antioxidantsprooxidants should befollowed
DHPs primarily suppress the initiation stages of LPprocessThey do not entirely stop the LP propagation Actingsynergistically with tocopherol diludine may prevent patho-logical excess of ROS production within the lipid moiety ofthe cellular membranes and LDL However due to its lowsolubility and fast metabolism its concentration in the cellsis low For that reason it cannot cause antioxidative stresseven if used for an extended period of time Thus diludine(diethone) could be only a mild antioxidant it has potentialfor restoring the pool of natural antioxidants (as synergist of120572-tocopherol and polyphenols) in the cells
Moreover DHPs CA used for cardioprotection andvasodilatation as commercial drugs in low concentrationsare fast metabolized via CYP3A4 and for that reason theirapplication does not induce cellular AO stress [53 160]However Godfraind and Salomone [257] have postulated noevidence that allows recommending dietary supplementationwith antioxidants for the primary or secondary prevention ofcardiovascular disease
So far there are no reports on antioxidative stress causedby some DHPs diludine and its analogues Diludine andits analogues therefore could act as adaptogens supportinghormetic effects of mild oxidative stress These compoundsmay act as potential multisided modulators of Yin-Yang
cycles of redox and cell functions (the electroplasmic cycle)(Wagner et al [258])
4 Conclusions
14-Dihydropyridines (14-DHPs) have broad spectrum ofOS modulating activities DHPs have reducing and lipidperoxidation inhibitor properties act as reductants in simplechemical systems and stabilize various biological systems(LDL mitochondria microsomes cells and tissues) againstOS Examples and peculiarities and mechanisms of antiox-idant activity (AOA) and antiradical activity (ARA) as wellas stress-protective effect of DHPs including commercialcalcium antagonists (CA) were highlighted These activitiesdepend on various structural parameters related to DHPs(presence and character of substituents) lipophilicity anddepth of the incorporation in the biologicalmembranesTheyalso depend on the experimental model system for exploringthe lipid peroxidation or oxidative stress Stress-protectiveeffect of some metabolites of CA (nifedipine) is reviewedAlthough some DHPs including CA have prooxidant prop-erties (on epididymal sperm cells) they can generally beconsidered as potent antioxidants Therefore comparisonof the AOA and ARA of different DHPs (mutually andwith other AOs) was described in detail According to thedata presented the DHPs might be considered as bellwetheramong synthetic compounds targeting OS and as a kind ofpharmacological measure for respective field of organic andmedicinal chemistry
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
Authors from Latvian IOS acknowledge ESF 201300021DP1112013APIAVIAA011 and National Research Pro-gramme PUBLIC HEALTHBiomedicine of the Republicof Latvia for financial support administration of the Insti-tute for technical support and Rufus Smits PhD for con-sultations in English The support of Cooperation in Euro-pean System of Science and Technology (COST) Domain ofChemistry Molecular Sciences and Technologies (CMST)was of highest importance for preparation of this paper
[2] D J Triggle ldquo14-Dihydropyridines as calcium channel ligandsand privileged structuresrdquoCellular andMolecular Neurobiologyvol 23 no 3 pp 293ndash303 2003
[3] T Godfraind ldquoAntioxidant effects and the therapeutic modeof action of calcium channel blockers in hypertension andatherosclerosisrdquo Philosophical Transactions of the Royal SocietyB Biological Sciences vol 360 no 1464 pp 2259ndash2272 2005
[4] E Cadenas ldquoMitochondrial free radical production and cellsignalingrdquoMolecular Aspects of Medicine vol 25 no 1-2 pp 17ndash26 2004
[5] E Cadenas ldquoFree radicals oxidative stress and diseasesrdquo inLecture PSC 616 p 38 Missouri University of Science andTechnology Rolla Mo USA httpwwwcarnicominstituteorgarticlesenrique cadenaspdf
[6] K Rahman ldquoStudies on free radicals antioxidants and co-fac-torsrdquo Clinical Interventions in Aging vol 2 no 2 pp 219ndash2362007
[7] V Bocci and G Valacchi ldquoFree radicals and antioxidants howto reestablish redox homeostasis in chronic diseasesrdquo CurrentMedicinal Chemistry vol 20 no 27 pp 3397ndash3415 2013
[8] M Valko C J Rhodes J Moncol M Izakovic and M MazurldquoFree radicals metals and antioxidants in oxidative stress-induced cancerrdquo Chemico-Biological Interactions vol 160 no 1pp 1ndash40 2006
[9] G Bartosz ldquoReactive oxygen species destroyers or messen-gersrdquo Biochemical Pharmacology vol 77 no 8 pp 1303ndash13152009
[10] R Visconti and D Grieco ldquoNew insights on oxidative stress incancerrdquo Current Opinion in Drug Discovery and Developmentvol 12 no 2 pp 240ndash245 2009
[11] R N Kujundzic N Zarkovic and K G Troselj ldquoPyridinenucleotides in regulation of cell death and survival by redoxand non-redox reactionsrdquo Critical Reviews in Eukaryotic GeneExpression vol 24 no 4 pp 287ndash309 2014
[12] B Halliwell and J M C Gutteridge ldquoThe definition and mea-surement of antioxidants in biological systemsrdquo Free RadicalBiology and Medicine vol 18 no 1 pp 125ndash126 1995
[13] V D Kancheva and O T Kasaikina ldquoBio-antioxidantsmdashachemical base of their antioxidant activity and beneficial effect
on human healthrdquo Current Medicinal Chemistry vol 20 no 37pp 4784ndash4805 2013
[14] H V Panglossi Ed Frontiers in Antioxidants Research NovaScience Publishers New York NY USA 2006
[15] E B Burlakova E M Molochkina and G A NikiforovldquoHybrid antioxidantsrdquo Oxidation Communications vol 31 no4 pp 739ndash757 2008 httpmembraneustceducnpaperpdfHybrid20Antioxidantspdf
[16] A Bast and G R M M Haenen ldquoTen misconceptions aboutantioxidantsrdquo Trends in Pharmacological Sciences vol 34 no 8pp 430ndash436 2013
[17] E B Burlakova A V 0lesenko E M Molochkina N PPalmina and N G Khrapova Bioantioxidants for RadiationDamage and Malignant Growth Nauka Moscow Russia 1975(Russian)
[18] J Fang T Seki and H Maeda ldquoTherapeutic strategies by mod-ulating oxygen stress in cancer and inflammationrdquo AdvancedDrug Delivery Reviews vol 61 no 4 pp 290ndash302 2009
[19] M Valko D Leibfritz J Moncol M T D Cronin M Mazurand J Telser ldquoFree radicals and antioxidants in normal physi-ological functions and human diseaserdquo International Journal ofBiochemistry and Cell Biology vol 39 no 1 pp 44ndash84 2007
[20] M Jimenez-Del-Rio and C Velez-Pardo ldquoThe bad the goodand the ugly about oxidative stressrdquo Oxidative Medicine andCellular Longevity vol 2012 Article ID 163913 13 pages 2012
[21] C D Kamat S Gadal M Mhatre K S Williamson Q N Pyeand K Hensley ldquoAntioxidants in central nervous system dis-eases preclinical promise and translational challengesrdquo Journalof Alzheimerrsquos Disease vol 15 no 3 pp 473ndash493 2008
[22] A Pompella H Sies R Wacker et al ldquoThe use of totalantioxidant capacity as surrogate marker for food quality andits effect on health is to be discouragedrdquo Nutrition vol 30 no7-8 pp 791ndash793 2014
[23] Z Ye and H Song ldquoAntioxidant vitamins intake and the risk ofcoronary heart disease meta-analysis of cohort studiesrdquo Euro-pean Journal of Cardiovascular Prevention and Rehabilitationvol 15 no 1 pp 26ndash34 2008
[24] P Knekt J Ritz M A Pereira et al ldquoAntioxidant vitamins andcoronary heart disease risk a pooled analysis of 9 cohortsrdquoTheAmerican Journal of Clinical Nutrition vol 80 no 6 pp 1508ndash1520 2004
[25] A C Carr and M C M Vissers ldquoSynthetic or food-derivedvitamin Cmdashare they equally bioavailablerdquo Nutrients vol 5 no11 pp 4284ndash4304 2013
[26] R Tabrizchi ldquoEdaravoneMitsubishi-TokyordquoCurrentOpinion inInvestigational Drugs vol 1 no 3 pp 347ndash354 2000
[27] K Kikuchi S Tancharoen N Takeshige et al ldquoThe efficacy ofedaravone (radicut) a free radical scavenger for cardiovasculardiseaserdquo International Journal of Molecular Sciences vol 14 no7 pp 13909ndash13930 2013
[28] D Mauzerall and F H Westheimer ldquo1-Benzyldihydronicoti-namidemdasha model for reduced DPNrdquo Journal of the AmericanChemical Society vol 77 no 8 pp 2261ndash2264 1955 ChemicalAbstracts vol 50 Article ID 2588i 1956
[29] F Bossert and W Vater ldquo14-Dihydropyridinesmdasha basis fordeveloping new drugsrdquo Medicinal Research Reviews vol 9 no3 pp 291ndash324 1989
[30] G Swarnalatha G Prasanthi N Sirisha and CMadhusudhanaChetty ldquo14-Dihydropyridines a multtifunctional moleculemdash areviewrdquo International Journal of ChemTech Research vol 3 no1 pp 75ndash89 2011
28 Oxidative Medicine and Cellular Longevity
[31] M Cataldi and F Bruno ldquo14-Dihydropyridines the multiplepersonalities of a blockbuster drug familyrdquo Translational Medi-cine UniSa vol 4 no 2 pp 12ndash26 2012 httpwwwncbinlmnihgovpmcarticlesPMC3728803
[32] R Vitolina A Krauze G Duburs and A Velena ldquoAspects ofthe amlodipine pleiotropy in biochemistry pharmacology andclinicsrdquo International Journal of Pharmaceutical Sciences andResearch vol 3 no 5 pp 1215ndash1232 2012
[33] D Grover S N Mokale and M T Shete ldquoDihydropyridinea novel pharmacophorerdquo International Journal of Pharmaceu-tical Erudition vol 1 no 2 pp 16ndash29 2011 httppharmaeru-ditionorgContentPaper20111-RV-320Final2016-29pdf
[34] A M Vijesh A M Isloor S K Peethambar K N ShivanandaT Arulmoli and N A Isloor ldquoHantzsch reaction synthesis andcharacterization of somenew 14-dihydropyridine derivatives aspotent antimicrobial and antioxidant agentsrdquo European Journalof Medicinal Chemistry vol 46 no 11 pp 5591ndash5597 2011
[35] P Mehta and P Verma ldquoAntimicrobial activity of some deriva-tives of 14-dihydropyridinesrdquo Journal of Chemistry vol 2013Article ID 865128 4 pages 2013
[36] P Olejnıkova L Svorc D Olsovska et al ldquoAntimicrobialactivity of novel C2-substituted 14-dihydropyridine analoguesrdquoScientia Pharmaceutica vol 82 no 2 pp 221ndash232 2014
[37] S Sepehri H Perez Sanchez and A Fassihi ldquoHantzsch-typedihydropyridines and biginelli-type tetra-hydropyrimidinesa review of their chemotherapeutic activitiesrdquo Journal of Phar-macy amp Pharmaceutical Sciences vol 18 no 1 pp 1ndash52 2015httpsejournalslibraryualbertacaindexphpJPPSarticleview2383617863
[38] S A Khedkar and P B Auti ldquo14-Dihydropyridines a classof pharmacologically important moleculesrdquo Mini-Reviews inMedicinal Chemistry vol 14 no 3 pp 282ndash290 2014
[39] G D Tirzit and G Ya Duburs ldquo14-dihydropyridines as inhi-bitors of free-radical reactionsrdquo Chemistry of Heterocyclic Com-pounds vol 8 no 1 pp 126ndash127 1972 Translated from KhimiyaGeterotsiklicheskikh Soedinenii no1 pp 133ndash134 1972 (Rus-sian)
[40] I Bogeski R Kappl C Kummerow R Gulaboski M Hothand B A Niemeyer ldquoRedox regulation of calcium ion channelschemical and physiological aspectsrdquoCell Calcium vol 50 no 5pp 407ndash423 2011
[41] S A Giller G Y Dubur Y R Uldrikis et al ldquoDiludine [Themethod to obtain 35-dicarbonylderivatives of 26-dimethyl-14-dihydropyridines]rdquo Authors certificate of USSR no 3004651971 [Byull Izobret no13 p 95 1971] and following patentsPatent of England no 1294650 1973 Patent of France no2055458 1971 Patent of Japan no 702883 1973 Patent ofHolland no 149787 1976 Patent of Italy no 969022 1974 Patentof FRG no 2036403 1978 US Patent no 3883673 1975 USPatent no 3948924 1976
[42] S A Giller G Y Dubur Y R Uldrikis et al ldquoImprovementsin or relating to the stabilization of carotenerdquo GB Patent no1294650 1972
[43] S A Giller G Y Dubur Y R Uldrikis et al ldquoStabilization ofcarotenerdquo US Patent no 3883673 1975 Chemical Abstracts vol83 Article ID 95193 1975
[44] Yu A Zilber G Ya Dubur K K Kumsar and A Kh VelenaldquoThe effect of antioxidants on the peroxidation of bimole-cular phospholipid membranesrdquo Latvijas PSR ZA Vestis Izves-tia Akademii Nauk Latviyskoy SSR vol 6 pp 80ndash82 1971(Russian) translated from the original Russian Doc Accesion
No AD0771751 distributed by NTIS US Department of Com-merce httpwwwdticmildtictrfulltextu2771751pdf
[45] G Ya Dubur Yu A Zilbers A Kh Velena A O Kumerovaand G D Tirzitis ldquoMultistage study of regulation of peroxida-tion processes in biological membranes by antioxidants of 14-dihydropyridine grouprdquo Izvestiya Akademii Nauk LatviyskoySSR vol 336 no 7 pp 65ndash68 1975 (Russian)
[46] R P Mason and M W Trumbore ldquoDifferential membraneinteractions of calcium channel blockers Implications forantioxidant activityrdquo Biochemical Pharmacology vol 51 no 5pp 653ndash660 1996
[47] R P Mason M F Walter M W Trumbore E G Olmstead Jrand P E Mason ldquoMembrane antioxidant effects of the chargeddihydropyridine calcium antagonist amlodipinerdquo Journal ofMolecular and Cellular Cardiology vol 31 no 1 pp 275ndash2811999
[48] R PMason I T MakMW Trumbore and P EMason ldquoAnti-oxidant properties of calcium antagonists related to membranebiophysical interactionsrdquo American Journal of Cardiology vol84 no 4 pp 16ndash22 1999
[49] R PMasonMW Trumbore and P EMason ldquoMembrane bio-physical interaction of amlodipine and antioxidant propertiesrdquoDrugs vol 59 no 2 pp 9ndash16 2000 (French)
[50] R P Mason P Marche and T H Hintze ldquoNovel vascularbiology of third-generation L-type calcium channel antagonistsAncillary actions of amlodipinerdquo Arteriosclerosis Thrombosisand Vascular Biology vol 23 no 12 pp 2155ndash2163 2003
[51] A Augustyniak G Bartosz A Cipak et al ldquoNatural andsynthetic antioxidants an updated overviewrdquo Free RadicalResearch vol 44 no 10 pp 1216ndash1262 2010
[52] T Grune N Zarkovic and K Kostelidou ldquoLipid peroxidationresearch in Europe and the COST B35 action lsquoLipid Peroxida-tion Associated Disordersrsquordquo Free Radical Research vol 44 no10 pp 1095ndash1097 2010
[53] E Carosati P Ioan M Micucci et al ldquo14-Dihydropyridinescaffold in medicinal chemistry the story so far and perspec-tives (part 2) action in other targets and antitargetsrdquo CurrentMedicinal Chemistry vol 19 no 25 pp 4306ndash4323 2012
[54] U Eisner and J Kuthan ldquoThe chemistry of dihydropyridinesrdquoChemical Reviews vol 72 no 1 pp 1ndash42 1972 httpwwwsci-encemadnessorgtalkfilesphppid=138742ampaid=6475
[55] J Kuthan and A Kurfurst ldquoDevelopment in dihydropyri-dine chemistryrdquo Industrial amp Engineering Chemistry ProductResearch and Development vol 21 no 2 pp 191ndash261 1982
[56] A Sausins and G Duburs ldquoSynthesis of 14-dihydropyridinesby cyclocondensation reactionsrdquo Heterocycles vol 27 no 1 pp269ndash289 1988
[57] A E Sausins and G Y Duburs ldquoSynthesis of 14-dihydro-pyridines in cyclocondensation reactions (review)rdquo Chemistryof Heterocyclic Compounds vol 28 no 4 pp 363ndash391 1992Translated from Khimiya Geterotsiklicheskikh Soedinenii no 4pp 435ndash467 1992 (Russian)
[58] S Kazda ldquoTwenty years of dihydropyridinesrdquo in Dihydropy-ridines Progress in Pharmacology and Therapy W-D Busse BGarthoff and F Seuter Eds pp 1ndash12 Springer Verlag BerlinGermany 1993
[59] J-P Wan and Y Liu ldquoRecent advances in new multicomponentsynthesis of structurally diversified 14-dihydropyridinesrdquo RSCAdvances vol 2 no 26 pp 9763ndash9777 2012
[61] Reaxys Database[62] J Tuttle ldquoStructure mechanism and reactivity of hantzsch
estersrdquo in MacMillan Lab Group Meeting (082504) p 332004 httpwwwprincetoneduchemistrymacmillangroup-meetingsJBT20Hantzschpdf
[63] A Saini S Kumar and J S Sandhu ldquoHantzsch reaction recentadvances in Hantzsch 14-dihydropyridinesrdquo Journal of Sci-entific amp Industrial Research vol 67 pp 95ndash111 2008
[64] L LW Cheung S A Styler and A P Dicks ldquoRapid and conve-nient synthesis of the 14-dihydropyridine privileged structurerdquoJournal of Chemical Education vol 87 no 6 pp 628ndash630 2010
[65] A Kumar R A Maurya S Sharma M Kumar and G BhatialdquoSynthesis and biological evaluation of N-aryl-14-dihydro-pyridines as novel antidyslipidemic and antioxidant agentsrdquoEuropean Journal of Medicinal Chemistry vol 45 no 2 pp 501ndash509 2010
[66] R S Kumar A Idhayadhulla A J Abdul Nasser and J SelvinldquoSynthesis and anticoagulant activity of a new series of 14-dihydropyridine derivativesrdquo European Journal of MedicinalChemistry vol 46 no 2 pp 804ndash810 2011
[67] H A Stefani C B Oliveira R B Almeida et al ldquoDihydro-pyrimidin-(2H)-ones obtained by ultrasound irradiation anew class of potential antioxidant agentsrdquo European Journal ofMedicinal Chemistry vol 41 no 4 pp 513ndash518 2006
[68] H Sun C Shang L Jin and J Zhang ldquoSynthesis and antiox-idant activity of a series of novel 3-chalcone-substituted 14-dihydropyridine derivativesrdquoHeterocyclic Communications vol18 no 5-6 pp 239ndash243 2012
[69] D B Tikhonov and B S Zhorov ldquoStructural model for dihy-dropyridine binding to L-type calcium channelsrdquo The Journalof Biological Chemistry vol 284 no 28 pp 19006ndash19017 2009
[70] G Y Dubur and Y R Uldrikis ldquoThe oxidation of 14-dihydro-pyridinesrdquo Chemistry of Heterocyclic Compounds vol 6 no 1pp 80ndash84 1970 Translated from Khimiya GeterotsiklicheskikhSoedinenii no 1 pp 83ndash88 1970 (Russian)
[71] G Ya Duburs A O Kumerova and Ya R Uldrikis ldquoEnzymicoxidation of hydrogenated pyridines with peroxidase-hydrogenperoxide systemrdquoLatvijas PSRZAVestis vol 73 no 7 pp 73ndash771970 (Russian) Chemical Abstracts vol 73 Article ID 94913g1970
[72] K Xie Y-C Liu Y Cui J-GWang Y Fu andT CWMak ldquoN-methyl-(R)-3-(tert-butyl)-sulfinyl-14-dihydropyridine a novelNADHmodel compoundrdquoMolecules vol 12 no 3 pp 415ndash4222007
[73] S Tamagaki T Mimura and W Tagaki ldquoMetal-ion-facilitatedoxidations of dihydropyridines with molecular oxygen andhydrogen peroxiderdquo Journal of the Chemical Society PerkinTransactions 2 no 10 pp 1645ndash1650 1990
[74] D Tirzite G Tirzitis andD Antipova ldquoReductive ability of 14-dihydropyridine derivatives in relation to ions of trivalent ironrdquoChemistry of Heterocyclic Compounds vol 35 no 5 pp 592ndash594 1999
[76] J Ogle J Stradins and L Baumane ldquoFormation and decay offree cation-radicals in the course of electro-oxidation of 12- and14-dihydropyridines (Hantzsch esters)rdquo Electrochimica Actavol 39 no 1 pp 73ndash79 1994
[77] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for the
synthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts C Wittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Berlin Germany 2010
[78] WDu and Zh Yu ldquoBiomimetic in situ regeneration of cofactorsNAD(P)+ and NAD(P)H models hantzsch esters and dihy-drophenanthridinerdquo Synlett vol 23 no 9 pp 1300ndash1304 2012
[79] H K Chenault and G M Whitesides ldquoRegeneration ofnicotinamide cofactors for use in organic synthesisrdquo AppliedBiochemistry and Biotechnology vol 14 no 2 pp 147ndash197 1987
[80] Y R Uldrikis A A Zidermane E A Biseniex I E Preisa GY Dubur and G D Tirzit ldquoEsters of 26-dimethyl-14-dihydro-pyridine-35-dicarboxylic acid and method of obtainingthereofrdquo WO 8000345 A1 1978 httpworldwideespacenetcompublicationDetailsbiblioDB=EPODOCampII=1ampND=3ampadjacent=trueamplocale=en EPampFT=Dampdate=19800306ampCC=WOampNR=8000345A1ampKC=A1
[81] Y Sambongi H Nitta K Ichihashi M Futai and I Ueda ldquoAnovel water-soluble Hantzsch 14-dihydropyridine compoundthat functions in biological processes through NADH regener-ationrdquo Journal of Organic Chemistry vol 67 no 10 pp 3499ndash3501 2002
[82] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for thesynthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts ChWittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Verlag Berlin Germany 2010
[83] T Okamura T Kikuchi A Nagamine et al ldquoAn approach formeasuring in vivo cerebral redox states using the oxidative con-version of dihydropyridine to pyridinium ion and themetabolictrapping principlerdquo Free Radical Biology and Medicine vol 38no 9 pp 1197ndash1205 2005
[84] K A Schellenberg and F H Westheimer ldquoA free-radicaloxidation of a dihydropyridine1ardquo The Journal of OrganicChemistry vol 30 no 6 pp 1859ndash1862 1965
[85] K A Schellenberg ldquoReaction of hydroxyl radical with thymi-dine Scavenging by a dihydropyridinerdquo Federation Proceedingsvol 38 no 3 I p 1433 1979
[86] E S Huyser J A K Harmony and F L McMillian ldquoPeroxideoxidations of dihydropyridine derivativesrdquo Journal of the Amer-ican Chemical Society vol 94 no 9 pp 3176ndash3180 1972
[87] A Sakamoto S T Ohnishi and R Ogawa ldquoInhibition of lipidperoxidation by some dihydropyridine derivativesrdquo Journal ofAnesthesia vol 7 no 2 pp 193ndash197 1993
[88] R Hardeland ldquoReview Neuroprotection by radical avoidancesearch for suitable agentsrdquo Molecules vol 14 no 12 pp 5054ndash5102 2009
[89] G Ya Dubur A Kh Velena V M Gukasov and Yu AVladimirov ldquoRegulation of peroxidation of mitochondrialmembrane lipids initiated by Fe2+ ions by antoxidants of the14-dihydropyridine series in experiments in vitrordquo Biomed-itsinskaya Khimiya vol 22 no 5 pp 665ndash673 1976 (Russian)Chemical Abstracts vol 88 Article ID 2640 1977
[90] G RMMHaenenM J T J Arts A Bast andMD ColemanldquoStructure and activity in assessing antioxidant activity in vitroand in vivo a critical appraisal illustrated with the flavonoidsrdquoEnvironmental Toxicology and Pharmacology vol 21 no 2 pp191ndash198 2006
[91] G Tirzitis and G Bartosz ldquoDetermination of antiradical andantioxidant activity basic principles and new insightsrdquo ActaBiochimica Polonica vol 57 no 2 pp 139ndash142 2010
30 Oxidative Medicine and Cellular Longevity
[92] G R Buettner and R P Mason ldquoSpin-trapping methods fordetecting superoxide and hydroxyl free radicals in vitro and invivordquo inCritical Reviews of Oxidative Stress and Aging Advancesin Basic Science Diagnostics and Intervention R G Cutler andH Rodriguez Eds vol 1 chapter 2 pp 27ndash38World ScientificLondon UK 2003
[93] M M Tarpey and I Fridovich ldquoMethods of detection ofvascular reactive species Nitric oxide superoxide hydrogenperoxide and peroxynitriterdquo Circulation Research vol 89 no3 pp 224ndash236 2001
[94] E Y Kazush E I Sagun G D Tirzit and G Y DaburldquoQuenching of singlet oxygen by electron donating derivativesof 14-dihydropyridinerdquo Chemistry of Heterocyclic Compoundsvol 30 no 5 pp 562ndash563 1994
[95] G Tirzitis E Kazush and G Duburs ldquoReaction of 14-dihydropyridine derivatives with peroxynitrite anionrdquo Chem-istry of Heterocyclic Compounds vol 34 no 3 pp 321ndash3231998 (Russian) Translated from Khimiya GeterotsiklicheskikhSoedinenii no 3 pp 355ndash357 1998
[96] L J Nunez-Vergara C Lopez-Alarcon P A Navarrete-EncinaA M Atria C Camargo and J A Squella ldquoElectrochemicaland EPR characterization of 14-dihydropyridines Reactivitytowards alkyl radicalsrdquo Free Radical Research vol 37 no 1 pp109ndash120 2003
[97] D Tirzite A Krauze A Zubareva G Tirzitis and G DubursldquoSynthesis and antiradical activity of 5-acetyl-2-alkylthio-4-aryl-6-methyl-14-dihydropyridine-3-carboxylic acid nitrilesrdquoChemistry of Heterocyclic Compounds vol 38 no 7 pp 795ndash800 2002
[98] H Ohkawa N Ohishi and K Yagi ldquoAssay for lipid peroxidesin animal tissues by thiobarbituric acid reactionrdquo AnalyticalBiochemistry vol 95 no 2 pp 351ndash358 1979
[99] N Zarkovic ldquo4-Hydroxynonenal as a bioactive marker ofpathophysiological processesrdquo Molecular Aspects of Medicinevol 24 no 4-5 pp 281ndash291 2003
[100] M Parola G Bellomo G Robino G Barrera and M UDianzani ldquo4-Hydroxynonenal as a biological signal molecularbasis and pathophysiological implicationsrdquo Antioxidants andRedox Signaling vol 1 no 3 pp 255ndash284 1999
[101] T Lovakovic M Poljak-Blazi G Duburs et al ldquoGrowthmodulation of human cells in vitro by mild oxidative stressand 14-dihydropyridine derivative antioxidantsrdquo CollegiumAntropologicum vol 35 no 1 pp 137ndash141 2011
[102] R van den Berg G R M M Haenen H van den Bergand A Bast ldquoApplicability of an improved Trolox equivalentantioxidant capacity (TEAC) assay for evaluation of antioxidantcapacity measurements of mixturesrdquo Food Chemistry vol 66no 4 pp 511ndash517 1999
[103] C Lopez-Alarcon P Navarrete C Camargo J A Squella andL J Nunez-Vergara ldquoReactivity of 14-dihydropyridines towardalkyl alkylperoxyl radicals and ABTS radical cationrdquo ChemicalResearch in Toxicology vol 16 no 2 pp 208ndash215 2003
[104] V Valenzuela P Santander C Camargo J A Squella C Lopez-Alarcon and L J Nunez-Vergara ldquo14-Dihydropyridines reac-tivity of nitrosoaryl and nitroaryl derivatives with alkylperoxylradicals andABTS radical cationrdquo Free Radical Research vol 38no 7 pp 715ndash727 2004
[105] L G Tsetlin N A Chebotareva B I Kurganov A K VelenaG Y Dubur and V Z Lankin ldquoStudy of 14-dihydropyridinesas lipoxygenase inhibitors with the use of hydrated reversedmicellesrdquo Pharmaceutical Chemistry Journal vol 22 no 6 pp425ndash428 1988 (Russian)
[106] J Panek Z Reblova L Kocirkova et al ldquoAntioxidant activityof dihydropyridine derivativesrdquo Czech Journal of Food Sciencesvol 18 pp 144ndash145 2000
[107] G Tirzitis I Kirule and G Duburs ldquoAntioxidationsaktivitatder 35-dicarbonylderivate des 26-demethyl-14-dihydropyri-dinsrdquo Fett Wissenschaft TechnologieFat Science Technology vol90 no 10 pp 411ndash413 1988
[108] M Plotniece G Tirzitis Y Uldrikis et al ldquoSynthesis of 14-dihydropyridine derivatives having an oxy- alkoxy- or dimeth-ylaminophenyl substituent in the 4 position their antioxidantactivity and their binding to phospholipid membranesrdquo Chem-istry of Heterocyclic Compounds vol 32 no 10 pp 1166ndash11721996 Translated from Khimiya Geterotsiklicheskikh Soedineniino 10(352) pp 1358ndash1365 1996 (Russian)
[109] D Y Rubene V S Sharov V I Olenev G D Tirzit G Y Duburand Y A Vladimirov ldquoUse of chemiluminescent method forthe evaluation of antioxidant activity of some derivatives of 14-dihydropyridinerdquo Russian Journal of Physical Chemistry A vol55 no 2 pp 511ndash512 1981 (Russian)
[110] M C R Symons and JM C Gutteridge Free Radicals and IronChemistry Biology and Medicine Oxford Science PublicationsOxford University Press Oxford UK 1998
[111] M Repetto J Semprine and A Boveris ldquoLipid peroxidationchemical mechanism biological implications and analyticaldeterminationrdquo in Lipid Peroxidation A Catala Ed Section ILipid Peroxidation Chemical Mechanisms Antioxidants Bio-logical Implications of Biochemistry Genetics and MolecularBiology chapter 1 pp 3ndash30 InTech Rijeka Croatia 2012
[112] A Velena J Zilbers and G Duburs ldquoDerivatives of 14-dihydropyridines asmodulators of ascorbate-induced lipid per-oxidation and high-amplitude swelling ofmitochondria causedby ascorbate sodium linoleate and sodiumpyrophosphaterdquoCellBiochemistry and Function vol 17 no 4 pp 237ndash252 1999
[113] M V Bilenko L N Shelenkova G Y Dubur and A K VelenaldquoUse of antioxidants to prevent renal damage during acuteischemia and reperfusionrdquo Bulletin of Experimental Biology andMedicine vol 96 no 3 pp 1195ndash1198 1983 Translated fromByulletenrsquo Eksperimentalrsquonoi Biologii i Meditsiny vol 96 no 9pp 8ndash11 1983 (Russian)
[114] R Toniolo F Tubaro F Ursini and G Bontempelli ldquoAn elec-troanalytical investigation on the redox properties of calciumantagonist dihydropyridinesrdquo Electroanalysis vol 15 no 10 pp855ndash861 2003
[115] L Kourimska J Pokorny and G Tirzitis ldquoThe antioxidant aci-tivity of 26-dimethyl-35-diethoxycarbonyl-14-dihydropyri-dine in edible oilsrdquo Nahrung vol 37 no 1 pp 91ndash93 1993
[116] C Lopez-Alarcon H Speisky J A Squella C Olea-Azar CCamargo and L J Nunez-Vergara ldquoReactivity of 14-dihydro-pyridines toward SIN-1-derived peroxynitriterdquo PharmaceuticalResearch vol 21 no 10 pp 1750ndash1757 2004
[117] R A Olek W Ziolkowski J J Kaczor L Greci J Popinigisand J Antosiewicz ldquoAntioxidant activity of NADH and its ana-loguemdashan in vitro studyrdquo Journal of Biochemistry andMolecularBiology vol 37 no 4 pp 416ndash421 2004
[118] E Niki N Noguchi and N Gotoh ldquoInhibition of oxidativemodification of low density lipoprotein by antioxidantsrdquo Jour-nal of Nutritional Science andVitaminology vol 39 supplementpp S1ndashS8 1993
[119] N Rojstaczer and D J Triggle ldquoStructure-function relation-ships of calcium antagonists effect on oxidative modificationof low density lipoproteinrdquo Biochemical Pharmacology vol 51no 2 pp 141ndash150 1996
Oxidative Medicine and Cellular Longevity 31
[120] A Sevanian L Shen and FUrsini ldquoInhibition of LDLoxidationand oxidized LDL-induced cytotoxicity by dihydropyridinecalcium antagonistsrdquo Pharmaceutical Research vol 17 no 8 pp999ndash1006 2000
[121] A Negre-Salvayre and R Salvayre ldquoProtection by Ca2+ channelblockers (nifedipine diltiazem and verapamil) against the tox-icity of oxidized low density lipoprotein to cultured lymphoidcellsrdquo British Journal of Pharmacology vol 107 no 3 pp 738ndash744 1992
[122] A Negre-Salvayre G FitoussiM Troly and R Salvayre ldquoCom-parative cytoprotective effect of dihydropyridine calcium chan-nel blockers against the toxicity of oxidized low density lipopro-tein for cultured lymphoid cellsrdquo Biochemical Pharmacologyvol 44 no 12 pp 2379ndash2386 1992
[123] L Cominacini A F Pasini U Garbin et al ldquoAntioxidant activ-ity of different dihydropyridinesrdquo Biochemical and BiophysicalResearch Communications vol 302 no 4 pp 679ndash684 2003
[124] L Cominacini U Garbin A Fratta Pasini et al ldquoOxidized low-density lipoprotein increases the production of intracellularreactive oxygen species in endothelial cells inhibitory effect oflacidipinerdquo Journal of Hypertension vol 16 no 12 part 2 pp1913ndash1919 1998
[125] H M Lander ldquoAn essential role for free radicals and derivedspecies in signal transductionrdquo The FASEB Journal vol 11 no2 pp 118ndash124 1997
[126] M L L Martinez E Rizzi M M Castro et al ldquoLercanidipinedecreases vascular matrix metalloproteinase-2 activity andprotects against vascular dysfunction in diabetic ratsrdquo EuropeanJournal of Pharmacology vol 599 no 1ndash3 pp 110ndash116 2008
[127] P Lesnik C Dachet L Petit et al ldquoImpact of a combinationof a calcium antagonist and a 120573-blocker on cell- and copper-mediated oxidation of LDL and on the accumulation and effluxof cholesterol in human macrophages and murine J774 cellsrdquoArteriosclerosis Thrombosis and Vascular Biology vol 17 no 5pp 979ndash988 1997
[128] G Sobal E J Menzel and H Sinzinger ldquoCalcium antagonistsas inhibitors of in vitro low density lipoprotein oxidation andglycationrdquoBiochemical Pharmacology vol 61 no 3 pp 373ndash3792001
[129] E Lupo R Locher B Weisser and W Vetter ldquoIn vitro antiox-idant activity of calcium antagonists against LDL oxidationcompared with 120572-tocopherolrdquo Biochemical and BiophysicalResearch Communications vol 203 no 3 pp 1803ndash1808 1994
[130] J Zou Y Li H-Q Fan and J-G Wang ldquoEffects of dihydropy-ridine calcium channel blockers on oxidized low-density lipo-protein induced proliferation and oxidative stress of vascularsmooth muscle cellsrdquo BMC Research Notes vol 5 article 1682012
[131] C Napoli S Salomone T Godfraind et al ldquo14-Dihydro-pyridine calcium channel blockers inhibit plasma and LDL oxi-dation and formation of oxidation-specific epitopes in the arte-rial wall and prolong survival in stroke-prone spontaneouslyhypertensive ratsrdquo Stroke vol 30 no 9 pp 1907ndash1915 1999
[132] G Zernig I Graziadei T Moshammer C Zech N Reider andH Glossmann ldquoMitochondrial Ca2+ antagonist binding sitesare associated with an inner mitochondrial membrane anionchannelrdquo Molecular Pharmacology vol 38 no 3 pp 362ndash3691990
[133] F E Hunter Jr A Scott P E Hochstein et al ldquoStudies of themechanism of ascorbate-induced swelling and lysis of isolatedliver mitochondriardquo The Journal of Biological Chemistry vol239 pp 604ndash613 1964
[134] D R Janero B Burghardt and R Lopez ldquoProtection of cardiacmembrane phospholipid against oxidative injury by calciumantagonistsrdquoBiochemical Pharmacology vol 37 no 21 pp 4197ndash4203 1988
[135] A Karadag B Ozcelik and S S Saner ldquoReview of methods todetermine antioxidant capacitiesrdquo FoodAnalyticalMethods vol2 no 1 pp 41ndash60 2009
[136] Y I Gubskiı N V Litvinova and E V Shnurko-TabakovaldquoAntioxidant and antiradical activity of various classes of antiox-idantsrdquo Ukrainskiı Biokhimicheskiı Zhurnal vol 66 no 4 pp114ndash116 1994 (Russian)
[137] M Takei M Hiramatsu and A Mori ldquoInhibitory effects ofcalcium antagonists onmitochondrial swelling induced by lipidperoxidation or arachidonic acid in the rat brain in vitrordquoNeurochemical Research vol 19 no 9 pp 1199ndash1206 1994
[138] M Takei M Hiramatsu R Edamatsu and A Mori ldquoFreeradical scavenging by calcium antagonistsrdquo Neurosciences vol20 no 2 pp 75ndash82 1994
[139] Ya P Stradin G Ya Dubur Yu A Beilis Ya R Uldrikis andA F Korotkova ldquoVoltammetry of 14-dihydropyridine deriva-tives I Potentials of electrochemical oxidation of 35-diacyl-and 35-di(alkoxycarbonyl)-14-dihydropyridines in acetoni-trilerdquo Chemistry of Heterocyclic Compounds no 1 pp 84ndash871972 (Russian)
[140] E V Ivanov T V Ponomarjova G N Merkusev et al ldquoEinneuer Haut-Radioprotektor Diethon (experimentelle Unter-suchung)rdquo Radiobiologia Radiotherapia vol 31 no 1 pp 69ndash78 1990
[141] E V Ivanov T V Ponomareva G N Merkushev et al ldquoRadia-tion modulating properties of derivates of 14-dihydropyridineand 12345678910-decahydroacridine-18 dionerdquo Radiat-sionnaia Biologiia Radioecologiia vol 44 no 5 pp 550ndash5592004 (Russian)
[142] R O Vitolinia D A Berzinia A K Velena I A Vutsina A AKimenis and G Y Duburs ldquoThe protective effects of the cal-cium antagonist foridon in acute myocardial ischaemiardquo Kardi-ologiya vol 27 no 3 pp 90ndash93 1987 (Russian)
[143] A H Velena G Ya Duburs R O Vitolina et al ldquoEffect ofryodipine on electromechanical parameters of heart and vesselscAMP phosphodiesterase activity and swelling-contractioncycle of mitochondriardquo Arzneimittelforschung vol 35 no 6 pp907ndash914 1985
[144] L I Utno Z E Lipsberga A A Silova M I Girgensone EA Bisenieks and G I Ia ldquoCardioprotective properties of a 14-dihydropyridine derivative glutapyrone in deep hypothermiardquoBiulletenrsquo Eksperimentalrsquonoı Biologii i Meditsiny vol 108 no 11pp 558ndash561 1989 (Russian)
[145] M A S FernandesM S Santos J A F Vicente et al ldquoEffects of14-dihydropyridine derivatives (cerebrocrast gammapyroneglutapyrone and diethone) onmitochondrial bioenergetics andoxidative stress a comparative studyrdquoMitochondrion vol 3 no1 pp 47ndash59 2003
[146] M A S Fernandes M S Santos A J M Moreno et al ldquoEffectsof 5-acetyl(carbamoyl)-6-methylsulfanyl-14-dihydropyridine-5-carbonitriles on rat liver mitochondrial functionrdquo Toxicologyin Vitro vol 23 no 7 pp 1333ndash1341 2009
[147] L Klimaviciusa A Kalda A Kaasik et al ldquoNeuroprotectiveactivity of 14-dihydropyridine derivatives structure determi-nantsrdquo Proceedings of the Latvian Academy of Sciences BNatural Exact and Applied Sciences vol 61 no 1-2 pp 33ndash372007
32 Oxidative Medicine and Cellular Longevity
[148] L Klimaviciusa M A S Fernandes N Lencberga et alldquoTargeting the mitochondria by novel adamantane-containing14-dihydropyridine compoundsrdquo in Bioenergetics K B ClarkEd pp 257ndash272 InTech 2012
[149] V Klusa L Klimaviciusa G Duburs J Poikans and AZharkovsky ldquoAnti-neurotoxic effects of tauropyrone a taurineanaloguerdquo Advances in Experimental Medicine and Biology vol583 pp 499ndash508 2006
[150] N Sampson P Berger and Ch Zenzmaier ldquoRedox signalingas a therapeutic target to inhibit myofibroblast activation indegenerative fibrotic diseaserdquo BioMed Research Internationalvol 2014 Article ID 131737 14 pages 2014
[151] T L Leto and M Geiszt ldquoRole of Nox family NADPH oxidasesin host defenserdquoAntioxidantsampRedox Signaling vol 8 no 9-10pp 1549ndash1561 2006
[152] K K Griendling D Sorescu and M Ushio-Fukai ldquoNAD(P)Hoxidase role in cardiovascular biology and diseaserdquo CirculationResearch vol 86 no 5 pp 494ndash501 2000
[153] H Chen Y S Song and P H Chan ldquoInhibition of NADPHoxi-dase is neuroprotective after ischemia-reperfusionrdquo Journal ofCerebral Blood Flow and Metabolism vol 29 no 7 pp 1262ndash1272 2009
[154] P Hochstein and L Ernster ldquoADP-activated lipid peroxidationcoupled to the TPNH oxidase system of microsomesrdquo Biochem-ical and Biophysical Research Communications vol 12 no 5 pp388ndash394 1963
[155] I I Gubskiı AGGoriushkoNV Litvinova et al ldquoAntioxidantproperties and membranotropic effect of certain derivatives of14-dihydropyridinerdquo Ukrainskiı Biokhimicheskiı Zhurnal vol71 no 4 pp 35ndash39 1999 (Russian)
[156] F Engineer and R Sridhar ldquoInhibition of rat heart andliver microsomal lipid peroxidation by nifedipinerdquo BiochemicalPharmacology vol 38 no 8 pp 1279ndash1285 1989
[157] T Goncalves A P Carvalho and C R Oliveira ldquoAntioxidanteffect of calcium antagonists on microsomai membranes iso-lated from different brain areasrdquo European Journal of Pharma-cology vol 204 no 3 pp 315ndash322 1991
[158] M E Letelier P Izquierdo L Godoy A M Lepe and MFaundez ldquoLiver microsomal biotransformation of nitro-aryldrugs mechanism for potential oxidative stress inductionrdquoJournal of Applied Toxicology vol 24 no 6 pp 519ndash525 2004
[159] M E Letelier P Entrala C Lopez-Alarcon et al ldquoNitroaryl-14-dihydropyridines as antioxidants against rat liver microsomesoxidation induced by ironascorbate Nitrofurantoin and naph-thalenerdquo Toxicology in Vitro vol 21 no 8 pp 1610ndash1618 2007
[160] F P Guengerich W R Brian M Iwasaki M-A Sari CBaarnhielm and P Berntsson ldquoOxidation of dihydropyridinecalcium channel blockers and analogues by human liver cyto-chrome P-450 IIIA4rdquo Journal of Medicinal Chemistry vol 34no 6 pp 1838ndash1844 1991
[161] S H Park S-W RhaW-Y Shin et al ldquoAS-160 Calcium channelblockers of dihydropyridine class reduce the antiplatelet effectof Clopidogrel what is clinical impactrdquo The American Journalof Cardiology vol 107 no 8 supplement p 47A 2011
[162] C Asma and D M Reda ldquoEvaluation of dihydropyridinecalcium antagonist effects on the stress bioindicator orga-nism Saccharomyces cerevisiaerdquo Annals of Biological Researchvol 4 no 10 pp 40ndash46 2013 httpscholarsresearchlibrarycomABR-vol4-iss10ABR-2013-4-10-40-46pdf
[163] G Gaviraghi A M Pastorino E Ratti and D G TristldquoCalcium channel blockers with antioxidant activityrdquo in Free
Radicals Lipoprotein Oxidation andAtherosclerosis G BellomoG Finardi E Maggi and E Rice-Evans Eds pp 431ndash456Richelieu Press London UK 1995
[164] G Gaviraghi AM Pastorino E Ratti and D G Trist ldquoAntiox-idant dihydropyridines a new and comprehensive therapy forfree radical-induced cardiovascular diseasesrdquo in Free Radicalsin Biology and Environment F Minisci Ed vol 27 of NATOASI Series pp 193ndash221 Springer Dordrecht The Netherlands1997
[165] P D Henry ldquoAntiperoxidative actions of calcium antagonistsand atherogenesisrdquo Journal of Cardiovascular Pharmacologyvol 18 supplement 1 pp S6ndashS10 1991
[166] F Kouoh B Gressier T Dine et al ldquoAntioxidant effects andanti-elastase activity of the calcium antagonist nicardipine onactivated human and rabbit neutrophilsmdasha potential antiath-erosclerotic property of calcium antagonistsrdquo CardiovascularDrugs andTherapy vol 16 no 6 pp 515ndash520 2002
[167] S Parthasarathy D Litvinov K Selvarajan and M GarelnabildquoLipid peroxidation and decompositionmdashconflicting roles inplaque vulnerability and stabilityrdquo Biochimica et BiophysicaActa vol 1781 no 5 pp 221ndash231 2008
[168] D-Q Liu Z-Q Pang D-H Zhao and B-H Sheng ldquoEffects offuryl-dihydropyridines I on lipid peroxides of ischemic myo-cardium and ATPases activity of erythrocyte membranes inratsrdquo Acta Pharmacologica Sinica vol 12 no 3 pp 253ndash2561991
[169] V Lukic-Panin T Kamiya H Zhang et al ldquoPrevention of neu-ronal damage by calcium channel blockers with antioxidativeeffects after transient focal ischemia in ratsrdquo Brain Research vol1176 no 1 pp 143ndash150 2007
[170] Y Allanore D Borderie H Lemarechal O G Ekindjian andA Kahan ldquoAcute and sustained effects of dihydropyridine-typecalcium channel antagonists on oxidative stress in systemicsclerosisrdquo American Journal of Medicine vol 116 no 9 pp 595ndash600 2004
[171] I Casetta V Govoni and E Granieri ldquoOxidative stress antioxi-dants and neurodegenerative diseasesrdquo Current PharmaceuticalDesign vol 11 no 16 pp 2033ndash2052 2005
[172] M J T J Arts Assessing antioxidant activity [PhD the-sis] Maastricht University Maastricht The Netherlands 2007httparnounimaasnlshowcgifid=8676
[173] G Dıaz-Araya L Godoy L Naranjo A Squella M E Letelierand L J Nunez-Vergara ldquoAntioxidant effects of 14-dihydro-pyridine and nitroso aryl derivatives on the Fe+3ascorbate-stimulated lipid peroxidation in rat brain slicesrdquo General Phar-macology The Vascular System vol 31 no 3 pp 385ndash391 1998
[174] Y Fukuhara K Tsuchiya Y Horinouchi et al ldquoProtectiveeffect of photodegradation product of nifedipine against tumornecrosis factor 120572-induced oxidative stress in human glomerularendothelial cellsrdquo Journal of Medical Investigation vol 58 no1-2 pp 118ndash126 2011
[175] W Stengel M Jainz and K Andreas ldquoDifferent potencies ofdihydropyridine derivatives in blocking T-type but not L-typeCa2+ channels in neuroblastoma-glioma hybrid cellsrdquo EuropeanJournal of Pharmacology vol 342 no 2-3 pp 339ndash345 1998
[176] O M Panasenko D J Tirzite G D Tirzitis and G J DubursldquoEffect of some 14-dihydropyridine derivatives on structuralorganization of erythrocyte membranesrdquo Biologicheskie Mem-brany (Biochemistry (Moscow) Series A Membrane and CellBiology) vol 1 pp 919ndash925 1984 (Russian)
[177] L G Herbette Y M H Vant Erve and D G Rhodes ldquoInter-action of 14 dihydropyridine calcium channel antagonists with
Oxidative Medicine and Cellular Longevity 33
biological membranes lipid bilayer partitioning could occurbefore drug binding to receptorsrdquo Journal of Molecular andCellular Cardiology vol 21 no 2 pp 187ndash201 1989
[178] L G Herbette P E Mason G Gaviraghi T N Tulenko andR P Mason ldquoThe molecular basis for lacidipinersquos unique phar-macokinetics optimal hydrophobicity results in membraneinteractions that may facilitate the treatment of atherosclerosisrdquoJournal of Cardiovascular Pharmacology vol 23 supplement 5pp S16ndashS25 1994
[179] G V Belevitch G Y Dubur G E Dobretsov N K Kurek andM M Spirin ldquoCalcium antagonists riodipine nifedipine andverapamil binding to model and biological membranes fluore-scence analysisrdquo Biologicheskie Membrany (Biochemistry(Moscow) Series A Membrane and Cell Biology) vol 5 pp768ndash776 1988 (Russian)
[180] R P Mason G E Gonye D W Chester and L G HerbetteldquoPartitioning and location of Bay K 8644 14-dihydropyridinecalcium channel agonist in model and biological membranesrdquoBiophysical Journal vol 55 no 4 pp 769ndash778 1989
[181] M Cindric A Cipak J Serly et al ldquoReversal of multidrugresistance inmurine lymphoma cells by amphiphilic dihydropy-ridine antioxidant derivativerdquo Anticancer Research vol 30 no10 pp 4063ndash4070 2010
[182] F Shekari H Sadeghpour K Javidnia et al ldquoCytotoxic andmultidrug resistance reversal activities of novel 14-dihydro-pyridines against human cancer cellsrdquo European Journal ofPharmacology vol 746 no 1 pp 233ndash244 2015
[183] X-F Zhou Q Shao R A Coburn and M E Morris ldquoQuanti-tative structure-activity relationship and quantitative structure-pharmacokinetics relationship of 14-dihydropyridines andpyridines as multidrug resistance modulatorsrdquo PharmaceuticalResearch vol 22 no 12 pp 1989ndash1996 2005
[184] R Berkels T Breitenbach H Bartels et al ldquoDifferent antioxida-tive potencies of dihydropyridine calcium channel modulatorsin various modelsrdquo Vascular Pharmacology vol 42 no 4 pp145ndash152 2005
[185] S Borovic G Tirzitis D Tirzite et al ldquoBioactive 14-dihydro-isonicotinic acid derivatives prevent oxidative damage of livercellsrdquo European Journal of Pharmacology vol 537 no 1ndash3 pp12ndash19 2006
[186] D Ya Rubene G D Tirzitis and G Ya Duburs ldquoInteractionof some 14-dihydropyridine derivatives with Fentonrsquos reagentrdquoLatvijas PSRZinatnuAkademijas Vestis Kimijas Serija Proceed-ings of the Latvian SSR Academy of Sciences Chemistry Seriespp 212ndash216 1982 (Russian)
[187] K Ondrias V Misık D Gergel and A Stasko ldquoLipid per-oxidation of phosphatidylcholine liposomes depressed by thecalcium channel blockers nifedipine and verapamil and bythe antiarrhythmic-antihypoxic drug stobadinerdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1003 no 3pp 238ndash245 1989
[188] I T Mak and W B Weglicki ldquoComparative antioxidant acti-vities of propranolol nifedipine verapamil and diltiazemagainst sarcolemmal membrane lipid peroxidationrdquoCirculationResearch vol 66 no 5 pp 1449ndash1452 1990
[189] I T Mak P Boehme and W B Weglicki ldquoProtective effects ofcalcium channel blockers against free radical-impaired endo-thelial cell proliferationrdquo Biochemical Pharmacology vol 50 no9 pp 1531ndash1534 1995
[190] S Ray S Mondal and N Dana ldquoEvaluation of protective roleof nifedipine on lipid peroxidation using reduced glutathione as
model markerrdquo Oxidants and Antioxidants in Medical Sciencevol 1 no 2 pp 97ndash100 2012
[191] M Yamato T Shiba T Ide Y Honda K-I Yamada andH Tsutsui ldquoNifedipine treatment reduces brain damage aftertransient focal ischemia possibly through its antioxidativeeffectsrdquoHypertension Research vol 34 no 7 pp 840ndash845 2011
[192] V Chander and K Chopra ldquoNifedipine attenuates changes innitric oxide levels renal oxidative stress and nephrotoxicityinduced by cyclosporinerdquo Renal Failure vol 27 no 4 pp 441ndash450 2005
[193] K M Gaafa M M Badawy and A A Hamza ldquoThe protectiveeffects of ascorbic acid cimetidine and nifedipine on diethyl-dithiocarbamate-induced hepatic toxicity in albino ratsrdquo Drugand Chemical Toxicology vol 34 no 4 pp 405ndash419 2011
[194] H Sugawara K Tobise and S Onodera ldquoAbsence of antiox-idant effects of nifedipine and diltiazem on myocardial mem-brane lipid peroxidation in contrast with those of nisoldipineand propranololrdquo Biochemical Pharmacology vol 47 no 5 pp887ndash892 1994
[195] I E Kirule D Y Rubene E A Bisenieks G D Tirzit and GY Dubur ldquo4-Nitrophenyl-14-dihydropyridinesmdasha new groupof inhibitors of peroxide oxidationrdquo Chemistry of HeterocyclicCompounds vol 18 no 3 p 316 1982
[196] G D Tirzit I E Kirule L K Baumane R A Gavar Y PStradynrsquo andG YDubur ldquoMechanism of the antioxidant actionof 26-dimethyl-35-dimethoxy-carbonyl-4-(2-nitrophenyl)14-dihydropyridinerdquoChemistry ofHeterocyclic Compounds vol 20no 8 pp 915ndash918 1984
[197] C Yanez C Lopez-Alarcon C Camargo V Valenzuela J ASquella and L J Nunez-Vergara ldquoStructural effects on thereactivity 14-dihydropyridines with alkylperoxyl radicals andABTS radical cationrdquo Bioorganic and Medicinal Chemistry vol12 no 9 pp 2459ndash2468 2004
[198] VMisik A J Stasko D Gergel and K Ondrias ldquoSpin-trappingand antioxidant properties of illuminated and nonilluminatednifedipine and nimodipine in heart homogenate and modelsystemrdquo Molecular Pharmacology vol 40 no 3 pp 435ndash4391991
[199] K Ondrias V Misık A Stasko D Gergelrsquo and M HromadovaldquoComparison of antioxidant properties of nifedipine and illu-minated nifedipine with nitroso spin traps in low densitylipoproteins and phosphatidylcholine liposomesrdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1211 no 1pp 114ndash119 1994
[200] A Stasko V Brezova S Biskupic K Ondrias and V MisıkldquoReactive radical intermediates formed from illuminated nife-dipinerdquoFree Radical Biology andMedicine vol 17 no 6 pp 545ndash556 1994
[201] K Ishizawa Y Izawa-Ishizawa N Yamano et al ldquoNitrosoni-fedipine ameliorates the progression of type 2 diabetic nephro-pathy by exerting antioxidative effectsrdquo PLoS ONE vol 9 no 1Article ID e86335 2014
[202] H Fujii and L J Berliner ldquoIn vivo EPR evidence for free radicaladducts of nifedipinerdquoMagnetic Resonance in Medicine vol 42no 4 pp 691ndash694 1999
[203] S Bollo S Finger J C Sturm L J Nunez-Vergara and JA Squella ldquoCyclic voltammetry and scanning electrochemicalmicroscopy studies of the heterogeneous electron transferreaction of some nitrosoaromatic compoundsrdquo ElectrochimicaActa vol 52 no 15 pp 4892ndash4898 2007
34 Oxidative Medicine and Cellular Longevity
[204] F Ursini ldquoTissue protection by lacidipine insight from redoxbehaviorrdquo Journal of Cardiovascular Pharmacology vol 30supplement 2 pp S28ndashS30 1997
[205] P G Cristofori F A Crivellente I Faustinelli et al ldquoInvolve-ment of the nitric oxide system in the anti-atheroscleroticpotential of lacidipine in the apoE-deficient mouse a mor-phological functional and electrochemical studyrdquo ToxicologicPathology vol 32 no 4 pp 493ndash499 2004
[206] X-P Zhang E L Kit S Mital S Chahwala and T HHintze ldquoParadoxical release of nitric oxide by an L-type calciumchannel antagonist the R+ enantiomer of amlodipinerdquo Journalof Cardiovascular Pharmacology vol 39 no 2 pp 208ndash2142002
[207] F Franzoni G Santoro F Regoli et al ldquoAn in vitro study of theperoxyl and hydroxyl radical scavenging capacity of the calciumantagonist amlodipinerdquo Biomedicine and Pharmacotherapy vol58 no 8 pp 423ndash426 2004
[208] S V Gatsura ldquoOxygen-dependent mechanisms underlying theantiischemic effect of verapamil and amlodipinerdquo Bulletin ofExperimental Biology and Medicine vol 137 no 1 pp 40ndash422004
[209] Y Hirooka Y Kimura M Nozoe Y Sagara K Ito and KSunagawa ldquoAmlodipine-induced reduction of oxidative stressin the brain is associated with sympatho-inhibitory effects instroke-prone spontaneously hypertensive ratsrdquo HypertensionResearch vol 29 no 1 pp 49ndash56 2006
[210] B Tomlinson and I F F Benzie ldquoAntioxidant effect of lercani-dipine (note)rdquo Hypertension vol 42 no 4 pp e10ndashe11 2003
[211] A A Faraqui ldquoNeurochemical aspects of 4-hydroxynonenalrdquoin Lipid Mediators and Their Metabolism in the Brain A AFaraqui Ed chapter 6 pp 159ndash191 Springer New York NYUSA 2011
[212] V S NascimentoM S DrsquoAlva A AOliveira et al ldquoAntioxidanteffect of nimodipine in young rats after pilocarpine-inducedseizuresrdquo Pharmacology Biochemistry and Behavior vol 82 no1 pp 11ndash16 2005
[213] O Ismailoglu P Atilla S Palaoglu et al ldquoThe therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjuryrdquo Turkish Neurosurgery vol 22 no 6 pp 740ndash746 2012
[214] M Matsubara and K Hasegawa ldquoBenidipine a dihydropy-ridine-calcium channel blocker prevents lysophosphatidyl-choline-induced injury and reactive oxygen species productionin human aortic endothelial cellsrdquo Atherosclerosis vol 178 no1 pp 57ndash66 2005
[215] M Matsubara K Yao and K Hasegawa ldquoBenidipine adihydropyridine-calcium channel blocker inhibits lysophos-phatidylcholine-induced endothelial injury via stimulation ofnitric oxide releaserdquo Pharmacological Research vol 53 no 1 pp35ndash43 2006
[216] MMatsubara and K Hasegawa ldquoEffects of benidipine a dihyd-ropyridine-Ca2+ channel blocker on expression of cytokine-induced adhesion molecules and chemoattractants in humanaortic endothelial cellsrdquo European Journal of Pharmacology vol498 no 1ndash3 pp 303ndash314 2004
[217] M Matsubara O Akizuki J-I Ikeda K Saeki K Yao and KSasaki ldquoBenidipine an anti-hypertensive drug inhibits reactiveoxygen species production in polymorphonuclear leukocytesand oxidative stress in salt-loaded stroke-prone spontaneouslyhypertensive ratsrdquo European Journal of Pharmacology vol 580no 1-2 pp 201ndash213 2008
[218] A C Rosenkranz H Lob T Breitenbach R Berkels and RRoesen ldquoEndothelial antioxidant actions of dihydropyridines
and angiotensin converting enzyme inhibitorsrdquo European Jour-nal of Pharmacology vol 529 no 1ndash3 pp 55ndash62 2006
[219] V Kain S Kumar and S L Sitasawad ldquoAzelnidipine preventscardiac dysfunction in streptozotocin-diabetic rats by reducingintracellular calcium accumulation oxidative stress and apop-tosisrdquo Cardiovascular Diabetology vol 10 article 97 2011
[220] K Nakamura S Yamagishi and H Inoue ldquoUnique atheropro-tective property of azelnidipine a dihydropyridine-based cal-cium antagonistrdquoMedical Hypotheses vol 65 no 1 pp 155ndash1572005
[221] TMatsui S Yamagishi K Nakamura S Kikuchi andH InoueldquoAzelnidipine a dihydropyridine-based calcium antagonistinhibits angiotensin II-induced oxidative stress generation anddownregulation of pigment epithelium-derived factor mRNAlevels in microvascular endothelial cellsrdquo Drugs under Experi-mental and Clinical Research vol 31 no 5-6 pp 215ndash219 2005
[222] C Ohmura H Watada T Shimizu et al ldquoCalcium channelblocker azelnidipine reduces lipid hydroperoxides in patientswith type 2 diabetes independent of blood pressurerdquo EndocrineJournal vol 54 no 5 pp 805ndash811 2007
[223] H Daikuhara F Kikuchi and T Ishida ldquoThe combination ofOLmesartan and a CAlcium channel blocker (azelnidipine) orcandesartan and a calcium channel blocker (amlodipine) intype 2 diabetic hypertensive patients theOLCA studyrdquoDiabetesand Vascular Disease Research vol 9 no 4 pp 280ndash286 2012
[224] MAbe NMaruyama KOkada SMatsumoto KMatsumotoand M Soma ldquoAdditive antioxidative effects of azelnidipine onangiotensin receptor blocker olmesartan treatment for type 2diabetic patients with albuminuriardquoHypertension Research vol34 no 8 pp 935ndash941 2011
[225] K Mizushige ldquoAntioxidative activities of thiazolidinedionesand dihydropyridine-type calcium antagonistsrdquo IRYOmdashJapa-nese Journal of National Medical Services vol 59 no 11 pp 581ndash592 2005
[226] S Manabe T Okura T Fukuoka and J Higaki ldquoAntioxidativeeffects of azelnidipine on mesangial cell proliferation inducedby highly concentrated insulinrdquo European Journal of Pharma-cology vol 567 no 3 pp 252ndash257 2007
[227] Y Koyama Y Takeishi H Takahashi et al ldquoAzelnidipine inhi-bits H
2O2-induced cell death in neonatal rat cardiomyocytesrdquo
CardiovascularDrugs andTherapy vol 21 no 1 pp 69ndash72 2007[228] K Shinomiya K Mizushige M Fukunaga et al ldquoAntioxidant
effect of a new calcium antagonist azelnipidine in culturedhuman arterial endothelial cellsrdquo Journal of International Med-ical Research vol 32 no 2 pp 170ndash175 2004
[229] T Ohyama K Sato K Kishimoto et al ldquoAzelnidipine is acalcium blocker that attenuates liver fibrosis and may increaseantioxidant defencerdquo British Journal of Pharmacology vol 165no 4 pp 1173ndash1187 2012
[230] L A Calo F Zaghetto E Pagnin P A Davis A Sempliciniand A C Pessina ldquoEffect of manidipine on gene expressionand protein level of oxidative stress-related proteins p22phoxand HO-1 Relevance for antihypertensive and anti-remodelingeffectsrdquo Journal of Cardiovascular Pharmacology vol 43 no 4pp 531ndash538 2004
[231] R Ghyasi G Sepehri M Mohammadi R Badalzadeh and AGhyasi ldquoEffect of mebudipine on oxidative stress and lipid per-oxidation in myocardial ischemic-reperfusion injury in maleratrdquo Journal of Research in Medical Sciences vol 17 no 12 pp1150ndash1155 2012
Oxidative Medicine and Cellular Longevity 35
[232] DCAndersson J Fauconnier T Yamada et al ldquoMitochondrialproduction of reactive oxygen species contributes to the 120573-adrenergic stimulation of mouse cardiomycytesrdquoThe Journal ofPhysiology vol 589 no 7 pp 1791ndash1801 2011
[233] A F Ceylan-Isik N Ari M Stefek et al ldquoEffects of a long-term treatment with an antioxidant pyridoindole on vascularresponsiveness in diabetes-induced aging ratsrdquo Current AgingScience vol 4 no 2 pp 150ndash157 2011
[234] S Saponara G Sgaragli and F Fusi ldquoQuercetin antagonismof Bay K 8644 effects on rat tail artery L-type Ca2+ channelsrdquoEuropean Journal of Pharmacology vol 598 no 1ndash3 pp 75ndash802008
[235] D A Sica ldquoInteraction of grapefruit juice and calcium channelblockersrdquo American Journal of Hypertension vol 19 no 7 pp768ndash773 2006
[236] P Mulder G Litwinienko S Lin P D MacLean L R CBarclay and K U Ingold ldquoThe L-type calcium channel block-ers Hantzsch 14-dihydropyridines are not peroxyl radical-trapping chain-breaking antioxidantsrdquo Chemical Research inToxicology vol 19 no 1 pp 79ndash85 2006
[237] L J Nunez-Vergara R Salazar C Camargo et al ldquoOxidation ofC4-hydroxyphenyl 14-dihydropyridines in dimethylsulfoxideand its reactivity towards alkylperoxyl radicals in aqueousmediumrdquo Bioorganic and Medicinal Chemistry vol 15 no 12pp 4318ndash4326 2007
[238] M E Ortiz L J Nunez-Vergara and J A Squella ldquoRelativereactivity of dihydropyridine derivatives to electrogeneratedsuperoxide ion in DMSO solutions a voltammetric approachrdquoPharmaceutical Research vol 20 no 2 pp 292ndash296 2003
[239] M E Ortiz L J Nunez-Vergara C Camargo and J A SquellaldquoOxidation of Hantzsch 14-dihydropyridines of pharmacolog-ical significance by electrogenerated superoxiderdquo Pharmaceuti-cal Research vol 21 no 3 pp 428ndash435 2004
[240] R S Raghuvanshi and K N Singh ldquoSuperoxide induced oxida-tive aromatization of Hantzsch 14-dihydropyridinesrdquo IndianJournal of Chemistry Section B Organic and Medicinal Chem-istry vol 47 no 11 pp 1735ndash1738 2008
[241] I Kruk A Kladna K Lichszteld et al ldquoAntioxidant activityof 4-flavonil-14-dihydropyridine derivativesrdquo Biopolymers vol62 no 3 pp 163ndash167 2001
[242] G D Tirzit I M Byteva K I Salokhiddinov G P Gurinovichand G Y Dubur ldquo14-Dihydropyridine derivatives as deactiva-tors of singlet oxygenrdquo Chemistry of Heterocyclic Compoundsvol 17 no 7 pp 682ndash684 1981
[243] G D Tirzit E Y Kazush and G Y Dubur ldquoInfluence of14-dihydropyridine derivatives on the generation of hydroxylradicalsrdquo Chemistry of Heterocyclic Compounds vol 28 no 4pp 435ndash437 1992
[244] N A Pizarro-Urzua and L J Nunez-Vergara ldquoNifedipine andnitrendipine reactivity toward singlet oxygenrdquo Journal of Photo-chemistry and Photobiology A Chemistry vol 175 no 2-3 pp129ndash137 2005
[245] L-F Wang H-Y Zhang L Konga Z-W Chena and J-G ShildquoDFT calculations indicate that 14-dihydropyridine is a promis-ing lead antioxidantrdquo Helvetica Chimica Acta vol 87 no 6 pp1515ndash1521 2004
[246] P Mulder H-G Korth and K U Ingold ldquoWhy quantum-thermochemical calculations must be used with caution toindicate lsquoa promising lead antioxidantrsquordquoHelvetica Chimica Actavol 88 no 2 pp 370ndash374 2005
[247] K Yao Y Ina K Nagashima K Ohmori and T Ohno ldquoAntiox-idant effects of calcium antagonists in rat brain homogenatesrdquo
Biological and Pharmaceutical Bulletin vol 23 no 6 pp 766ndash769 2000
[248] T Matsui S-I Yamagishi K Nakamura and H Inoue ldquoBayw 9798 a dihydropyridine structurally related to nifedipinewith no calcium channel-blocking properties inhibits tumournecrosis factor-120572-induced vascular cell adhesion molecule-1expression in endothelial cells by suppressing reactive oxygenspecies generationrdquo Journal of International Medical Researchvol 35 no 6 pp 886ndash891 2007
[249] K AMitrega B VargheseM Porc and T F Krzeminski ldquoAnti-arrhythmic and hemodynamic effects of oxy nifedipine oxynimodipine oxy nitrendipine and oxy nisoldipinerdquo Pharmaco-logical Research vol 66 no 4 pp 300ndash308 2012
[250] V Herbert ldquoSymposium prooxidant effects of antioxidantvitamins Introductionrdquo The Journal of Nutrition vol 126 no4 supplement pp 1197Sndash1200S 1996 httpjnnutritionorgcontent1264 Suppl1197Sfullpdf
[251] B Halliwell ldquoAre polyphenols antioxidants or pro-oxidantsWhat do we learn from cell culture and in vivo studiesrdquoArchives of Biochemistry and Biophysics vol 476 no 2 pp 107ndash112 2008
[252] C Winterbourn Pro-Oxidants or Antioxidants ChristchurchSchool of Medicine Depatment of Pathology Free RadicalSchool SFRBMUniversity of Otago San Francisco Calif USA2009 httpwwwsfrbmorgfrsWinterbournpdf
[253] A Morakinyo B Iranloye and O Adegoke ldquoCalcium antag-onists modulate oxidative stress and acrosomal reaction in ratspermatozoardquo Archives of Medical Science vol 7 no 4 pp 613ndash618 2011
[254] The Alpha-Tocopherol Beta Carotene Cancer Prevention StudyGroup ldquoThe effect of vitamin E and beta carotene on theincidence of lung cancer and other cancers in male smokersrdquoTheNew England Journal of Medicine vol 330 no 15 pp 1029ndash1035 1994
[255] B Poljsak ldquoStrategies for reducing or preventing the generationof oxidative stressrdquo Oxidative Medicine and Cellular Longevityvol 2011 Article ID 194586 15 pages 2011
[256] B Poljsak and I Milisav ldquoThe neglected significance of lsquoanti-oxidative stressrsquordquoOxidativeMedicine and Cellular Longevity vol2012 Article ID 480895 12 pages 2012
[257] T Godfraind and S Salomone ldquoAmbiguities in dietary antiox-idant supplementation compared to calcium channel blockerstherapyrdquo Frontiers in Pharmacology vol 6 article 10 2015
[258] H Wagner H Norr and H Winterhoff ldquoDrugs with adap-togenic effects for strengthening the powers of resistancerdquoZeitschrift fur Phytotherapie vol 13 no 2 pp 42ndash54 1992
Oxidative Medicine and Cellular Longevity 13
It was interesting to compare the AOAofDHPswith theirsusceptibility to oxidation that is electron and hydrogendonating properties
It has been estimated that electron donor substituentsin positions 2 and 6 of 14-DHP cycle usually promoteoxidation while electron acceptor substituents promotequench oxidation Stronger electron acceptors in positions 3and 5 also significantly quench oxidation These estimationsare based on studies including chemical enzymatic andelectrochemical oxidation of 14-DHPderivatives (Dubur andUldrikis [70] Duburs et al [71] and Stradin et al [139])
On the other hand diminished AOA of 14-DHP relatesto presence of substituents in position 4 (both electron donorand electron acceptor) (Velena et al [112])
35-Dicarbamoyl substituents possess minimal quench-ing feature and are followed by benzoyl- acetyl- andalkoxycarbonyl- groups Maximal decrease was obtainedwith condensed substituents (ie oxoindeno- or oxocyclo-hexeno- groups) and a CN-group 4-Unsubstituted 35-dicar-bamoyl derivatives can be easily oxidized and consequen-tially inactivated whereas 4-substituted 35-dicarbamoyl-14-DHPs possess an oxidation potential analogous to the 4-unsubstituted 35-COOR derivatives Therefore they haveadequate electron donor properties and are considerablystableThismay be the reason for significantmembrane stabi-lization upon exposure to 4-substituted derivatives Ofimportance their AOA was usually more pronounced incomparison to 4-unsubstituted derivatives
Among them 26-dimethyl-35-difurfuryloxycarbonyl-14-DHP showed the highest antioxidative activity In thegroup of 35-dialkoxycarbonyl derivatives the strongestactivity was attributed to compounds with medium lengthalkyl chains (i-butyl- t-butyl- and i-amyl- substituents) highlevel of lipophilicity minimal electron acceptor propertiesand moderate steric hindrance as contrasted to short or longalkyl chain ester derivatives (35-dimethoxycarbonyl- 35-diethoxycarbonyl derivatives and 35-didodecyloxycarbonylderivative) These data demonstrate the bell-shaped depen-dence of AOA on alkyl chain length [112] and are in accordwith results obtained in liposomes However these datadiffer from those obtained in emulsions where diludine wasthe most active compound Finally oxidized heteroaromaticderivatives showed only minimal activity
In both LP systems studied (AsA-dependent in mito-chondria and NADPH-dependent in microsomes) some of14-DHPs showed activity similar to classical antioxidantbutylated hydroxytoluene (ionol BHT) (Velena et al [112])However there was a significant difference related to con-centration and incubation time It allowed us to postu-late that 14-dihydropyridines (InH) acting as antioxidants-reductants and scavengers of reactive oxygen species and lipidfree radicals preferably influence initiation and propagation(prolongation) of lipid peroxidation chain reactions (1)ndash(5) according to Scheme 2 The phenomenon is particularlyprominent in the presence of Fe2+ and other ions of variablevalency
Chain break and termination reactions (6)ndash(10) of theLP reaction cascade [89] were influenced by 14-DHPs in alesser degree than were initiation and propagation steps This
may be important for their therapeutic effects even in theadvanced stages of LP
Scheme 2 (stages of initiation propagation and terminationof lipid peroxidation chain reactions (1ndash10)) Initiation andpropagation reactions are as follows
(8) RO∙ + In∙minus rarr Y (Y = molecular products)(9) ROO∙ + Fe2+ rarr Fe3+ + X (X = molecular products)(10) RO∙ + RO∙minus rarr Y (Y = molecular products)
In the reversible swelling of mitochondria accompanyingLP (initiated by mixture of 5mM GSSG1mM GSH) several14-DHPs showed low or no activity manifested only as adecrease of the swelling amplitude without a rate decreaseAn addition of GSH (4mM) or ATP to swollenmitochondriacaused their contraction in both control and tested systemIt may be suggested that 14-DHPs acting as antioxidantsin mitochondria preferably influence LP reactions initiatedby ions with variable valency or their complexes with hemetype compounds methemoglobin hemin hematin and soforth (Velena et al [112]) If the peroxidation process has amaximal velocity and 50 percent of initial O
2were consumed
14-DHPs cannot completely break the chain reactions andprevent subsequent membrane damage by addition of DHPsubstance at 10 120583M concentration at the moment of 50percent oxygen consumption the subsequent oxygen uptakeproceeded unchanged This observation is important for theapplication of DHPs as inhibitors of initiation and to a lesserdegree propagation stages of LP chain reactions
The influence of 14-DHPs on Mit swelling is not strictlyassociated with their own oxidation There is the possibilitythat the labilizing (or stabilizing) effect relates to surfaceactivity (connected with substituent lipophilicity) or may bethe consequence of complexation with some -OH (or -CH
3)
group sensitive receptors at the mitochondrial membraneNamely a bathochromic shift of the absorption band maxi-mum (about 10 nm) was observed in the visible region beforeswelling However after swelling in the presence of Na+linoleate the spectrum returns to its initial value [112]
Some 14-DHPs not only protect mitochondria againstswelling caused by AsA-dependent LP salts of fatty acids
14 Oxidative Medicine and Cellular Longevity
in vitro [112] but also have beneficial effects on repairingtheir integrity in vivo after exposure to irradiation hepato-toxins ischemia hypoxia or hypothermia Some of themwere shown to normalize the process of intracellular repara-tion and physiological regeneration of ultrastructures Theywere also shown to stimulate reparative processes If pre-treated with 14-DHPs irradiatedmitochondria will not swell(Ivanov et al [140 141])
Diludine ionol and some other AOs mitochondria pro-tectors act as anti-ischemic agents If applied prophylacticallyin vivo they may prevent ischemic and reperfusion lesionsin heart kidney and other organs (Bilenko et al [113]) Theeffect is dependent on applied dose timing and way ofapplicationWhen added onto the cryoconservationmediumfor mitochondria preservation 14-DHPs prevented decreaseof membrane potential normalized facilitated respirationand prevented loss of mitochondrial Na+ and Ca2+ ionsafter thawing ([112] see citation number 36 (Subbota et alKharkov 1984) therein) Diludine was stronger protectorwhen compared to ionol
CA drug foridone (riodipine) was shown to possesscardioprotective features primarily due to is protective effecton mitochondria exposed to OS [142 143]
Similarly the DHP water-soluble antiarrhythmic com-pound glutapyrone inhibits initiation of LP by free radicalsin erythrocytes and heart mitochondria Its cardioprotectiveeffect has been experimentally shown in heart mitochondrialmembranes especially during deep hypothermia (Utno et al[144])
Cerebrocrast was effective in several translation modelsmimicking pathological situations known to be associatedwith cellular OS The potential protective action of 14-DHP derivatives (4-substituted compounds cerebrocrastgammapyrone glutapyrone and 4-unsubstituted drug dieth-one) has been studied in rat liver in experimental modelsrelevant for oxidative stress and mitochondrial bioenergetics(Fernandes et al [145]) When succinate was used as therespiratory substrate higher concentrations (gt25 120583M) ofcerebrocrast depressed respiratory control ratio (RCR) ADPto oxygen ratio (ADPO) state 3 and uncoupled respirationrates transmembrane potential (deltapsi) and the phosphatecarrier rate At the same time state 4 respiration rate wasthree times increased At concentrations lower than 25120583Mcerebrocrast inhibited mitochondrial IMAC and partiallyprevented Ca2+-induced opening of the mitochondrial PTPGammapyrone glutapyrone and diethone did not inducethese phenomena When applied at concentrations up to100 120583M cerebrocrast gammapyrone and glutapyrone didnot affect ADPFe2+-induced LP of mitochondria in rat liver(as measured by oxygen consumption and TBARS forma-tion) On the other hand low diethone concentrations (upto 5 120583M) inhibited it in a dose-dependent manner Diethonealso prevented against deltapsi dissipation induced by LPinitiated by ADPFe2+ Based on these data it may bespeculated that cerebrocrast (inhibition of the IMAC) anddiethone (acting as an AO) may provide effective protectionof mitochondria during OS Cerebrocrast has shown sometherapeutic potential for treatment of several pathologicalconditions related to cellular OS [145]
5-Acetyl(carbamoyl)-6-methylsulfanyl-14-DHP-carbo-nitriles (Figure 3) with minor differences in their molecularstructure displaying antioxidant and antiradical activitiesin vitro show different biological activities Namely 4-p-chlorophenyl derivative OSI-1146 displays AO and anti-radical activities in cardiovascular OS models whereasOSI-3701 and OSI-3761 display hepatoprotective activityThus these compounds may be potentially useful for treat-ing several pathological processes including those associatedwith OS (Fernandes et al [146]) However besides mito-chondria the cellular targets for their pharmacologicalactions have not been fully investigated [146] All these com-pounds increase the susceptibility of Mit to MPT The mostpotent is OSI-3701 although it does not affect bioenergeticparameters
Although all these compounds protected mitochondriaagainst LP induced by the oxidant pair ADPFe2+ OSI-1146was shown to be the most potent Current data point outmitochondria as potential targets for protective and toxicactions of DHPs suggesting that the potential for their use astherapeutic agents should also take into consideration theirtoxic effects on mitochondria (Fernandes et al [146])
Several structurally different DHP derivatives (antioxi-dant diludine (diethone) as a 4-unsubstituted DHP 4-substi-tuted DHPs CA foridone (bicyclic compound) and the 4-phenyldiethone compound where phenyl group is joined tothe DHP in position 4) inhibited the 1-methyl-4-phenyl-pyridinium iodide (MPP+) induced ROS production incerebellar granule cells (CGC) with a distinct potency orderforidone (26-dimethyl-35-dimethoxycarbonyl-4-(o-difluo-romethoxyphenyl)-14-dihydropyridine) gt 26-dimethyl-35-diethoxycarbonyl-4-phenyl-14-dihydropyridine gt diludineThey also reversed the MPP+-induced decrease of the mito-chondrial membrane potential in the same order (Klimavi-ciusa et al [147]) Accordingly it was postulated that theclassical two-ring (bicyclic) structure of DHP derivativesrepresents an advantage in relation to neuroprotection andROS defense and is independent on compoundrsquos propertiesrelated to calcium ions
Novel adamantane-containing 14-DHP compounds (Kli-maviciusa et al [148]) were also found to improve mitochon-drial functions (MPP+ model) (Klimaviciusa et al [148])Klusa et al [149] have discovered antineurotoxic effects of14-DHP taurine derivative tauropyrone recorded as Mitfunction improvement
Many 14-DHPs including Ca2+ antagonists and AOmodify LP processes and influencemitochondrial function invarious organs (liver heart kidney and brain) in a differentway and degree Their beneficial action oxygen or lipidfree radical scavenging antioxidative effects binding withor intercalating into phospholipid bilayer regulation of iongating and regulation of mitochondrial permeability transi-tion pores (Tirzit and Duburs [39] Zilber et al [44] andDubur et al [45]) separately or in combination with eachother depends on two strong elements (1) their individ-ual structure including nature of substituents and theirpositions and (2) the nature of the biological system Forexample the direction of LP (inhibition of promotion) wasshown to depend on structure and concentration of applied
Oxidative Medicine and Cellular Longevity 15
14-DHPs as well as stages of chain reactions Accordinglymitochondrial swelling may be prolonged (retarded) accel-erated (promoted) or inhibited (Velena et al [112])
Therefore there is a ground for 14-dihydropyridineseither Ca2+ antagonists or antioxidants to be nominated asuseful tools in development of ldquomitochondrial drugsrdquo relatedto the control of OS
(c) DHPs as AOs in Endoplasmic Reticulum (Inhibition ofNADPH-Dependent LP System) Inhibition of NADPH Oxi-dase by DHPs Elevated level of NADPH oxidase 4- (NOX4-)derived hydrogen peroxide (H
2O2) joined with concomitant
decrease of nitric oxide (NO) mediated signaling and reac-tive oxygen species scavengers are considered to be centralfactor in molecular pathogenesis of fibrosis (Sampson etal [150]) Inhibition of microsomal NADPH-dependent LPwith particular focus on NADPH oxidases (NOX1ndash5 andDUOX1) may be very important for neuro- cardio- andhepatoprotection (Velena et al [112] Leto and Geiszt [151]Griendling et al [152] and Chen et al [153]) Endoplasmicreticulum may be an important target as this is where 14-DHPs could display their antioxidative properties (Velena etal [112] Leto and Geiszt [151] Griendling et al [152] andChen et al [153])
However the initiation of LP in the NADPH-dependentmicrosomal system does not appear to involve either super-oxide or hydrogen peroxide since neither SOD nor cata-lase can inhibit it On the other hand reduced iron playsan important role in both the initiation and propaga-tion of NADPH-dependent microsomal lipid peroxidation(Hochstein and Ernster [154] and Repetto et al [111])
Many DHPs possess inhibitory activity not only towardsAsA-dependent LP in mitochondria but also towardsNADPH-dependent LP as shown in isolated rat liver micro-somes (Velena et al [112]) This means that these compoundsinteract with the shared parts (nonenzymatic and enzymatic)of LP pathways
Microcalorimetry and fluorescent probes procedureswere used for studying the interaction of alpha-tocopheroland 14-DHPs with endoplasmic reticulum membranes andmodel systems human serum albumin and phospholipidbilayers [155] Modification of microviscosity of the endo-plasmatic reticular membranes depends on localization ofantioxidants within the protein structures or phospholipidphase Increase of membrane structuralization under theinfluence of 14-DHPs blocked their antioxidant action inspontaneous and induced lipid peroxidation
Inhibition of rat heart and liver microsomal lipid perox-idation by nifedipine was observed [156] while Goncalves etal [157] found antioxidant effect of calcium antagonists onmicrosomal membranes isolated from different brain areas
Nitroaryl-14-DHPs are both calcium channel antagonistsand antioxidant agents (Letelier et al [158 159]) commonlyused for treatment of cardiovascular diseases These drugsmust be metabolized through cytochrome P450 oxidativesystem (NADPH-cytochrome P450 reductase) mainly local-ized in the hepatic endoplasmic reticulum Several lipophilicdrugs generate OS while being metabolized by this cellularsystem Thus DHP antioxidant properties may prevent the
OS associated with hepatic biotransformation of drugs Var-ious commercial and new nitro-phenyl-DHPs were studiedagainst LP using rat liver microsomes under oxidative stress[159]
Incubation of rat liver microsomes with the 41015840-nitro-4-phenyl-14-DHP compounds (26-dimethyl-4-(41015840-nitro-phenyl)-14-dihydropyridin-35-diethyl-dicarboxylate andN-ethyl-26-dimethyl-4-(41015840-nitrophenyl)-14-dihydropyri-din-35-dimethyl-dicarboxylate) results in an inhibitionof LP the UDPGT (UDP-glucuronyltransferase) oxidativeactivation and the microsomal thiol oxidation induced byFe3+ascorbate a generator system of ROS This effect wasalso produced by nitrofurantoin and naphthalene in thepresence of NADPH
Interestingly IC50
ofDHPs obtained frommicrosomal LPassays decreased to the same extent as the microsomal thiolsoxidation provoked by Fe3+ascorbate [159] Neverthelessthe AO effects of a nitrophenyl-DHP compound in whichhydrogen at position one of the DHP ring was replaced bythe ethyl groupwere significantlyweaker Authors speculatedthat DHPs can resemble NADH transferring one hydrogenatom of 4-position (Hminus) to anion superoxide and another ofthe 1-position (H+) by way of a cationic radical intermediateto generate pyridine derivatives and water [159]
The AO effects of various tested DHP derivatives (m- andp-NO
2phenyl as well as methyl or ethyl and isopropyl-DHP
35-dicarboxylate derivatives) were not significantly differentThe authors assumed that the -NH- group of the dihydropy-ridine ring could contribute both to the development ofthe calcium channel antagonism and to the antioxidativeproperties of DHPs [159]
Prevention of the membrane LP seemingly depends onthe concentration of potential antioxidants such as vitaminE or even 14-DHP in lipids However only the differencesin synthetic DHPs lipophilicity cannot explain significantvariations of DHPs concentration in microsomal membraneand cannot clarify the strength of their antioxidative activityThis work [159] has further demonstrated that 14-DHPsmay prevent the OS induced by biotransformation of somedrugs for example antibiotic nitrofurantoin Simultaneousadministration of DHPs and nitrofurantoinmay be beneficialin reducing nitrofurantoin side effects
While most of Ca antagonist 14-DHPs are metabolizedby CYP3A4 (Guengerich et al [160]) not all of them are goodinhibitors of its activity Thus nicardipine but not nifedipineand nitrendipine inhibits CYP3A4 in vitro [53] Interactionof different DHPs with various types of cytochrome P450 wasdescribed by Carosati et al [53] It was also reported thatDHP class calcium channel blockers reduce the antiplateleteffect of clopidogrel (Park et al [161])This implies themutualinteractions of both drugs with CYP3A4
(3) In Vivo Evaluation of nifedipine effects on Saccharomycescerevisiaewas recently published (Asma andReda [162]) Sur-prisingly nifedipine exercised a toxic effect on Saccharomycescerevisiae shown through measuring cellular proliferationrespiratory activity and the level of some biomarkers (CATand MDA)
16 Oxidative Medicine and Cellular Longevity
However majority of data obtained on various animalcells and tissues by other authors show the protective role ofDHPs against both LP and oxidative stress [113 163 164]
The AOA attributed to many 14-DHPs Ca2+ antag-onists and other compounds reflecting on catalytic LDLperoxidation (see Section 331 (2) and Section 35) shouldencourage their testing for treating cardiovascular diseasesandor alterations of lipid metabolism
The possibility that 14-DHP-based calcium antagonistsexert an antiatherosclerotic action (via inhibition of LDLoxidation and other mechanisms) has been proved by manyexperimental data [165] and several clinical trials Besidesantihypertensive effect nicardipine was shown to possessantioxidative and antielastase activity [165 166] These prop-erties may be useful for prevention of inflammatory reactionwhich is relevant for hypertension pathogenesis
14-DHPs administration inhibits LDL oxidation medi-ated by oxygen radicals leading to decreased carotid inti-mal media thickness and reduced progression of coronaryatherosclerosis [130] It additionally preserves Apo B-100integrity against ROS Of importance antiatherogenic mech-anisms differ between animals and humans (primarily inthe stage of conversion of aldehydes to carboxylic acids)(Parthasarathy et al [167])
For example furyl-DHP compound (FDP-1 diethyl 26-dimethyl-4-(furyl)-14-dihydropyridine-35-dicarboxylate)was shown to act as an antioxidant (decreasing MDA GOTand FFA release of ischemic myocardium and inhibiting Ca-ATPase of erythrocyte membranes) preventing against heartmyocardium ischemia-reperfusion injury and arrhythmiawhen applied (in rats) at 10mgkg (Liu et al [168])
Similarly antioxidative effects of azelnidipine andamlodipine prevented neuronal damage by CCBs aftertransient focal ischemia in rats (Lukic-Panin et al [169])
Allanore et al [170] found that both nifedipine andnicardipine significantly decrease the mean level of plasmamarkers for oxidative stress in patients suffering from sys-temic sclerosis
Antioxidants may be considered as promising neuropro-tective compounds Still while experimental data demon-strate neuroprotective effect in vitro and in animal mod-els clinical evidence is still unsatisfactory and insufficient[171]
(a) Role of Metabolism of DHPs in Their AOA Metabolicpathways and ldquobioavailabilityrdquo of the probable AOA com-pound determine antioxidant activity in vivo Antioxidantmetabolites may vary in stability and activity leading to twoopposite scenarios lack or presence of activity substantiallycontributing to the overall AOA [172] Metabolic biotransfor-mation of DHPs includes oxidation (heteroaromatization)side chain ester group cleavage (deesterification) and 4-substituent abstraction ao [160] None of the DHPs metabo-lites was shown to be more toxic than original reduced formof the compound The commonly detected metabolites ofthe DHPs do not seem to possess the AO activity (withsome exceptions as in the case of metabolites of nifedipineand its analogues including nitrosonifedipine [173 174]) (seefurther in Section 35) Due to DHPs intrinsic instability
achieving andmaintaining an adequate concentrationmay beproblematic both in vitro and in vivo
(b) Role of Concentration and Lipophilicity (MembraneWateror LipidWater Partition Coefficients) of DHPs inTheir Actionas AOs and Antiradical Compounds Antioxidative effects ofany antioxidant depend on its concentration at the site ofaction This parameter is hardly measurable especially intwo-phase systems representing one of obstacles in com-parison to AOA upon applying various compounds [172]It is often incorrectly assumed that the concentrations inthe aqueous solution and at the site of action are the sameHowever even when the concentration in the aqueous phasemay be well controlled the concentration at the site ofaction in the lipid matrix of the membranes might fluctuatebetween different test compounds depending on a differencein lipophilicity [175] The prevention of the membrane LPalso seems to be dependent on the DHP concentration in thelipidmatrix (Mason andTrumbore [46]) and its amphiphilic-ity For example AOA of diludine is associated with itslipophilicity and consequential ability to be incorporatedinto liposomes (Panasenko et al [176]) It was also foundthat diludine easily incorporates into the outer monolayer oferythrocyte membranes [176]
Membranebuffer partition coefficients (lambda) weredirectly measured in the sarcolemma and sarcoplasmicreticulum membranes for three CA DHPs The obtainedvalues were in a broad range between 5000 and 150000(Herbette et al [177])These drugs interact primarily with themembrane bilayer component but may also bind to proteinsboth nonreceptors and receptors The intrinsic forward rateconstants for DHP binding to sarcolemmal calcium channelreceptors were apparently not strongly dependent on theirmembrane partition coefficients For example nimodipine(lambda = 6300) had a forward rate constant of 68 plusmn 06 times106Ms whereas the forward rate constant for Bay P 8857
(lambda = 149000) was 14plusmn08times107Ms Since these DHPsare highly liposoluble model calculations for this bindingreaction demonstrated that these rates on lipid solubilitywould probably not be reflected in the experimental forwardrate constants In addition the intrinsic forward rate constantfor nimodipine binding to sarcolemmal calcium channelreceptors was found not to be linearly dependent on theviscosity of the buffer medium over a fivefold range The rateof drug nonspecific binding to nonreceptor protein present inhighly purified sarcoplasmic reticulum membranes appearsto be extremely fast at least 103 times faster than specificdrug binding to the receptor in the sarcolemma Authorsconcluded that partitioning into the lipid bilayer matrix ofthe sarcolemma could be a general property of CA DHPsand may be a prerequisite for their binding to sarcolemmalmembrane receptors (Herbette et al [177])
The binding of DHP calcium channel agonists and antag-onists (including those with AO properties) to receptors incardiac sarcolemmal membranes is a complex reaction thatmay involve an interaction with the lipid bilayer matrix ofthe sarcolemma (Herbette et al [178]) Belevitch et al [179]studied the binding of DHP CCBs (riodipine and nifedip-ine) and verapamil to model and biological membranes by
Oxidative Medicine and Cellular Longevity 17
fluorescence analysis The consistent location of Ca agonistBay K 8644 was determined to be within the region ofthe first few methylene segments of the fatty acyl chains ofthe membranes (Mason et al [180]) This position is nearto that observed for the DHP calcium channel antagonistsnimodipine and Bay P 8857
Themajority of studies onOSwere performedwithDHPswith various lipophilicity but only a few studies reportedamphiphilicity ofDHPderivatives AmphiphilicDHPderiva-tive K-2-11 reduced the cellular generation of ROS It alsorevealed complete reversal of multidrug resistance (MDR) ofthe resistant cells K-2-11 was more efficient than well-knownMDR inhibitor verapamil Cytotoxic effects of anticancerdrug doxorubicin were enhanced by K-2-11 in bothMDR andparental nonresistant cell line (Cindric et al [181]) K-2-11suppresses increase of ROS and consequentially prevents NF-120581B activation leading to decreased expression of MDR1 andincreased expression of antiapoptotic genes This signalingswitch is necessary for restoring the chemosensitivity ofcancer cells This phenomenon is characteristic both for14-DHPs [182] (18 novel asymmetrical DHPs bearing 3-pyridyl methyl carboxylate and alkyl carboxylate moietiesat C3 and C5 positions resp as well as nitrophenyl orheteroaromatic rings at C4) and for their oxidized formspyridine compounds (Zhou et al [183])
34 Dependence of AOA of DHPs on the Experimental SystemAO effect of DHPs depends on their structure and theexperimental system used (in vitromodel system subcellularorganelle and cells ex vivo and in vivo) Ideally for theevaluation of the profile and value of DHPs AO propertieseach compound should be tested in as many systems aspossible (Dubur et al [45])
Lipidomics studies have been traditionally explored forstudying AOA of DHPs Proteomics methods are less rep-resented and are mostly focused on the properties of DHPsrelated to scavenging of protein free radicals So far there areno studies on the role of DHPs in scavenging nitrosoperoxy-carbonate the reactive species formed out of peroxynitrite inthe presence of carbon dioxide Although it was shown thatalbumin binds diludine no studies revealed the relevance ofthis effect for the AOA of diludine
There are findings showing that dihydropyridine calciumantagonists (DHPs CA) could indirectly play a beneficialprotective role during development of atherosclerosisNamely Berkels et al [184] have studied antioxidativeproperties of four substances the DHP prototype CAnifedipine the long-acting CA lacidipine the DHP calciumchannel agonist BayK8644 and the bulkyDHPderivate BayO 5572 in three different models (1) in an in vitro superoxideanion generating system (hypoxanthinexanthine oxidase)for testing the ldquopurerdquo antioxidative effect (2) in an artificialmembrane preparation (dimyristoylphosphatidylcholine) formimicking a more physiological environment and (3) underconditions of stimulated ROS release (hyperglycemia) fromnative endothelial cells derived from porcine coronary arter-ies
The study also revealed the potential correlation betweenlipophilic and AO properties of DHPs In the first model
Bay K 8644 was significantly more effective in scavengingsuperoxide anions than lacidipine Bay O 5572 or nifedipine(micro- to millimolar concentration range) Addition of anartificial membrane preparation resulted in an enhancedAO effect with lacidipine being the most effective DHP inquenching radicals (low micromolar concentration range)In the third model mimicking hyperglycemia (30mmolL)nifedipine was significantly more potent antioxidant (ther-apeutical nanomolar concentration range) than the otherDHPs Calculated lipophilicity of these four substances(lacidipine gt Bay O 5572 gt Bay K 8644 gt nifedipine) waspositively correlated with antioxidative potential only in thesecond experimental model It has been concluded that AOproperties of DHP substances need to be tested in variousmodels for demonstrating that nifedipine exhibits ROS-quenching properties in a therapeutic concentration range[184]
341 AOA of DHPs in Isolated Cells and Cell Cultures(Comparison with Other Simplest Systems) Although DHPspossess neuromodulatory andor antimutagenic propertiesthe mechanisms of action related to these phenomena arenot entirely elucidated Borovic et al [185] have studied 14-dihydroisonicotinic acid (14-DHINA) derivatives of 14-DHP water-soluble analogues of a well-known AO diludine(diethone) 26-dimethyl-35-diethoxycarbonyl-14-dihydro-isonicotinic acid sodium 2-(26-dimethyl-35-diethoxycar-bonyl-14-dihydropyridine-4-carboxamido)glutamate gluta-pyrone and sodium 2-(26-dimethyl-35-diethoxycarbonyl-14-dihydropyridine-4-carboxamido)ethane-sulphate tauro-pyrone as AO and bioprotectors (Figure 4)
14-DHINArsquos activities were studied in comparison toTrolox by NN-diphenyl-N1015840-picrylhydrazyl (DPPH∙) deoxy-ribose degradation ABTS∙ radical scavenging and AOA(antioxidative capacity method) assays copper-induced LPof cultured rat liver cells (MDA determination by HPLCand 4-hydroxynonenal-protein conjugates by dot-blot) 3H-thymidine incorporation and trypan blue assay for liver cellsgrowth and viability Ic decreased the amount of 4-HNE-protein adducts In all assays Ia was the most potent AOable to completely abolish copper induced LP of liver cellswhile Ic only slightly decreased it Thus AOA is importantactivity principle of Ia which was even superior to Trolox intreated cell cultures Ia (and its analogues) are easily oxidizedin the Fenton system (Rubene et al [186]) exerting ARA too
35 Peculiarities Related to Antioxidative and AntiradicalActivity of Some 14-DHPs Ca Antagonists Nine commer-cialized structurally and functionally different DHPs CAwill be discussed further Their common feature is ability toprevent OS This also counts for some of their metabolitesas already discussed The comparative effects of some DHPsCA on oxidative stress-induced modification of LDL werealready reviewed in Section 331 (2)-(a) AOA of CA DHPswas discussed in Sections 331 (2)-(b) and 331 (2)-(c)
351 Nifedipine and Its Close Analogues Nifedipine vera-pamil and antiarrhythmic-antihypoxic drug stobadin wereshown to depress lipid peroxidation of phosphatidylcholine
18 Oxidative Medicine and Cellular Longevity
NH
COOH
NH
COONa
Glutapyrone
NH
Gammapyrone
NH
C 2H5OOC COOC2H5
Tauropyrone
14-DHINA
H3C H3C
H3C
H3CCH3 CH3
CH3
CH3
COOC2H5COOC2H5
COOC2H5 C2H5OOCC2H5OOCC2H5OOC
CONHCH(CH2)2COONa CONH(CH2)3COONa
CONH(CH2)2SO3Na
Figure 4 Derivatives of 14-dihydroisonicotinic acid (14-DHINA)
liposomes (Ondrias et al [187]) However data obtained insome other experimental systems are conflicting
In an in vitromodel of sarcolemmal membrane lipid per-oxidation three calcium blockers (nifedipine verapamil anddiltiazem) exhibited concentration-dependent (10ndash400 120583M)inhibitory effects [188 189] Nifedipine the most effectivecalcium blocker was more than two-fold potent compared topropranolol achieving significant effect at 10 120583M Nifedipineprotective role on LP using reduced glutathione as modelmarker was recently described (Ray et al [190]) Antiper-oxidative properties of CA nifedipine and its analogueswere explored in different systemspathogenic processesatherogenesis (Henry [165]) brain focal ischemia (Yamatoet al [191]) nephroprotection related to cyclosporine intake(Chander and Chopra [192]) and hepatoprotection relatedto intake of diethyldithiocarbamate (Gaafa et al [193])Recent data suggest that nifedipine action as protector forendothelial cells proceeds independently from its CA proper-ties
The absence of antioxidant effects of nifedipine anddiltiazemonmyocardialmembrane lipid peroxidation oppo-site to nisoldipine and propranolol was also described[194] Nisoldipine and propranolol were shown to havea concentration-dependent antiperoxidant effect with IC
50
values of 282 and 501 120583M respectively Finally nisol-dipine appeared to possess dual antiperoxidant mecha-nisms involving both preventive and chain-breaking proper-ties
These findings were confirmed in some other studiesincluding reports on the lack of antioxidative activity ofnifedipine and nicardipine even at 500120583M concentrationin heart membrane lipid peroxidation tests [134] SimilarlyROS formation in bovine aorta smooth muscle cells was notaffected by addition of amlodipine nimodipine and nife-dipine [123]
(1) Metabolites of Nifedipine and Its Analogues as Antioxidantsand Regulators of OS Antioxidant activity of nifedipine35-dimethoxycarbonyl-26-dimethyl-4-(2-nitrophenyl)-14-dihydropyridine was originally studied in vitro by Kirule etal [195] and Tirzit et al [196] According to the kinetic dataof peroxide accumulation and the ESR spectra (inhibition ofthe autoxidation of methyl oleate in presence of nifedipine)AO action was exerted by the formation of nitroso analogueof the oxidized nifedipine nitroso nifedipine 26-dimethyl-4-(2-nitrosophenyl)-35-pyridine dicarboxylate (NO-NIF)This nitroso aromatic derivative can form nitroxyl radicalsexhibiting remarkable AOA in the presence of unsaturatedfatty acids and lipids [196]
The primary species of free radicals that have beenobtained and identified were ion radicals of the nitrophenyltype (Ogle et al [76]) Such a mechanism coincides withmechanisms proposed afterwards by Nunez-Vergara et al[96] Lopez-Alarcon et al [103] Valenzuela et al [104]Fukuhara et al [174] and Yanez et al [197]
There are also data showing that nitroso compounds mayinhibit LP by direct radical trapping and subsequent forma-tion of stable nitroxide radicals It was further found that thereactivity between the synthesized 14-DHP derivatives withalkylperoxyl radicals involves electron transfer reactionsThisis documented by the presence of pyridine as a final productof the reaction and complete oxidation of the nitroso groupin the case of the nitrosoaryl 14-dihydropyridine derivatives(Valenzuela et al [104]) Tested compounds reacted fastertoward alkylperoxyl radicals and ABTS radical cation thanalkyl ones (Lopez-Alarcon et al [103])
Nitrosonifedipine a photodegradation product of nifedi-pine significantly recovers cellular damage induced by tumornecrosis factor-alpha It also prevents toxic effects of cumeneperoxide which hampers integrity of cell membranes throughoxidative stress Its positive effects are equal to Trolox-C
Oxidative Medicine and Cellular Longevity 19
As a result nitrosonifedipine was already a long time agoclaimed as a candidate for a new class of antioxidative drugs(Kirule et al [195]) cellular protectors against oxidative stressin glomerular endothelial cells [174]
Moreover Misik et al [198] Ondrias et al [199] andStasko et al [200] studied AOA of nifedipine and its oxidizednitroso analogue NO-NIF prevents the progression of type2 diabetic nephropathy associated with endothelial dysfunc-tion through selective AO effects (Ishizawa et al [201]) NO-NIF administration reduces albuminuria and proteinuriaas well as glomerular expansion without affecting glucosemetabolism or systolic blood pressure NO-NIF also sup-presses renal and systemic OS and decreases the expressionof intercellular adhesion molecule-1 (ICAM-1) a marker ofendothelial cell injury in the glomeruli of the KKAy miceSimilar effects were achieved in endothelial nitric oxide syn-thase (eNOS) knockout mice Moreover NO-NIF suppressesurinary angiotensinogen (AGT) excretion and intrarenalAGT protein expression in proximal tubular cells in theKKAy mice On the other hand hyperglycemia-inducedmitochondrial superoxide production was not attenuated byNO-NIF in cultured endothelial cells
Fujii and Berliner found EPR evidence for free radicaladducts of nifedipine in vivo [202] The nature of these rad-icals was surmised by comparing the reaction of illuminatednitrosonifedipine with polyunsaturated fatty acids Surpris-ingly identical radical spectra were detected from excisedliver doped with nonilluminated nifedipine suggesting thatthis drug can be enzymatically converted in vivo to its nitrosoanalogue without the requirement for illumination This isone of the first reports of in vivo EPR evidence for a class ofunsaturated fatty acid radical conjugates resulting from thenormal metabolism of a common drug
Dıaz-Araya et al [173] studied some 4-nitrophenyl-DHPson Fe3+ initiated LP in rat brain slices LP as measuredby MDA formation was inhibited by all the tested nitro-aryl derivatives of 14-DHP over a wide range of concen-trations On the basis of both time course and IC
50experi-
ments the tentative order of AOA on rat brain slices wasnicardipine gt nisoldipine gt (RSSR)-furnidipine gt (RRSS)-furnidipine gt nitrendipine gt nimodipine gt nifedipine14-DHP derivatives that lack a nitro group in the mole-cule (isradipine and amlodipine) also inhibited LP in ratbrain slices but at higher concentrations than that of nitro-substituted derivatives All tested compounds reduced andoxidized nitrosoaryl derivatives (26-dimethyl-4-(2-nitro-sophenyl)-35-pyridinedicarboxylic acid dimethyl ester (pho-tooxidation product of nifedipine ndash NTP) ao) and weremore potent inhibitors of LP than their parent molecules(Valenzuela et al [104])
The electrooxidation process of 4-nitrosoaromatic DHPsis a strongly pH-dependent (two-electron two-proton mech-anism) ECEC type of mechanism that is the sequenceeminusH+eminusH+ at pH gt 85 ECCE mechanism (eminusH+H+eminus)at pH lt 85 dominates Reduction reaction of nitroso groupis as follows R-NO + 2eminus + 2H+ rarr RNHOH (Bollo et al[203])
352 Lacidipine It is a generic DHP type antihypertensiveCA 35-diethyl 4-2-[(1E)-3-(tert-butoxy)-3-oxoprop-1-en-1-yl]phenyl-26-dimethyl-14-dihydropyridine-35-dicarboxy-late
Ursini [204] described redox behaviour of lacidipine andshowed its tissue protective features Cristofori et al studiedantiatherosclerotic activity in addition to lacidipinersquos CAand AO properties [205] Lacidipine reduced the extent ofatherosclerotic area in hypercholesterolemic apoE-deficientmice (these mice show widespread vascular lesions whichclosely resemble the inflammatory fibrous plaques seen inhumans in atherosclerosis) The reduction may be associatedwith the capacity of the drug to maintain endothelial NOlevels at concentrations useful to protect against vasculardamage This work suggested that DHPs modulate vascularrelaxation via increased release of NO
Herbette et al [178] remarked optimal hydrophobicity oflacidipine due to cinnamic acid substituent so membraneinteractions and facilitation of the treatment of atherosclero-sis could proceed (see also Section 331 (2)-(a))
353 Amlodipine Amlodipine (Norvasc) (RS)-3-ethyl5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-14-dihydropyridine-35-dicarboxylate (AML) hasan antioxidant effect on vessels in vitro and is a 3rd genera-tion of charged dihydropyridine CCB that is widely used forthe treatment of hypertensive patients
Amlodipine was shown to have the highest affinity(amlodipine gt verapamil ≫ diltiazem) for the membranebilayer (119870
119901= 104) It produced the significant changes in
membrane thermodynamic properties including a reductionin the thermal phase transition temperature (minus11) enthalpy(minus14) and cooperative unit size (minus59) relative to thecontrol phosphatidylcholine liposomes (Mason et al [49])
Amlodipine AOA is related to its reductant nature orhydrogen donor properties respectively Its ability for donat-ing protons and electrons to the lipid peroxide moleculesblocks the LP process
Amlodipine and even its enantiomers (Zhang et al [206])act as ROS andNOS effectors in several model systems of OSAntioxidant properties of amlodipine were recently reviewedby Vitolina et al [32] Both in vitro and in vivo studiesof amlodipine AO properties revealed inhibition of lipidsoxidative damage primarily those associated with cellularmembranes and lipoprotein particles (LDL) (Mason et al[50])
Under controlled experimental conditions in vitro amlo-dipine showed AOA and ARA by inhibition of lipid peroxideformation and trapping ROS Its scavenging activity forhydroxyl and peroxyl radicals at concentrations as low as100 nmolL (which is remarkably less compared to the classi-cal antioxidants GSH uric acid and Trolox) was shown to beindependent of the calcium channel modulation (Franzoni etal [207])
AML showed efficiency as scavenger of peroxyl radicals(TOSC assay 5945 plusmn 544 unitsmg) significantly stronger(gt50 119875 lt 0001) than GSH (2733plusmn 636 unitsmg) and 70weaker (119875 lt 00001) than uric acid (18144 plusmn 696 unitsmg)and Trolox (17522 plusmn 734 unitsmg)
20 Oxidative Medicine and Cellular Longevity
Of interest the scavenging capacity of AML towardshydroxyl radicals (1455 plusmn 154 unitsmg) was 320 higher(119875 lt 000001) than that of GSH (358 plusmn 112 unitsmg) 20higher than that of uric acid (1198plusmn121 unitsmg) and 100higher than that of Trolox (759 plusmn 143 unitsmg)
Amlodipine was shown to increase enzyme activity ofparaoxonase (PON) and glutathione peroxidase (GSH-Px)However it also decreases glutathione reductase (GSSG-R)activity and diminishes the concentration of the endogenousantioxidant 120572-tocopherol (vitamin E) Moreover AML in aconcentration of 2 ngmL decreased the content of malonicdialdehyde and activity of superoxide dismutase in the blood(Gatsura [208])
Verapamil and amlodipine produced a potent anti-ischemic effect and reduced area of myocardial infarction inrats The observed changes were accompanied by inhibitionof LP In contrast to verapamil in vitro application of AML ina dose of 50 ngmL decreased hemoglobin affinity for oxygenWhen present in a concentration of 2 ngmLAMDdecreasedthe content of MDA and activity of SOD in the blood
On the other hand amlodipine shows no activity relatedto inhibition of macrophage superoxide release and cellmigration which occurs as a consequence of decreasedTNF120572induced O
2
∙ releaseAmlodipine-induced reduction of OS in the brain is
associated with sympathoinhibitory effects in stroke-pronespontaneously hypertensive rats (SHRSP) (Hirooka et al[209]) Antihypertensive treatment with amlodipine reducedOS in all examined areas of the brain and decreased bloodpressure without a reflex increase in sympathetic nerveactivity Nicardipine another CA DHP surprisingly wassignificantly less active than amlodipine
354 Lercanidipine Tomlinson and Benzie reported AOeffect of lercanidipine [210] which is well known as anti-hypertensive drug Zanidip 2[(33-diphenylpropyl)(methyl)-amino]-11-dimethylethyl methyl 26-dimethyl-4-(3-nitro-phenyl)-14-dihydropyridine-35-dicarboxylate Compara-tive data about this drug AOA were presented in parts of thispaper about other individual CA DHPs and in the part aboutthe ex vivo DHPs effects on LDL
355 Nimodipine Nimodipine (ND) commercially knownas Nimotop is 3-(2-methoxyethyl) 5-propan-2-yl 26-dim-ethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxy-late It is centrally active CA
Treatment with glutathione blocked andwith nimodipineattenuated neuronal cell death caused by prolonged exposureof cell culture to 4-HNE (Faraqui [211])
Nascimento et al [212] found AO effect of nimodipine inyoung rats after pilocarpine- (PIL-) induced (in 400mgkg)seizures The PIL administration increased the striatal cata-lase (CAT) activity The administration of ND 30mgkg30min before PIL preserved normal value of CAT activityOn the other hand no difference was detected in the animalstreated with lower dose 10mgkg These results confirmthe neuroprotectiveantiepileptic effect of ND in young ratssuggesting that this drug acts positively on lipid peroxidation
(in both doses) Nimodipine cannot induce these effects viablockade of Ca2+ channel
Ismailoglu et al [213] studied the therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjury These beneficial effects in rats after cerebral corticalinjury seemed to be related to AOA of nimodipine
356 Benidipine Licensed in Japan and South Asia as CA(CCB) benidipine possesses AO properties Chemically it is5-methyl 3-[(3R)-1-(phenylmethyl)piperidin-3-yl] 26-dim-ethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxy-late (or its hydrochloride (4R)-rel-35-pyridinedicarboxylicacid 14-dihydro-26-dimethyl-4-(3-nitrophenyl)- 3-methyl5-[(3R)-1-(phenylmethyl)-3-piperidinyl] ester hydrochloride(1 1))
Benidipine influences processes connected with OS inseveral ways It prevents lysophosphatidylcholine- (lysoPC)-induced injury and ROS production in human aorticendothelial cells (HAECs) (Matsubara and Hasegawa [214])Matsubara et al [215] explained this effect based on stimula-tion of nitric oxide release
LysoPC is a component of oxidized low-density lipopro-teins (oxLDLs) which plays an important role in the patho-genesis of atherosclerosis Pretreatmentwith benidipine (03ndash3 120583molL) for 24 h protected against lysoPC-induced cyto-toxicity in the HAECs through inhibition of both lysoPC-stimulated ROS production and caspase-37-like activationwith a similar potency Since caspase-37 is involved inexecuting the apoptotic process the reduction of the activityof this enzyme by benidipine may explain the antiapoptoticeffect of the drug However benidipine did not suppresslysoPC-induced phosphorylation of mitogen-activated pro-tein kinases and Ca2+ influx in HAECs These results suggestthat the antioxidant properties of benidipine may be respon-sible for its ability to inhibit ROS production a possiblereason for reduced activation of caspase-37 In conclusionbenidipine suppresses lysoPC-induced endothelial dysfunc-tion through inhibition of ROS production which is due atleast in part to its antioxidant effect and not through theinhibition of L-type voltage-dependent calcium channels
Matsubara and Hasegawa [216] examined the effectsof benidipine on cytokine-induced expression of adhesionmolecules and chemokines (chemoattractants) which areimportant for the adhesion of monocytes to endotheliumPretreatment of HAECs with benidipine (03ndash10 120583molL)for 24 h significantly suppressed cytokine-induced vascularcell adhesion molecule-1 (VCAM-1) and intracellular celladhesion molecule-1 (ICAM-1) mRNA and protein expres-sion resulting in reduced adhesion of THP-1 monocytesBenidipine also suppressed induction of monocyte chemoat-tractant protein-1 (MCP-1) and interleukin-8 Benidipinealso inhibited redox-sensitive transcriptional nuclear factor-120581B (NF-120581B) pathway as determined by Western blotting ofinhibitory 120581B (I120581B) phosphorylation and luciferase reporterassay Results of analysis using optical isomers of benidip-ine and antioxidants suggest that these inhibitory effectswere dependent on pharmacological effects other than Ca2+antagonism Benidipine may thus have anti-inflammatoryproperties and benefits for the treatment of atherosclerosis
Oxidative Medicine and Cellular Longevity 21
Benidipine was also shown to inhibit ROS production inpolymorphonuclear leukocytes and oxidative stress in salt-loaded stroke-prone spontaneously hypertensive rats (Mat-subara et al [217])
It should be mentioned that other DHPs also haveendothelial AO actions [218]
357 Azelnidipine (AZL) Azelnidipine 3-[1-[di(phen-yl)methyl]azetidin-3-yl] 5-propan-2-yl 2-amino-6-methyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate(AZL) CAS number 123524-52-7 is commercially available4-nitroaryl-DHP type calcium antagonist with long-actingantihypertensive action (long-acting CA (CCB)) and a lowreported incidence of tachycardia It additionally possessesbeneficial effects in OS and diabetic conditions
Azelnidipine prevents cardiac dysfunction in strepto-zotocin-diabetic rats by reducing intracellular calcium accu-mulation (altering intracellular Ca2+ handling proteins) OSand apoptosis (Kain et al [219]) AZL can reduce the superox-ide production It exerts its protective effects by targeting theNADPH oxidase and mitochondrial redox enzymes AZL-treated diabetic rats express enhanced level of bcl-2 in thelysates of heart muscle indicating that AZL plays protectiverole in cardiac apoptosis
It has been previously observed that azelnidipine inhibitstumor necrosis factor-alpha-induced endothelial cell (EC)oxidative stress through its AO properties (Nakamura etal [220]) Azelnidipine but not nitrendipine completelyinhibits the Ang II-induced ROS generation in ECs (Matsuiet al [221])
Furthermore azelnidipine but not nitrendipine wasfound to partially restore decreased pigment epithelium-derived factor (PEDF) mRNA levels in Ang II-exposed ECsThis study suggests that AZL influence depends on its antiox-idative properties Authors concluded that upregulation ofPEDF by azelnidipine may become a therapeutic targetfor the treatment of diabetic retinopathy associated withhypertension
Antihypertensive agents with AO effects are potentiallyuseful for diabetic patients with hypertension While DHPtypeCAare among themost frequently used antihypertensivedrugs azelnidipine has been reported to have a unique AOeffect in vitro and in vivo in experimental animals (Ohmuraet al [222]) In hypertensive diabetic patients azelnidipinetreatment for 12 weeks induced a more significant decreasein erythrocyte LOOH level than amlodipine although thevalues related to blood pressure during each treatmentremained comparable These data confirm the usefulness ofLOOH level in erythrocyte membrane as a marker of OS invivo and indicate that azelnidipine has a unique antioxidativeproperty in humans
Daikuhara et al [223] reported the results of the OLCAstudy based on combination of (1) olmesartan and a calciumchannel blocker (azelnidipine) or (2) candesartan and a CCBamlodipine in two groups of diabetic hypertensive patientsPatients treated with the first combination presented highlypersistent early morning antihypertensive effect and strongerdecrease in heart rate fasting blood glucose andHbA1c levels
and microalbuminuria when compared to patients treatedwith the combination (2) Because diabetes is associated withsevere chronic OS the observed results might be at least in apart due to the AOA of azelnidipine
In favor of this are findings of Abe et al [224] who foundadditive antioxidative effects of azelnidipine on angiotensinreceptor blocker olmesartan treatment for type 2 diabeticpatients with albuminuria
Similarly the AOA of thiazolidinediones (insulin sensi-tizer) and their effect on cardiovascular function in type 2diabetic model rats and also those of some DHPs (nifedipineamlodipine or AZL commonly used antianginal and anti-hypertensive agents) in cultured human endothelial cells LPwere examined (Mizushige [225]) The AOA was evaluatedby measuring 8-iso-prostaglandine F
2120572concentration and
azelnidipine exhibited potent AOAInsulin (INS) resistance combined with hyperinsuline-
mia is involved in the generation of OS A relation-ship exists between increased production of ROS and thediverse pathogenic mechanisms involved in diabetic vascularcomplications including nephropathy Manabe et al [226]revealed that high doses of INS augmented mesangial cellproliferation through generation of intracellular ROS andactivation of redox signaling pathways Cell proliferation wasincreased in a dose-dependent manner by high doses of INS(01ndash10 120583M) but was inhibited by 01120583M AZL Namely theINS-increased phosphorylation of mitogen activated proteinkinaseextracellular signal-regulated kinase 12 (MAPKERK12) was inhibited by 01 120583MAZL The same AZL concen-tration blocked intracellular ROS production more effec-tively than 01 120583M nifedipine The NADPH oxidase inhibitorapocynin (001ndash01120583M) prevented INS-induced mesangialcell proliferation So azelnidipine inhibits insulin-inducedmesangial cell proliferation by inhibiting the productionof ROS Therefore azelnidipine may have the potential toprotect against the onset of diabetic nephropathy and slowits progression
Azelnidipine inhibited H2O2-induced cell death in
neonatal rat cardiomyocytes (Koyama et al [227]) Azelnidip-ine and nifedipine did not affect theH
2O2-induced activation
of extracellular signal-regulated protein kinases (ERK) andp38 MAPK (mitogen-activated protein kinase) In contrastazelnidipine but not nifedipine inhibited H
2O2-induced c-
Jun NH2-terminal kinases (JNK) activation Authors con-
cluded that azelnidipine has inhibited theH2O2-induced JNK
activation and cardiac cell death Therefore azelnidipine mayhave cardioprotective effects against OS
A specific atheroprotection activity of azelnidipine relatesto inhibition of TNF-120572-induced activator protein-1 activa-tion and interleukin-8 expression in human umbilical veinendothelial cells (HUVEC) through suppression of NADPHoxidase-mediated reactive oxygen species generation (Naka-mura et al [220]) TNF-120572 could play a central role in patho-genesis of insulin resistance and accelerated atherosclerosis inthe metabolic syndrome The concentration of AZL found tobe effective in these in vitro experiments is within therapeuticrange As EC do not possess voltage-operated L-type calciumchannels it is suggested that the beneficial effects of azelni-dipine are not likely due to CA property but to its unique AO
22 Oxidative Medicine and Cellular Longevity
ability Furthermore it has been recently found that serumlevels of monocyte chemoattractant protein-1 a biomarkerfor subclinical atherosclerosis were significantly decreased bythe AZL treatment in patients with essential hypertension Inthis paper [220] authors hypothesize that due to its uniqueTNF-120572 signalmodulatory activity and antioxidative propertyazelnidipine may be a promising DHP for targeting diabetesand cardiovascular diseases in hypertensive patients withmetabolic syndrome
Shinomiya et al [228] evaluated its AOA in culturedhuman arterial EC under OS Azelnidipine has shown apotent antioxidative effect that could be of significant clinicalbenefit when combined with its long-lasting antihypertensiveaction and low incidence of tachycardia
Azelnidipine inhibited TGF-1205731 and angiotensin II- (AngII-) activated 1205721(I) collagen mRNA expression in hepaticstellate cells (HSCs) (Ohyama et al [229]) FurthermoreTGF-1205731- and Ang II-induced OS and TGF-1205731-induced p38and JNK phosphorylation were reduced inHSCs treated withAZL Azelnidipine significantly decreased inflammatory cellinfiltration profibrotic genes expression HSC activation LPoxidative DNA damage and fibrosis in liver of CCl
4- or
TAA-treated mice Finally AZL prevented decrease of theexpression of some AO enzymes and accelerated regressionof liver fibrosis in CCl
4-treated mice Hence the antifibrotic
mechanism of AZL against CCl4-induced liver fibrosis in
mice may have been due to an increased level of AO defenseAs azelnidipine is widely used in clinical practice withoutserious adverse effects it may provide an effective newstrategy for antifibrotic therapy
358 Manidipine Manidipine (2-[4-(diphenylmethyl)pip-erazin-1-yl]ethyl methyl 26-dimethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate) is a DHP CCB withreported nephroprotective properties Calo et al [230] stud-ied effect of manidipine on gene expression and proteinlevel of OS related proteins p22(phox) (human neutrophilcytochrome b light chain (CYBA)) and heme oxygenase-1HO-1 Relevance for antihypertensive effects was revealedThe study assessed the effect of manidipine on normalsubjectsrsquo monocyte gene and protein expression of OS relatedproteins such as p22phox a NADPH oxidase system subunitcritical in generating O
2
∙minus and HO-1 induced by and pro-tective against OS Manidipine was compared with the ACEinhibitor captopril and the CCB nifedipine in the presenceand in the absence of sodiumarsenite (NaAsO
2) as an inducer
of OS Monocyte p22phox (CYBA) mRNA production wasreduced by both manidipine and captopril while no changeswere induced by nifedipine Manidipine increased monocyteHO-1 mRNA production while nifedipine and captoprilshowed no effect The effects of manidipine on p22phoxand HO-1 gene expression in the presence of OS were alsoconfirmed at the protein level Thus manidipine seems tosuppress p22phox and to increase the HO-1 mRNA produc-tion and protein level The manidipine-induced increase ofHO-1 gene and protein expression seems to be a peculiareffect of this drug since it is not observed with captopriland nifedipine This effect together with the reduction of
p22phoxmRNAproduction could play a role in its protectivemechanism against OS
359 Mebudipine The protective effect of mebudipine (14-dihydro-26-dimethyl-4-(3-nitrophenyl)-35-pyridinedicar-boxylic acid 3-methyl-5-tert-butyl ester BAY-n-6391) wasrevealed on OS and LP (MDA decrease SOD GPX andcatalase increase) in myocardial ischemic-reperfusion injuryin male rats (Ghyasi et al [231])
There are articles about other commercial and experi-mental DHPs on OS but we have reviewed only the mostcommonly studied compounds Effects of other commercialCA DHPs on OS are also mentioned in several parts of thisreview
36 14-DHPs Ca Agonists andTheir AOA and ARA For themost popular calcium agonist DHP Bay K 8644 no reactionwith peroxyl radicals was registered (Toniolo et al [114])However interactionwith other compounds possessing AOAand ARA (quercetin) was found
Opposite to that AON-acetylcysteine (NAC) diminishedincrease in Ca2+ transient amplitude and cell shorteninginduced by ISO and forskolin whereas NAC had no effecton the (S)-(minus)-methyl-14-dihydro-26-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylatemdash(minus)-BayK 8644-induced increases (Andersson et al [232])
Increased vasoconstriction responses to Bay K 8644 (3 times10minus7ndash3times 10minus5M)were significantly decreased by pyridoindoleantioxidant stobadine treatment in diabetes (Ceylan-Isik etal [233])
The functional interaction between two L-type Ca2+channel activators quercetin and Bay K 8644 has beeninvestigated in vascular smooth muscle cells Biological ARAcompound quercetin at nutritionally meaningful concen-trations limited the responsiveness of vascular L-type Ca2+channels to the pharmacological stimulation operated by BayK 8644 These data contribute to a better understanding ofquercetin effects on experimental in vivo cardioprotection(Saponara et al [234]) Thus these findings indicated thatalthough Bay K 8644 does not exert potent and direct AOAyet acting as calcium agonist it may affect efficiency of AOsubstances and vice versa
Interaction of grapefruit juice (containing quercetin andits analogues) with DHPs CA diminished effectiveness of CAaction of DHPs (Sica [235])
37 Interpretations of the Mechanism(s) of RadicalScavenging and AOA by DHPs
371 Molecular Mechanism(s) of Radical Scavenging andAOA of DHPs in the Model Systems 35-Dicarbonyl-14-di-hydropyridine derivatives possess powerful bis-120573-carbony-lvinyl-amino conjugation and for that reason cannot be con-sidered as ordinary amino antioxidants The electron andorH donation from DHPs ensures their reductant role andresults in AOA and ARA Oxidation reaction from DHPsresults in production of corresponding heteroaromatic pyri-dine derivatives
Oxidative Medicine and Cellular Longevity 23
Detailed studies were made about substituent in DHPring positions 14- namely 4-unsubstituted- 4-substituted4-alkyl- 4-aryl- 4-alkylaryl- ao 26- 35- (diacetyl ordialkoxycarbonyl chain ao) electronic and steric effects onAOA and ARA of DHPs [44 45 51] see Sections 331and 35 The bell-shaped dependence of DHPs AOA onthe 35-dialkoxycarbonyl- chain length was observed [4445 107 109 112] with the maximum activity at C
2H5ndash
C4H9 Decrease of AOA and incorporation into liposomes for
DHPs with alkyl chains longer than R gt C4H9further were
clarified as probable tendency to self-aggregation of thesecompounds ([51] and citation number 245 therein) Electronacceptorelectron donor properties are relevant for expres-sion of AOA or ARA of 35-disubstituted DHPs 35-Diacyl-substituted and 35-dicarbanilido- and 35-dipyridylamido-substituted DHPs are more active as AOs as their 35-dicyano-substituted analogues which have electron acceptorproperties [186]
Dubur et al [89] observed overwhelming steric influenceof substituents in position 4 of the DHP ring Gaviraghiet al [163 164] proposed that AO activity of DHPs ispartly dependent on capacity of the 14-DHP ring to donateelectrons to the propagating radical (ROO∙ or RO∙) and toreduce it to a less reactive form The abstraction (donation)of electron andor H in the oxidation and LP reactionstakes place from all 35-dicarbonyl-14-DHP systems andresults in the formation of corresponding pyridine derivatives(Augustyniak et al [51]) The physicochemical mechanism ofARA and AOA of 14-DHP has been extensively studied anddiscussed (Mulder et al [236]) but precise mechanisms oftheir activity need further clarification
The reactivity of C-4 substituted 14-DHPs possessingeither secondary or tertiary nitrogen atom in the DHP ringtoward alkyl alkylperoxyl radicals and ABTS radical cationwas determined in aqueous media at pH 74 [103] Thesecompounds reacted faster toward alkylperoxyl radicals andABTS radical cation than alkyl ones N-Ethyl-substitutedDHPs showed the lowest reactivity
The 4-methyl substituted DHP was the most reac-tive compound in previously mentioned reactions (Lopez-Alarcon et al [103]) However it was less active (068versus 10) than Trolox-C DHPs having electron-donatingsubstituents (4-Me-DHP and p-MeO-Phe-DHP) showed thehighest kinetic rate constants toward ABTS radical cation p-nitro-Phe-DHP a compound with an electron-withdrawingsubstituent showed a lower kinetic rate constant and N-alkyl-DHP compounds show kinetic rate constants lowerthan the -NH-DHP
Hydrogen at the 1-position of the DHP ring was revealedaccording to the deuteriumkinetic isotope effect studies to beinvolved in the proposedARAmechanismThis fact ismostlynoticeable in the case of alkyl radicals N-Ethyl-substitutedDHPs show the lowest reactivity when compared to Troloxor nisoldipine In all cases the respective pyridine derivativewas detected as the main product of the reaction (Lopez-Alarcon et al [103]) Authors indicate that the kinetic rateconstants toward alkyl alkylperoxyl andABTS radical cationdepend on the nature of the substituents in the C-4 positionof DHP and the presence of the secondary amine group in the
dihydropyridine ring that is the presence of the hydrogen in1-position
Yanez et al [197] have studied the reactivity of 11derivatives of 14-DHPs (including commercial CA) withalkylperoxyl radicals and ABTS radical cation The tested14-DHPs were 83-fold more reactive towards alkylperoxylradicals than to the ABTS cation radical All commercial14-DHP type CCBs were weaker than Trolox-C The par-ticipation of the hydrogen atom in the 1-position appearsto be very relevant for exhibited reactivity Hantzsch ester(diludine)was again found to be themost active compound inthe reaction with alkylperoxyl radicals 23-fold more activethan Trolox The photodegradation product of nifedipine(nitrosophenyl derivative of pyridine) also showed a highactivity Kinetic rate constants for the reaction between 14-DHP compounds and alkylperoxyl radicals exhibited a fairlygood linear correlation with the oxidation peak potentialof DHP derivatives However the activity of tested 14-DHPs towards ABTS radical cation showed an independencebetween kinetic rate constants and oxidation peak potentials
Kirule et al [195] andTirzit et al [196] studiedmechanismof AOA of 4-nitrophenyl-14-DHPs nifedipine and its ana-logues involving formation of 4-(21015840-nitrosophenyl)-pyridinederivative (as active principle) as a result of intramolecularredox reaction using chemical electrochemical and bio-chemical approaches (see Sections 331 and 351)
Nunez-Vergara et al [237] reported the electrochemicaloxidation of C4-hydroxyphenyl-substituted 14-DHP deriva-tives The oxidation proceeds via formation of the unstabledihydropyridyl radical as confirmed by controlled-potentialelectrolysis (CPE) and ESR experiments This type of 14-DHPs has significant activity towards the radicals even whencompared with commercial 14-DHP drugs with well-knownantioxidant ability
It was observed that nicardipine preferentially targets RO∙radicals and is inactive against ROO∙ Lacidipine on theother hand is equally active towards both types of radicals(Gaviraghi et al [164]) The cytoprotective effect againstexposure to H
2O2was more significant for lacidipine (ID
50=
14 nM its log119875 = 54 membrane partition = 136000 assumesposition located 7 A near to the membrane center otherless lipophilic DHPs located 12ndash16 A far from the center)as compared to amlodipine nifedipine and nicardipine insmooth muscle cell culture (Gaviraghi et al [164]) Oxidativeeffect of H
2O2shifts the Ca channel toward an open state
Thus the redox property of CCBs DHPs may augment theirCCB properties
Oxidation of pharmacologically active Hantzsch 14-dihydropyridines was found by electrogenerated superoxideusing a voltammetric approach in DMSO solutions (Ortiz etal [238] and Ortiz et al [239]) Raghuvanshi and Singh [240]have also reported oxidative aromatization of these DHPsinduced by superoxide
Chemiluminescence (CL) was used in the studies ana-lyzing the antioxidant activity of 12 various 4-flavonil-14-dihydropyridine derivatives (Kruk et al [241]) on a chemicalsystem involving a superoxide radical anion These deriva-tives showed structural similarity to flavonoids with respectto the presence of rings A B and C The results obtained in
24 Oxidative Medicine and Cellular Longevity
this study indicate that the tested derivatives may catalyzeconversion of superoxide radicals through mimicking theactivity of superoxide dismutase by delivering H+ for reac-tion
O2
minus∙+O2
minus∙+ 2H+ 997888rarr H
2O2+1O2
(3)
The enhanced emission of the light in the presence oftested compounds was significant and related to stimulatedproduction ofH
2O2and 1O
2fromO
2
∙The latter specieswereremoved from the reactionmixture by the following sequenceof reactions
H+
O2
minus∙997888rarr HO
2
∙
HO2
∙+O2
∙minus997888rarr HO
2
minus+1O2
2HO2
∙997888rarr H
2O2+1O2
2 (1O2) 997888rarr (O
2)2+ h]lowast
(4)
or to take part in spontaneous dismutation of H2O2
2H2O2997888rarr 2H
2O + 1O
2(5)
The authors have offered an original concept of action for 4-flavonil-14-dihydropyridine derivatives unrelated to that ofO2
∙ radical-trapping chain-breaking antioxidants Insteadthey showed that these compounds act similar to superoxidedismutases converting O
2
∙ to H2O2 Hydrogen peroxide
is less toxic for cells than O2
∙ because it is predominantlyremoved by peroxidases and catalases Finally AO effect ofthese DHPs differed from those mediated by flavonoids witha catechol structure of ring B which are well-known 1O
2
quenchersMulder and collaborators came to similar conclusions
especially related to molecular mechanisms of antioxidativeactivity of DHPs [236]TheAOproperties of Hantzsch 14-di-hydropyridine esters and two dibenzo-14-dihydropyridines910-dihydroacridine (DHAC) and N-methyl-910-dihydro-acridine (N-Me-DHAC) have been explored by determin-ing the autoxidation of styrene or cumene at 30∘C Theseexperiments showed that Hantzsch esters are virtually inac-tive as chain-breaking antioxidants (CB-AOs) contrary tothe findings observed by Lopez-Alarcon et al [103] whoused CB-AOA in aqueous media at pH 74 Their reactivitytoward peroxyl radicals was shown to be some 5 orders ofmagnitude lower than that of the excellent CB-AO 22578-pentamethyl-6-hydroxy-chroman (PMHC)
DHAC was found to be sim10 times less reactive thanPMHC kinetic measurements using DHAC N-deuterio-DHAC and N-Me-DHAC pointing out the abstraction ofN-H hydrogen in DHAC by peroxyl radicals despite the factthat the calculated C-H bond dissociation enthalpy (BDE) inDHAC is about 11 kcalmol lower than the N-H BDE Therates of hydrogen atom abstraction by the 22-diphenyl-1-picrylhydrazyl radical (DPPH∙) have also been determined
for the same series of compounds The trends in the peroxyl∙and DPPH∙ rate constants were found to be similar [236]
Tirzit et al [242] have observed quenching of singletoxygen by DHPs This observation paved the ground forfurther research related to reactions of DHPs with hydroxylradicals (Tirzit et al [243]) singlet oxygen (Kazush etal [94]) and mechanisms of action A series of 14-DHPderivatives in NAD-H-Cu2+-H
2O2system inhibited forming
of the hydroxyl radical (HO∙) while 14-DHP derivativeswith electron donor substituents in the molecule were shownto be capable themselves of generating HO∙ in the presenceof Cu2+ and H
2O2 Rubene et al [186] also described
interaction of 14-DHP derivatives with Fentonrsquos reagentwhich produces hydroxyl radical (HO∙) Rate constants ofthe DHPs reaction (1st order) with HO∙ radical were highin the range 109 L times mol times secminus1 close to that of NADHcysteine and thiourea 35-Diacetyl- derivatives reacted fastercompared to 35-dialkoxycarbonyl- ones The reaction ratedecrease was observed in the case of substitution at position4 as compared to 4-unsubstituted DHPs Some DHPs havingelectron donor -COOminus groups in the 35- or 26- positionsof DHP ring reacted immediately (having rate constantshigher as 109 L times mol times secminus1) Rate constants with HO
2
∙
and O2
∙minus radicals were of lower degree Thus DHPs actingas oxygen radical scavengers could effectively inhibit ROSrelated reactions of LP initiation stage
Nifedipine and nitrendipine reactivity toward singletoxygen was also studied [244] Nifedipine was shown tobe a good scavenger of excited oxygen mainly via physicaldeactivation with values of the total rate constant rangingfrom 208 times 105Mminus1 sminus1 (in dioxane) to 930 times 105Mminus1 sminus1(in propylene carbonate)The less reactive pathway generateda photooxidation product For that reason a mechanisminvolving a perepoxide-like encounter complex in the firststep of the reaction path was proposed (see [244] Figures8 and 9 therein) The dependence was observed on solventmicroscopic parameters of the total rate constant for the reac-tion between singlet oxygen and 14-DHPs These findingsshow that nifedipine possesses stronger protective activity inbiological systems than nitrendipine
Density-functional-theory (DFT) calculations made byWang et al [245] confirmed the former experimental obser-vations that Hantzsch ester diludine is potent antioxi-dant with high H atom-donating ability and relatively lowprooxidant activity Possible reaction pathways for radicalsderived from 14-dihydropyridine and the resonance modesfor radical species were given [245]
Moreover two ethoxycarbonyl (EtOCO) substituentsat C(2) and C(6) should further enhance Hantzsch esterdiludine H-atom-donating ability due to resonance effectsHowever DHPs should be used in nonpolar rather than inpolar solvents since in the latter not H-atom but electrontransfer is preferred in the radical scavenging process [245]
Mulder et al [246] proposed that quantum-thermochem-ical calculations must be used with caution to indicate ldquoapromising lead antioxidantrdquo as they criticized the density-functional-theory (DFT) calculations made by Wang et al[245]
Oxidative Medicine and Cellular Longevity 25
372 Possible Mechanisms of DHPs ARA and AOA in the Bio-logical Systems Interaction with Other OSModifiers Some ofthese mechanisms were already described (Sections 331 (2)-(b) 331 (2)-(c) 331 (3)-(b) 35)
Enzymatic sources of ROSwith confirmed functional rolein hypertension are NADPH oxidase NO synthase (NOS)xanthine oxidase and cyclooxygenase Godfraind [3] hasreviewed AO effects and protective action of calcium channelblockers (CCBs) Yao et al [247] observed antioxidant effects(as inhibition of LP) for cardio- and neuroprotective CCBs(3ndash300 120583molL) including 7 DHPs in homogenates of ratbrain IC
50values (120583M) were as follows nifedipine (515) gt
barnidipine (586) gt benidipine (712) gt nicardipine (1293)gt amlodipine (1355) gt nilvadipine (1673) gt nitrendipine(2521) gt diltiazem (gt300) = verapamil (gt300) There arealso research articles describing the AO properties of CCBsthrough direct scavenging effect or through preservationof the endogenous SOD activity These findings indicatethat CCBs may also act by reducing the production ofvasoconstrictors angiotensin and endothelin
When present in concentrations that can be achievedin plasma CCBs may inhibit LP formation [3] This AOactivity seems to be typical for high lipophilic CCBs becausetheir chemical structure facilitates proton-donating andresonance-stabilization mechanisms that quench the freeradical reaction Their insertion in the membrane nearpolyunsaturated fatty acids at relatively high concentrationspotentiates proton donation (or atomary H) to lipid peroxidemolecules thereby blocking the peroxidation process Theremaining unpaired free electron associated with the CCBmolecule can be stabilized in well-defined resonance struc-tures associated with the DHP ring (Mason et al [48])
The radical reaction (according to Godfraind [3]) thatdescribes the AO effects of a DHP CCBs is LOOlowast + DHPrarr LOOH + DHPlowast (where LOOlowast is lipid peroxide radical)which in general is reaction (7) of the LP reaction cascadeconsisting of sim10 reactions (Scheme 2) [89]
As the rate constants of in vitro interaction of 4-substituted DHPs with peroxyl radicals are three ordersof magnitude lower than that of the vitamin E derivativethese DHPs must be considered as weak AO (Ursini [204])However due to partition coefficient of DHPs in membranesand in case of specific binding high local concentration ofDHPs may be obtained
DHPs without CCB properties for instance Bay w 9798although structurally related to nifedipine inhibit TNF-120572-induced vascular cell adhesion molecule-1 expression inendothelial cells by suppressing reactive oxygen speciesgeneration [248]
Mitrega et al [249] have discovered that antiarrhythmicand hemodynamic effects of oxidized heteroaromatic DHPsoxy nifedipine oxy nimodipine oxy nitrendipine and oxynisoldipine suggest that CCB DHPs and their metabolitescould act at least in two ways targeting OS related eventsas reductants (see Section 351 (1)) andor bypassing OSrelatedmetabolic routes Authors postulated that contrary tocurrent belief NIF metabolites are pharmacologically activeATP sensitive potassium channels were mentioned as a tar-get
38 DHPs Anti- or Prooxidants Several substances (ascorbicacid being the most commonly studied) can serve either asantioxidants or as prooxidants depending on given condi-tions (Herbert [250]) Therefore Halliwell [251] has reporteddilemma related to polyphenols as possible antioxidantsand prooxidants causing experimental artifacts (about 25)by oxidation of antioxidant compounds in the cell culturemedia Nevertheless it is generally accepted opinion thatpolyphenols act as antioxidants in vivo Studies on DHPs alsoface such a dilemmaThe exact roles (anti- or prooxidative) ofany specific DHP depend on its structure appliedachievedconcentration and specificity of the targetexperimentaltesting system
This situation resembles the case of antioxidative effectsof tocopherol which depends on the fate of the secondaryradical as proposed by Winterbourn [252] The question wasldquoVitamin E - Pro- or Antioxidantrdquo
997888rarr chain termination of lipid peroxidation
(6)
Prooxidant
Toc∙ + Lipid-H 997888rarr Lipid∙ (in LDL particles) (7)
This example shows that generally speaking any AO mustfulfil several criteria to be considered as an effective com-pound physiologically
(i) It must be able to functionally interact with endoge-nous scavengers even at low concentrations
(ii) It must affect endogenous pathways of OS(iii) It should not have undesirable adverse effect(iv) It should manifest the antioxidant efficacy dependent
on the oxidant(v) It must discriminate among different strategies
needed for 1-electron and 2-electron processes(vi) Radical scavengers can be prooxidant unless linked to
a radical sink (Winterbourn [252])
According to these statements DHPs could be effective asAO under physiological conditions in vivo (Godfraind [3]and others [30 31 38]) and in vitro in various experimentalsystems (cell and tissue) (see Sections 33 34 35)
Hence calcium antagonists appeared to disrupt thefine balance between the production and scavenging ofROS Nifedipine verapamil and diltiazem were shown toinduce significant oxidative stress in the epididymal sperm(increased MDA and decreased catalase and superoxidedismutase activity) This may be the reason for the inductionof male infertility [253]
The dualism of 14-DHP effects has been recorded asinhibition or promotion of LP as quenching or initiating
26 Oxidative Medicine and Cellular Longevity
oxygen and nitrogen free radical chain reactions radiopro-tecting or radiosensitizing antagonizing or synergizing Ca2+in electromechanical coupling as well as in the membranestabilization or labilization
39 Could DHPs Be Involved in Antioxidative Stress Beforebeing applied in vivo the optimal dose and optimal timeintervals forDHPs applicationmust be knownNamely whileROS have been traditionally considered as toxic byproductsof aerobic metabolism we know nowadays that ROS may actas essential signaling molecules needed for the control ofmany different physiological processes Whether the role ofROS will be damaging protective or signaling depends onthe delicate equilibrium between time- and location-specificROS production and scavenging Accordingly the imbalanceof the increased AO potential so-called antioxidative stresscould be dangerous similar to chronic OS in particular incase of extended exposure Inappropriate interventions inthe oxidative homeostasis by excessive antioxidants especiallyin case of chronic exposure to antioxidants might havevery negative effects as was published in the ATBC studyshowing an increased cancer incidence in smokers treatedby excessive beta-carotene [254] Therefore overconsump-tion of any natural or synthetic AO including DHPs asdietary supplements or drugs must be avoided in order tosuppress oxidative damage and must not disrupt the well-integrated antioxidant defense network (Poljsak [255] andPoljsak and Milisav [256]) This is especially important whenadministrating lipid-soluble antioxidants that can be storedin biomembranes thus not only attenuating or preventing LPbut also affecting physiological effects of the natural antiox-idants in particular tocopherol The interrelationship withthe status of endogenous antioxidantsprooxidants should befollowed
DHPs primarily suppress the initiation stages of LPprocessThey do not entirely stop the LP propagation Actingsynergistically with tocopherol diludine may prevent patho-logical excess of ROS production within the lipid moiety ofthe cellular membranes and LDL However due to its lowsolubility and fast metabolism its concentration in the cellsis low For that reason it cannot cause antioxidative stresseven if used for an extended period of time Thus diludine(diethone) could be only a mild antioxidant it has potentialfor restoring the pool of natural antioxidants (as synergist of120572-tocopherol and polyphenols) in the cells
Moreover DHPs CA used for cardioprotection andvasodilatation as commercial drugs in low concentrationsare fast metabolized via CYP3A4 and for that reason theirapplication does not induce cellular AO stress [53 160]However Godfraind and Salomone [257] have postulated noevidence that allows recommending dietary supplementationwith antioxidants for the primary or secondary prevention ofcardiovascular disease
So far there are no reports on antioxidative stress causedby some DHPs diludine and its analogues Diludine andits analogues therefore could act as adaptogens supportinghormetic effects of mild oxidative stress These compoundsmay act as potential multisided modulators of Yin-Yang
cycles of redox and cell functions (the electroplasmic cycle)(Wagner et al [258])
4 Conclusions
14-Dihydropyridines (14-DHPs) have broad spectrum ofOS modulating activities DHPs have reducing and lipidperoxidation inhibitor properties act as reductants in simplechemical systems and stabilize various biological systems(LDL mitochondria microsomes cells and tissues) againstOS Examples and peculiarities and mechanisms of antiox-idant activity (AOA) and antiradical activity (ARA) as wellas stress-protective effect of DHPs including commercialcalcium antagonists (CA) were highlighted These activitiesdepend on various structural parameters related to DHPs(presence and character of substituents) lipophilicity anddepth of the incorporation in the biologicalmembranesTheyalso depend on the experimental model system for exploringthe lipid peroxidation or oxidative stress Stress-protectiveeffect of some metabolites of CA (nifedipine) is reviewedAlthough some DHPs including CA have prooxidant prop-erties (on epididymal sperm cells) they can generally beconsidered as potent antioxidants Therefore comparisonof the AOA and ARA of different DHPs (mutually andwith other AOs) was described in detail According to thedata presented the DHPs might be considered as bellwetheramong synthetic compounds targeting OS and as a kind ofpharmacological measure for respective field of organic andmedicinal chemistry
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
Authors from Latvian IOS acknowledge ESF 201300021DP1112013APIAVIAA011 and National Research Pro-gramme PUBLIC HEALTHBiomedicine of the Republicof Latvia for financial support administration of the Insti-tute for technical support and Rufus Smits PhD for con-sultations in English The support of Cooperation in Euro-pean System of Science and Technology (COST) Domain ofChemistry Molecular Sciences and Technologies (CMST)was of highest importance for preparation of this paper
[2] D J Triggle ldquo14-Dihydropyridines as calcium channel ligandsand privileged structuresrdquoCellular andMolecular Neurobiologyvol 23 no 3 pp 293ndash303 2003
[3] T Godfraind ldquoAntioxidant effects and the therapeutic modeof action of calcium channel blockers in hypertension andatherosclerosisrdquo Philosophical Transactions of the Royal SocietyB Biological Sciences vol 360 no 1464 pp 2259ndash2272 2005
[4] E Cadenas ldquoMitochondrial free radical production and cellsignalingrdquoMolecular Aspects of Medicine vol 25 no 1-2 pp 17ndash26 2004
[5] E Cadenas ldquoFree radicals oxidative stress and diseasesrdquo inLecture PSC 616 p 38 Missouri University of Science andTechnology Rolla Mo USA httpwwwcarnicominstituteorgarticlesenrique cadenaspdf
[6] K Rahman ldquoStudies on free radicals antioxidants and co-fac-torsrdquo Clinical Interventions in Aging vol 2 no 2 pp 219ndash2362007
[7] V Bocci and G Valacchi ldquoFree radicals and antioxidants howto reestablish redox homeostasis in chronic diseasesrdquo CurrentMedicinal Chemistry vol 20 no 27 pp 3397ndash3415 2013
[8] M Valko C J Rhodes J Moncol M Izakovic and M MazurldquoFree radicals metals and antioxidants in oxidative stress-induced cancerrdquo Chemico-Biological Interactions vol 160 no 1pp 1ndash40 2006
[9] G Bartosz ldquoReactive oxygen species destroyers or messen-gersrdquo Biochemical Pharmacology vol 77 no 8 pp 1303ndash13152009
[10] R Visconti and D Grieco ldquoNew insights on oxidative stress incancerrdquo Current Opinion in Drug Discovery and Developmentvol 12 no 2 pp 240ndash245 2009
[11] R N Kujundzic N Zarkovic and K G Troselj ldquoPyridinenucleotides in regulation of cell death and survival by redoxand non-redox reactionsrdquo Critical Reviews in Eukaryotic GeneExpression vol 24 no 4 pp 287ndash309 2014
[12] B Halliwell and J M C Gutteridge ldquoThe definition and mea-surement of antioxidants in biological systemsrdquo Free RadicalBiology and Medicine vol 18 no 1 pp 125ndash126 1995
[13] V D Kancheva and O T Kasaikina ldquoBio-antioxidantsmdashachemical base of their antioxidant activity and beneficial effect
on human healthrdquo Current Medicinal Chemistry vol 20 no 37pp 4784ndash4805 2013
[14] H V Panglossi Ed Frontiers in Antioxidants Research NovaScience Publishers New York NY USA 2006
[15] E B Burlakova E M Molochkina and G A NikiforovldquoHybrid antioxidantsrdquo Oxidation Communications vol 31 no4 pp 739ndash757 2008 httpmembraneustceducnpaperpdfHybrid20Antioxidantspdf
[16] A Bast and G R M M Haenen ldquoTen misconceptions aboutantioxidantsrdquo Trends in Pharmacological Sciences vol 34 no 8pp 430ndash436 2013
[17] E B Burlakova A V 0lesenko E M Molochkina N PPalmina and N G Khrapova Bioantioxidants for RadiationDamage and Malignant Growth Nauka Moscow Russia 1975(Russian)
[18] J Fang T Seki and H Maeda ldquoTherapeutic strategies by mod-ulating oxygen stress in cancer and inflammationrdquo AdvancedDrug Delivery Reviews vol 61 no 4 pp 290ndash302 2009
[19] M Valko D Leibfritz J Moncol M T D Cronin M Mazurand J Telser ldquoFree radicals and antioxidants in normal physi-ological functions and human diseaserdquo International Journal ofBiochemistry and Cell Biology vol 39 no 1 pp 44ndash84 2007
[20] M Jimenez-Del-Rio and C Velez-Pardo ldquoThe bad the goodand the ugly about oxidative stressrdquo Oxidative Medicine andCellular Longevity vol 2012 Article ID 163913 13 pages 2012
[21] C D Kamat S Gadal M Mhatre K S Williamson Q N Pyeand K Hensley ldquoAntioxidants in central nervous system dis-eases preclinical promise and translational challengesrdquo Journalof Alzheimerrsquos Disease vol 15 no 3 pp 473ndash493 2008
[22] A Pompella H Sies R Wacker et al ldquoThe use of totalantioxidant capacity as surrogate marker for food quality andits effect on health is to be discouragedrdquo Nutrition vol 30 no7-8 pp 791ndash793 2014
[23] Z Ye and H Song ldquoAntioxidant vitamins intake and the risk ofcoronary heart disease meta-analysis of cohort studiesrdquo Euro-pean Journal of Cardiovascular Prevention and Rehabilitationvol 15 no 1 pp 26ndash34 2008
[24] P Knekt J Ritz M A Pereira et al ldquoAntioxidant vitamins andcoronary heart disease risk a pooled analysis of 9 cohortsrdquoTheAmerican Journal of Clinical Nutrition vol 80 no 6 pp 1508ndash1520 2004
[25] A C Carr and M C M Vissers ldquoSynthetic or food-derivedvitamin Cmdashare they equally bioavailablerdquo Nutrients vol 5 no11 pp 4284ndash4304 2013
[26] R Tabrizchi ldquoEdaravoneMitsubishi-TokyordquoCurrentOpinion inInvestigational Drugs vol 1 no 3 pp 347ndash354 2000
[27] K Kikuchi S Tancharoen N Takeshige et al ldquoThe efficacy ofedaravone (radicut) a free radical scavenger for cardiovasculardiseaserdquo International Journal of Molecular Sciences vol 14 no7 pp 13909ndash13930 2013
[28] D Mauzerall and F H Westheimer ldquo1-Benzyldihydronicoti-namidemdasha model for reduced DPNrdquo Journal of the AmericanChemical Society vol 77 no 8 pp 2261ndash2264 1955 ChemicalAbstracts vol 50 Article ID 2588i 1956
[29] F Bossert and W Vater ldquo14-Dihydropyridinesmdasha basis fordeveloping new drugsrdquo Medicinal Research Reviews vol 9 no3 pp 291ndash324 1989
[30] G Swarnalatha G Prasanthi N Sirisha and CMadhusudhanaChetty ldquo14-Dihydropyridines a multtifunctional moleculemdash areviewrdquo International Journal of ChemTech Research vol 3 no1 pp 75ndash89 2011
28 Oxidative Medicine and Cellular Longevity
[31] M Cataldi and F Bruno ldquo14-Dihydropyridines the multiplepersonalities of a blockbuster drug familyrdquo Translational Medi-cine UniSa vol 4 no 2 pp 12ndash26 2012 httpwwwncbinlmnihgovpmcarticlesPMC3728803
[32] R Vitolina A Krauze G Duburs and A Velena ldquoAspects ofthe amlodipine pleiotropy in biochemistry pharmacology andclinicsrdquo International Journal of Pharmaceutical Sciences andResearch vol 3 no 5 pp 1215ndash1232 2012
[33] D Grover S N Mokale and M T Shete ldquoDihydropyridinea novel pharmacophorerdquo International Journal of Pharmaceu-tical Erudition vol 1 no 2 pp 16ndash29 2011 httppharmaeru-ditionorgContentPaper20111-RV-320Final2016-29pdf
[34] A M Vijesh A M Isloor S K Peethambar K N ShivanandaT Arulmoli and N A Isloor ldquoHantzsch reaction synthesis andcharacterization of somenew 14-dihydropyridine derivatives aspotent antimicrobial and antioxidant agentsrdquo European Journalof Medicinal Chemistry vol 46 no 11 pp 5591ndash5597 2011
[35] P Mehta and P Verma ldquoAntimicrobial activity of some deriva-tives of 14-dihydropyridinesrdquo Journal of Chemistry vol 2013Article ID 865128 4 pages 2013
[36] P Olejnıkova L Svorc D Olsovska et al ldquoAntimicrobialactivity of novel C2-substituted 14-dihydropyridine analoguesrdquoScientia Pharmaceutica vol 82 no 2 pp 221ndash232 2014
[37] S Sepehri H Perez Sanchez and A Fassihi ldquoHantzsch-typedihydropyridines and biginelli-type tetra-hydropyrimidinesa review of their chemotherapeutic activitiesrdquo Journal of Phar-macy amp Pharmaceutical Sciences vol 18 no 1 pp 1ndash52 2015httpsejournalslibraryualbertacaindexphpJPPSarticleview2383617863
[38] S A Khedkar and P B Auti ldquo14-Dihydropyridines a classof pharmacologically important moleculesrdquo Mini-Reviews inMedicinal Chemistry vol 14 no 3 pp 282ndash290 2014
[39] G D Tirzit and G Ya Duburs ldquo14-dihydropyridines as inhi-bitors of free-radical reactionsrdquo Chemistry of Heterocyclic Com-pounds vol 8 no 1 pp 126ndash127 1972 Translated from KhimiyaGeterotsiklicheskikh Soedinenii no1 pp 133ndash134 1972 (Rus-sian)
[40] I Bogeski R Kappl C Kummerow R Gulaboski M Hothand B A Niemeyer ldquoRedox regulation of calcium ion channelschemical and physiological aspectsrdquoCell Calcium vol 50 no 5pp 407ndash423 2011
[41] S A Giller G Y Dubur Y R Uldrikis et al ldquoDiludine [Themethod to obtain 35-dicarbonylderivatives of 26-dimethyl-14-dihydropyridines]rdquo Authors certificate of USSR no 3004651971 [Byull Izobret no13 p 95 1971] and following patentsPatent of England no 1294650 1973 Patent of France no2055458 1971 Patent of Japan no 702883 1973 Patent ofHolland no 149787 1976 Patent of Italy no 969022 1974 Patentof FRG no 2036403 1978 US Patent no 3883673 1975 USPatent no 3948924 1976
[42] S A Giller G Y Dubur Y R Uldrikis et al ldquoImprovementsin or relating to the stabilization of carotenerdquo GB Patent no1294650 1972
[43] S A Giller G Y Dubur Y R Uldrikis et al ldquoStabilization ofcarotenerdquo US Patent no 3883673 1975 Chemical Abstracts vol83 Article ID 95193 1975
[44] Yu A Zilber G Ya Dubur K K Kumsar and A Kh VelenaldquoThe effect of antioxidants on the peroxidation of bimole-cular phospholipid membranesrdquo Latvijas PSR ZA Vestis Izves-tia Akademii Nauk Latviyskoy SSR vol 6 pp 80ndash82 1971(Russian) translated from the original Russian Doc Accesion
No AD0771751 distributed by NTIS US Department of Com-merce httpwwwdticmildtictrfulltextu2771751pdf
[45] G Ya Dubur Yu A Zilbers A Kh Velena A O Kumerovaand G D Tirzitis ldquoMultistage study of regulation of peroxida-tion processes in biological membranes by antioxidants of 14-dihydropyridine grouprdquo Izvestiya Akademii Nauk LatviyskoySSR vol 336 no 7 pp 65ndash68 1975 (Russian)
[46] R P Mason and M W Trumbore ldquoDifferential membraneinteractions of calcium channel blockers Implications forantioxidant activityrdquo Biochemical Pharmacology vol 51 no 5pp 653ndash660 1996
[47] R P Mason M F Walter M W Trumbore E G Olmstead Jrand P E Mason ldquoMembrane antioxidant effects of the chargeddihydropyridine calcium antagonist amlodipinerdquo Journal ofMolecular and Cellular Cardiology vol 31 no 1 pp 275ndash2811999
[48] R PMason I T MakMW Trumbore and P EMason ldquoAnti-oxidant properties of calcium antagonists related to membranebiophysical interactionsrdquo American Journal of Cardiology vol84 no 4 pp 16ndash22 1999
[49] R PMasonMW Trumbore and P EMason ldquoMembrane bio-physical interaction of amlodipine and antioxidant propertiesrdquoDrugs vol 59 no 2 pp 9ndash16 2000 (French)
[50] R P Mason P Marche and T H Hintze ldquoNovel vascularbiology of third-generation L-type calcium channel antagonistsAncillary actions of amlodipinerdquo Arteriosclerosis Thrombosisand Vascular Biology vol 23 no 12 pp 2155ndash2163 2003
[51] A Augustyniak G Bartosz A Cipak et al ldquoNatural andsynthetic antioxidants an updated overviewrdquo Free RadicalResearch vol 44 no 10 pp 1216ndash1262 2010
[52] T Grune N Zarkovic and K Kostelidou ldquoLipid peroxidationresearch in Europe and the COST B35 action lsquoLipid Peroxida-tion Associated Disordersrsquordquo Free Radical Research vol 44 no10 pp 1095ndash1097 2010
[53] E Carosati P Ioan M Micucci et al ldquo14-Dihydropyridinescaffold in medicinal chemistry the story so far and perspec-tives (part 2) action in other targets and antitargetsrdquo CurrentMedicinal Chemistry vol 19 no 25 pp 4306ndash4323 2012
[54] U Eisner and J Kuthan ldquoThe chemistry of dihydropyridinesrdquoChemical Reviews vol 72 no 1 pp 1ndash42 1972 httpwwwsci-encemadnessorgtalkfilesphppid=138742ampaid=6475
[55] J Kuthan and A Kurfurst ldquoDevelopment in dihydropyri-dine chemistryrdquo Industrial amp Engineering Chemistry ProductResearch and Development vol 21 no 2 pp 191ndash261 1982
[56] A Sausins and G Duburs ldquoSynthesis of 14-dihydropyridinesby cyclocondensation reactionsrdquo Heterocycles vol 27 no 1 pp269ndash289 1988
[57] A E Sausins and G Y Duburs ldquoSynthesis of 14-dihydro-pyridines in cyclocondensation reactions (review)rdquo Chemistryof Heterocyclic Compounds vol 28 no 4 pp 363ndash391 1992Translated from Khimiya Geterotsiklicheskikh Soedinenii no 4pp 435ndash467 1992 (Russian)
[58] S Kazda ldquoTwenty years of dihydropyridinesrdquo in Dihydropy-ridines Progress in Pharmacology and Therapy W-D Busse BGarthoff and F Seuter Eds pp 1ndash12 Springer Verlag BerlinGermany 1993
[59] J-P Wan and Y Liu ldquoRecent advances in new multicomponentsynthesis of structurally diversified 14-dihydropyridinesrdquo RSCAdvances vol 2 no 26 pp 9763ndash9777 2012
[61] Reaxys Database[62] J Tuttle ldquoStructure mechanism and reactivity of hantzsch
estersrdquo in MacMillan Lab Group Meeting (082504) p 332004 httpwwwprincetoneduchemistrymacmillangroup-meetingsJBT20Hantzschpdf
[63] A Saini S Kumar and J S Sandhu ldquoHantzsch reaction recentadvances in Hantzsch 14-dihydropyridinesrdquo Journal of Sci-entific amp Industrial Research vol 67 pp 95ndash111 2008
[64] L LW Cheung S A Styler and A P Dicks ldquoRapid and conve-nient synthesis of the 14-dihydropyridine privileged structurerdquoJournal of Chemical Education vol 87 no 6 pp 628ndash630 2010
[65] A Kumar R A Maurya S Sharma M Kumar and G BhatialdquoSynthesis and biological evaluation of N-aryl-14-dihydro-pyridines as novel antidyslipidemic and antioxidant agentsrdquoEuropean Journal of Medicinal Chemistry vol 45 no 2 pp 501ndash509 2010
[66] R S Kumar A Idhayadhulla A J Abdul Nasser and J SelvinldquoSynthesis and anticoagulant activity of a new series of 14-dihydropyridine derivativesrdquo European Journal of MedicinalChemistry vol 46 no 2 pp 804ndash810 2011
[67] H A Stefani C B Oliveira R B Almeida et al ldquoDihydro-pyrimidin-(2H)-ones obtained by ultrasound irradiation anew class of potential antioxidant agentsrdquo European Journal ofMedicinal Chemistry vol 41 no 4 pp 513ndash518 2006
[68] H Sun C Shang L Jin and J Zhang ldquoSynthesis and antiox-idant activity of a series of novel 3-chalcone-substituted 14-dihydropyridine derivativesrdquoHeterocyclic Communications vol18 no 5-6 pp 239ndash243 2012
[69] D B Tikhonov and B S Zhorov ldquoStructural model for dihy-dropyridine binding to L-type calcium channelsrdquo The Journalof Biological Chemistry vol 284 no 28 pp 19006ndash19017 2009
[70] G Y Dubur and Y R Uldrikis ldquoThe oxidation of 14-dihydro-pyridinesrdquo Chemistry of Heterocyclic Compounds vol 6 no 1pp 80ndash84 1970 Translated from Khimiya GeterotsiklicheskikhSoedinenii no 1 pp 83ndash88 1970 (Russian)
[71] G Ya Duburs A O Kumerova and Ya R Uldrikis ldquoEnzymicoxidation of hydrogenated pyridines with peroxidase-hydrogenperoxide systemrdquoLatvijas PSRZAVestis vol 73 no 7 pp 73ndash771970 (Russian) Chemical Abstracts vol 73 Article ID 94913g1970
[72] K Xie Y-C Liu Y Cui J-GWang Y Fu andT CWMak ldquoN-methyl-(R)-3-(tert-butyl)-sulfinyl-14-dihydropyridine a novelNADHmodel compoundrdquoMolecules vol 12 no 3 pp 415ndash4222007
[73] S Tamagaki T Mimura and W Tagaki ldquoMetal-ion-facilitatedoxidations of dihydropyridines with molecular oxygen andhydrogen peroxiderdquo Journal of the Chemical Society PerkinTransactions 2 no 10 pp 1645ndash1650 1990
[74] D Tirzite G Tirzitis andD Antipova ldquoReductive ability of 14-dihydropyridine derivatives in relation to ions of trivalent ironrdquoChemistry of Heterocyclic Compounds vol 35 no 5 pp 592ndash594 1999
[76] J Ogle J Stradins and L Baumane ldquoFormation and decay offree cation-radicals in the course of electro-oxidation of 12- and14-dihydropyridines (Hantzsch esters)rdquo Electrochimica Actavol 39 no 1 pp 73ndash79 1994
[77] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for the
synthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts C Wittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Berlin Germany 2010
[78] WDu and Zh Yu ldquoBiomimetic in situ regeneration of cofactorsNAD(P)+ and NAD(P)H models hantzsch esters and dihy-drophenanthridinerdquo Synlett vol 23 no 9 pp 1300ndash1304 2012
[79] H K Chenault and G M Whitesides ldquoRegeneration ofnicotinamide cofactors for use in organic synthesisrdquo AppliedBiochemistry and Biotechnology vol 14 no 2 pp 147ndash197 1987
[80] Y R Uldrikis A A Zidermane E A Biseniex I E Preisa GY Dubur and G D Tirzit ldquoEsters of 26-dimethyl-14-dihydro-pyridine-35-dicarboxylic acid and method of obtainingthereofrdquo WO 8000345 A1 1978 httpworldwideespacenetcompublicationDetailsbiblioDB=EPODOCampII=1ampND=3ampadjacent=trueamplocale=en EPampFT=Dampdate=19800306ampCC=WOampNR=8000345A1ampKC=A1
[81] Y Sambongi H Nitta K Ichihashi M Futai and I Ueda ldquoAnovel water-soluble Hantzsch 14-dihydropyridine compoundthat functions in biological processes through NADH regener-ationrdquo Journal of Organic Chemistry vol 67 no 10 pp 3499ndash3501 2002
[82] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for thesynthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts ChWittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Verlag Berlin Germany 2010
[83] T Okamura T Kikuchi A Nagamine et al ldquoAn approach formeasuring in vivo cerebral redox states using the oxidative con-version of dihydropyridine to pyridinium ion and themetabolictrapping principlerdquo Free Radical Biology and Medicine vol 38no 9 pp 1197ndash1205 2005
[84] K A Schellenberg and F H Westheimer ldquoA free-radicaloxidation of a dihydropyridine1ardquo The Journal of OrganicChemistry vol 30 no 6 pp 1859ndash1862 1965
[85] K A Schellenberg ldquoReaction of hydroxyl radical with thymi-dine Scavenging by a dihydropyridinerdquo Federation Proceedingsvol 38 no 3 I p 1433 1979
[86] E S Huyser J A K Harmony and F L McMillian ldquoPeroxideoxidations of dihydropyridine derivativesrdquo Journal of the Amer-ican Chemical Society vol 94 no 9 pp 3176ndash3180 1972
[87] A Sakamoto S T Ohnishi and R Ogawa ldquoInhibition of lipidperoxidation by some dihydropyridine derivativesrdquo Journal ofAnesthesia vol 7 no 2 pp 193ndash197 1993
[88] R Hardeland ldquoReview Neuroprotection by radical avoidancesearch for suitable agentsrdquo Molecules vol 14 no 12 pp 5054ndash5102 2009
[89] G Ya Dubur A Kh Velena V M Gukasov and Yu AVladimirov ldquoRegulation of peroxidation of mitochondrialmembrane lipids initiated by Fe2+ ions by antoxidants of the14-dihydropyridine series in experiments in vitrordquo Biomed-itsinskaya Khimiya vol 22 no 5 pp 665ndash673 1976 (Russian)Chemical Abstracts vol 88 Article ID 2640 1977
[90] G RMMHaenenM J T J Arts A Bast andMD ColemanldquoStructure and activity in assessing antioxidant activity in vitroand in vivo a critical appraisal illustrated with the flavonoidsrdquoEnvironmental Toxicology and Pharmacology vol 21 no 2 pp191ndash198 2006
[91] G Tirzitis and G Bartosz ldquoDetermination of antiradical andantioxidant activity basic principles and new insightsrdquo ActaBiochimica Polonica vol 57 no 2 pp 139ndash142 2010
30 Oxidative Medicine and Cellular Longevity
[92] G R Buettner and R P Mason ldquoSpin-trapping methods fordetecting superoxide and hydroxyl free radicals in vitro and invivordquo inCritical Reviews of Oxidative Stress and Aging Advancesin Basic Science Diagnostics and Intervention R G Cutler andH Rodriguez Eds vol 1 chapter 2 pp 27ndash38World ScientificLondon UK 2003
[93] M M Tarpey and I Fridovich ldquoMethods of detection ofvascular reactive species Nitric oxide superoxide hydrogenperoxide and peroxynitriterdquo Circulation Research vol 89 no3 pp 224ndash236 2001
[94] E Y Kazush E I Sagun G D Tirzit and G Y DaburldquoQuenching of singlet oxygen by electron donating derivativesof 14-dihydropyridinerdquo Chemistry of Heterocyclic Compoundsvol 30 no 5 pp 562ndash563 1994
[95] G Tirzitis E Kazush and G Duburs ldquoReaction of 14-dihydropyridine derivatives with peroxynitrite anionrdquo Chem-istry of Heterocyclic Compounds vol 34 no 3 pp 321ndash3231998 (Russian) Translated from Khimiya GeterotsiklicheskikhSoedinenii no 3 pp 355ndash357 1998
[96] L J Nunez-Vergara C Lopez-Alarcon P A Navarrete-EncinaA M Atria C Camargo and J A Squella ldquoElectrochemicaland EPR characterization of 14-dihydropyridines Reactivitytowards alkyl radicalsrdquo Free Radical Research vol 37 no 1 pp109ndash120 2003
[97] D Tirzite A Krauze A Zubareva G Tirzitis and G DubursldquoSynthesis and antiradical activity of 5-acetyl-2-alkylthio-4-aryl-6-methyl-14-dihydropyridine-3-carboxylic acid nitrilesrdquoChemistry of Heterocyclic Compounds vol 38 no 7 pp 795ndash800 2002
[98] H Ohkawa N Ohishi and K Yagi ldquoAssay for lipid peroxidesin animal tissues by thiobarbituric acid reactionrdquo AnalyticalBiochemistry vol 95 no 2 pp 351ndash358 1979
[99] N Zarkovic ldquo4-Hydroxynonenal as a bioactive marker ofpathophysiological processesrdquo Molecular Aspects of Medicinevol 24 no 4-5 pp 281ndash291 2003
[100] M Parola G Bellomo G Robino G Barrera and M UDianzani ldquo4-Hydroxynonenal as a biological signal molecularbasis and pathophysiological implicationsrdquo Antioxidants andRedox Signaling vol 1 no 3 pp 255ndash284 1999
[101] T Lovakovic M Poljak-Blazi G Duburs et al ldquoGrowthmodulation of human cells in vitro by mild oxidative stressand 14-dihydropyridine derivative antioxidantsrdquo CollegiumAntropologicum vol 35 no 1 pp 137ndash141 2011
[102] R van den Berg G R M M Haenen H van den Bergand A Bast ldquoApplicability of an improved Trolox equivalentantioxidant capacity (TEAC) assay for evaluation of antioxidantcapacity measurements of mixturesrdquo Food Chemistry vol 66no 4 pp 511ndash517 1999
[103] C Lopez-Alarcon P Navarrete C Camargo J A Squella andL J Nunez-Vergara ldquoReactivity of 14-dihydropyridines towardalkyl alkylperoxyl radicals and ABTS radical cationrdquo ChemicalResearch in Toxicology vol 16 no 2 pp 208ndash215 2003
[104] V Valenzuela P Santander C Camargo J A Squella C Lopez-Alarcon and L J Nunez-Vergara ldquo14-Dihydropyridines reac-tivity of nitrosoaryl and nitroaryl derivatives with alkylperoxylradicals andABTS radical cationrdquo Free Radical Research vol 38no 7 pp 715ndash727 2004
[105] L G Tsetlin N A Chebotareva B I Kurganov A K VelenaG Y Dubur and V Z Lankin ldquoStudy of 14-dihydropyridinesas lipoxygenase inhibitors with the use of hydrated reversedmicellesrdquo Pharmaceutical Chemistry Journal vol 22 no 6 pp425ndash428 1988 (Russian)
[106] J Panek Z Reblova L Kocirkova et al ldquoAntioxidant activityof dihydropyridine derivativesrdquo Czech Journal of Food Sciencesvol 18 pp 144ndash145 2000
[107] G Tirzitis I Kirule and G Duburs ldquoAntioxidationsaktivitatder 35-dicarbonylderivate des 26-demethyl-14-dihydropyri-dinsrdquo Fett Wissenschaft TechnologieFat Science Technology vol90 no 10 pp 411ndash413 1988
[108] M Plotniece G Tirzitis Y Uldrikis et al ldquoSynthesis of 14-dihydropyridine derivatives having an oxy- alkoxy- or dimeth-ylaminophenyl substituent in the 4 position their antioxidantactivity and their binding to phospholipid membranesrdquo Chem-istry of Heterocyclic Compounds vol 32 no 10 pp 1166ndash11721996 Translated from Khimiya Geterotsiklicheskikh Soedineniino 10(352) pp 1358ndash1365 1996 (Russian)
[109] D Y Rubene V S Sharov V I Olenev G D Tirzit G Y Duburand Y A Vladimirov ldquoUse of chemiluminescent method forthe evaluation of antioxidant activity of some derivatives of 14-dihydropyridinerdquo Russian Journal of Physical Chemistry A vol55 no 2 pp 511ndash512 1981 (Russian)
[110] M C R Symons and JM C Gutteridge Free Radicals and IronChemistry Biology and Medicine Oxford Science PublicationsOxford University Press Oxford UK 1998
[111] M Repetto J Semprine and A Boveris ldquoLipid peroxidationchemical mechanism biological implications and analyticaldeterminationrdquo in Lipid Peroxidation A Catala Ed Section ILipid Peroxidation Chemical Mechanisms Antioxidants Bio-logical Implications of Biochemistry Genetics and MolecularBiology chapter 1 pp 3ndash30 InTech Rijeka Croatia 2012
[112] A Velena J Zilbers and G Duburs ldquoDerivatives of 14-dihydropyridines asmodulators of ascorbate-induced lipid per-oxidation and high-amplitude swelling ofmitochondria causedby ascorbate sodium linoleate and sodiumpyrophosphaterdquoCellBiochemistry and Function vol 17 no 4 pp 237ndash252 1999
[113] M V Bilenko L N Shelenkova G Y Dubur and A K VelenaldquoUse of antioxidants to prevent renal damage during acuteischemia and reperfusionrdquo Bulletin of Experimental Biology andMedicine vol 96 no 3 pp 1195ndash1198 1983 Translated fromByulletenrsquo Eksperimentalrsquonoi Biologii i Meditsiny vol 96 no 9pp 8ndash11 1983 (Russian)
[114] R Toniolo F Tubaro F Ursini and G Bontempelli ldquoAn elec-troanalytical investigation on the redox properties of calciumantagonist dihydropyridinesrdquo Electroanalysis vol 15 no 10 pp855ndash861 2003
[115] L Kourimska J Pokorny and G Tirzitis ldquoThe antioxidant aci-tivity of 26-dimethyl-35-diethoxycarbonyl-14-dihydropyri-dine in edible oilsrdquo Nahrung vol 37 no 1 pp 91ndash93 1993
[116] C Lopez-Alarcon H Speisky J A Squella C Olea-Azar CCamargo and L J Nunez-Vergara ldquoReactivity of 14-dihydro-pyridines toward SIN-1-derived peroxynitriterdquo PharmaceuticalResearch vol 21 no 10 pp 1750ndash1757 2004
[117] R A Olek W Ziolkowski J J Kaczor L Greci J Popinigisand J Antosiewicz ldquoAntioxidant activity of NADH and its ana-loguemdashan in vitro studyrdquo Journal of Biochemistry andMolecularBiology vol 37 no 4 pp 416ndash421 2004
[118] E Niki N Noguchi and N Gotoh ldquoInhibition of oxidativemodification of low density lipoprotein by antioxidantsrdquo Jour-nal of Nutritional Science andVitaminology vol 39 supplementpp S1ndashS8 1993
[119] N Rojstaczer and D J Triggle ldquoStructure-function relation-ships of calcium antagonists effect on oxidative modificationof low density lipoproteinrdquo Biochemical Pharmacology vol 51no 2 pp 141ndash150 1996
Oxidative Medicine and Cellular Longevity 31
[120] A Sevanian L Shen and FUrsini ldquoInhibition of LDLoxidationand oxidized LDL-induced cytotoxicity by dihydropyridinecalcium antagonistsrdquo Pharmaceutical Research vol 17 no 8 pp999ndash1006 2000
[121] A Negre-Salvayre and R Salvayre ldquoProtection by Ca2+ channelblockers (nifedipine diltiazem and verapamil) against the tox-icity of oxidized low density lipoprotein to cultured lymphoidcellsrdquo British Journal of Pharmacology vol 107 no 3 pp 738ndash744 1992
[122] A Negre-Salvayre G FitoussiM Troly and R Salvayre ldquoCom-parative cytoprotective effect of dihydropyridine calcium chan-nel blockers against the toxicity of oxidized low density lipopro-tein for cultured lymphoid cellsrdquo Biochemical Pharmacologyvol 44 no 12 pp 2379ndash2386 1992
[123] L Cominacini A F Pasini U Garbin et al ldquoAntioxidant activ-ity of different dihydropyridinesrdquo Biochemical and BiophysicalResearch Communications vol 302 no 4 pp 679ndash684 2003
[124] L Cominacini U Garbin A Fratta Pasini et al ldquoOxidized low-density lipoprotein increases the production of intracellularreactive oxygen species in endothelial cells inhibitory effect oflacidipinerdquo Journal of Hypertension vol 16 no 12 part 2 pp1913ndash1919 1998
[125] H M Lander ldquoAn essential role for free radicals and derivedspecies in signal transductionrdquo The FASEB Journal vol 11 no2 pp 118ndash124 1997
[126] M L L Martinez E Rizzi M M Castro et al ldquoLercanidipinedecreases vascular matrix metalloproteinase-2 activity andprotects against vascular dysfunction in diabetic ratsrdquo EuropeanJournal of Pharmacology vol 599 no 1ndash3 pp 110ndash116 2008
[127] P Lesnik C Dachet L Petit et al ldquoImpact of a combinationof a calcium antagonist and a 120573-blocker on cell- and copper-mediated oxidation of LDL and on the accumulation and effluxof cholesterol in human macrophages and murine J774 cellsrdquoArteriosclerosis Thrombosis and Vascular Biology vol 17 no 5pp 979ndash988 1997
[128] G Sobal E J Menzel and H Sinzinger ldquoCalcium antagonistsas inhibitors of in vitro low density lipoprotein oxidation andglycationrdquoBiochemical Pharmacology vol 61 no 3 pp 373ndash3792001
[129] E Lupo R Locher B Weisser and W Vetter ldquoIn vitro antiox-idant activity of calcium antagonists against LDL oxidationcompared with 120572-tocopherolrdquo Biochemical and BiophysicalResearch Communications vol 203 no 3 pp 1803ndash1808 1994
[130] J Zou Y Li H-Q Fan and J-G Wang ldquoEffects of dihydropy-ridine calcium channel blockers on oxidized low-density lipo-protein induced proliferation and oxidative stress of vascularsmooth muscle cellsrdquo BMC Research Notes vol 5 article 1682012
[131] C Napoli S Salomone T Godfraind et al ldquo14-Dihydro-pyridine calcium channel blockers inhibit plasma and LDL oxi-dation and formation of oxidation-specific epitopes in the arte-rial wall and prolong survival in stroke-prone spontaneouslyhypertensive ratsrdquo Stroke vol 30 no 9 pp 1907ndash1915 1999
[132] G Zernig I Graziadei T Moshammer C Zech N Reider andH Glossmann ldquoMitochondrial Ca2+ antagonist binding sitesare associated with an inner mitochondrial membrane anionchannelrdquo Molecular Pharmacology vol 38 no 3 pp 362ndash3691990
[133] F E Hunter Jr A Scott P E Hochstein et al ldquoStudies of themechanism of ascorbate-induced swelling and lysis of isolatedliver mitochondriardquo The Journal of Biological Chemistry vol239 pp 604ndash613 1964
[134] D R Janero B Burghardt and R Lopez ldquoProtection of cardiacmembrane phospholipid against oxidative injury by calciumantagonistsrdquoBiochemical Pharmacology vol 37 no 21 pp 4197ndash4203 1988
[135] A Karadag B Ozcelik and S S Saner ldquoReview of methods todetermine antioxidant capacitiesrdquo FoodAnalyticalMethods vol2 no 1 pp 41ndash60 2009
[136] Y I Gubskiı N V Litvinova and E V Shnurko-TabakovaldquoAntioxidant and antiradical activity of various classes of antiox-idantsrdquo Ukrainskiı Biokhimicheskiı Zhurnal vol 66 no 4 pp114ndash116 1994 (Russian)
[137] M Takei M Hiramatsu and A Mori ldquoInhibitory effects ofcalcium antagonists onmitochondrial swelling induced by lipidperoxidation or arachidonic acid in the rat brain in vitrordquoNeurochemical Research vol 19 no 9 pp 1199ndash1206 1994
[138] M Takei M Hiramatsu R Edamatsu and A Mori ldquoFreeradical scavenging by calcium antagonistsrdquo Neurosciences vol20 no 2 pp 75ndash82 1994
[139] Ya P Stradin G Ya Dubur Yu A Beilis Ya R Uldrikis andA F Korotkova ldquoVoltammetry of 14-dihydropyridine deriva-tives I Potentials of electrochemical oxidation of 35-diacyl-and 35-di(alkoxycarbonyl)-14-dihydropyridines in acetoni-trilerdquo Chemistry of Heterocyclic Compounds no 1 pp 84ndash871972 (Russian)
[140] E V Ivanov T V Ponomarjova G N Merkusev et al ldquoEinneuer Haut-Radioprotektor Diethon (experimentelle Unter-suchung)rdquo Radiobiologia Radiotherapia vol 31 no 1 pp 69ndash78 1990
[141] E V Ivanov T V Ponomareva G N Merkushev et al ldquoRadia-tion modulating properties of derivates of 14-dihydropyridineand 12345678910-decahydroacridine-18 dionerdquo Radiat-sionnaia Biologiia Radioecologiia vol 44 no 5 pp 550ndash5592004 (Russian)
[142] R O Vitolinia D A Berzinia A K Velena I A Vutsina A AKimenis and G Y Duburs ldquoThe protective effects of the cal-cium antagonist foridon in acute myocardial ischaemiardquo Kardi-ologiya vol 27 no 3 pp 90ndash93 1987 (Russian)
[143] A H Velena G Ya Duburs R O Vitolina et al ldquoEffect ofryodipine on electromechanical parameters of heart and vesselscAMP phosphodiesterase activity and swelling-contractioncycle of mitochondriardquo Arzneimittelforschung vol 35 no 6 pp907ndash914 1985
[144] L I Utno Z E Lipsberga A A Silova M I Girgensone EA Bisenieks and G I Ia ldquoCardioprotective properties of a 14-dihydropyridine derivative glutapyrone in deep hypothermiardquoBiulletenrsquo Eksperimentalrsquonoı Biologii i Meditsiny vol 108 no 11pp 558ndash561 1989 (Russian)
[145] M A S FernandesM S Santos J A F Vicente et al ldquoEffects of14-dihydropyridine derivatives (cerebrocrast gammapyroneglutapyrone and diethone) onmitochondrial bioenergetics andoxidative stress a comparative studyrdquoMitochondrion vol 3 no1 pp 47ndash59 2003
[146] M A S Fernandes M S Santos A J M Moreno et al ldquoEffectsof 5-acetyl(carbamoyl)-6-methylsulfanyl-14-dihydropyridine-5-carbonitriles on rat liver mitochondrial functionrdquo Toxicologyin Vitro vol 23 no 7 pp 1333ndash1341 2009
[147] L Klimaviciusa A Kalda A Kaasik et al ldquoNeuroprotectiveactivity of 14-dihydropyridine derivatives structure determi-nantsrdquo Proceedings of the Latvian Academy of Sciences BNatural Exact and Applied Sciences vol 61 no 1-2 pp 33ndash372007
32 Oxidative Medicine and Cellular Longevity
[148] L Klimaviciusa M A S Fernandes N Lencberga et alldquoTargeting the mitochondria by novel adamantane-containing14-dihydropyridine compoundsrdquo in Bioenergetics K B ClarkEd pp 257ndash272 InTech 2012
[149] V Klusa L Klimaviciusa G Duburs J Poikans and AZharkovsky ldquoAnti-neurotoxic effects of tauropyrone a taurineanaloguerdquo Advances in Experimental Medicine and Biology vol583 pp 499ndash508 2006
[150] N Sampson P Berger and Ch Zenzmaier ldquoRedox signalingas a therapeutic target to inhibit myofibroblast activation indegenerative fibrotic diseaserdquo BioMed Research Internationalvol 2014 Article ID 131737 14 pages 2014
[151] T L Leto and M Geiszt ldquoRole of Nox family NADPH oxidasesin host defenserdquoAntioxidantsampRedox Signaling vol 8 no 9-10pp 1549ndash1561 2006
[152] K K Griendling D Sorescu and M Ushio-Fukai ldquoNAD(P)Hoxidase role in cardiovascular biology and diseaserdquo CirculationResearch vol 86 no 5 pp 494ndash501 2000
[153] H Chen Y S Song and P H Chan ldquoInhibition of NADPHoxi-dase is neuroprotective after ischemia-reperfusionrdquo Journal ofCerebral Blood Flow and Metabolism vol 29 no 7 pp 1262ndash1272 2009
[154] P Hochstein and L Ernster ldquoADP-activated lipid peroxidationcoupled to the TPNH oxidase system of microsomesrdquo Biochem-ical and Biophysical Research Communications vol 12 no 5 pp388ndash394 1963
[155] I I Gubskiı AGGoriushkoNV Litvinova et al ldquoAntioxidantproperties and membranotropic effect of certain derivatives of14-dihydropyridinerdquo Ukrainskiı Biokhimicheskiı Zhurnal vol71 no 4 pp 35ndash39 1999 (Russian)
[156] F Engineer and R Sridhar ldquoInhibition of rat heart andliver microsomal lipid peroxidation by nifedipinerdquo BiochemicalPharmacology vol 38 no 8 pp 1279ndash1285 1989
[157] T Goncalves A P Carvalho and C R Oliveira ldquoAntioxidanteffect of calcium antagonists on microsomai membranes iso-lated from different brain areasrdquo European Journal of Pharma-cology vol 204 no 3 pp 315ndash322 1991
[158] M E Letelier P Izquierdo L Godoy A M Lepe and MFaundez ldquoLiver microsomal biotransformation of nitro-aryldrugs mechanism for potential oxidative stress inductionrdquoJournal of Applied Toxicology vol 24 no 6 pp 519ndash525 2004
[159] M E Letelier P Entrala C Lopez-Alarcon et al ldquoNitroaryl-14-dihydropyridines as antioxidants against rat liver microsomesoxidation induced by ironascorbate Nitrofurantoin and naph-thalenerdquo Toxicology in Vitro vol 21 no 8 pp 1610ndash1618 2007
[160] F P Guengerich W R Brian M Iwasaki M-A Sari CBaarnhielm and P Berntsson ldquoOxidation of dihydropyridinecalcium channel blockers and analogues by human liver cyto-chrome P-450 IIIA4rdquo Journal of Medicinal Chemistry vol 34no 6 pp 1838ndash1844 1991
[161] S H Park S-W RhaW-Y Shin et al ldquoAS-160 Calcium channelblockers of dihydropyridine class reduce the antiplatelet effectof Clopidogrel what is clinical impactrdquo The American Journalof Cardiology vol 107 no 8 supplement p 47A 2011
[162] C Asma and D M Reda ldquoEvaluation of dihydropyridinecalcium antagonist effects on the stress bioindicator orga-nism Saccharomyces cerevisiaerdquo Annals of Biological Researchvol 4 no 10 pp 40ndash46 2013 httpscholarsresearchlibrarycomABR-vol4-iss10ABR-2013-4-10-40-46pdf
[163] G Gaviraghi A M Pastorino E Ratti and D G TristldquoCalcium channel blockers with antioxidant activityrdquo in Free
Radicals Lipoprotein Oxidation andAtherosclerosis G BellomoG Finardi E Maggi and E Rice-Evans Eds pp 431ndash456Richelieu Press London UK 1995
[164] G Gaviraghi AM Pastorino E Ratti and D G Trist ldquoAntiox-idant dihydropyridines a new and comprehensive therapy forfree radical-induced cardiovascular diseasesrdquo in Free Radicalsin Biology and Environment F Minisci Ed vol 27 of NATOASI Series pp 193ndash221 Springer Dordrecht The Netherlands1997
[165] P D Henry ldquoAntiperoxidative actions of calcium antagonistsand atherogenesisrdquo Journal of Cardiovascular Pharmacologyvol 18 supplement 1 pp S6ndashS10 1991
[166] F Kouoh B Gressier T Dine et al ldquoAntioxidant effects andanti-elastase activity of the calcium antagonist nicardipine onactivated human and rabbit neutrophilsmdasha potential antiath-erosclerotic property of calcium antagonistsrdquo CardiovascularDrugs andTherapy vol 16 no 6 pp 515ndash520 2002
[167] S Parthasarathy D Litvinov K Selvarajan and M GarelnabildquoLipid peroxidation and decompositionmdashconflicting roles inplaque vulnerability and stabilityrdquo Biochimica et BiophysicaActa vol 1781 no 5 pp 221ndash231 2008
[168] D-Q Liu Z-Q Pang D-H Zhao and B-H Sheng ldquoEffects offuryl-dihydropyridines I on lipid peroxides of ischemic myo-cardium and ATPases activity of erythrocyte membranes inratsrdquo Acta Pharmacologica Sinica vol 12 no 3 pp 253ndash2561991
[169] V Lukic-Panin T Kamiya H Zhang et al ldquoPrevention of neu-ronal damage by calcium channel blockers with antioxidativeeffects after transient focal ischemia in ratsrdquo Brain Research vol1176 no 1 pp 143ndash150 2007
[170] Y Allanore D Borderie H Lemarechal O G Ekindjian andA Kahan ldquoAcute and sustained effects of dihydropyridine-typecalcium channel antagonists on oxidative stress in systemicsclerosisrdquo American Journal of Medicine vol 116 no 9 pp 595ndash600 2004
[171] I Casetta V Govoni and E Granieri ldquoOxidative stress antioxi-dants and neurodegenerative diseasesrdquo Current PharmaceuticalDesign vol 11 no 16 pp 2033ndash2052 2005
[172] M J T J Arts Assessing antioxidant activity [PhD the-sis] Maastricht University Maastricht The Netherlands 2007httparnounimaasnlshowcgifid=8676
[173] G Dıaz-Araya L Godoy L Naranjo A Squella M E Letelierand L J Nunez-Vergara ldquoAntioxidant effects of 14-dihydro-pyridine and nitroso aryl derivatives on the Fe+3ascorbate-stimulated lipid peroxidation in rat brain slicesrdquo General Phar-macology The Vascular System vol 31 no 3 pp 385ndash391 1998
[174] Y Fukuhara K Tsuchiya Y Horinouchi et al ldquoProtectiveeffect of photodegradation product of nifedipine against tumornecrosis factor 120572-induced oxidative stress in human glomerularendothelial cellsrdquo Journal of Medical Investigation vol 58 no1-2 pp 118ndash126 2011
[175] W Stengel M Jainz and K Andreas ldquoDifferent potencies ofdihydropyridine derivatives in blocking T-type but not L-typeCa2+ channels in neuroblastoma-glioma hybrid cellsrdquo EuropeanJournal of Pharmacology vol 342 no 2-3 pp 339ndash345 1998
[176] O M Panasenko D J Tirzite G D Tirzitis and G J DubursldquoEffect of some 14-dihydropyridine derivatives on structuralorganization of erythrocyte membranesrdquo Biologicheskie Mem-brany (Biochemistry (Moscow) Series A Membrane and CellBiology) vol 1 pp 919ndash925 1984 (Russian)
[177] L G Herbette Y M H Vant Erve and D G Rhodes ldquoInter-action of 14 dihydropyridine calcium channel antagonists with
Oxidative Medicine and Cellular Longevity 33
biological membranes lipid bilayer partitioning could occurbefore drug binding to receptorsrdquo Journal of Molecular andCellular Cardiology vol 21 no 2 pp 187ndash201 1989
[178] L G Herbette P E Mason G Gaviraghi T N Tulenko andR P Mason ldquoThe molecular basis for lacidipinersquos unique phar-macokinetics optimal hydrophobicity results in membraneinteractions that may facilitate the treatment of atherosclerosisrdquoJournal of Cardiovascular Pharmacology vol 23 supplement 5pp S16ndashS25 1994
[179] G V Belevitch G Y Dubur G E Dobretsov N K Kurek andM M Spirin ldquoCalcium antagonists riodipine nifedipine andverapamil binding to model and biological membranes fluore-scence analysisrdquo Biologicheskie Membrany (Biochemistry(Moscow) Series A Membrane and Cell Biology) vol 5 pp768ndash776 1988 (Russian)
[180] R P Mason G E Gonye D W Chester and L G HerbetteldquoPartitioning and location of Bay K 8644 14-dihydropyridinecalcium channel agonist in model and biological membranesrdquoBiophysical Journal vol 55 no 4 pp 769ndash778 1989
[181] M Cindric A Cipak J Serly et al ldquoReversal of multidrugresistance inmurine lymphoma cells by amphiphilic dihydropy-ridine antioxidant derivativerdquo Anticancer Research vol 30 no10 pp 4063ndash4070 2010
[182] F Shekari H Sadeghpour K Javidnia et al ldquoCytotoxic andmultidrug resistance reversal activities of novel 14-dihydro-pyridines against human cancer cellsrdquo European Journal ofPharmacology vol 746 no 1 pp 233ndash244 2015
[183] X-F Zhou Q Shao R A Coburn and M E Morris ldquoQuanti-tative structure-activity relationship and quantitative structure-pharmacokinetics relationship of 14-dihydropyridines andpyridines as multidrug resistance modulatorsrdquo PharmaceuticalResearch vol 22 no 12 pp 1989ndash1996 2005
[184] R Berkels T Breitenbach H Bartels et al ldquoDifferent antioxida-tive potencies of dihydropyridine calcium channel modulatorsin various modelsrdquo Vascular Pharmacology vol 42 no 4 pp145ndash152 2005
[185] S Borovic G Tirzitis D Tirzite et al ldquoBioactive 14-dihydro-isonicotinic acid derivatives prevent oxidative damage of livercellsrdquo European Journal of Pharmacology vol 537 no 1ndash3 pp12ndash19 2006
[186] D Ya Rubene G D Tirzitis and G Ya Duburs ldquoInteractionof some 14-dihydropyridine derivatives with Fentonrsquos reagentrdquoLatvijas PSRZinatnuAkademijas Vestis Kimijas Serija Proceed-ings of the Latvian SSR Academy of Sciences Chemistry Seriespp 212ndash216 1982 (Russian)
[187] K Ondrias V Misık D Gergel and A Stasko ldquoLipid per-oxidation of phosphatidylcholine liposomes depressed by thecalcium channel blockers nifedipine and verapamil and bythe antiarrhythmic-antihypoxic drug stobadinerdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1003 no 3pp 238ndash245 1989
[188] I T Mak and W B Weglicki ldquoComparative antioxidant acti-vities of propranolol nifedipine verapamil and diltiazemagainst sarcolemmal membrane lipid peroxidationrdquoCirculationResearch vol 66 no 5 pp 1449ndash1452 1990
[189] I T Mak P Boehme and W B Weglicki ldquoProtective effects ofcalcium channel blockers against free radical-impaired endo-thelial cell proliferationrdquo Biochemical Pharmacology vol 50 no9 pp 1531ndash1534 1995
[190] S Ray S Mondal and N Dana ldquoEvaluation of protective roleof nifedipine on lipid peroxidation using reduced glutathione as
model markerrdquo Oxidants and Antioxidants in Medical Sciencevol 1 no 2 pp 97ndash100 2012
[191] M Yamato T Shiba T Ide Y Honda K-I Yamada andH Tsutsui ldquoNifedipine treatment reduces brain damage aftertransient focal ischemia possibly through its antioxidativeeffectsrdquoHypertension Research vol 34 no 7 pp 840ndash845 2011
[192] V Chander and K Chopra ldquoNifedipine attenuates changes innitric oxide levels renal oxidative stress and nephrotoxicityinduced by cyclosporinerdquo Renal Failure vol 27 no 4 pp 441ndash450 2005
[193] K M Gaafa M M Badawy and A A Hamza ldquoThe protectiveeffects of ascorbic acid cimetidine and nifedipine on diethyl-dithiocarbamate-induced hepatic toxicity in albino ratsrdquo Drugand Chemical Toxicology vol 34 no 4 pp 405ndash419 2011
[194] H Sugawara K Tobise and S Onodera ldquoAbsence of antiox-idant effects of nifedipine and diltiazem on myocardial mem-brane lipid peroxidation in contrast with those of nisoldipineand propranololrdquo Biochemical Pharmacology vol 47 no 5 pp887ndash892 1994
[195] I E Kirule D Y Rubene E A Bisenieks G D Tirzit and GY Dubur ldquo4-Nitrophenyl-14-dihydropyridinesmdasha new groupof inhibitors of peroxide oxidationrdquo Chemistry of HeterocyclicCompounds vol 18 no 3 p 316 1982
[196] G D Tirzit I E Kirule L K Baumane R A Gavar Y PStradynrsquo andG YDubur ldquoMechanism of the antioxidant actionof 26-dimethyl-35-dimethoxy-carbonyl-4-(2-nitrophenyl)14-dihydropyridinerdquoChemistry ofHeterocyclic Compounds vol 20no 8 pp 915ndash918 1984
[197] C Yanez C Lopez-Alarcon C Camargo V Valenzuela J ASquella and L J Nunez-Vergara ldquoStructural effects on thereactivity 14-dihydropyridines with alkylperoxyl radicals andABTS radical cationrdquo Bioorganic and Medicinal Chemistry vol12 no 9 pp 2459ndash2468 2004
[198] VMisik A J Stasko D Gergel and K Ondrias ldquoSpin-trappingand antioxidant properties of illuminated and nonilluminatednifedipine and nimodipine in heart homogenate and modelsystemrdquo Molecular Pharmacology vol 40 no 3 pp 435ndash4391991
[199] K Ondrias V Misık A Stasko D Gergelrsquo and M HromadovaldquoComparison of antioxidant properties of nifedipine and illu-minated nifedipine with nitroso spin traps in low densitylipoproteins and phosphatidylcholine liposomesrdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1211 no 1pp 114ndash119 1994
[200] A Stasko V Brezova S Biskupic K Ondrias and V MisıkldquoReactive radical intermediates formed from illuminated nife-dipinerdquoFree Radical Biology andMedicine vol 17 no 6 pp 545ndash556 1994
[201] K Ishizawa Y Izawa-Ishizawa N Yamano et al ldquoNitrosoni-fedipine ameliorates the progression of type 2 diabetic nephro-pathy by exerting antioxidative effectsrdquo PLoS ONE vol 9 no 1Article ID e86335 2014
[202] H Fujii and L J Berliner ldquoIn vivo EPR evidence for free radicaladducts of nifedipinerdquoMagnetic Resonance in Medicine vol 42no 4 pp 691ndash694 1999
[203] S Bollo S Finger J C Sturm L J Nunez-Vergara and JA Squella ldquoCyclic voltammetry and scanning electrochemicalmicroscopy studies of the heterogeneous electron transferreaction of some nitrosoaromatic compoundsrdquo ElectrochimicaActa vol 52 no 15 pp 4892ndash4898 2007
34 Oxidative Medicine and Cellular Longevity
[204] F Ursini ldquoTissue protection by lacidipine insight from redoxbehaviorrdquo Journal of Cardiovascular Pharmacology vol 30supplement 2 pp S28ndashS30 1997
[205] P G Cristofori F A Crivellente I Faustinelli et al ldquoInvolve-ment of the nitric oxide system in the anti-atheroscleroticpotential of lacidipine in the apoE-deficient mouse a mor-phological functional and electrochemical studyrdquo ToxicologicPathology vol 32 no 4 pp 493ndash499 2004
[206] X-P Zhang E L Kit S Mital S Chahwala and T HHintze ldquoParadoxical release of nitric oxide by an L-type calciumchannel antagonist the R+ enantiomer of amlodipinerdquo Journalof Cardiovascular Pharmacology vol 39 no 2 pp 208ndash2142002
[207] F Franzoni G Santoro F Regoli et al ldquoAn in vitro study of theperoxyl and hydroxyl radical scavenging capacity of the calciumantagonist amlodipinerdquo Biomedicine and Pharmacotherapy vol58 no 8 pp 423ndash426 2004
[208] S V Gatsura ldquoOxygen-dependent mechanisms underlying theantiischemic effect of verapamil and amlodipinerdquo Bulletin ofExperimental Biology and Medicine vol 137 no 1 pp 40ndash422004
[209] Y Hirooka Y Kimura M Nozoe Y Sagara K Ito and KSunagawa ldquoAmlodipine-induced reduction of oxidative stressin the brain is associated with sympatho-inhibitory effects instroke-prone spontaneously hypertensive ratsrdquo HypertensionResearch vol 29 no 1 pp 49ndash56 2006
[210] B Tomlinson and I F F Benzie ldquoAntioxidant effect of lercani-dipine (note)rdquo Hypertension vol 42 no 4 pp e10ndashe11 2003
[211] A A Faraqui ldquoNeurochemical aspects of 4-hydroxynonenalrdquoin Lipid Mediators and Their Metabolism in the Brain A AFaraqui Ed chapter 6 pp 159ndash191 Springer New York NYUSA 2011
[212] V S NascimentoM S DrsquoAlva A AOliveira et al ldquoAntioxidanteffect of nimodipine in young rats after pilocarpine-inducedseizuresrdquo Pharmacology Biochemistry and Behavior vol 82 no1 pp 11ndash16 2005
[213] O Ismailoglu P Atilla S Palaoglu et al ldquoThe therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjuryrdquo Turkish Neurosurgery vol 22 no 6 pp 740ndash746 2012
[214] M Matsubara and K Hasegawa ldquoBenidipine a dihydropy-ridine-calcium channel blocker prevents lysophosphatidyl-choline-induced injury and reactive oxygen species productionin human aortic endothelial cellsrdquo Atherosclerosis vol 178 no1 pp 57ndash66 2005
[215] M Matsubara K Yao and K Hasegawa ldquoBenidipine adihydropyridine-calcium channel blocker inhibits lysophos-phatidylcholine-induced endothelial injury via stimulation ofnitric oxide releaserdquo Pharmacological Research vol 53 no 1 pp35ndash43 2006
[216] MMatsubara and K Hasegawa ldquoEffects of benidipine a dihyd-ropyridine-Ca2+ channel blocker on expression of cytokine-induced adhesion molecules and chemoattractants in humanaortic endothelial cellsrdquo European Journal of Pharmacology vol498 no 1ndash3 pp 303ndash314 2004
[217] M Matsubara O Akizuki J-I Ikeda K Saeki K Yao and KSasaki ldquoBenidipine an anti-hypertensive drug inhibits reactiveoxygen species production in polymorphonuclear leukocytesand oxidative stress in salt-loaded stroke-prone spontaneouslyhypertensive ratsrdquo European Journal of Pharmacology vol 580no 1-2 pp 201ndash213 2008
[218] A C Rosenkranz H Lob T Breitenbach R Berkels and RRoesen ldquoEndothelial antioxidant actions of dihydropyridines
and angiotensin converting enzyme inhibitorsrdquo European Jour-nal of Pharmacology vol 529 no 1ndash3 pp 55ndash62 2006
[219] V Kain S Kumar and S L Sitasawad ldquoAzelnidipine preventscardiac dysfunction in streptozotocin-diabetic rats by reducingintracellular calcium accumulation oxidative stress and apop-tosisrdquo Cardiovascular Diabetology vol 10 article 97 2011
[220] K Nakamura S Yamagishi and H Inoue ldquoUnique atheropro-tective property of azelnidipine a dihydropyridine-based cal-cium antagonistrdquoMedical Hypotheses vol 65 no 1 pp 155ndash1572005
[221] TMatsui S Yamagishi K Nakamura S Kikuchi andH InoueldquoAzelnidipine a dihydropyridine-based calcium antagonistinhibits angiotensin II-induced oxidative stress generation anddownregulation of pigment epithelium-derived factor mRNAlevels in microvascular endothelial cellsrdquo Drugs under Experi-mental and Clinical Research vol 31 no 5-6 pp 215ndash219 2005
[222] C Ohmura H Watada T Shimizu et al ldquoCalcium channelblocker azelnidipine reduces lipid hydroperoxides in patientswith type 2 diabetes independent of blood pressurerdquo EndocrineJournal vol 54 no 5 pp 805ndash811 2007
[223] H Daikuhara F Kikuchi and T Ishida ldquoThe combination ofOLmesartan and a CAlcium channel blocker (azelnidipine) orcandesartan and a calcium channel blocker (amlodipine) intype 2 diabetic hypertensive patients theOLCA studyrdquoDiabetesand Vascular Disease Research vol 9 no 4 pp 280ndash286 2012
[224] MAbe NMaruyama KOkada SMatsumoto KMatsumotoand M Soma ldquoAdditive antioxidative effects of azelnidipine onangiotensin receptor blocker olmesartan treatment for type 2diabetic patients with albuminuriardquoHypertension Research vol34 no 8 pp 935ndash941 2011
[225] K Mizushige ldquoAntioxidative activities of thiazolidinedionesand dihydropyridine-type calcium antagonistsrdquo IRYOmdashJapa-nese Journal of National Medical Services vol 59 no 11 pp 581ndash592 2005
[226] S Manabe T Okura T Fukuoka and J Higaki ldquoAntioxidativeeffects of azelnidipine on mesangial cell proliferation inducedby highly concentrated insulinrdquo European Journal of Pharma-cology vol 567 no 3 pp 252ndash257 2007
[227] Y Koyama Y Takeishi H Takahashi et al ldquoAzelnidipine inhi-bits H
2O2-induced cell death in neonatal rat cardiomyocytesrdquo
CardiovascularDrugs andTherapy vol 21 no 1 pp 69ndash72 2007[228] K Shinomiya K Mizushige M Fukunaga et al ldquoAntioxidant
effect of a new calcium antagonist azelnipidine in culturedhuman arterial endothelial cellsrdquo Journal of International Med-ical Research vol 32 no 2 pp 170ndash175 2004
[229] T Ohyama K Sato K Kishimoto et al ldquoAzelnidipine is acalcium blocker that attenuates liver fibrosis and may increaseantioxidant defencerdquo British Journal of Pharmacology vol 165no 4 pp 1173ndash1187 2012
[230] L A Calo F Zaghetto E Pagnin P A Davis A Sempliciniand A C Pessina ldquoEffect of manidipine on gene expressionand protein level of oxidative stress-related proteins p22phoxand HO-1 Relevance for antihypertensive and anti-remodelingeffectsrdquo Journal of Cardiovascular Pharmacology vol 43 no 4pp 531ndash538 2004
[231] R Ghyasi G Sepehri M Mohammadi R Badalzadeh and AGhyasi ldquoEffect of mebudipine on oxidative stress and lipid per-oxidation in myocardial ischemic-reperfusion injury in maleratrdquo Journal of Research in Medical Sciences vol 17 no 12 pp1150ndash1155 2012
Oxidative Medicine and Cellular Longevity 35
[232] DCAndersson J Fauconnier T Yamada et al ldquoMitochondrialproduction of reactive oxygen species contributes to the 120573-adrenergic stimulation of mouse cardiomycytesrdquoThe Journal ofPhysiology vol 589 no 7 pp 1791ndash1801 2011
[233] A F Ceylan-Isik N Ari M Stefek et al ldquoEffects of a long-term treatment with an antioxidant pyridoindole on vascularresponsiveness in diabetes-induced aging ratsrdquo Current AgingScience vol 4 no 2 pp 150ndash157 2011
[234] S Saponara G Sgaragli and F Fusi ldquoQuercetin antagonismof Bay K 8644 effects on rat tail artery L-type Ca2+ channelsrdquoEuropean Journal of Pharmacology vol 598 no 1ndash3 pp 75ndash802008
[235] D A Sica ldquoInteraction of grapefruit juice and calcium channelblockersrdquo American Journal of Hypertension vol 19 no 7 pp768ndash773 2006
[236] P Mulder G Litwinienko S Lin P D MacLean L R CBarclay and K U Ingold ldquoThe L-type calcium channel block-ers Hantzsch 14-dihydropyridines are not peroxyl radical-trapping chain-breaking antioxidantsrdquo Chemical Research inToxicology vol 19 no 1 pp 79ndash85 2006
[237] L J Nunez-Vergara R Salazar C Camargo et al ldquoOxidation ofC4-hydroxyphenyl 14-dihydropyridines in dimethylsulfoxideand its reactivity towards alkylperoxyl radicals in aqueousmediumrdquo Bioorganic and Medicinal Chemistry vol 15 no 12pp 4318ndash4326 2007
[238] M E Ortiz L J Nunez-Vergara and J A Squella ldquoRelativereactivity of dihydropyridine derivatives to electrogeneratedsuperoxide ion in DMSO solutions a voltammetric approachrdquoPharmaceutical Research vol 20 no 2 pp 292ndash296 2003
[239] M E Ortiz L J Nunez-Vergara C Camargo and J A SquellaldquoOxidation of Hantzsch 14-dihydropyridines of pharmacolog-ical significance by electrogenerated superoxiderdquo Pharmaceuti-cal Research vol 21 no 3 pp 428ndash435 2004
[240] R S Raghuvanshi and K N Singh ldquoSuperoxide induced oxida-tive aromatization of Hantzsch 14-dihydropyridinesrdquo IndianJournal of Chemistry Section B Organic and Medicinal Chem-istry vol 47 no 11 pp 1735ndash1738 2008
[241] I Kruk A Kladna K Lichszteld et al ldquoAntioxidant activityof 4-flavonil-14-dihydropyridine derivativesrdquo Biopolymers vol62 no 3 pp 163ndash167 2001
[242] G D Tirzit I M Byteva K I Salokhiddinov G P Gurinovichand G Y Dubur ldquo14-Dihydropyridine derivatives as deactiva-tors of singlet oxygenrdquo Chemistry of Heterocyclic Compoundsvol 17 no 7 pp 682ndash684 1981
[243] G D Tirzit E Y Kazush and G Y Dubur ldquoInfluence of14-dihydropyridine derivatives on the generation of hydroxylradicalsrdquo Chemistry of Heterocyclic Compounds vol 28 no 4pp 435ndash437 1992
[244] N A Pizarro-Urzua and L J Nunez-Vergara ldquoNifedipine andnitrendipine reactivity toward singlet oxygenrdquo Journal of Photo-chemistry and Photobiology A Chemistry vol 175 no 2-3 pp129ndash137 2005
[245] L-F Wang H-Y Zhang L Konga Z-W Chena and J-G ShildquoDFT calculations indicate that 14-dihydropyridine is a promis-ing lead antioxidantrdquo Helvetica Chimica Acta vol 87 no 6 pp1515ndash1521 2004
[246] P Mulder H-G Korth and K U Ingold ldquoWhy quantum-thermochemical calculations must be used with caution toindicate lsquoa promising lead antioxidantrsquordquoHelvetica Chimica Actavol 88 no 2 pp 370ndash374 2005
[247] K Yao Y Ina K Nagashima K Ohmori and T Ohno ldquoAntiox-idant effects of calcium antagonists in rat brain homogenatesrdquo
Biological and Pharmaceutical Bulletin vol 23 no 6 pp 766ndash769 2000
[248] T Matsui S-I Yamagishi K Nakamura and H Inoue ldquoBayw 9798 a dihydropyridine structurally related to nifedipinewith no calcium channel-blocking properties inhibits tumournecrosis factor-120572-induced vascular cell adhesion molecule-1expression in endothelial cells by suppressing reactive oxygenspecies generationrdquo Journal of International Medical Researchvol 35 no 6 pp 886ndash891 2007
[249] K AMitrega B VargheseM Porc and T F Krzeminski ldquoAnti-arrhythmic and hemodynamic effects of oxy nifedipine oxynimodipine oxy nitrendipine and oxy nisoldipinerdquo Pharmaco-logical Research vol 66 no 4 pp 300ndash308 2012
[250] V Herbert ldquoSymposium prooxidant effects of antioxidantvitamins Introductionrdquo The Journal of Nutrition vol 126 no4 supplement pp 1197Sndash1200S 1996 httpjnnutritionorgcontent1264 Suppl1197Sfullpdf
[251] B Halliwell ldquoAre polyphenols antioxidants or pro-oxidantsWhat do we learn from cell culture and in vivo studiesrdquoArchives of Biochemistry and Biophysics vol 476 no 2 pp 107ndash112 2008
[252] C Winterbourn Pro-Oxidants or Antioxidants ChristchurchSchool of Medicine Depatment of Pathology Free RadicalSchool SFRBMUniversity of Otago San Francisco Calif USA2009 httpwwwsfrbmorgfrsWinterbournpdf
[253] A Morakinyo B Iranloye and O Adegoke ldquoCalcium antag-onists modulate oxidative stress and acrosomal reaction in ratspermatozoardquo Archives of Medical Science vol 7 no 4 pp 613ndash618 2011
[254] The Alpha-Tocopherol Beta Carotene Cancer Prevention StudyGroup ldquoThe effect of vitamin E and beta carotene on theincidence of lung cancer and other cancers in male smokersrdquoTheNew England Journal of Medicine vol 330 no 15 pp 1029ndash1035 1994
[255] B Poljsak ldquoStrategies for reducing or preventing the generationof oxidative stressrdquo Oxidative Medicine and Cellular Longevityvol 2011 Article ID 194586 15 pages 2011
[256] B Poljsak and I Milisav ldquoThe neglected significance of lsquoanti-oxidative stressrsquordquoOxidativeMedicine and Cellular Longevity vol2012 Article ID 480895 12 pages 2012
[257] T Godfraind and S Salomone ldquoAmbiguities in dietary antiox-idant supplementation compared to calcium channel blockerstherapyrdquo Frontiers in Pharmacology vol 6 article 10 2015
[258] H Wagner H Norr and H Winterhoff ldquoDrugs with adap-togenic effects for strengthening the powers of resistancerdquoZeitschrift fur Phytotherapie vol 13 no 2 pp 42ndash54 1992
14 Oxidative Medicine and Cellular Longevity
in vitro [112] but also have beneficial effects on repairingtheir integrity in vivo after exposure to irradiation hepato-toxins ischemia hypoxia or hypothermia Some of themwere shown to normalize the process of intracellular repara-tion and physiological regeneration of ultrastructures Theywere also shown to stimulate reparative processes If pre-treated with 14-DHPs irradiatedmitochondria will not swell(Ivanov et al [140 141])
Diludine ionol and some other AOs mitochondria pro-tectors act as anti-ischemic agents If applied prophylacticallyin vivo they may prevent ischemic and reperfusion lesionsin heart kidney and other organs (Bilenko et al [113]) Theeffect is dependent on applied dose timing and way ofapplicationWhen added onto the cryoconservationmediumfor mitochondria preservation 14-DHPs prevented decreaseof membrane potential normalized facilitated respirationand prevented loss of mitochondrial Na+ and Ca2+ ionsafter thawing ([112] see citation number 36 (Subbota et alKharkov 1984) therein) Diludine was stronger protectorwhen compared to ionol
CA drug foridone (riodipine) was shown to possesscardioprotective features primarily due to is protective effecton mitochondria exposed to OS [142 143]
Similarly the DHP water-soluble antiarrhythmic com-pound glutapyrone inhibits initiation of LP by free radicalsin erythrocytes and heart mitochondria Its cardioprotectiveeffect has been experimentally shown in heart mitochondrialmembranes especially during deep hypothermia (Utno et al[144])
Cerebrocrast was effective in several translation modelsmimicking pathological situations known to be associatedwith cellular OS The potential protective action of 14-DHP derivatives (4-substituted compounds cerebrocrastgammapyrone glutapyrone and 4-unsubstituted drug dieth-one) has been studied in rat liver in experimental modelsrelevant for oxidative stress and mitochondrial bioenergetics(Fernandes et al [145]) When succinate was used as therespiratory substrate higher concentrations (gt25 120583M) ofcerebrocrast depressed respiratory control ratio (RCR) ADPto oxygen ratio (ADPO) state 3 and uncoupled respirationrates transmembrane potential (deltapsi) and the phosphatecarrier rate At the same time state 4 respiration rate wasthree times increased At concentrations lower than 25120583Mcerebrocrast inhibited mitochondrial IMAC and partiallyprevented Ca2+-induced opening of the mitochondrial PTPGammapyrone glutapyrone and diethone did not inducethese phenomena When applied at concentrations up to100 120583M cerebrocrast gammapyrone and glutapyrone didnot affect ADPFe2+-induced LP of mitochondria in rat liver(as measured by oxygen consumption and TBARS forma-tion) On the other hand low diethone concentrations (upto 5 120583M) inhibited it in a dose-dependent manner Diethonealso prevented against deltapsi dissipation induced by LPinitiated by ADPFe2+ Based on these data it may bespeculated that cerebrocrast (inhibition of the IMAC) anddiethone (acting as an AO) may provide effective protectionof mitochondria during OS Cerebrocrast has shown sometherapeutic potential for treatment of several pathologicalconditions related to cellular OS [145]
5-Acetyl(carbamoyl)-6-methylsulfanyl-14-DHP-carbo-nitriles (Figure 3) with minor differences in their molecularstructure displaying antioxidant and antiradical activitiesin vitro show different biological activities Namely 4-p-chlorophenyl derivative OSI-1146 displays AO and anti-radical activities in cardiovascular OS models whereasOSI-3701 and OSI-3761 display hepatoprotective activityThus these compounds may be potentially useful for treat-ing several pathological processes including those associatedwith OS (Fernandes et al [146]) However besides mito-chondria the cellular targets for their pharmacologicalactions have not been fully investigated [146] All these com-pounds increase the susceptibility of Mit to MPT The mostpotent is OSI-3701 although it does not affect bioenergeticparameters
Although all these compounds protected mitochondriaagainst LP induced by the oxidant pair ADPFe2+ OSI-1146was shown to be the most potent Current data point outmitochondria as potential targets for protective and toxicactions of DHPs suggesting that the potential for their use astherapeutic agents should also take into consideration theirtoxic effects on mitochondria (Fernandes et al [146])
Several structurally different DHP derivatives (antioxi-dant diludine (diethone) as a 4-unsubstituted DHP 4-substi-tuted DHPs CA foridone (bicyclic compound) and the 4-phenyldiethone compound where phenyl group is joined tothe DHP in position 4) inhibited the 1-methyl-4-phenyl-pyridinium iodide (MPP+) induced ROS production incerebellar granule cells (CGC) with a distinct potency orderforidone (26-dimethyl-35-dimethoxycarbonyl-4-(o-difluo-romethoxyphenyl)-14-dihydropyridine) gt 26-dimethyl-35-diethoxycarbonyl-4-phenyl-14-dihydropyridine gt diludineThey also reversed the MPP+-induced decrease of the mito-chondrial membrane potential in the same order (Klimavi-ciusa et al [147]) Accordingly it was postulated that theclassical two-ring (bicyclic) structure of DHP derivativesrepresents an advantage in relation to neuroprotection andROS defense and is independent on compoundrsquos propertiesrelated to calcium ions
Novel adamantane-containing 14-DHP compounds (Kli-maviciusa et al [148]) were also found to improve mitochon-drial functions (MPP+ model) (Klimaviciusa et al [148])Klusa et al [149] have discovered antineurotoxic effects of14-DHP taurine derivative tauropyrone recorded as Mitfunction improvement
Many 14-DHPs including Ca2+ antagonists and AOmodify LP processes and influencemitochondrial function invarious organs (liver heart kidney and brain) in a differentway and degree Their beneficial action oxygen or lipidfree radical scavenging antioxidative effects binding withor intercalating into phospholipid bilayer regulation of iongating and regulation of mitochondrial permeability transi-tion pores (Tirzit and Duburs [39] Zilber et al [44] andDubur et al [45]) separately or in combination with eachother depends on two strong elements (1) their individ-ual structure including nature of substituents and theirpositions and (2) the nature of the biological system Forexample the direction of LP (inhibition of promotion) wasshown to depend on structure and concentration of applied
Oxidative Medicine and Cellular Longevity 15
14-DHPs as well as stages of chain reactions Accordinglymitochondrial swelling may be prolonged (retarded) accel-erated (promoted) or inhibited (Velena et al [112])
Therefore there is a ground for 14-dihydropyridineseither Ca2+ antagonists or antioxidants to be nominated asuseful tools in development of ldquomitochondrial drugsrdquo relatedto the control of OS
(c) DHPs as AOs in Endoplasmic Reticulum (Inhibition ofNADPH-Dependent LP System) Inhibition of NADPH Oxi-dase by DHPs Elevated level of NADPH oxidase 4- (NOX4-)derived hydrogen peroxide (H
2O2) joined with concomitant
decrease of nitric oxide (NO) mediated signaling and reac-tive oxygen species scavengers are considered to be centralfactor in molecular pathogenesis of fibrosis (Sampson etal [150]) Inhibition of microsomal NADPH-dependent LPwith particular focus on NADPH oxidases (NOX1ndash5 andDUOX1) may be very important for neuro- cardio- andhepatoprotection (Velena et al [112] Leto and Geiszt [151]Griendling et al [152] and Chen et al [153]) Endoplasmicreticulum may be an important target as this is where 14-DHPs could display their antioxidative properties (Velena etal [112] Leto and Geiszt [151] Griendling et al [152] andChen et al [153])
However the initiation of LP in the NADPH-dependentmicrosomal system does not appear to involve either super-oxide or hydrogen peroxide since neither SOD nor cata-lase can inhibit it On the other hand reduced iron playsan important role in both the initiation and propaga-tion of NADPH-dependent microsomal lipid peroxidation(Hochstein and Ernster [154] and Repetto et al [111])
Many DHPs possess inhibitory activity not only towardsAsA-dependent LP in mitochondria but also towardsNADPH-dependent LP as shown in isolated rat liver micro-somes (Velena et al [112]) This means that these compoundsinteract with the shared parts (nonenzymatic and enzymatic)of LP pathways
Microcalorimetry and fluorescent probes procedureswere used for studying the interaction of alpha-tocopheroland 14-DHPs with endoplasmic reticulum membranes andmodel systems human serum albumin and phospholipidbilayers [155] Modification of microviscosity of the endo-plasmatic reticular membranes depends on localization ofantioxidants within the protein structures or phospholipidphase Increase of membrane structuralization under theinfluence of 14-DHPs blocked their antioxidant action inspontaneous and induced lipid peroxidation
Inhibition of rat heart and liver microsomal lipid perox-idation by nifedipine was observed [156] while Goncalves etal [157] found antioxidant effect of calcium antagonists onmicrosomal membranes isolated from different brain areas
Nitroaryl-14-DHPs are both calcium channel antagonistsand antioxidant agents (Letelier et al [158 159]) commonlyused for treatment of cardiovascular diseases These drugsmust be metabolized through cytochrome P450 oxidativesystem (NADPH-cytochrome P450 reductase) mainly local-ized in the hepatic endoplasmic reticulum Several lipophilicdrugs generate OS while being metabolized by this cellularsystem Thus DHP antioxidant properties may prevent the
OS associated with hepatic biotransformation of drugs Var-ious commercial and new nitro-phenyl-DHPs were studiedagainst LP using rat liver microsomes under oxidative stress[159]
Incubation of rat liver microsomes with the 41015840-nitro-4-phenyl-14-DHP compounds (26-dimethyl-4-(41015840-nitro-phenyl)-14-dihydropyridin-35-diethyl-dicarboxylate andN-ethyl-26-dimethyl-4-(41015840-nitrophenyl)-14-dihydropyri-din-35-dimethyl-dicarboxylate) results in an inhibitionof LP the UDPGT (UDP-glucuronyltransferase) oxidativeactivation and the microsomal thiol oxidation induced byFe3+ascorbate a generator system of ROS This effect wasalso produced by nitrofurantoin and naphthalene in thepresence of NADPH
Interestingly IC50
ofDHPs obtained frommicrosomal LPassays decreased to the same extent as the microsomal thiolsoxidation provoked by Fe3+ascorbate [159] Neverthelessthe AO effects of a nitrophenyl-DHP compound in whichhydrogen at position one of the DHP ring was replaced bythe ethyl groupwere significantlyweaker Authors speculatedthat DHPs can resemble NADH transferring one hydrogenatom of 4-position (Hminus) to anion superoxide and another ofthe 1-position (H+) by way of a cationic radical intermediateto generate pyridine derivatives and water [159]
The AO effects of various tested DHP derivatives (m- andp-NO
2phenyl as well as methyl or ethyl and isopropyl-DHP
35-dicarboxylate derivatives) were not significantly differentThe authors assumed that the -NH- group of the dihydropy-ridine ring could contribute both to the development ofthe calcium channel antagonism and to the antioxidativeproperties of DHPs [159]
Prevention of the membrane LP seemingly depends onthe concentration of potential antioxidants such as vitaminE or even 14-DHP in lipids However only the differencesin synthetic DHPs lipophilicity cannot explain significantvariations of DHPs concentration in microsomal membraneand cannot clarify the strength of their antioxidative activityThis work [159] has further demonstrated that 14-DHPsmay prevent the OS induced by biotransformation of somedrugs for example antibiotic nitrofurantoin Simultaneousadministration of DHPs and nitrofurantoinmay be beneficialin reducing nitrofurantoin side effects
While most of Ca antagonist 14-DHPs are metabolizedby CYP3A4 (Guengerich et al [160]) not all of them are goodinhibitors of its activity Thus nicardipine but not nifedipineand nitrendipine inhibits CYP3A4 in vitro [53] Interactionof different DHPs with various types of cytochrome P450 wasdescribed by Carosati et al [53] It was also reported thatDHP class calcium channel blockers reduce the antiplateleteffect of clopidogrel (Park et al [161])This implies themutualinteractions of both drugs with CYP3A4
(3) In Vivo Evaluation of nifedipine effects on Saccharomycescerevisiaewas recently published (Asma andReda [162]) Sur-prisingly nifedipine exercised a toxic effect on Saccharomycescerevisiae shown through measuring cellular proliferationrespiratory activity and the level of some biomarkers (CATand MDA)
16 Oxidative Medicine and Cellular Longevity
However majority of data obtained on various animalcells and tissues by other authors show the protective role ofDHPs against both LP and oxidative stress [113 163 164]
The AOA attributed to many 14-DHPs Ca2+ antag-onists and other compounds reflecting on catalytic LDLperoxidation (see Section 331 (2) and Section 35) shouldencourage their testing for treating cardiovascular diseasesandor alterations of lipid metabolism
The possibility that 14-DHP-based calcium antagonistsexert an antiatherosclerotic action (via inhibition of LDLoxidation and other mechanisms) has been proved by manyexperimental data [165] and several clinical trials Besidesantihypertensive effect nicardipine was shown to possessantioxidative and antielastase activity [165 166] These prop-erties may be useful for prevention of inflammatory reactionwhich is relevant for hypertension pathogenesis
14-DHPs administration inhibits LDL oxidation medi-ated by oxygen radicals leading to decreased carotid inti-mal media thickness and reduced progression of coronaryatherosclerosis [130] It additionally preserves Apo B-100integrity against ROS Of importance antiatherogenic mech-anisms differ between animals and humans (primarily inthe stage of conversion of aldehydes to carboxylic acids)(Parthasarathy et al [167])
For example furyl-DHP compound (FDP-1 diethyl 26-dimethyl-4-(furyl)-14-dihydropyridine-35-dicarboxylate)was shown to act as an antioxidant (decreasing MDA GOTand FFA release of ischemic myocardium and inhibiting Ca-ATPase of erythrocyte membranes) preventing against heartmyocardium ischemia-reperfusion injury and arrhythmiawhen applied (in rats) at 10mgkg (Liu et al [168])
Similarly antioxidative effects of azelnidipine andamlodipine prevented neuronal damage by CCBs aftertransient focal ischemia in rats (Lukic-Panin et al [169])
Allanore et al [170] found that both nifedipine andnicardipine significantly decrease the mean level of plasmamarkers for oxidative stress in patients suffering from sys-temic sclerosis
Antioxidants may be considered as promising neuropro-tective compounds Still while experimental data demon-strate neuroprotective effect in vitro and in animal mod-els clinical evidence is still unsatisfactory and insufficient[171]
(a) Role of Metabolism of DHPs in Their AOA Metabolicpathways and ldquobioavailabilityrdquo of the probable AOA com-pound determine antioxidant activity in vivo Antioxidantmetabolites may vary in stability and activity leading to twoopposite scenarios lack or presence of activity substantiallycontributing to the overall AOA [172] Metabolic biotransfor-mation of DHPs includes oxidation (heteroaromatization)side chain ester group cleavage (deesterification) and 4-substituent abstraction ao [160] None of the DHPs metabo-lites was shown to be more toxic than original reduced formof the compound The commonly detected metabolites ofthe DHPs do not seem to possess the AO activity (withsome exceptions as in the case of metabolites of nifedipineand its analogues including nitrosonifedipine [173 174]) (seefurther in Section 35) Due to DHPs intrinsic instability
achieving andmaintaining an adequate concentrationmay beproblematic both in vitro and in vivo
(b) Role of Concentration and Lipophilicity (MembraneWateror LipidWater Partition Coefficients) of DHPs inTheir Actionas AOs and Antiradical Compounds Antioxidative effects ofany antioxidant depend on its concentration at the site ofaction This parameter is hardly measurable especially intwo-phase systems representing one of obstacles in com-parison to AOA upon applying various compounds [172]It is often incorrectly assumed that the concentrations inthe aqueous solution and at the site of action are the sameHowever even when the concentration in the aqueous phasemay be well controlled the concentration at the site ofaction in the lipid matrix of the membranes might fluctuatebetween different test compounds depending on a differencein lipophilicity [175] The prevention of the membrane LPalso seems to be dependent on the DHP concentration in thelipidmatrix (Mason andTrumbore [46]) and its amphiphilic-ity For example AOA of diludine is associated with itslipophilicity and consequential ability to be incorporatedinto liposomes (Panasenko et al [176]) It was also foundthat diludine easily incorporates into the outer monolayer oferythrocyte membranes [176]
Membranebuffer partition coefficients (lambda) weredirectly measured in the sarcolemma and sarcoplasmicreticulum membranes for three CA DHPs The obtainedvalues were in a broad range between 5000 and 150000(Herbette et al [177])These drugs interact primarily with themembrane bilayer component but may also bind to proteinsboth nonreceptors and receptors The intrinsic forward rateconstants for DHP binding to sarcolemmal calcium channelreceptors were apparently not strongly dependent on theirmembrane partition coefficients For example nimodipine(lambda = 6300) had a forward rate constant of 68 plusmn 06 times106Ms whereas the forward rate constant for Bay P 8857
(lambda = 149000) was 14plusmn08times107Ms Since these DHPsare highly liposoluble model calculations for this bindingreaction demonstrated that these rates on lipid solubilitywould probably not be reflected in the experimental forwardrate constants In addition the intrinsic forward rate constantfor nimodipine binding to sarcolemmal calcium channelreceptors was found not to be linearly dependent on theviscosity of the buffer medium over a fivefold range The rateof drug nonspecific binding to nonreceptor protein present inhighly purified sarcoplasmic reticulum membranes appearsto be extremely fast at least 103 times faster than specificdrug binding to the receptor in the sarcolemma Authorsconcluded that partitioning into the lipid bilayer matrix ofthe sarcolemma could be a general property of CA DHPsand may be a prerequisite for their binding to sarcolemmalmembrane receptors (Herbette et al [177])
The binding of DHP calcium channel agonists and antag-onists (including those with AO properties) to receptors incardiac sarcolemmal membranes is a complex reaction thatmay involve an interaction with the lipid bilayer matrix ofthe sarcolemma (Herbette et al [178]) Belevitch et al [179]studied the binding of DHP CCBs (riodipine and nifedip-ine) and verapamil to model and biological membranes by
Oxidative Medicine and Cellular Longevity 17
fluorescence analysis The consistent location of Ca agonistBay K 8644 was determined to be within the region ofthe first few methylene segments of the fatty acyl chains ofthe membranes (Mason et al [180]) This position is nearto that observed for the DHP calcium channel antagonistsnimodipine and Bay P 8857
Themajority of studies onOSwere performedwithDHPswith various lipophilicity but only a few studies reportedamphiphilicity ofDHPderivatives AmphiphilicDHPderiva-tive K-2-11 reduced the cellular generation of ROS It alsorevealed complete reversal of multidrug resistance (MDR) ofthe resistant cells K-2-11 was more efficient than well-knownMDR inhibitor verapamil Cytotoxic effects of anticancerdrug doxorubicin were enhanced by K-2-11 in bothMDR andparental nonresistant cell line (Cindric et al [181]) K-2-11suppresses increase of ROS and consequentially prevents NF-120581B activation leading to decreased expression of MDR1 andincreased expression of antiapoptotic genes This signalingswitch is necessary for restoring the chemosensitivity ofcancer cells This phenomenon is characteristic both for14-DHPs [182] (18 novel asymmetrical DHPs bearing 3-pyridyl methyl carboxylate and alkyl carboxylate moietiesat C3 and C5 positions resp as well as nitrophenyl orheteroaromatic rings at C4) and for their oxidized formspyridine compounds (Zhou et al [183])
34 Dependence of AOA of DHPs on the Experimental SystemAO effect of DHPs depends on their structure and theexperimental system used (in vitromodel system subcellularorganelle and cells ex vivo and in vivo) Ideally for theevaluation of the profile and value of DHPs AO propertieseach compound should be tested in as many systems aspossible (Dubur et al [45])
Lipidomics studies have been traditionally explored forstudying AOA of DHPs Proteomics methods are less rep-resented and are mostly focused on the properties of DHPsrelated to scavenging of protein free radicals So far there areno studies on the role of DHPs in scavenging nitrosoperoxy-carbonate the reactive species formed out of peroxynitrite inthe presence of carbon dioxide Although it was shown thatalbumin binds diludine no studies revealed the relevance ofthis effect for the AOA of diludine
There are findings showing that dihydropyridine calciumantagonists (DHPs CA) could indirectly play a beneficialprotective role during development of atherosclerosisNamely Berkels et al [184] have studied antioxidativeproperties of four substances the DHP prototype CAnifedipine the long-acting CA lacidipine the DHP calciumchannel agonist BayK8644 and the bulkyDHPderivate BayO 5572 in three different models (1) in an in vitro superoxideanion generating system (hypoxanthinexanthine oxidase)for testing the ldquopurerdquo antioxidative effect (2) in an artificialmembrane preparation (dimyristoylphosphatidylcholine) formimicking a more physiological environment and (3) underconditions of stimulated ROS release (hyperglycemia) fromnative endothelial cells derived from porcine coronary arter-ies
The study also revealed the potential correlation betweenlipophilic and AO properties of DHPs In the first model
Bay K 8644 was significantly more effective in scavengingsuperoxide anions than lacidipine Bay O 5572 or nifedipine(micro- to millimolar concentration range) Addition of anartificial membrane preparation resulted in an enhancedAO effect with lacidipine being the most effective DHP inquenching radicals (low micromolar concentration range)In the third model mimicking hyperglycemia (30mmolL)nifedipine was significantly more potent antioxidant (ther-apeutical nanomolar concentration range) than the otherDHPs Calculated lipophilicity of these four substances(lacidipine gt Bay O 5572 gt Bay K 8644 gt nifedipine) waspositively correlated with antioxidative potential only in thesecond experimental model It has been concluded that AOproperties of DHP substances need to be tested in variousmodels for demonstrating that nifedipine exhibits ROS-quenching properties in a therapeutic concentration range[184]
341 AOA of DHPs in Isolated Cells and Cell Cultures(Comparison with Other Simplest Systems) Although DHPspossess neuromodulatory andor antimutagenic propertiesthe mechanisms of action related to these phenomena arenot entirely elucidated Borovic et al [185] have studied 14-dihydroisonicotinic acid (14-DHINA) derivatives of 14-DHP water-soluble analogues of a well-known AO diludine(diethone) 26-dimethyl-35-diethoxycarbonyl-14-dihydro-isonicotinic acid sodium 2-(26-dimethyl-35-diethoxycar-bonyl-14-dihydropyridine-4-carboxamido)glutamate gluta-pyrone and sodium 2-(26-dimethyl-35-diethoxycarbonyl-14-dihydropyridine-4-carboxamido)ethane-sulphate tauro-pyrone as AO and bioprotectors (Figure 4)
14-DHINArsquos activities were studied in comparison toTrolox by NN-diphenyl-N1015840-picrylhydrazyl (DPPH∙) deoxy-ribose degradation ABTS∙ radical scavenging and AOA(antioxidative capacity method) assays copper-induced LPof cultured rat liver cells (MDA determination by HPLCand 4-hydroxynonenal-protein conjugates by dot-blot) 3H-thymidine incorporation and trypan blue assay for liver cellsgrowth and viability Ic decreased the amount of 4-HNE-protein adducts In all assays Ia was the most potent AOable to completely abolish copper induced LP of liver cellswhile Ic only slightly decreased it Thus AOA is importantactivity principle of Ia which was even superior to Trolox intreated cell cultures Ia (and its analogues) are easily oxidizedin the Fenton system (Rubene et al [186]) exerting ARA too
35 Peculiarities Related to Antioxidative and AntiradicalActivity of Some 14-DHPs Ca Antagonists Nine commer-cialized structurally and functionally different DHPs CAwill be discussed further Their common feature is ability toprevent OS This also counts for some of their metabolitesas already discussed The comparative effects of some DHPsCA on oxidative stress-induced modification of LDL werealready reviewed in Section 331 (2)-(a) AOA of CA DHPswas discussed in Sections 331 (2)-(b) and 331 (2)-(c)
351 Nifedipine and Its Close Analogues Nifedipine vera-pamil and antiarrhythmic-antihypoxic drug stobadin wereshown to depress lipid peroxidation of phosphatidylcholine
18 Oxidative Medicine and Cellular Longevity
NH
COOH
NH
COONa
Glutapyrone
NH
Gammapyrone
NH
C 2H5OOC COOC2H5
Tauropyrone
14-DHINA
H3C H3C
H3C
H3CCH3 CH3
CH3
CH3
COOC2H5COOC2H5
COOC2H5 C2H5OOCC2H5OOCC2H5OOC
CONHCH(CH2)2COONa CONH(CH2)3COONa
CONH(CH2)2SO3Na
Figure 4 Derivatives of 14-dihydroisonicotinic acid (14-DHINA)
liposomes (Ondrias et al [187]) However data obtained insome other experimental systems are conflicting
In an in vitromodel of sarcolemmal membrane lipid per-oxidation three calcium blockers (nifedipine verapamil anddiltiazem) exhibited concentration-dependent (10ndash400 120583M)inhibitory effects [188 189] Nifedipine the most effectivecalcium blocker was more than two-fold potent compared topropranolol achieving significant effect at 10 120583M Nifedipineprotective role on LP using reduced glutathione as modelmarker was recently described (Ray et al [190]) Antiper-oxidative properties of CA nifedipine and its analogueswere explored in different systemspathogenic processesatherogenesis (Henry [165]) brain focal ischemia (Yamatoet al [191]) nephroprotection related to cyclosporine intake(Chander and Chopra [192]) and hepatoprotection relatedto intake of diethyldithiocarbamate (Gaafa et al [193])Recent data suggest that nifedipine action as protector forendothelial cells proceeds independently from its CA proper-ties
The absence of antioxidant effects of nifedipine anddiltiazemonmyocardialmembrane lipid peroxidation oppo-site to nisoldipine and propranolol was also described[194] Nisoldipine and propranolol were shown to havea concentration-dependent antiperoxidant effect with IC
50
values of 282 and 501 120583M respectively Finally nisol-dipine appeared to possess dual antiperoxidant mecha-nisms involving both preventive and chain-breaking proper-ties
These findings were confirmed in some other studiesincluding reports on the lack of antioxidative activity ofnifedipine and nicardipine even at 500120583M concentrationin heart membrane lipid peroxidation tests [134] SimilarlyROS formation in bovine aorta smooth muscle cells was notaffected by addition of amlodipine nimodipine and nife-dipine [123]
(1) Metabolites of Nifedipine and Its Analogues as Antioxidantsand Regulators of OS Antioxidant activity of nifedipine35-dimethoxycarbonyl-26-dimethyl-4-(2-nitrophenyl)-14-dihydropyridine was originally studied in vitro by Kirule etal [195] and Tirzit et al [196] According to the kinetic dataof peroxide accumulation and the ESR spectra (inhibition ofthe autoxidation of methyl oleate in presence of nifedipine)AO action was exerted by the formation of nitroso analogueof the oxidized nifedipine nitroso nifedipine 26-dimethyl-4-(2-nitrosophenyl)-35-pyridine dicarboxylate (NO-NIF)This nitroso aromatic derivative can form nitroxyl radicalsexhibiting remarkable AOA in the presence of unsaturatedfatty acids and lipids [196]
The primary species of free radicals that have beenobtained and identified were ion radicals of the nitrophenyltype (Ogle et al [76]) Such a mechanism coincides withmechanisms proposed afterwards by Nunez-Vergara et al[96] Lopez-Alarcon et al [103] Valenzuela et al [104]Fukuhara et al [174] and Yanez et al [197]
There are also data showing that nitroso compounds mayinhibit LP by direct radical trapping and subsequent forma-tion of stable nitroxide radicals It was further found that thereactivity between the synthesized 14-DHP derivatives withalkylperoxyl radicals involves electron transfer reactionsThisis documented by the presence of pyridine as a final productof the reaction and complete oxidation of the nitroso groupin the case of the nitrosoaryl 14-dihydropyridine derivatives(Valenzuela et al [104]) Tested compounds reacted fastertoward alkylperoxyl radicals and ABTS radical cation thanalkyl ones (Lopez-Alarcon et al [103])
Nitrosonifedipine a photodegradation product of nifedi-pine significantly recovers cellular damage induced by tumornecrosis factor-alpha It also prevents toxic effects of cumeneperoxide which hampers integrity of cell membranes throughoxidative stress Its positive effects are equal to Trolox-C
Oxidative Medicine and Cellular Longevity 19
As a result nitrosonifedipine was already a long time agoclaimed as a candidate for a new class of antioxidative drugs(Kirule et al [195]) cellular protectors against oxidative stressin glomerular endothelial cells [174]
Moreover Misik et al [198] Ondrias et al [199] andStasko et al [200] studied AOA of nifedipine and its oxidizednitroso analogue NO-NIF prevents the progression of type2 diabetic nephropathy associated with endothelial dysfunc-tion through selective AO effects (Ishizawa et al [201]) NO-NIF administration reduces albuminuria and proteinuriaas well as glomerular expansion without affecting glucosemetabolism or systolic blood pressure NO-NIF also sup-presses renal and systemic OS and decreases the expressionof intercellular adhesion molecule-1 (ICAM-1) a marker ofendothelial cell injury in the glomeruli of the KKAy miceSimilar effects were achieved in endothelial nitric oxide syn-thase (eNOS) knockout mice Moreover NO-NIF suppressesurinary angiotensinogen (AGT) excretion and intrarenalAGT protein expression in proximal tubular cells in theKKAy mice On the other hand hyperglycemia-inducedmitochondrial superoxide production was not attenuated byNO-NIF in cultured endothelial cells
Fujii and Berliner found EPR evidence for free radicaladducts of nifedipine in vivo [202] The nature of these rad-icals was surmised by comparing the reaction of illuminatednitrosonifedipine with polyunsaturated fatty acids Surpris-ingly identical radical spectra were detected from excisedliver doped with nonilluminated nifedipine suggesting thatthis drug can be enzymatically converted in vivo to its nitrosoanalogue without the requirement for illumination This isone of the first reports of in vivo EPR evidence for a class ofunsaturated fatty acid radical conjugates resulting from thenormal metabolism of a common drug
Dıaz-Araya et al [173] studied some 4-nitrophenyl-DHPson Fe3+ initiated LP in rat brain slices LP as measuredby MDA formation was inhibited by all the tested nitro-aryl derivatives of 14-DHP over a wide range of concen-trations On the basis of both time course and IC
50experi-
ments the tentative order of AOA on rat brain slices wasnicardipine gt nisoldipine gt (RSSR)-furnidipine gt (RRSS)-furnidipine gt nitrendipine gt nimodipine gt nifedipine14-DHP derivatives that lack a nitro group in the mole-cule (isradipine and amlodipine) also inhibited LP in ratbrain slices but at higher concentrations than that of nitro-substituted derivatives All tested compounds reduced andoxidized nitrosoaryl derivatives (26-dimethyl-4-(2-nitro-sophenyl)-35-pyridinedicarboxylic acid dimethyl ester (pho-tooxidation product of nifedipine ndash NTP) ao) and weremore potent inhibitors of LP than their parent molecules(Valenzuela et al [104])
The electrooxidation process of 4-nitrosoaromatic DHPsis a strongly pH-dependent (two-electron two-proton mech-anism) ECEC type of mechanism that is the sequenceeminusH+eminusH+ at pH gt 85 ECCE mechanism (eminusH+H+eminus)at pH lt 85 dominates Reduction reaction of nitroso groupis as follows R-NO + 2eminus + 2H+ rarr RNHOH (Bollo et al[203])
352 Lacidipine It is a generic DHP type antihypertensiveCA 35-diethyl 4-2-[(1E)-3-(tert-butoxy)-3-oxoprop-1-en-1-yl]phenyl-26-dimethyl-14-dihydropyridine-35-dicarboxy-late
Ursini [204] described redox behaviour of lacidipine andshowed its tissue protective features Cristofori et al studiedantiatherosclerotic activity in addition to lacidipinersquos CAand AO properties [205] Lacidipine reduced the extent ofatherosclerotic area in hypercholesterolemic apoE-deficientmice (these mice show widespread vascular lesions whichclosely resemble the inflammatory fibrous plaques seen inhumans in atherosclerosis) The reduction may be associatedwith the capacity of the drug to maintain endothelial NOlevels at concentrations useful to protect against vasculardamage This work suggested that DHPs modulate vascularrelaxation via increased release of NO
Herbette et al [178] remarked optimal hydrophobicity oflacidipine due to cinnamic acid substituent so membraneinteractions and facilitation of the treatment of atherosclero-sis could proceed (see also Section 331 (2)-(a))
353 Amlodipine Amlodipine (Norvasc) (RS)-3-ethyl5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-14-dihydropyridine-35-dicarboxylate (AML) hasan antioxidant effect on vessels in vitro and is a 3rd genera-tion of charged dihydropyridine CCB that is widely used forthe treatment of hypertensive patients
Amlodipine was shown to have the highest affinity(amlodipine gt verapamil ≫ diltiazem) for the membranebilayer (119870
119901= 104) It produced the significant changes in
membrane thermodynamic properties including a reductionin the thermal phase transition temperature (minus11) enthalpy(minus14) and cooperative unit size (minus59) relative to thecontrol phosphatidylcholine liposomes (Mason et al [49])
Amlodipine AOA is related to its reductant nature orhydrogen donor properties respectively Its ability for donat-ing protons and electrons to the lipid peroxide moleculesblocks the LP process
Amlodipine and even its enantiomers (Zhang et al [206])act as ROS andNOS effectors in several model systems of OSAntioxidant properties of amlodipine were recently reviewedby Vitolina et al [32] Both in vitro and in vivo studiesof amlodipine AO properties revealed inhibition of lipidsoxidative damage primarily those associated with cellularmembranes and lipoprotein particles (LDL) (Mason et al[50])
Under controlled experimental conditions in vitro amlo-dipine showed AOA and ARA by inhibition of lipid peroxideformation and trapping ROS Its scavenging activity forhydroxyl and peroxyl radicals at concentrations as low as100 nmolL (which is remarkably less compared to the classi-cal antioxidants GSH uric acid and Trolox) was shown to beindependent of the calcium channel modulation (Franzoni etal [207])
AML showed efficiency as scavenger of peroxyl radicals(TOSC assay 5945 plusmn 544 unitsmg) significantly stronger(gt50 119875 lt 0001) than GSH (2733plusmn 636 unitsmg) and 70weaker (119875 lt 00001) than uric acid (18144 plusmn 696 unitsmg)and Trolox (17522 plusmn 734 unitsmg)
20 Oxidative Medicine and Cellular Longevity
Of interest the scavenging capacity of AML towardshydroxyl radicals (1455 plusmn 154 unitsmg) was 320 higher(119875 lt 000001) than that of GSH (358 plusmn 112 unitsmg) 20higher than that of uric acid (1198plusmn121 unitsmg) and 100higher than that of Trolox (759 plusmn 143 unitsmg)
Amlodipine was shown to increase enzyme activity ofparaoxonase (PON) and glutathione peroxidase (GSH-Px)However it also decreases glutathione reductase (GSSG-R)activity and diminishes the concentration of the endogenousantioxidant 120572-tocopherol (vitamin E) Moreover AML in aconcentration of 2 ngmL decreased the content of malonicdialdehyde and activity of superoxide dismutase in the blood(Gatsura [208])
Verapamil and amlodipine produced a potent anti-ischemic effect and reduced area of myocardial infarction inrats The observed changes were accompanied by inhibitionof LP In contrast to verapamil in vitro application of AML ina dose of 50 ngmL decreased hemoglobin affinity for oxygenWhen present in a concentration of 2 ngmLAMDdecreasedthe content of MDA and activity of SOD in the blood
On the other hand amlodipine shows no activity relatedto inhibition of macrophage superoxide release and cellmigration which occurs as a consequence of decreasedTNF120572induced O
2
∙ releaseAmlodipine-induced reduction of OS in the brain is
associated with sympathoinhibitory effects in stroke-pronespontaneously hypertensive rats (SHRSP) (Hirooka et al[209]) Antihypertensive treatment with amlodipine reducedOS in all examined areas of the brain and decreased bloodpressure without a reflex increase in sympathetic nerveactivity Nicardipine another CA DHP surprisingly wassignificantly less active than amlodipine
354 Lercanidipine Tomlinson and Benzie reported AOeffect of lercanidipine [210] which is well known as anti-hypertensive drug Zanidip 2[(33-diphenylpropyl)(methyl)-amino]-11-dimethylethyl methyl 26-dimethyl-4-(3-nitro-phenyl)-14-dihydropyridine-35-dicarboxylate Compara-tive data about this drug AOA were presented in parts of thispaper about other individual CA DHPs and in the part aboutthe ex vivo DHPs effects on LDL
355 Nimodipine Nimodipine (ND) commercially knownas Nimotop is 3-(2-methoxyethyl) 5-propan-2-yl 26-dim-ethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxy-late It is centrally active CA
Treatment with glutathione blocked andwith nimodipineattenuated neuronal cell death caused by prolonged exposureof cell culture to 4-HNE (Faraqui [211])
Nascimento et al [212] found AO effect of nimodipine inyoung rats after pilocarpine- (PIL-) induced (in 400mgkg)seizures The PIL administration increased the striatal cata-lase (CAT) activity The administration of ND 30mgkg30min before PIL preserved normal value of CAT activityOn the other hand no difference was detected in the animalstreated with lower dose 10mgkg These results confirmthe neuroprotectiveantiepileptic effect of ND in young ratssuggesting that this drug acts positively on lipid peroxidation
(in both doses) Nimodipine cannot induce these effects viablockade of Ca2+ channel
Ismailoglu et al [213] studied the therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjury These beneficial effects in rats after cerebral corticalinjury seemed to be related to AOA of nimodipine
356 Benidipine Licensed in Japan and South Asia as CA(CCB) benidipine possesses AO properties Chemically it is5-methyl 3-[(3R)-1-(phenylmethyl)piperidin-3-yl] 26-dim-ethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxy-late (or its hydrochloride (4R)-rel-35-pyridinedicarboxylicacid 14-dihydro-26-dimethyl-4-(3-nitrophenyl)- 3-methyl5-[(3R)-1-(phenylmethyl)-3-piperidinyl] ester hydrochloride(1 1))
Benidipine influences processes connected with OS inseveral ways It prevents lysophosphatidylcholine- (lysoPC)-induced injury and ROS production in human aorticendothelial cells (HAECs) (Matsubara and Hasegawa [214])Matsubara et al [215] explained this effect based on stimula-tion of nitric oxide release
LysoPC is a component of oxidized low-density lipopro-teins (oxLDLs) which plays an important role in the patho-genesis of atherosclerosis Pretreatmentwith benidipine (03ndash3 120583molL) for 24 h protected against lysoPC-induced cyto-toxicity in the HAECs through inhibition of both lysoPC-stimulated ROS production and caspase-37-like activationwith a similar potency Since caspase-37 is involved inexecuting the apoptotic process the reduction of the activityof this enzyme by benidipine may explain the antiapoptoticeffect of the drug However benidipine did not suppresslysoPC-induced phosphorylation of mitogen-activated pro-tein kinases and Ca2+ influx in HAECs These results suggestthat the antioxidant properties of benidipine may be respon-sible for its ability to inhibit ROS production a possiblereason for reduced activation of caspase-37 In conclusionbenidipine suppresses lysoPC-induced endothelial dysfunc-tion through inhibition of ROS production which is due atleast in part to its antioxidant effect and not through theinhibition of L-type voltage-dependent calcium channels
Matsubara and Hasegawa [216] examined the effectsof benidipine on cytokine-induced expression of adhesionmolecules and chemokines (chemoattractants) which areimportant for the adhesion of monocytes to endotheliumPretreatment of HAECs with benidipine (03ndash10 120583molL)for 24 h significantly suppressed cytokine-induced vascularcell adhesion molecule-1 (VCAM-1) and intracellular celladhesion molecule-1 (ICAM-1) mRNA and protein expres-sion resulting in reduced adhesion of THP-1 monocytesBenidipine also suppressed induction of monocyte chemoat-tractant protein-1 (MCP-1) and interleukin-8 Benidipinealso inhibited redox-sensitive transcriptional nuclear factor-120581B (NF-120581B) pathway as determined by Western blotting ofinhibitory 120581B (I120581B) phosphorylation and luciferase reporterassay Results of analysis using optical isomers of benidip-ine and antioxidants suggest that these inhibitory effectswere dependent on pharmacological effects other than Ca2+antagonism Benidipine may thus have anti-inflammatoryproperties and benefits for the treatment of atherosclerosis
Oxidative Medicine and Cellular Longevity 21
Benidipine was also shown to inhibit ROS production inpolymorphonuclear leukocytes and oxidative stress in salt-loaded stroke-prone spontaneously hypertensive rats (Mat-subara et al [217])
It should be mentioned that other DHPs also haveendothelial AO actions [218]
357 Azelnidipine (AZL) Azelnidipine 3-[1-[di(phen-yl)methyl]azetidin-3-yl] 5-propan-2-yl 2-amino-6-methyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate(AZL) CAS number 123524-52-7 is commercially available4-nitroaryl-DHP type calcium antagonist with long-actingantihypertensive action (long-acting CA (CCB)) and a lowreported incidence of tachycardia It additionally possessesbeneficial effects in OS and diabetic conditions
Azelnidipine prevents cardiac dysfunction in strepto-zotocin-diabetic rats by reducing intracellular calcium accu-mulation (altering intracellular Ca2+ handling proteins) OSand apoptosis (Kain et al [219]) AZL can reduce the superox-ide production It exerts its protective effects by targeting theNADPH oxidase and mitochondrial redox enzymes AZL-treated diabetic rats express enhanced level of bcl-2 in thelysates of heart muscle indicating that AZL plays protectiverole in cardiac apoptosis
It has been previously observed that azelnidipine inhibitstumor necrosis factor-alpha-induced endothelial cell (EC)oxidative stress through its AO properties (Nakamura etal [220]) Azelnidipine but not nitrendipine completelyinhibits the Ang II-induced ROS generation in ECs (Matsuiet al [221])
Furthermore azelnidipine but not nitrendipine wasfound to partially restore decreased pigment epithelium-derived factor (PEDF) mRNA levels in Ang II-exposed ECsThis study suggests that AZL influence depends on its antiox-idative properties Authors concluded that upregulation ofPEDF by azelnidipine may become a therapeutic targetfor the treatment of diabetic retinopathy associated withhypertension
Antihypertensive agents with AO effects are potentiallyuseful for diabetic patients with hypertension While DHPtypeCAare among themost frequently used antihypertensivedrugs azelnidipine has been reported to have a unique AOeffect in vitro and in vivo in experimental animals (Ohmuraet al [222]) In hypertensive diabetic patients azelnidipinetreatment for 12 weeks induced a more significant decreasein erythrocyte LOOH level than amlodipine although thevalues related to blood pressure during each treatmentremained comparable These data confirm the usefulness ofLOOH level in erythrocyte membrane as a marker of OS invivo and indicate that azelnidipine has a unique antioxidativeproperty in humans
Daikuhara et al [223] reported the results of the OLCAstudy based on combination of (1) olmesartan and a calciumchannel blocker (azelnidipine) or (2) candesartan and a CCBamlodipine in two groups of diabetic hypertensive patientsPatients treated with the first combination presented highlypersistent early morning antihypertensive effect and strongerdecrease in heart rate fasting blood glucose andHbA1c levels
and microalbuminuria when compared to patients treatedwith the combination (2) Because diabetes is associated withsevere chronic OS the observed results might be at least in apart due to the AOA of azelnidipine
In favor of this are findings of Abe et al [224] who foundadditive antioxidative effects of azelnidipine on angiotensinreceptor blocker olmesartan treatment for type 2 diabeticpatients with albuminuria
Similarly the AOA of thiazolidinediones (insulin sensi-tizer) and their effect on cardiovascular function in type 2diabetic model rats and also those of some DHPs (nifedipineamlodipine or AZL commonly used antianginal and anti-hypertensive agents) in cultured human endothelial cells LPwere examined (Mizushige [225]) The AOA was evaluatedby measuring 8-iso-prostaglandine F
2120572concentration and
azelnidipine exhibited potent AOAInsulin (INS) resistance combined with hyperinsuline-
mia is involved in the generation of OS A relation-ship exists between increased production of ROS and thediverse pathogenic mechanisms involved in diabetic vascularcomplications including nephropathy Manabe et al [226]revealed that high doses of INS augmented mesangial cellproliferation through generation of intracellular ROS andactivation of redox signaling pathways Cell proliferation wasincreased in a dose-dependent manner by high doses of INS(01ndash10 120583M) but was inhibited by 01120583M AZL Namely theINS-increased phosphorylation of mitogen activated proteinkinaseextracellular signal-regulated kinase 12 (MAPKERK12) was inhibited by 01 120583MAZL The same AZL concen-tration blocked intracellular ROS production more effec-tively than 01 120583M nifedipine The NADPH oxidase inhibitorapocynin (001ndash01120583M) prevented INS-induced mesangialcell proliferation So azelnidipine inhibits insulin-inducedmesangial cell proliferation by inhibiting the productionof ROS Therefore azelnidipine may have the potential toprotect against the onset of diabetic nephropathy and slowits progression
Azelnidipine inhibited H2O2-induced cell death in
neonatal rat cardiomyocytes (Koyama et al [227]) Azelnidip-ine and nifedipine did not affect theH
2O2-induced activation
of extracellular signal-regulated protein kinases (ERK) andp38 MAPK (mitogen-activated protein kinase) In contrastazelnidipine but not nifedipine inhibited H
2O2-induced c-
Jun NH2-terminal kinases (JNK) activation Authors con-
cluded that azelnidipine has inhibited theH2O2-induced JNK
activation and cardiac cell death Therefore azelnidipine mayhave cardioprotective effects against OS
A specific atheroprotection activity of azelnidipine relatesto inhibition of TNF-120572-induced activator protein-1 activa-tion and interleukin-8 expression in human umbilical veinendothelial cells (HUVEC) through suppression of NADPHoxidase-mediated reactive oxygen species generation (Naka-mura et al [220]) TNF-120572 could play a central role in patho-genesis of insulin resistance and accelerated atherosclerosis inthe metabolic syndrome The concentration of AZL found tobe effective in these in vitro experiments is within therapeuticrange As EC do not possess voltage-operated L-type calciumchannels it is suggested that the beneficial effects of azelni-dipine are not likely due to CA property but to its unique AO
22 Oxidative Medicine and Cellular Longevity
ability Furthermore it has been recently found that serumlevels of monocyte chemoattractant protein-1 a biomarkerfor subclinical atherosclerosis were significantly decreased bythe AZL treatment in patients with essential hypertension Inthis paper [220] authors hypothesize that due to its uniqueTNF-120572 signalmodulatory activity and antioxidative propertyazelnidipine may be a promising DHP for targeting diabetesand cardiovascular diseases in hypertensive patients withmetabolic syndrome
Shinomiya et al [228] evaluated its AOA in culturedhuman arterial EC under OS Azelnidipine has shown apotent antioxidative effect that could be of significant clinicalbenefit when combined with its long-lasting antihypertensiveaction and low incidence of tachycardia
Azelnidipine inhibited TGF-1205731 and angiotensin II- (AngII-) activated 1205721(I) collagen mRNA expression in hepaticstellate cells (HSCs) (Ohyama et al [229]) FurthermoreTGF-1205731- and Ang II-induced OS and TGF-1205731-induced p38and JNK phosphorylation were reduced inHSCs treated withAZL Azelnidipine significantly decreased inflammatory cellinfiltration profibrotic genes expression HSC activation LPoxidative DNA damage and fibrosis in liver of CCl
4- or
TAA-treated mice Finally AZL prevented decrease of theexpression of some AO enzymes and accelerated regressionof liver fibrosis in CCl
4-treated mice Hence the antifibrotic
mechanism of AZL against CCl4-induced liver fibrosis in
mice may have been due to an increased level of AO defenseAs azelnidipine is widely used in clinical practice withoutserious adverse effects it may provide an effective newstrategy for antifibrotic therapy
358 Manidipine Manidipine (2-[4-(diphenylmethyl)pip-erazin-1-yl]ethyl methyl 26-dimethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate) is a DHP CCB withreported nephroprotective properties Calo et al [230] stud-ied effect of manidipine on gene expression and proteinlevel of OS related proteins p22(phox) (human neutrophilcytochrome b light chain (CYBA)) and heme oxygenase-1HO-1 Relevance for antihypertensive effects was revealedThe study assessed the effect of manidipine on normalsubjectsrsquo monocyte gene and protein expression of OS relatedproteins such as p22phox a NADPH oxidase system subunitcritical in generating O
2
∙minus and HO-1 induced by and pro-tective against OS Manidipine was compared with the ACEinhibitor captopril and the CCB nifedipine in the presenceand in the absence of sodiumarsenite (NaAsO
2) as an inducer
of OS Monocyte p22phox (CYBA) mRNA production wasreduced by both manidipine and captopril while no changeswere induced by nifedipine Manidipine increased monocyteHO-1 mRNA production while nifedipine and captoprilshowed no effect The effects of manidipine on p22phoxand HO-1 gene expression in the presence of OS were alsoconfirmed at the protein level Thus manidipine seems tosuppress p22phox and to increase the HO-1 mRNA produc-tion and protein level The manidipine-induced increase ofHO-1 gene and protein expression seems to be a peculiareffect of this drug since it is not observed with captopriland nifedipine This effect together with the reduction of
p22phoxmRNAproduction could play a role in its protectivemechanism against OS
359 Mebudipine The protective effect of mebudipine (14-dihydro-26-dimethyl-4-(3-nitrophenyl)-35-pyridinedicar-boxylic acid 3-methyl-5-tert-butyl ester BAY-n-6391) wasrevealed on OS and LP (MDA decrease SOD GPX andcatalase increase) in myocardial ischemic-reperfusion injuryin male rats (Ghyasi et al [231])
There are articles about other commercial and experi-mental DHPs on OS but we have reviewed only the mostcommonly studied compounds Effects of other commercialCA DHPs on OS are also mentioned in several parts of thisreview
36 14-DHPs Ca Agonists andTheir AOA and ARA For themost popular calcium agonist DHP Bay K 8644 no reactionwith peroxyl radicals was registered (Toniolo et al [114])However interactionwith other compounds possessing AOAand ARA (quercetin) was found
Opposite to that AON-acetylcysteine (NAC) diminishedincrease in Ca2+ transient amplitude and cell shorteninginduced by ISO and forskolin whereas NAC had no effecton the (S)-(minus)-methyl-14-dihydro-26-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylatemdash(minus)-BayK 8644-induced increases (Andersson et al [232])
Increased vasoconstriction responses to Bay K 8644 (3 times10minus7ndash3times 10minus5M)were significantly decreased by pyridoindoleantioxidant stobadine treatment in diabetes (Ceylan-Isik etal [233])
The functional interaction between two L-type Ca2+channel activators quercetin and Bay K 8644 has beeninvestigated in vascular smooth muscle cells Biological ARAcompound quercetin at nutritionally meaningful concen-trations limited the responsiveness of vascular L-type Ca2+channels to the pharmacological stimulation operated by BayK 8644 These data contribute to a better understanding ofquercetin effects on experimental in vivo cardioprotection(Saponara et al [234]) Thus these findings indicated thatalthough Bay K 8644 does not exert potent and direct AOAyet acting as calcium agonist it may affect efficiency of AOsubstances and vice versa
Interaction of grapefruit juice (containing quercetin andits analogues) with DHPs CA diminished effectiveness of CAaction of DHPs (Sica [235])
37 Interpretations of the Mechanism(s) of RadicalScavenging and AOA by DHPs
371 Molecular Mechanism(s) of Radical Scavenging andAOA of DHPs in the Model Systems 35-Dicarbonyl-14-di-hydropyridine derivatives possess powerful bis-120573-carbony-lvinyl-amino conjugation and for that reason cannot be con-sidered as ordinary amino antioxidants The electron andorH donation from DHPs ensures their reductant role andresults in AOA and ARA Oxidation reaction from DHPsresults in production of corresponding heteroaromatic pyri-dine derivatives
Oxidative Medicine and Cellular Longevity 23
Detailed studies were made about substituent in DHPring positions 14- namely 4-unsubstituted- 4-substituted4-alkyl- 4-aryl- 4-alkylaryl- ao 26- 35- (diacetyl ordialkoxycarbonyl chain ao) electronic and steric effects onAOA and ARA of DHPs [44 45 51] see Sections 331and 35 The bell-shaped dependence of DHPs AOA onthe 35-dialkoxycarbonyl- chain length was observed [4445 107 109 112] with the maximum activity at C
2H5ndash
C4H9 Decrease of AOA and incorporation into liposomes for
DHPs with alkyl chains longer than R gt C4H9further were
clarified as probable tendency to self-aggregation of thesecompounds ([51] and citation number 245 therein) Electronacceptorelectron donor properties are relevant for expres-sion of AOA or ARA of 35-disubstituted DHPs 35-Diacyl-substituted and 35-dicarbanilido- and 35-dipyridylamido-substituted DHPs are more active as AOs as their 35-dicyano-substituted analogues which have electron acceptorproperties [186]
Dubur et al [89] observed overwhelming steric influenceof substituents in position 4 of the DHP ring Gaviraghiet al [163 164] proposed that AO activity of DHPs ispartly dependent on capacity of the 14-DHP ring to donateelectrons to the propagating radical (ROO∙ or RO∙) and toreduce it to a less reactive form The abstraction (donation)of electron andor H in the oxidation and LP reactionstakes place from all 35-dicarbonyl-14-DHP systems andresults in the formation of corresponding pyridine derivatives(Augustyniak et al [51]) The physicochemical mechanism ofARA and AOA of 14-DHP has been extensively studied anddiscussed (Mulder et al [236]) but precise mechanisms oftheir activity need further clarification
The reactivity of C-4 substituted 14-DHPs possessingeither secondary or tertiary nitrogen atom in the DHP ringtoward alkyl alkylperoxyl radicals and ABTS radical cationwas determined in aqueous media at pH 74 [103] Thesecompounds reacted faster toward alkylperoxyl radicals andABTS radical cation than alkyl ones N-Ethyl-substitutedDHPs showed the lowest reactivity
The 4-methyl substituted DHP was the most reac-tive compound in previously mentioned reactions (Lopez-Alarcon et al [103]) However it was less active (068versus 10) than Trolox-C DHPs having electron-donatingsubstituents (4-Me-DHP and p-MeO-Phe-DHP) showed thehighest kinetic rate constants toward ABTS radical cation p-nitro-Phe-DHP a compound with an electron-withdrawingsubstituent showed a lower kinetic rate constant and N-alkyl-DHP compounds show kinetic rate constants lowerthan the -NH-DHP
Hydrogen at the 1-position of the DHP ring was revealedaccording to the deuteriumkinetic isotope effect studies to beinvolved in the proposedARAmechanismThis fact ismostlynoticeable in the case of alkyl radicals N-Ethyl-substitutedDHPs show the lowest reactivity when compared to Troloxor nisoldipine In all cases the respective pyridine derivativewas detected as the main product of the reaction (Lopez-Alarcon et al [103]) Authors indicate that the kinetic rateconstants toward alkyl alkylperoxyl andABTS radical cationdepend on the nature of the substituents in the C-4 positionof DHP and the presence of the secondary amine group in the
dihydropyridine ring that is the presence of the hydrogen in1-position
Yanez et al [197] have studied the reactivity of 11derivatives of 14-DHPs (including commercial CA) withalkylperoxyl radicals and ABTS radical cation The tested14-DHPs were 83-fold more reactive towards alkylperoxylradicals than to the ABTS cation radical All commercial14-DHP type CCBs were weaker than Trolox-C The par-ticipation of the hydrogen atom in the 1-position appearsto be very relevant for exhibited reactivity Hantzsch ester(diludine)was again found to be themost active compound inthe reaction with alkylperoxyl radicals 23-fold more activethan Trolox The photodegradation product of nifedipine(nitrosophenyl derivative of pyridine) also showed a highactivity Kinetic rate constants for the reaction between 14-DHP compounds and alkylperoxyl radicals exhibited a fairlygood linear correlation with the oxidation peak potentialof DHP derivatives However the activity of tested 14-DHPs towards ABTS radical cation showed an independencebetween kinetic rate constants and oxidation peak potentials
Kirule et al [195] andTirzit et al [196] studiedmechanismof AOA of 4-nitrophenyl-14-DHPs nifedipine and its ana-logues involving formation of 4-(21015840-nitrosophenyl)-pyridinederivative (as active principle) as a result of intramolecularredox reaction using chemical electrochemical and bio-chemical approaches (see Sections 331 and 351)
Nunez-Vergara et al [237] reported the electrochemicaloxidation of C4-hydroxyphenyl-substituted 14-DHP deriva-tives The oxidation proceeds via formation of the unstabledihydropyridyl radical as confirmed by controlled-potentialelectrolysis (CPE) and ESR experiments This type of 14-DHPs has significant activity towards the radicals even whencompared with commercial 14-DHP drugs with well-knownantioxidant ability
It was observed that nicardipine preferentially targets RO∙radicals and is inactive against ROO∙ Lacidipine on theother hand is equally active towards both types of radicals(Gaviraghi et al [164]) The cytoprotective effect againstexposure to H
2O2was more significant for lacidipine (ID
50=
14 nM its log119875 = 54 membrane partition = 136000 assumesposition located 7 A near to the membrane center otherless lipophilic DHPs located 12ndash16 A far from the center)as compared to amlodipine nifedipine and nicardipine insmooth muscle cell culture (Gaviraghi et al [164]) Oxidativeeffect of H
2O2shifts the Ca channel toward an open state
Thus the redox property of CCBs DHPs may augment theirCCB properties
Oxidation of pharmacologically active Hantzsch 14-dihydropyridines was found by electrogenerated superoxideusing a voltammetric approach in DMSO solutions (Ortiz etal [238] and Ortiz et al [239]) Raghuvanshi and Singh [240]have also reported oxidative aromatization of these DHPsinduced by superoxide
Chemiluminescence (CL) was used in the studies ana-lyzing the antioxidant activity of 12 various 4-flavonil-14-dihydropyridine derivatives (Kruk et al [241]) on a chemicalsystem involving a superoxide radical anion These deriva-tives showed structural similarity to flavonoids with respectto the presence of rings A B and C The results obtained in
24 Oxidative Medicine and Cellular Longevity
this study indicate that the tested derivatives may catalyzeconversion of superoxide radicals through mimicking theactivity of superoxide dismutase by delivering H+ for reac-tion
O2
minus∙+O2
minus∙+ 2H+ 997888rarr H
2O2+1O2
(3)
The enhanced emission of the light in the presence oftested compounds was significant and related to stimulatedproduction ofH
2O2and 1O
2fromO
2
∙The latter specieswereremoved from the reactionmixture by the following sequenceof reactions
H+
O2
minus∙997888rarr HO
2
∙
HO2
∙+O2
∙minus997888rarr HO
2
minus+1O2
2HO2
∙997888rarr H
2O2+1O2
2 (1O2) 997888rarr (O
2)2+ h]lowast
(4)
or to take part in spontaneous dismutation of H2O2
2H2O2997888rarr 2H
2O + 1O
2(5)
The authors have offered an original concept of action for 4-flavonil-14-dihydropyridine derivatives unrelated to that ofO2
∙ radical-trapping chain-breaking antioxidants Insteadthey showed that these compounds act similar to superoxidedismutases converting O
2
∙ to H2O2 Hydrogen peroxide
is less toxic for cells than O2
∙ because it is predominantlyremoved by peroxidases and catalases Finally AO effect ofthese DHPs differed from those mediated by flavonoids witha catechol structure of ring B which are well-known 1O
2
quenchersMulder and collaborators came to similar conclusions
especially related to molecular mechanisms of antioxidativeactivity of DHPs [236]TheAOproperties of Hantzsch 14-di-hydropyridine esters and two dibenzo-14-dihydropyridines910-dihydroacridine (DHAC) and N-methyl-910-dihydro-acridine (N-Me-DHAC) have been explored by determin-ing the autoxidation of styrene or cumene at 30∘C Theseexperiments showed that Hantzsch esters are virtually inac-tive as chain-breaking antioxidants (CB-AOs) contrary tothe findings observed by Lopez-Alarcon et al [103] whoused CB-AOA in aqueous media at pH 74 Their reactivitytoward peroxyl radicals was shown to be some 5 orders ofmagnitude lower than that of the excellent CB-AO 22578-pentamethyl-6-hydroxy-chroman (PMHC)
DHAC was found to be sim10 times less reactive thanPMHC kinetic measurements using DHAC N-deuterio-DHAC and N-Me-DHAC pointing out the abstraction ofN-H hydrogen in DHAC by peroxyl radicals despite the factthat the calculated C-H bond dissociation enthalpy (BDE) inDHAC is about 11 kcalmol lower than the N-H BDE Therates of hydrogen atom abstraction by the 22-diphenyl-1-picrylhydrazyl radical (DPPH∙) have also been determined
for the same series of compounds The trends in the peroxyl∙and DPPH∙ rate constants were found to be similar [236]
Tirzit et al [242] have observed quenching of singletoxygen by DHPs This observation paved the ground forfurther research related to reactions of DHPs with hydroxylradicals (Tirzit et al [243]) singlet oxygen (Kazush etal [94]) and mechanisms of action A series of 14-DHPderivatives in NAD-H-Cu2+-H
2O2system inhibited forming
of the hydroxyl radical (HO∙) while 14-DHP derivativeswith electron donor substituents in the molecule were shownto be capable themselves of generating HO∙ in the presenceof Cu2+ and H
2O2 Rubene et al [186] also described
interaction of 14-DHP derivatives with Fentonrsquos reagentwhich produces hydroxyl radical (HO∙) Rate constants ofthe DHPs reaction (1st order) with HO∙ radical were highin the range 109 L times mol times secminus1 close to that of NADHcysteine and thiourea 35-Diacetyl- derivatives reacted fastercompared to 35-dialkoxycarbonyl- ones The reaction ratedecrease was observed in the case of substitution at position4 as compared to 4-unsubstituted DHPs Some DHPs havingelectron donor -COOminus groups in the 35- or 26- positionsof DHP ring reacted immediately (having rate constantshigher as 109 L times mol times secminus1) Rate constants with HO
2
∙
and O2
∙minus radicals were of lower degree Thus DHPs actingas oxygen radical scavengers could effectively inhibit ROSrelated reactions of LP initiation stage
Nifedipine and nitrendipine reactivity toward singletoxygen was also studied [244] Nifedipine was shown tobe a good scavenger of excited oxygen mainly via physicaldeactivation with values of the total rate constant rangingfrom 208 times 105Mminus1 sminus1 (in dioxane) to 930 times 105Mminus1 sminus1(in propylene carbonate)The less reactive pathway generateda photooxidation product For that reason a mechanisminvolving a perepoxide-like encounter complex in the firststep of the reaction path was proposed (see [244] Figures8 and 9 therein) The dependence was observed on solventmicroscopic parameters of the total rate constant for the reac-tion between singlet oxygen and 14-DHPs These findingsshow that nifedipine possesses stronger protective activity inbiological systems than nitrendipine
Density-functional-theory (DFT) calculations made byWang et al [245] confirmed the former experimental obser-vations that Hantzsch ester diludine is potent antioxi-dant with high H atom-donating ability and relatively lowprooxidant activity Possible reaction pathways for radicalsderived from 14-dihydropyridine and the resonance modesfor radical species were given [245]
Moreover two ethoxycarbonyl (EtOCO) substituentsat C(2) and C(6) should further enhance Hantzsch esterdiludine H-atom-donating ability due to resonance effectsHowever DHPs should be used in nonpolar rather than inpolar solvents since in the latter not H-atom but electrontransfer is preferred in the radical scavenging process [245]
Mulder et al [246] proposed that quantum-thermochem-ical calculations must be used with caution to indicate ldquoapromising lead antioxidantrdquo as they criticized the density-functional-theory (DFT) calculations made by Wang et al[245]
Oxidative Medicine and Cellular Longevity 25
372 Possible Mechanisms of DHPs ARA and AOA in the Bio-logical Systems Interaction with Other OSModifiers Some ofthese mechanisms were already described (Sections 331 (2)-(b) 331 (2)-(c) 331 (3)-(b) 35)
Enzymatic sources of ROSwith confirmed functional rolein hypertension are NADPH oxidase NO synthase (NOS)xanthine oxidase and cyclooxygenase Godfraind [3] hasreviewed AO effects and protective action of calcium channelblockers (CCBs) Yao et al [247] observed antioxidant effects(as inhibition of LP) for cardio- and neuroprotective CCBs(3ndash300 120583molL) including 7 DHPs in homogenates of ratbrain IC
50values (120583M) were as follows nifedipine (515) gt
barnidipine (586) gt benidipine (712) gt nicardipine (1293)gt amlodipine (1355) gt nilvadipine (1673) gt nitrendipine(2521) gt diltiazem (gt300) = verapamil (gt300) There arealso research articles describing the AO properties of CCBsthrough direct scavenging effect or through preservationof the endogenous SOD activity These findings indicatethat CCBs may also act by reducing the production ofvasoconstrictors angiotensin and endothelin
When present in concentrations that can be achievedin plasma CCBs may inhibit LP formation [3] This AOactivity seems to be typical for high lipophilic CCBs becausetheir chemical structure facilitates proton-donating andresonance-stabilization mechanisms that quench the freeradical reaction Their insertion in the membrane nearpolyunsaturated fatty acids at relatively high concentrationspotentiates proton donation (or atomary H) to lipid peroxidemolecules thereby blocking the peroxidation process Theremaining unpaired free electron associated with the CCBmolecule can be stabilized in well-defined resonance struc-tures associated with the DHP ring (Mason et al [48])
The radical reaction (according to Godfraind [3]) thatdescribes the AO effects of a DHP CCBs is LOOlowast + DHPrarr LOOH + DHPlowast (where LOOlowast is lipid peroxide radical)which in general is reaction (7) of the LP reaction cascadeconsisting of sim10 reactions (Scheme 2) [89]
As the rate constants of in vitro interaction of 4-substituted DHPs with peroxyl radicals are three ordersof magnitude lower than that of the vitamin E derivativethese DHPs must be considered as weak AO (Ursini [204])However due to partition coefficient of DHPs in membranesand in case of specific binding high local concentration ofDHPs may be obtained
DHPs without CCB properties for instance Bay w 9798although structurally related to nifedipine inhibit TNF-120572-induced vascular cell adhesion molecule-1 expression inendothelial cells by suppressing reactive oxygen speciesgeneration [248]
Mitrega et al [249] have discovered that antiarrhythmicand hemodynamic effects of oxidized heteroaromatic DHPsoxy nifedipine oxy nimodipine oxy nitrendipine and oxynisoldipine suggest that CCB DHPs and their metabolitescould act at least in two ways targeting OS related eventsas reductants (see Section 351 (1)) andor bypassing OSrelatedmetabolic routes Authors postulated that contrary tocurrent belief NIF metabolites are pharmacologically activeATP sensitive potassium channels were mentioned as a tar-get
38 DHPs Anti- or Prooxidants Several substances (ascorbicacid being the most commonly studied) can serve either asantioxidants or as prooxidants depending on given condi-tions (Herbert [250]) Therefore Halliwell [251] has reporteddilemma related to polyphenols as possible antioxidantsand prooxidants causing experimental artifacts (about 25)by oxidation of antioxidant compounds in the cell culturemedia Nevertheless it is generally accepted opinion thatpolyphenols act as antioxidants in vivo Studies on DHPs alsoface such a dilemmaThe exact roles (anti- or prooxidative) ofany specific DHP depend on its structure appliedachievedconcentration and specificity of the targetexperimentaltesting system
This situation resembles the case of antioxidative effectsof tocopherol which depends on the fate of the secondaryradical as proposed by Winterbourn [252] The question wasldquoVitamin E - Pro- or Antioxidantrdquo
997888rarr chain termination of lipid peroxidation
(6)
Prooxidant
Toc∙ + Lipid-H 997888rarr Lipid∙ (in LDL particles) (7)
This example shows that generally speaking any AO mustfulfil several criteria to be considered as an effective com-pound physiologically
(i) It must be able to functionally interact with endoge-nous scavengers even at low concentrations
(ii) It must affect endogenous pathways of OS(iii) It should not have undesirable adverse effect(iv) It should manifest the antioxidant efficacy dependent
on the oxidant(v) It must discriminate among different strategies
needed for 1-electron and 2-electron processes(vi) Radical scavengers can be prooxidant unless linked to
a radical sink (Winterbourn [252])
According to these statements DHPs could be effective asAO under physiological conditions in vivo (Godfraind [3]and others [30 31 38]) and in vitro in various experimentalsystems (cell and tissue) (see Sections 33 34 35)
Hence calcium antagonists appeared to disrupt thefine balance between the production and scavenging ofROS Nifedipine verapamil and diltiazem were shown toinduce significant oxidative stress in the epididymal sperm(increased MDA and decreased catalase and superoxidedismutase activity) This may be the reason for the inductionof male infertility [253]
The dualism of 14-DHP effects has been recorded asinhibition or promotion of LP as quenching or initiating
26 Oxidative Medicine and Cellular Longevity
oxygen and nitrogen free radical chain reactions radiopro-tecting or radiosensitizing antagonizing or synergizing Ca2+in electromechanical coupling as well as in the membranestabilization or labilization
39 Could DHPs Be Involved in Antioxidative Stress Beforebeing applied in vivo the optimal dose and optimal timeintervals forDHPs applicationmust be knownNamely whileROS have been traditionally considered as toxic byproductsof aerobic metabolism we know nowadays that ROS may actas essential signaling molecules needed for the control ofmany different physiological processes Whether the role ofROS will be damaging protective or signaling depends onthe delicate equilibrium between time- and location-specificROS production and scavenging Accordingly the imbalanceof the increased AO potential so-called antioxidative stresscould be dangerous similar to chronic OS in particular incase of extended exposure Inappropriate interventions inthe oxidative homeostasis by excessive antioxidants especiallyin case of chronic exposure to antioxidants might havevery negative effects as was published in the ATBC studyshowing an increased cancer incidence in smokers treatedby excessive beta-carotene [254] Therefore overconsump-tion of any natural or synthetic AO including DHPs asdietary supplements or drugs must be avoided in order tosuppress oxidative damage and must not disrupt the well-integrated antioxidant defense network (Poljsak [255] andPoljsak and Milisav [256]) This is especially important whenadministrating lipid-soluble antioxidants that can be storedin biomembranes thus not only attenuating or preventing LPbut also affecting physiological effects of the natural antiox-idants in particular tocopherol The interrelationship withthe status of endogenous antioxidantsprooxidants should befollowed
DHPs primarily suppress the initiation stages of LPprocessThey do not entirely stop the LP propagation Actingsynergistically with tocopherol diludine may prevent patho-logical excess of ROS production within the lipid moiety ofthe cellular membranes and LDL However due to its lowsolubility and fast metabolism its concentration in the cellsis low For that reason it cannot cause antioxidative stresseven if used for an extended period of time Thus diludine(diethone) could be only a mild antioxidant it has potentialfor restoring the pool of natural antioxidants (as synergist of120572-tocopherol and polyphenols) in the cells
Moreover DHPs CA used for cardioprotection andvasodilatation as commercial drugs in low concentrationsare fast metabolized via CYP3A4 and for that reason theirapplication does not induce cellular AO stress [53 160]However Godfraind and Salomone [257] have postulated noevidence that allows recommending dietary supplementationwith antioxidants for the primary or secondary prevention ofcardiovascular disease
So far there are no reports on antioxidative stress causedby some DHPs diludine and its analogues Diludine andits analogues therefore could act as adaptogens supportinghormetic effects of mild oxidative stress These compoundsmay act as potential multisided modulators of Yin-Yang
cycles of redox and cell functions (the electroplasmic cycle)(Wagner et al [258])
4 Conclusions
14-Dihydropyridines (14-DHPs) have broad spectrum ofOS modulating activities DHPs have reducing and lipidperoxidation inhibitor properties act as reductants in simplechemical systems and stabilize various biological systems(LDL mitochondria microsomes cells and tissues) againstOS Examples and peculiarities and mechanisms of antiox-idant activity (AOA) and antiradical activity (ARA) as wellas stress-protective effect of DHPs including commercialcalcium antagonists (CA) were highlighted These activitiesdepend on various structural parameters related to DHPs(presence and character of substituents) lipophilicity anddepth of the incorporation in the biologicalmembranesTheyalso depend on the experimental model system for exploringthe lipid peroxidation or oxidative stress Stress-protectiveeffect of some metabolites of CA (nifedipine) is reviewedAlthough some DHPs including CA have prooxidant prop-erties (on epididymal sperm cells) they can generally beconsidered as potent antioxidants Therefore comparisonof the AOA and ARA of different DHPs (mutually andwith other AOs) was described in detail According to thedata presented the DHPs might be considered as bellwetheramong synthetic compounds targeting OS and as a kind ofpharmacological measure for respective field of organic andmedicinal chemistry
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
Authors from Latvian IOS acknowledge ESF 201300021DP1112013APIAVIAA011 and National Research Pro-gramme PUBLIC HEALTHBiomedicine of the Republicof Latvia for financial support administration of the Insti-tute for technical support and Rufus Smits PhD for con-sultations in English The support of Cooperation in Euro-pean System of Science and Technology (COST) Domain ofChemistry Molecular Sciences and Technologies (CMST)was of highest importance for preparation of this paper
[2] D J Triggle ldquo14-Dihydropyridines as calcium channel ligandsand privileged structuresrdquoCellular andMolecular Neurobiologyvol 23 no 3 pp 293ndash303 2003
[3] T Godfraind ldquoAntioxidant effects and the therapeutic modeof action of calcium channel blockers in hypertension andatherosclerosisrdquo Philosophical Transactions of the Royal SocietyB Biological Sciences vol 360 no 1464 pp 2259ndash2272 2005
[4] E Cadenas ldquoMitochondrial free radical production and cellsignalingrdquoMolecular Aspects of Medicine vol 25 no 1-2 pp 17ndash26 2004
[5] E Cadenas ldquoFree radicals oxidative stress and diseasesrdquo inLecture PSC 616 p 38 Missouri University of Science andTechnology Rolla Mo USA httpwwwcarnicominstituteorgarticlesenrique cadenaspdf
[6] K Rahman ldquoStudies on free radicals antioxidants and co-fac-torsrdquo Clinical Interventions in Aging vol 2 no 2 pp 219ndash2362007
[7] V Bocci and G Valacchi ldquoFree radicals and antioxidants howto reestablish redox homeostasis in chronic diseasesrdquo CurrentMedicinal Chemistry vol 20 no 27 pp 3397ndash3415 2013
[8] M Valko C J Rhodes J Moncol M Izakovic and M MazurldquoFree radicals metals and antioxidants in oxidative stress-induced cancerrdquo Chemico-Biological Interactions vol 160 no 1pp 1ndash40 2006
[9] G Bartosz ldquoReactive oxygen species destroyers or messen-gersrdquo Biochemical Pharmacology vol 77 no 8 pp 1303ndash13152009
[10] R Visconti and D Grieco ldquoNew insights on oxidative stress incancerrdquo Current Opinion in Drug Discovery and Developmentvol 12 no 2 pp 240ndash245 2009
[11] R N Kujundzic N Zarkovic and K G Troselj ldquoPyridinenucleotides in regulation of cell death and survival by redoxand non-redox reactionsrdquo Critical Reviews in Eukaryotic GeneExpression vol 24 no 4 pp 287ndash309 2014
[12] B Halliwell and J M C Gutteridge ldquoThe definition and mea-surement of antioxidants in biological systemsrdquo Free RadicalBiology and Medicine vol 18 no 1 pp 125ndash126 1995
[13] V D Kancheva and O T Kasaikina ldquoBio-antioxidantsmdashachemical base of their antioxidant activity and beneficial effect
on human healthrdquo Current Medicinal Chemistry vol 20 no 37pp 4784ndash4805 2013
[14] H V Panglossi Ed Frontiers in Antioxidants Research NovaScience Publishers New York NY USA 2006
[15] E B Burlakova E M Molochkina and G A NikiforovldquoHybrid antioxidantsrdquo Oxidation Communications vol 31 no4 pp 739ndash757 2008 httpmembraneustceducnpaperpdfHybrid20Antioxidantspdf
[16] A Bast and G R M M Haenen ldquoTen misconceptions aboutantioxidantsrdquo Trends in Pharmacological Sciences vol 34 no 8pp 430ndash436 2013
[17] E B Burlakova A V 0lesenko E M Molochkina N PPalmina and N G Khrapova Bioantioxidants for RadiationDamage and Malignant Growth Nauka Moscow Russia 1975(Russian)
[18] J Fang T Seki and H Maeda ldquoTherapeutic strategies by mod-ulating oxygen stress in cancer and inflammationrdquo AdvancedDrug Delivery Reviews vol 61 no 4 pp 290ndash302 2009
[19] M Valko D Leibfritz J Moncol M T D Cronin M Mazurand J Telser ldquoFree radicals and antioxidants in normal physi-ological functions and human diseaserdquo International Journal ofBiochemistry and Cell Biology vol 39 no 1 pp 44ndash84 2007
[20] M Jimenez-Del-Rio and C Velez-Pardo ldquoThe bad the goodand the ugly about oxidative stressrdquo Oxidative Medicine andCellular Longevity vol 2012 Article ID 163913 13 pages 2012
[21] C D Kamat S Gadal M Mhatre K S Williamson Q N Pyeand K Hensley ldquoAntioxidants in central nervous system dis-eases preclinical promise and translational challengesrdquo Journalof Alzheimerrsquos Disease vol 15 no 3 pp 473ndash493 2008
[22] A Pompella H Sies R Wacker et al ldquoThe use of totalantioxidant capacity as surrogate marker for food quality andits effect on health is to be discouragedrdquo Nutrition vol 30 no7-8 pp 791ndash793 2014
[23] Z Ye and H Song ldquoAntioxidant vitamins intake and the risk ofcoronary heart disease meta-analysis of cohort studiesrdquo Euro-pean Journal of Cardiovascular Prevention and Rehabilitationvol 15 no 1 pp 26ndash34 2008
[24] P Knekt J Ritz M A Pereira et al ldquoAntioxidant vitamins andcoronary heart disease risk a pooled analysis of 9 cohortsrdquoTheAmerican Journal of Clinical Nutrition vol 80 no 6 pp 1508ndash1520 2004
[25] A C Carr and M C M Vissers ldquoSynthetic or food-derivedvitamin Cmdashare they equally bioavailablerdquo Nutrients vol 5 no11 pp 4284ndash4304 2013
[26] R Tabrizchi ldquoEdaravoneMitsubishi-TokyordquoCurrentOpinion inInvestigational Drugs vol 1 no 3 pp 347ndash354 2000
[27] K Kikuchi S Tancharoen N Takeshige et al ldquoThe efficacy ofedaravone (radicut) a free radical scavenger for cardiovasculardiseaserdquo International Journal of Molecular Sciences vol 14 no7 pp 13909ndash13930 2013
[28] D Mauzerall and F H Westheimer ldquo1-Benzyldihydronicoti-namidemdasha model for reduced DPNrdquo Journal of the AmericanChemical Society vol 77 no 8 pp 2261ndash2264 1955 ChemicalAbstracts vol 50 Article ID 2588i 1956
[29] F Bossert and W Vater ldquo14-Dihydropyridinesmdasha basis fordeveloping new drugsrdquo Medicinal Research Reviews vol 9 no3 pp 291ndash324 1989
[30] G Swarnalatha G Prasanthi N Sirisha and CMadhusudhanaChetty ldquo14-Dihydropyridines a multtifunctional moleculemdash areviewrdquo International Journal of ChemTech Research vol 3 no1 pp 75ndash89 2011
28 Oxidative Medicine and Cellular Longevity
[31] M Cataldi and F Bruno ldquo14-Dihydropyridines the multiplepersonalities of a blockbuster drug familyrdquo Translational Medi-cine UniSa vol 4 no 2 pp 12ndash26 2012 httpwwwncbinlmnihgovpmcarticlesPMC3728803
[32] R Vitolina A Krauze G Duburs and A Velena ldquoAspects ofthe amlodipine pleiotropy in biochemistry pharmacology andclinicsrdquo International Journal of Pharmaceutical Sciences andResearch vol 3 no 5 pp 1215ndash1232 2012
[33] D Grover S N Mokale and M T Shete ldquoDihydropyridinea novel pharmacophorerdquo International Journal of Pharmaceu-tical Erudition vol 1 no 2 pp 16ndash29 2011 httppharmaeru-ditionorgContentPaper20111-RV-320Final2016-29pdf
[34] A M Vijesh A M Isloor S K Peethambar K N ShivanandaT Arulmoli and N A Isloor ldquoHantzsch reaction synthesis andcharacterization of somenew 14-dihydropyridine derivatives aspotent antimicrobial and antioxidant agentsrdquo European Journalof Medicinal Chemistry vol 46 no 11 pp 5591ndash5597 2011
[35] P Mehta and P Verma ldquoAntimicrobial activity of some deriva-tives of 14-dihydropyridinesrdquo Journal of Chemistry vol 2013Article ID 865128 4 pages 2013
[36] P Olejnıkova L Svorc D Olsovska et al ldquoAntimicrobialactivity of novel C2-substituted 14-dihydropyridine analoguesrdquoScientia Pharmaceutica vol 82 no 2 pp 221ndash232 2014
[37] S Sepehri H Perez Sanchez and A Fassihi ldquoHantzsch-typedihydropyridines and biginelli-type tetra-hydropyrimidinesa review of their chemotherapeutic activitiesrdquo Journal of Phar-macy amp Pharmaceutical Sciences vol 18 no 1 pp 1ndash52 2015httpsejournalslibraryualbertacaindexphpJPPSarticleview2383617863
[38] S A Khedkar and P B Auti ldquo14-Dihydropyridines a classof pharmacologically important moleculesrdquo Mini-Reviews inMedicinal Chemistry vol 14 no 3 pp 282ndash290 2014
[39] G D Tirzit and G Ya Duburs ldquo14-dihydropyridines as inhi-bitors of free-radical reactionsrdquo Chemistry of Heterocyclic Com-pounds vol 8 no 1 pp 126ndash127 1972 Translated from KhimiyaGeterotsiklicheskikh Soedinenii no1 pp 133ndash134 1972 (Rus-sian)
[40] I Bogeski R Kappl C Kummerow R Gulaboski M Hothand B A Niemeyer ldquoRedox regulation of calcium ion channelschemical and physiological aspectsrdquoCell Calcium vol 50 no 5pp 407ndash423 2011
[41] S A Giller G Y Dubur Y R Uldrikis et al ldquoDiludine [Themethod to obtain 35-dicarbonylderivatives of 26-dimethyl-14-dihydropyridines]rdquo Authors certificate of USSR no 3004651971 [Byull Izobret no13 p 95 1971] and following patentsPatent of England no 1294650 1973 Patent of France no2055458 1971 Patent of Japan no 702883 1973 Patent ofHolland no 149787 1976 Patent of Italy no 969022 1974 Patentof FRG no 2036403 1978 US Patent no 3883673 1975 USPatent no 3948924 1976
[42] S A Giller G Y Dubur Y R Uldrikis et al ldquoImprovementsin or relating to the stabilization of carotenerdquo GB Patent no1294650 1972
[43] S A Giller G Y Dubur Y R Uldrikis et al ldquoStabilization ofcarotenerdquo US Patent no 3883673 1975 Chemical Abstracts vol83 Article ID 95193 1975
[44] Yu A Zilber G Ya Dubur K K Kumsar and A Kh VelenaldquoThe effect of antioxidants on the peroxidation of bimole-cular phospholipid membranesrdquo Latvijas PSR ZA Vestis Izves-tia Akademii Nauk Latviyskoy SSR vol 6 pp 80ndash82 1971(Russian) translated from the original Russian Doc Accesion
No AD0771751 distributed by NTIS US Department of Com-merce httpwwwdticmildtictrfulltextu2771751pdf
[45] G Ya Dubur Yu A Zilbers A Kh Velena A O Kumerovaand G D Tirzitis ldquoMultistage study of regulation of peroxida-tion processes in biological membranes by antioxidants of 14-dihydropyridine grouprdquo Izvestiya Akademii Nauk LatviyskoySSR vol 336 no 7 pp 65ndash68 1975 (Russian)
[46] R P Mason and M W Trumbore ldquoDifferential membraneinteractions of calcium channel blockers Implications forantioxidant activityrdquo Biochemical Pharmacology vol 51 no 5pp 653ndash660 1996
[47] R P Mason M F Walter M W Trumbore E G Olmstead Jrand P E Mason ldquoMembrane antioxidant effects of the chargeddihydropyridine calcium antagonist amlodipinerdquo Journal ofMolecular and Cellular Cardiology vol 31 no 1 pp 275ndash2811999
[48] R PMason I T MakMW Trumbore and P EMason ldquoAnti-oxidant properties of calcium antagonists related to membranebiophysical interactionsrdquo American Journal of Cardiology vol84 no 4 pp 16ndash22 1999
[49] R PMasonMW Trumbore and P EMason ldquoMembrane bio-physical interaction of amlodipine and antioxidant propertiesrdquoDrugs vol 59 no 2 pp 9ndash16 2000 (French)
[50] R P Mason P Marche and T H Hintze ldquoNovel vascularbiology of third-generation L-type calcium channel antagonistsAncillary actions of amlodipinerdquo Arteriosclerosis Thrombosisand Vascular Biology vol 23 no 12 pp 2155ndash2163 2003
[51] A Augustyniak G Bartosz A Cipak et al ldquoNatural andsynthetic antioxidants an updated overviewrdquo Free RadicalResearch vol 44 no 10 pp 1216ndash1262 2010
[52] T Grune N Zarkovic and K Kostelidou ldquoLipid peroxidationresearch in Europe and the COST B35 action lsquoLipid Peroxida-tion Associated Disordersrsquordquo Free Radical Research vol 44 no10 pp 1095ndash1097 2010
[53] E Carosati P Ioan M Micucci et al ldquo14-Dihydropyridinescaffold in medicinal chemistry the story so far and perspec-tives (part 2) action in other targets and antitargetsrdquo CurrentMedicinal Chemistry vol 19 no 25 pp 4306ndash4323 2012
[54] U Eisner and J Kuthan ldquoThe chemistry of dihydropyridinesrdquoChemical Reviews vol 72 no 1 pp 1ndash42 1972 httpwwwsci-encemadnessorgtalkfilesphppid=138742ampaid=6475
[55] J Kuthan and A Kurfurst ldquoDevelopment in dihydropyri-dine chemistryrdquo Industrial amp Engineering Chemistry ProductResearch and Development vol 21 no 2 pp 191ndash261 1982
[56] A Sausins and G Duburs ldquoSynthesis of 14-dihydropyridinesby cyclocondensation reactionsrdquo Heterocycles vol 27 no 1 pp269ndash289 1988
[57] A E Sausins and G Y Duburs ldquoSynthesis of 14-dihydro-pyridines in cyclocondensation reactions (review)rdquo Chemistryof Heterocyclic Compounds vol 28 no 4 pp 363ndash391 1992Translated from Khimiya Geterotsiklicheskikh Soedinenii no 4pp 435ndash467 1992 (Russian)
[58] S Kazda ldquoTwenty years of dihydropyridinesrdquo in Dihydropy-ridines Progress in Pharmacology and Therapy W-D Busse BGarthoff and F Seuter Eds pp 1ndash12 Springer Verlag BerlinGermany 1993
[59] J-P Wan and Y Liu ldquoRecent advances in new multicomponentsynthesis of structurally diversified 14-dihydropyridinesrdquo RSCAdvances vol 2 no 26 pp 9763ndash9777 2012
[61] Reaxys Database[62] J Tuttle ldquoStructure mechanism and reactivity of hantzsch
estersrdquo in MacMillan Lab Group Meeting (082504) p 332004 httpwwwprincetoneduchemistrymacmillangroup-meetingsJBT20Hantzschpdf
[63] A Saini S Kumar and J S Sandhu ldquoHantzsch reaction recentadvances in Hantzsch 14-dihydropyridinesrdquo Journal of Sci-entific amp Industrial Research vol 67 pp 95ndash111 2008
[64] L LW Cheung S A Styler and A P Dicks ldquoRapid and conve-nient synthesis of the 14-dihydropyridine privileged structurerdquoJournal of Chemical Education vol 87 no 6 pp 628ndash630 2010
[65] A Kumar R A Maurya S Sharma M Kumar and G BhatialdquoSynthesis and biological evaluation of N-aryl-14-dihydro-pyridines as novel antidyslipidemic and antioxidant agentsrdquoEuropean Journal of Medicinal Chemistry vol 45 no 2 pp 501ndash509 2010
[66] R S Kumar A Idhayadhulla A J Abdul Nasser and J SelvinldquoSynthesis and anticoagulant activity of a new series of 14-dihydropyridine derivativesrdquo European Journal of MedicinalChemistry vol 46 no 2 pp 804ndash810 2011
[67] H A Stefani C B Oliveira R B Almeida et al ldquoDihydro-pyrimidin-(2H)-ones obtained by ultrasound irradiation anew class of potential antioxidant agentsrdquo European Journal ofMedicinal Chemistry vol 41 no 4 pp 513ndash518 2006
[68] H Sun C Shang L Jin and J Zhang ldquoSynthesis and antiox-idant activity of a series of novel 3-chalcone-substituted 14-dihydropyridine derivativesrdquoHeterocyclic Communications vol18 no 5-6 pp 239ndash243 2012
[69] D B Tikhonov and B S Zhorov ldquoStructural model for dihy-dropyridine binding to L-type calcium channelsrdquo The Journalof Biological Chemistry vol 284 no 28 pp 19006ndash19017 2009
[70] G Y Dubur and Y R Uldrikis ldquoThe oxidation of 14-dihydro-pyridinesrdquo Chemistry of Heterocyclic Compounds vol 6 no 1pp 80ndash84 1970 Translated from Khimiya GeterotsiklicheskikhSoedinenii no 1 pp 83ndash88 1970 (Russian)
[71] G Ya Duburs A O Kumerova and Ya R Uldrikis ldquoEnzymicoxidation of hydrogenated pyridines with peroxidase-hydrogenperoxide systemrdquoLatvijas PSRZAVestis vol 73 no 7 pp 73ndash771970 (Russian) Chemical Abstracts vol 73 Article ID 94913g1970
[72] K Xie Y-C Liu Y Cui J-GWang Y Fu andT CWMak ldquoN-methyl-(R)-3-(tert-butyl)-sulfinyl-14-dihydropyridine a novelNADHmodel compoundrdquoMolecules vol 12 no 3 pp 415ndash4222007
[73] S Tamagaki T Mimura and W Tagaki ldquoMetal-ion-facilitatedoxidations of dihydropyridines with molecular oxygen andhydrogen peroxiderdquo Journal of the Chemical Society PerkinTransactions 2 no 10 pp 1645ndash1650 1990
[74] D Tirzite G Tirzitis andD Antipova ldquoReductive ability of 14-dihydropyridine derivatives in relation to ions of trivalent ironrdquoChemistry of Heterocyclic Compounds vol 35 no 5 pp 592ndash594 1999
[76] J Ogle J Stradins and L Baumane ldquoFormation and decay offree cation-radicals in the course of electro-oxidation of 12- and14-dihydropyridines (Hantzsch esters)rdquo Electrochimica Actavol 39 no 1 pp 73ndash79 1994
[77] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for the
synthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts C Wittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Berlin Germany 2010
[78] WDu and Zh Yu ldquoBiomimetic in situ regeneration of cofactorsNAD(P)+ and NAD(P)H models hantzsch esters and dihy-drophenanthridinerdquo Synlett vol 23 no 9 pp 1300ndash1304 2012
[79] H K Chenault and G M Whitesides ldquoRegeneration ofnicotinamide cofactors for use in organic synthesisrdquo AppliedBiochemistry and Biotechnology vol 14 no 2 pp 147ndash197 1987
[80] Y R Uldrikis A A Zidermane E A Biseniex I E Preisa GY Dubur and G D Tirzit ldquoEsters of 26-dimethyl-14-dihydro-pyridine-35-dicarboxylic acid and method of obtainingthereofrdquo WO 8000345 A1 1978 httpworldwideespacenetcompublicationDetailsbiblioDB=EPODOCampII=1ampND=3ampadjacent=trueamplocale=en EPampFT=Dampdate=19800306ampCC=WOampNR=8000345A1ampKC=A1
[81] Y Sambongi H Nitta K Ichihashi M Futai and I Ueda ldquoAnovel water-soluble Hantzsch 14-dihydropyridine compoundthat functions in biological processes through NADH regener-ationrdquo Journal of Organic Chemistry vol 67 no 10 pp 3499ndash3501 2002
[82] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for thesynthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts ChWittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Verlag Berlin Germany 2010
[83] T Okamura T Kikuchi A Nagamine et al ldquoAn approach formeasuring in vivo cerebral redox states using the oxidative con-version of dihydropyridine to pyridinium ion and themetabolictrapping principlerdquo Free Radical Biology and Medicine vol 38no 9 pp 1197ndash1205 2005
[84] K A Schellenberg and F H Westheimer ldquoA free-radicaloxidation of a dihydropyridine1ardquo The Journal of OrganicChemistry vol 30 no 6 pp 1859ndash1862 1965
[85] K A Schellenberg ldquoReaction of hydroxyl radical with thymi-dine Scavenging by a dihydropyridinerdquo Federation Proceedingsvol 38 no 3 I p 1433 1979
[86] E S Huyser J A K Harmony and F L McMillian ldquoPeroxideoxidations of dihydropyridine derivativesrdquo Journal of the Amer-ican Chemical Society vol 94 no 9 pp 3176ndash3180 1972
[87] A Sakamoto S T Ohnishi and R Ogawa ldquoInhibition of lipidperoxidation by some dihydropyridine derivativesrdquo Journal ofAnesthesia vol 7 no 2 pp 193ndash197 1993
[88] R Hardeland ldquoReview Neuroprotection by radical avoidancesearch for suitable agentsrdquo Molecules vol 14 no 12 pp 5054ndash5102 2009
[89] G Ya Dubur A Kh Velena V M Gukasov and Yu AVladimirov ldquoRegulation of peroxidation of mitochondrialmembrane lipids initiated by Fe2+ ions by antoxidants of the14-dihydropyridine series in experiments in vitrordquo Biomed-itsinskaya Khimiya vol 22 no 5 pp 665ndash673 1976 (Russian)Chemical Abstracts vol 88 Article ID 2640 1977
[90] G RMMHaenenM J T J Arts A Bast andMD ColemanldquoStructure and activity in assessing antioxidant activity in vitroand in vivo a critical appraisal illustrated with the flavonoidsrdquoEnvironmental Toxicology and Pharmacology vol 21 no 2 pp191ndash198 2006
[91] G Tirzitis and G Bartosz ldquoDetermination of antiradical andantioxidant activity basic principles and new insightsrdquo ActaBiochimica Polonica vol 57 no 2 pp 139ndash142 2010
30 Oxidative Medicine and Cellular Longevity
[92] G R Buettner and R P Mason ldquoSpin-trapping methods fordetecting superoxide and hydroxyl free radicals in vitro and invivordquo inCritical Reviews of Oxidative Stress and Aging Advancesin Basic Science Diagnostics and Intervention R G Cutler andH Rodriguez Eds vol 1 chapter 2 pp 27ndash38World ScientificLondon UK 2003
[93] M M Tarpey and I Fridovich ldquoMethods of detection ofvascular reactive species Nitric oxide superoxide hydrogenperoxide and peroxynitriterdquo Circulation Research vol 89 no3 pp 224ndash236 2001
[94] E Y Kazush E I Sagun G D Tirzit and G Y DaburldquoQuenching of singlet oxygen by electron donating derivativesof 14-dihydropyridinerdquo Chemistry of Heterocyclic Compoundsvol 30 no 5 pp 562ndash563 1994
[95] G Tirzitis E Kazush and G Duburs ldquoReaction of 14-dihydropyridine derivatives with peroxynitrite anionrdquo Chem-istry of Heterocyclic Compounds vol 34 no 3 pp 321ndash3231998 (Russian) Translated from Khimiya GeterotsiklicheskikhSoedinenii no 3 pp 355ndash357 1998
[96] L J Nunez-Vergara C Lopez-Alarcon P A Navarrete-EncinaA M Atria C Camargo and J A Squella ldquoElectrochemicaland EPR characterization of 14-dihydropyridines Reactivitytowards alkyl radicalsrdquo Free Radical Research vol 37 no 1 pp109ndash120 2003
[97] D Tirzite A Krauze A Zubareva G Tirzitis and G DubursldquoSynthesis and antiradical activity of 5-acetyl-2-alkylthio-4-aryl-6-methyl-14-dihydropyridine-3-carboxylic acid nitrilesrdquoChemistry of Heterocyclic Compounds vol 38 no 7 pp 795ndash800 2002
[98] H Ohkawa N Ohishi and K Yagi ldquoAssay for lipid peroxidesin animal tissues by thiobarbituric acid reactionrdquo AnalyticalBiochemistry vol 95 no 2 pp 351ndash358 1979
[99] N Zarkovic ldquo4-Hydroxynonenal as a bioactive marker ofpathophysiological processesrdquo Molecular Aspects of Medicinevol 24 no 4-5 pp 281ndash291 2003
[100] M Parola G Bellomo G Robino G Barrera and M UDianzani ldquo4-Hydroxynonenal as a biological signal molecularbasis and pathophysiological implicationsrdquo Antioxidants andRedox Signaling vol 1 no 3 pp 255ndash284 1999
[101] T Lovakovic M Poljak-Blazi G Duburs et al ldquoGrowthmodulation of human cells in vitro by mild oxidative stressand 14-dihydropyridine derivative antioxidantsrdquo CollegiumAntropologicum vol 35 no 1 pp 137ndash141 2011
[102] R van den Berg G R M M Haenen H van den Bergand A Bast ldquoApplicability of an improved Trolox equivalentantioxidant capacity (TEAC) assay for evaluation of antioxidantcapacity measurements of mixturesrdquo Food Chemistry vol 66no 4 pp 511ndash517 1999
[103] C Lopez-Alarcon P Navarrete C Camargo J A Squella andL J Nunez-Vergara ldquoReactivity of 14-dihydropyridines towardalkyl alkylperoxyl radicals and ABTS radical cationrdquo ChemicalResearch in Toxicology vol 16 no 2 pp 208ndash215 2003
[104] V Valenzuela P Santander C Camargo J A Squella C Lopez-Alarcon and L J Nunez-Vergara ldquo14-Dihydropyridines reac-tivity of nitrosoaryl and nitroaryl derivatives with alkylperoxylradicals andABTS radical cationrdquo Free Radical Research vol 38no 7 pp 715ndash727 2004
[105] L G Tsetlin N A Chebotareva B I Kurganov A K VelenaG Y Dubur and V Z Lankin ldquoStudy of 14-dihydropyridinesas lipoxygenase inhibitors with the use of hydrated reversedmicellesrdquo Pharmaceutical Chemistry Journal vol 22 no 6 pp425ndash428 1988 (Russian)
[106] J Panek Z Reblova L Kocirkova et al ldquoAntioxidant activityof dihydropyridine derivativesrdquo Czech Journal of Food Sciencesvol 18 pp 144ndash145 2000
[107] G Tirzitis I Kirule and G Duburs ldquoAntioxidationsaktivitatder 35-dicarbonylderivate des 26-demethyl-14-dihydropyri-dinsrdquo Fett Wissenschaft TechnologieFat Science Technology vol90 no 10 pp 411ndash413 1988
[108] M Plotniece G Tirzitis Y Uldrikis et al ldquoSynthesis of 14-dihydropyridine derivatives having an oxy- alkoxy- or dimeth-ylaminophenyl substituent in the 4 position their antioxidantactivity and their binding to phospholipid membranesrdquo Chem-istry of Heterocyclic Compounds vol 32 no 10 pp 1166ndash11721996 Translated from Khimiya Geterotsiklicheskikh Soedineniino 10(352) pp 1358ndash1365 1996 (Russian)
[109] D Y Rubene V S Sharov V I Olenev G D Tirzit G Y Duburand Y A Vladimirov ldquoUse of chemiluminescent method forthe evaluation of antioxidant activity of some derivatives of 14-dihydropyridinerdquo Russian Journal of Physical Chemistry A vol55 no 2 pp 511ndash512 1981 (Russian)
[110] M C R Symons and JM C Gutteridge Free Radicals and IronChemistry Biology and Medicine Oxford Science PublicationsOxford University Press Oxford UK 1998
[111] M Repetto J Semprine and A Boveris ldquoLipid peroxidationchemical mechanism biological implications and analyticaldeterminationrdquo in Lipid Peroxidation A Catala Ed Section ILipid Peroxidation Chemical Mechanisms Antioxidants Bio-logical Implications of Biochemistry Genetics and MolecularBiology chapter 1 pp 3ndash30 InTech Rijeka Croatia 2012
[112] A Velena J Zilbers and G Duburs ldquoDerivatives of 14-dihydropyridines asmodulators of ascorbate-induced lipid per-oxidation and high-amplitude swelling ofmitochondria causedby ascorbate sodium linoleate and sodiumpyrophosphaterdquoCellBiochemistry and Function vol 17 no 4 pp 237ndash252 1999
[113] M V Bilenko L N Shelenkova G Y Dubur and A K VelenaldquoUse of antioxidants to prevent renal damage during acuteischemia and reperfusionrdquo Bulletin of Experimental Biology andMedicine vol 96 no 3 pp 1195ndash1198 1983 Translated fromByulletenrsquo Eksperimentalrsquonoi Biologii i Meditsiny vol 96 no 9pp 8ndash11 1983 (Russian)
[114] R Toniolo F Tubaro F Ursini and G Bontempelli ldquoAn elec-troanalytical investigation on the redox properties of calciumantagonist dihydropyridinesrdquo Electroanalysis vol 15 no 10 pp855ndash861 2003
[115] L Kourimska J Pokorny and G Tirzitis ldquoThe antioxidant aci-tivity of 26-dimethyl-35-diethoxycarbonyl-14-dihydropyri-dine in edible oilsrdquo Nahrung vol 37 no 1 pp 91ndash93 1993
[116] C Lopez-Alarcon H Speisky J A Squella C Olea-Azar CCamargo and L J Nunez-Vergara ldquoReactivity of 14-dihydro-pyridines toward SIN-1-derived peroxynitriterdquo PharmaceuticalResearch vol 21 no 10 pp 1750ndash1757 2004
[117] R A Olek W Ziolkowski J J Kaczor L Greci J Popinigisand J Antosiewicz ldquoAntioxidant activity of NADH and its ana-loguemdashan in vitro studyrdquo Journal of Biochemistry andMolecularBiology vol 37 no 4 pp 416ndash421 2004
[118] E Niki N Noguchi and N Gotoh ldquoInhibition of oxidativemodification of low density lipoprotein by antioxidantsrdquo Jour-nal of Nutritional Science andVitaminology vol 39 supplementpp S1ndashS8 1993
[119] N Rojstaczer and D J Triggle ldquoStructure-function relation-ships of calcium antagonists effect on oxidative modificationof low density lipoproteinrdquo Biochemical Pharmacology vol 51no 2 pp 141ndash150 1996
Oxidative Medicine and Cellular Longevity 31
[120] A Sevanian L Shen and FUrsini ldquoInhibition of LDLoxidationand oxidized LDL-induced cytotoxicity by dihydropyridinecalcium antagonistsrdquo Pharmaceutical Research vol 17 no 8 pp999ndash1006 2000
[121] A Negre-Salvayre and R Salvayre ldquoProtection by Ca2+ channelblockers (nifedipine diltiazem and verapamil) against the tox-icity of oxidized low density lipoprotein to cultured lymphoidcellsrdquo British Journal of Pharmacology vol 107 no 3 pp 738ndash744 1992
[122] A Negre-Salvayre G FitoussiM Troly and R Salvayre ldquoCom-parative cytoprotective effect of dihydropyridine calcium chan-nel blockers against the toxicity of oxidized low density lipopro-tein for cultured lymphoid cellsrdquo Biochemical Pharmacologyvol 44 no 12 pp 2379ndash2386 1992
[123] L Cominacini A F Pasini U Garbin et al ldquoAntioxidant activ-ity of different dihydropyridinesrdquo Biochemical and BiophysicalResearch Communications vol 302 no 4 pp 679ndash684 2003
[124] L Cominacini U Garbin A Fratta Pasini et al ldquoOxidized low-density lipoprotein increases the production of intracellularreactive oxygen species in endothelial cells inhibitory effect oflacidipinerdquo Journal of Hypertension vol 16 no 12 part 2 pp1913ndash1919 1998
[125] H M Lander ldquoAn essential role for free radicals and derivedspecies in signal transductionrdquo The FASEB Journal vol 11 no2 pp 118ndash124 1997
[126] M L L Martinez E Rizzi M M Castro et al ldquoLercanidipinedecreases vascular matrix metalloproteinase-2 activity andprotects against vascular dysfunction in diabetic ratsrdquo EuropeanJournal of Pharmacology vol 599 no 1ndash3 pp 110ndash116 2008
[127] P Lesnik C Dachet L Petit et al ldquoImpact of a combinationof a calcium antagonist and a 120573-blocker on cell- and copper-mediated oxidation of LDL and on the accumulation and effluxof cholesterol in human macrophages and murine J774 cellsrdquoArteriosclerosis Thrombosis and Vascular Biology vol 17 no 5pp 979ndash988 1997
[128] G Sobal E J Menzel and H Sinzinger ldquoCalcium antagonistsas inhibitors of in vitro low density lipoprotein oxidation andglycationrdquoBiochemical Pharmacology vol 61 no 3 pp 373ndash3792001
[129] E Lupo R Locher B Weisser and W Vetter ldquoIn vitro antiox-idant activity of calcium antagonists against LDL oxidationcompared with 120572-tocopherolrdquo Biochemical and BiophysicalResearch Communications vol 203 no 3 pp 1803ndash1808 1994
[130] J Zou Y Li H-Q Fan and J-G Wang ldquoEffects of dihydropy-ridine calcium channel blockers on oxidized low-density lipo-protein induced proliferation and oxidative stress of vascularsmooth muscle cellsrdquo BMC Research Notes vol 5 article 1682012
[131] C Napoli S Salomone T Godfraind et al ldquo14-Dihydro-pyridine calcium channel blockers inhibit plasma and LDL oxi-dation and formation of oxidation-specific epitopes in the arte-rial wall and prolong survival in stroke-prone spontaneouslyhypertensive ratsrdquo Stroke vol 30 no 9 pp 1907ndash1915 1999
[132] G Zernig I Graziadei T Moshammer C Zech N Reider andH Glossmann ldquoMitochondrial Ca2+ antagonist binding sitesare associated with an inner mitochondrial membrane anionchannelrdquo Molecular Pharmacology vol 38 no 3 pp 362ndash3691990
[133] F E Hunter Jr A Scott P E Hochstein et al ldquoStudies of themechanism of ascorbate-induced swelling and lysis of isolatedliver mitochondriardquo The Journal of Biological Chemistry vol239 pp 604ndash613 1964
[134] D R Janero B Burghardt and R Lopez ldquoProtection of cardiacmembrane phospholipid against oxidative injury by calciumantagonistsrdquoBiochemical Pharmacology vol 37 no 21 pp 4197ndash4203 1988
[135] A Karadag B Ozcelik and S S Saner ldquoReview of methods todetermine antioxidant capacitiesrdquo FoodAnalyticalMethods vol2 no 1 pp 41ndash60 2009
[136] Y I Gubskiı N V Litvinova and E V Shnurko-TabakovaldquoAntioxidant and antiradical activity of various classes of antiox-idantsrdquo Ukrainskiı Biokhimicheskiı Zhurnal vol 66 no 4 pp114ndash116 1994 (Russian)
[137] M Takei M Hiramatsu and A Mori ldquoInhibitory effects ofcalcium antagonists onmitochondrial swelling induced by lipidperoxidation or arachidonic acid in the rat brain in vitrordquoNeurochemical Research vol 19 no 9 pp 1199ndash1206 1994
[138] M Takei M Hiramatsu R Edamatsu and A Mori ldquoFreeradical scavenging by calcium antagonistsrdquo Neurosciences vol20 no 2 pp 75ndash82 1994
[139] Ya P Stradin G Ya Dubur Yu A Beilis Ya R Uldrikis andA F Korotkova ldquoVoltammetry of 14-dihydropyridine deriva-tives I Potentials of electrochemical oxidation of 35-diacyl-and 35-di(alkoxycarbonyl)-14-dihydropyridines in acetoni-trilerdquo Chemistry of Heterocyclic Compounds no 1 pp 84ndash871972 (Russian)
[140] E V Ivanov T V Ponomarjova G N Merkusev et al ldquoEinneuer Haut-Radioprotektor Diethon (experimentelle Unter-suchung)rdquo Radiobiologia Radiotherapia vol 31 no 1 pp 69ndash78 1990
[141] E V Ivanov T V Ponomareva G N Merkushev et al ldquoRadia-tion modulating properties of derivates of 14-dihydropyridineand 12345678910-decahydroacridine-18 dionerdquo Radiat-sionnaia Biologiia Radioecologiia vol 44 no 5 pp 550ndash5592004 (Russian)
[142] R O Vitolinia D A Berzinia A K Velena I A Vutsina A AKimenis and G Y Duburs ldquoThe protective effects of the cal-cium antagonist foridon in acute myocardial ischaemiardquo Kardi-ologiya vol 27 no 3 pp 90ndash93 1987 (Russian)
[143] A H Velena G Ya Duburs R O Vitolina et al ldquoEffect ofryodipine on electromechanical parameters of heart and vesselscAMP phosphodiesterase activity and swelling-contractioncycle of mitochondriardquo Arzneimittelforschung vol 35 no 6 pp907ndash914 1985
[144] L I Utno Z E Lipsberga A A Silova M I Girgensone EA Bisenieks and G I Ia ldquoCardioprotective properties of a 14-dihydropyridine derivative glutapyrone in deep hypothermiardquoBiulletenrsquo Eksperimentalrsquonoı Biologii i Meditsiny vol 108 no 11pp 558ndash561 1989 (Russian)
[145] M A S FernandesM S Santos J A F Vicente et al ldquoEffects of14-dihydropyridine derivatives (cerebrocrast gammapyroneglutapyrone and diethone) onmitochondrial bioenergetics andoxidative stress a comparative studyrdquoMitochondrion vol 3 no1 pp 47ndash59 2003
[146] M A S Fernandes M S Santos A J M Moreno et al ldquoEffectsof 5-acetyl(carbamoyl)-6-methylsulfanyl-14-dihydropyridine-5-carbonitriles on rat liver mitochondrial functionrdquo Toxicologyin Vitro vol 23 no 7 pp 1333ndash1341 2009
[147] L Klimaviciusa A Kalda A Kaasik et al ldquoNeuroprotectiveactivity of 14-dihydropyridine derivatives structure determi-nantsrdquo Proceedings of the Latvian Academy of Sciences BNatural Exact and Applied Sciences vol 61 no 1-2 pp 33ndash372007
32 Oxidative Medicine and Cellular Longevity
[148] L Klimaviciusa M A S Fernandes N Lencberga et alldquoTargeting the mitochondria by novel adamantane-containing14-dihydropyridine compoundsrdquo in Bioenergetics K B ClarkEd pp 257ndash272 InTech 2012
[149] V Klusa L Klimaviciusa G Duburs J Poikans and AZharkovsky ldquoAnti-neurotoxic effects of tauropyrone a taurineanaloguerdquo Advances in Experimental Medicine and Biology vol583 pp 499ndash508 2006
[150] N Sampson P Berger and Ch Zenzmaier ldquoRedox signalingas a therapeutic target to inhibit myofibroblast activation indegenerative fibrotic diseaserdquo BioMed Research Internationalvol 2014 Article ID 131737 14 pages 2014
[151] T L Leto and M Geiszt ldquoRole of Nox family NADPH oxidasesin host defenserdquoAntioxidantsampRedox Signaling vol 8 no 9-10pp 1549ndash1561 2006
[152] K K Griendling D Sorescu and M Ushio-Fukai ldquoNAD(P)Hoxidase role in cardiovascular biology and diseaserdquo CirculationResearch vol 86 no 5 pp 494ndash501 2000
[153] H Chen Y S Song and P H Chan ldquoInhibition of NADPHoxi-dase is neuroprotective after ischemia-reperfusionrdquo Journal ofCerebral Blood Flow and Metabolism vol 29 no 7 pp 1262ndash1272 2009
[154] P Hochstein and L Ernster ldquoADP-activated lipid peroxidationcoupled to the TPNH oxidase system of microsomesrdquo Biochem-ical and Biophysical Research Communications vol 12 no 5 pp388ndash394 1963
[155] I I Gubskiı AGGoriushkoNV Litvinova et al ldquoAntioxidantproperties and membranotropic effect of certain derivatives of14-dihydropyridinerdquo Ukrainskiı Biokhimicheskiı Zhurnal vol71 no 4 pp 35ndash39 1999 (Russian)
[156] F Engineer and R Sridhar ldquoInhibition of rat heart andliver microsomal lipid peroxidation by nifedipinerdquo BiochemicalPharmacology vol 38 no 8 pp 1279ndash1285 1989
[157] T Goncalves A P Carvalho and C R Oliveira ldquoAntioxidanteffect of calcium antagonists on microsomai membranes iso-lated from different brain areasrdquo European Journal of Pharma-cology vol 204 no 3 pp 315ndash322 1991
[158] M E Letelier P Izquierdo L Godoy A M Lepe and MFaundez ldquoLiver microsomal biotransformation of nitro-aryldrugs mechanism for potential oxidative stress inductionrdquoJournal of Applied Toxicology vol 24 no 6 pp 519ndash525 2004
[159] M E Letelier P Entrala C Lopez-Alarcon et al ldquoNitroaryl-14-dihydropyridines as antioxidants against rat liver microsomesoxidation induced by ironascorbate Nitrofurantoin and naph-thalenerdquo Toxicology in Vitro vol 21 no 8 pp 1610ndash1618 2007
[160] F P Guengerich W R Brian M Iwasaki M-A Sari CBaarnhielm and P Berntsson ldquoOxidation of dihydropyridinecalcium channel blockers and analogues by human liver cyto-chrome P-450 IIIA4rdquo Journal of Medicinal Chemistry vol 34no 6 pp 1838ndash1844 1991
[161] S H Park S-W RhaW-Y Shin et al ldquoAS-160 Calcium channelblockers of dihydropyridine class reduce the antiplatelet effectof Clopidogrel what is clinical impactrdquo The American Journalof Cardiology vol 107 no 8 supplement p 47A 2011
[162] C Asma and D M Reda ldquoEvaluation of dihydropyridinecalcium antagonist effects on the stress bioindicator orga-nism Saccharomyces cerevisiaerdquo Annals of Biological Researchvol 4 no 10 pp 40ndash46 2013 httpscholarsresearchlibrarycomABR-vol4-iss10ABR-2013-4-10-40-46pdf
[163] G Gaviraghi A M Pastorino E Ratti and D G TristldquoCalcium channel blockers with antioxidant activityrdquo in Free
Radicals Lipoprotein Oxidation andAtherosclerosis G BellomoG Finardi E Maggi and E Rice-Evans Eds pp 431ndash456Richelieu Press London UK 1995
[164] G Gaviraghi AM Pastorino E Ratti and D G Trist ldquoAntiox-idant dihydropyridines a new and comprehensive therapy forfree radical-induced cardiovascular diseasesrdquo in Free Radicalsin Biology and Environment F Minisci Ed vol 27 of NATOASI Series pp 193ndash221 Springer Dordrecht The Netherlands1997
[165] P D Henry ldquoAntiperoxidative actions of calcium antagonistsand atherogenesisrdquo Journal of Cardiovascular Pharmacologyvol 18 supplement 1 pp S6ndashS10 1991
[166] F Kouoh B Gressier T Dine et al ldquoAntioxidant effects andanti-elastase activity of the calcium antagonist nicardipine onactivated human and rabbit neutrophilsmdasha potential antiath-erosclerotic property of calcium antagonistsrdquo CardiovascularDrugs andTherapy vol 16 no 6 pp 515ndash520 2002
[167] S Parthasarathy D Litvinov K Selvarajan and M GarelnabildquoLipid peroxidation and decompositionmdashconflicting roles inplaque vulnerability and stabilityrdquo Biochimica et BiophysicaActa vol 1781 no 5 pp 221ndash231 2008
[168] D-Q Liu Z-Q Pang D-H Zhao and B-H Sheng ldquoEffects offuryl-dihydropyridines I on lipid peroxides of ischemic myo-cardium and ATPases activity of erythrocyte membranes inratsrdquo Acta Pharmacologica Sinica vol 12 no 3 pp 253ndash2561991
[169] V Lukic-Panin T Kamiya H Zhang et al ldquoPrevention of neu-ronal damage by calcium channel blockers with antioxidativeeffects after transient focal ischemia in ratsrdquo Brain Research vol1176 no 1 pp 143ndash150 2007
[170] Y Allanore D Borderie H Lemarechal O G Ekindjian andA Kahan ldquoAcute and sustained effects of dihydropyridine-typecalcium channel antagonists on oxidative stress in systemicsclerosisrdquo American Journal of Medicine vol 116 no 9 pp 595ndash600 2004
[171] I Casetta V Govoni and E Granieri ldquoOxidative stress antioxi-dants and neurodegenerative diseasesrdquo Current PharmaceuticalDesign vol 11 no 16 pp 2033ndash2052 2005
[172] M J T J Arts Assessing antioxidant activity [PhD the-sis] Maastricht University Maastricht The Netherlands 2007httparnounimaasnlshowcgifid=8676
[173] G Dıaz-Araya L Godoy L Naranjo A Squella M E Letelierand L J Nunez-Vergara ldquoAntioxidant effects of 14-dihydro-pyridine and nitroso aryl derivatives on the Fe+3ascorbate-stimulated lipid peroxidation in rat brain slicesrdquo General Phar-macology The Vascular System vol 31 no 3 pp 385ndash391 1998
[174] Y Fukuhara K Tsuchiya Y Horinouchi et al ldquoProtectiveeffect of photodegradation product of nifedipine against tumornecrosis factor 120572-induced oxidative stress in human glomerularendothelial cellsrdquo Journal of Medical Investigation vol 58 no1-2 pp 118ndash126 2011
[175] W Stengel M Jainz and K Andreas ldquoDifferent potencies ofdihydropyridine derivatives in blocking T-type but not L-typeCa2+ channels in neuroblastoma-glioma hybrid cellsrdquo EuropeanJournal of Pharmacology vol 342 no 2-3 pp 339ndash345 1998
[176] O M Panasenko D J Tirzite G D Tirzitis and G J DubursldquoEffect of some 14-dihydropyridine derivatives on structuralorganization of erythrocyte membranesrdquo Biologicheskie Mem-brany (Biochemistry (Moscow) Series A Membrane and CellBiology) vol 1 pp 919ndash925 1984 (Russian)
[177] L G Herbette Y M H Vant Erve and D G Rhodes ldquoInter-action of 14 dihydropyridine calcium channel antagonists with
Oxidative Medicine and Cellular Longevity 33
biological membranes lipid bilayer partitioning could occurbefore drug binding to receptorsrdquo Journal of Molecular andCellular Cardiology vol 21 no 2 pp 187ndash201 1989
[178] L G Herbette P E Mason G Gaviraghi T N Tulenko andR P Mason ldquoThe molecular basis for lacidipinersquos unique phar-macokinetics optimal hydrophobicity results in membraneinteractions that may facilitate the treatment of atherosclerosisrdquoJournal of Cardiovascular Pharmacology vol 23 supplement 5pp S16ndashS25 1994
[179] G V Belevitch G Y Dubur G E Dobretsov N K Kurek andM M Spirin ldquoCalcium antagonists riodipine nifedipine andverapamil binding to model and biological membranes fluore-scence analysisrdquo Biologicheskie Membrany (Biochemistry(Moscow) Series A Membrane and Cell Biology) vol 5 pp768ndash776 1988 (Russian)
[180] R P Mason G E Gonye D W Chester and L G HerbetteldquoPartitioning and location of Bay K 8644 14-dihydropyridinecalcium channel agonist in model and biological membranesrdquoBiophysical Journal vol 55 no 4 pp 769ndash778 1989
[181] M Cindric A Cipak J Serly et al ldquoReversal of multidrugresistance inmurine lymphoma cells by amphiphilic dihydropy-ridine antioxidant derivativerdquo Anticancer Research vol 30 no10 pp 4063ndash4070 2010
[182] F Shekari H Sadeghpour K Javidnia et al ldquoCytotoxic andmultidrug resistance reversal activities of novel 14-dihydro-pyridines against human cancer cellsrdquo European Journal ofPharmacology vol 746 no 1 pp 233ndash244 2015
[183] X-F Zhou Q Shao R A Coburn and M E Morris ldquoQuanti-tative structure-activity relationship and quantitative structure-pharmacokinetics relationship of 14-dihydropyridines andpyridines as multidrug resistance modulatorsrdquo PharmaceuticalResearch vol 22 no 12 pp 1989ndash1996 2005
[184] R Berkels T Breitenbach H Bartels et al ldquoDifferent antioxida-tive potencies of dihydropyridine calcium channel modulatorsin various modelsrdquo Vascular Pharmacology vol 42 no 4 pp145ndash152 2005
[185] S Borovic G Tirzitis D Tirzite et al ldquoBioactive 14-dihydro-isonicotinic acid derivatives prevent oxidative damage of livercellsrdquo European Journal of Pharmacology vol 537 no 1ndash3 pp12ndash19 2006
[186] D Ya Rubene G D Tirzitis and G Ya Duburs ldquoInteractionof some 14-dihydropyridine derivatives with Fentonrsquos reagentrdquoLatvijas PSRZinatnuAkademijas Vestis Kimijas Serija Proceed-ings of the Latvian SSR Academy of Sciences Chemistry Seriespp 212ndash216 1982 (Russian)
[187] K Ondrias V Misık D Gergel and A Stasko ldquoLipid per-oxidation of phosphatidylcholine liposomes depressed by thecalcium channel blockers nifedipine and verapamil and bythe antiarrhythmic-antihypoxic drug stobadinerdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1003 no 3pp 238ndash245 1989
[188] I T Mak and W B Weglicki ldquoComparative antioxidant acti-vities of propranolol nifedipine verapamil and diltiazemagainst sarcolemmal membrane lipid peroxidationrdquoCirculationResearch vol 66 no 5 pp 1449ndash1452 1990
[189] I T Mak P Boehme and W B Weglicki ldquoProtective effects ofcalcium channel blockers against free radical-impaired endo-thelial cell proliferationrdquo Biochemical Pharmacology vol 50 no9 pp 1531ndash1534 1995
[190] S Ray S Mondal and N Dana ldquoEvaluation of protective roleof nifedipine on lipid peroxidation using reduced glutathione as
model markerrdquo Oxidants and Antioxidants in Medical Sciencevol 1 no 2 pp 97ndash100 2012
[191] M Yamato T Shiba T Ide Y Honda K-I Yamada andH Tsutsui ldquoNifedipine treatment reduces brain damage aftertransient focal ischemia possibly through its antioxidativeeffectsrdquoHypertension Research vol 34 no 7 pp 840ndash845 2011
[192] V Chander and K Chopra ldquoNifedipine attenuates changes innitric oxide levels renal oxidative stress and nephrotoxicityinduced by cyclosporinerdquo Renal Failure vol 27 no 4 pp 441ndash450 2005
[193] K M Gaafa M M Badawy and A A Hamza ldquoThe protectiveeffects of ascorbic acid cimetidine and nifedipine on diethyl-dithiocarbamate-induced hepatic toxicity in albino ratsrdquo Drugand Chemical Toxicology vol 34 no 4 pp 405ndash419 2011
[194] H Sugawara K Tobise and S Onodera ldquoAbsence of antiox-idant effects of nifedipine and diltiazem on myocardial mem-brane lipid peroxidation in contrast with those of nisoldipineand propranololrdquo Biochemical Pharmacology vol 47 no 5 pp887ndash892 1994
[195] I E Kirule D Y Rubene E A Bisenieks G D Tirzit and GY Dubur ldquo4-Nitrophenyl-14-dihydropyridinesmdasha new groupof inhibitors of peroxide oxidationrdquo Chemistry of HeterocyclicCompounds vol 18 no 3 p 316 1982
[196] G D Tirzit I E Kirule L K Baumane R A Gavar Y PStradynrsquo andG YDubur ldquoMechanism of the antioxidant actionof 26-dimethyl-35-dimethoxy-carbonyl-4-(2-nitrophenyl)14-dihydropyridinerdquoChemistry ofHeterocyclic Compounds vol 20no 8 pp 915ndash918 1984
[197] C Yanez C Lopez-Alarcon C Camargo V Valenzuela J ASquella and L J Nunez-Vergara ldquoStructural effects on thereactivity 14-dihydropyridines with alkylperoxyl radicals andABTS radical cationrdquo Bioorganic and Medicinal Chemistry vol12 no 9 pp 2459ndash2468 2004
[198] VMisik A J Stasko D Gergel and K Ondrias ldquoSpin-trappingand antioxidant properties of illuminated and nonilluminatednifedipine and nimodipine in heart homogenate and modelsystemrdquo Molecular Pharmacology vol 40 no 3 pp 435ndash4391991
[199] K Ondrias V Misık A Stasko D Gergelrsquo and M HromadovaldquoComparison of antioxidant properties of nifedipine and illu-minated nifedipine with nitroso spin traps in low densitylipoproteins and phosphatidylcholine liposomesrdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1211 no 1pp 114ndash119 1994
[200] A Stasko V Brezova S Biskupic K Ondrias and V MisıkldquoReactive radical intermediates formed from illuminated nife-dipinerdquoFree Radical Biology andMedicine vol 17 no 6 pp 545ndash556 1994
[201] K Ishizawa Y Izawa-Ishizawa N Yamano et al ldquoNitrosoni-fedipine ameliorates the progression of type 2 diabetic nephro-pathy by exerting antioxidative effectsrdquo PLoS ONE vol 9 no 1Article ID e86335 2014
[202] H Fujii and L J Berliner ldquoIn vivo EPR evidence for free radicaladducts of nifedipinerdquoMagnetic Resonance in Medicine vol 42no 4 pp 691ndash694 1999
[203] S Bollo S Finger J C Sturm L J Nunez-Vergara and JA Squella ldquoCyclic voltammetry and scanning electrochemicalmicroscopy studies of the heterogeneous electron transferreaction of some nitrosoaromatic compoundsrdquo ElectrochimicaActa vol 52 no 15 pp 4892ndash4898 2007
34 Oxidative Medicine and Cellular Longevity
[204] F Ursini ldquoTissue protection by lacidipine insight from redoxbehaviorrdquo Journal of Cardiovascular Pharmacology vol 30supplement 2 pp S28ndashS30 1997
[205] P G Cristofori F A Crivellente I Faustinelli et al ldquoInvolve-ment of the nitric oxide system in the anti-atheroscleroticpotential of lacidipine in the apoE-deficient mouse a mor-phological functional and electrochemical studyrdquo ToxicologicPathology vol 32 no 4 pp 493ndash499 2004
[206] X-P Zhang E L Kit S Mital S Chahwala and T HHintze ldquoParadoxical release of nitric oxide by an L-type calciumchannel antagonist the R+ enantiomer of amlodipinerdquo Journalof Cardiovascular Pharmacology vol 39 no 2 pp 208ndash2142002
[207] F Franzoni G Santoro F Regoli et al ldquoAn in vitro study of theperoxyl and hydroxyl radical scavenging capacity of the calciumantagonist amlodipinerdquo Biomedicine and Pharmacotherapy vol58 no 8 pp 423ndash426 2004
[208] S V Gatsura ldquoOxygen-dependent mechanisms underlying theantiischemic effect of verapamil and amlodipinerdquo Bulletin ofExperimental Biology and Medicine vol 137 no 1 pp 40ndash422004
[209] Y Hirooka Y Kimura M Nozoe Y Sagara K Ito and KSunagawa ldquoAmlodipine-induced reduction of oxidative stressin the brain is associated with sympatho-inhibitory effects instroke-prone spontaneously hypertensive ratsrdquo HypertensionResearch vol 29 no 1 pp 49ndash56 2006
[210] B Tomlinson and I F F Benzie ldquoAntioxidant effect of lercani-dipine (note)rdquo Hypertension vol 42 no 4 pp e10ndashe11 2003
[211] A A Faraqui ldquoNeurochemical aspects of 4-hydroxynonenalrdquoin Lipid Mediators and Their Metabolism in the Brain A AFaraqui Ed chapter 6 pp 159ndash191 Springer New York NYUSA 2011
[212] V S NascimentoM S DrsquoAlva A AOliveira et al ldquoAntioxidanteffect of nimodipine in young rats after pilocarpine-inducedseizuresrdquo Pharmacology Biochemistry and Behavior vol 82 no1 pp 11ndash16 2005
[213] O Ismailoglu P Atilla S Palaoglu et al ldquoThe therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjuryrdquo Turkish Neurosurgery vol 22 no 6 pp 740ndash746 2012
[214] M Matsubara and K Hasegawa ldquoBenidipine a dihydropy-ridine-calcium channel blocker prevents lysophosphatidyl-choline-induced injury and reactive oxygen species productionin human aortic endothelial cellsrdquo Atherosclerosis vol 178 no1 pp 57ndash66 2005
[215] M Matsubara K Yao and K Hasegawa ldquoBenidipine adihydropyridine-calcium channel blocker inhibits lysophos-phatidylcholine-induced endothelial injury via stimulation ofnitric oxide releaserdquo Pharmacological Research vol 53 no 1 pp35ndash43 2006
[216] MMatsubara and K Hasegawa ldquoEffects of benidipine a dihyd-ropyridine-Ca2+ channel blocker on expression of cytokine-induced adhesion molecules and chemoattractants in humanaortic endothelial cellsrdquo European Journal of Pharmacology vol498 no 1ndash3 pp 303ndash314 2004
[217] M Matsubara O Akizuki J-I Ikeda K Saeki K Yao and KSasaki ldquoBenidipine an anti-hypertensive drug inhibits reactiveoxygen species production in polymorphonuclear leukocytesand oxidative stress in salt-loaded stroke-prone spontaneouslyhypertensive ratsrdquo European Journal of Pharmacology vol 580no 1-2 pp 201ndash213 2008
[218] A C Rosenkranz H Lob T Breitenbach R Berkels and RRoesen ldquoEndothelial antioxidant actions of dihydropyridines
and angiotensin converting enzyme inhibitorsrdquo European Jour-nal of Pharmacology vol 529 no 1ndash3 pp 55ndash62 2006
[219] V Kain S Kumar and S L Sitasawad ldquoAzelnidipine preventscardiac dysfunction in streptozotocin-diabetic rats by reducingintracellular calcium accumulation oxidative stress and apop-tosisrdquo Cardiovascular Diabetology vol 10 article 97 2011
[220] K Nakamura S Yamagishi and H Inoue ldquoUnique atheropro-tective property of azelnidipine a dihydropyridine-based cal-cium antagonistrdquoMedical Hypotheses vol 65 no 1 pp 155ndash1572005
[221] TMatsui S Yamagishi K Nakamura S Kikuchi andH InoueldquoAzelnidipine a dihydropyridine-based calcium antagonistinhibits angiotensin II-induced oxidative stress generation anddownregulation of pigment epithelium-derived factor mRNAlevels in microvascular endothelial cellsrdquo Drugs under Experi-mental and Clinical Research vol 31 no 5-6 pp 215ndash219 2005
[222] C Ohmura H Watada T Shimizu et al ldquoCalcium channelblocker azelnidipine reduces lipid hydroperoxides in patientswith type 2 diabetes independent of blood pressurerdquo EndocrineJournal vol 54 no 5 pp 805ndash811 2007
[223] H Daikuhara F Kikuchi and T Ishida ldquoThe combination ofOLmesartan and a CAlcium channel blocker (azelnidipine) orcandesartan and a calcium channel blocker (amlodipine) intype 2 diabetic hypertensive patients theOLCA studyrdquoDiabetesand Vascular Disease Research vol 9 no 4 pp 280ndash286 2012
[224] MAbe NMaruyama KOkada SMatsumoto KMatsumotoand M Soma ldquoAdditive antioxidative effects of azelnidipine onangiotensin receptor blocker olmesartan treatment for type 2diabetic patients with albuminuriardquoHypertension Research vol34 no 8 pp 935ndash941 2011
[225] K Mizushige ldquoAntioxidative activities of thiazolidinedionesand dihydropyridine-type calcium antagonistsrdquo IRYOmdashJapa-nese Journal of National Medical Services vol 59 no 11 pp 581ndash592 2005
[226] S Manabe T Okura T Fukuoka and J Higaki ldquoAntioxidativeeffects of azelnidipine on mesangial cell proliferation inducedby highly concentrated insulinrdquo European Journal of Pharma-cology vol 567 no 3 pp 252ndash257 2007
[227] Y Koyama Y Takeishi H Takahashi et al ldquoAzelnidipine inhi-bits H
2O2-induced cell death in neonatal rat cardiomyocytesrdquo
CardiovascularDrugs andTherapy vol 21 no 1 pp 69ndash72 2007[228] K Shinomiya K Mizushige M Fukunaga et al ldquoAntioxidant
effect of a new calcium antagonist azelnipidine in culturedhuman arterial endothelial cellsrdquo Journal of International Med-ical Research vol 32 no 2 pp 170ndash175 2004
[229] T Ohyama K Sato K Kishimoto et al ldquoAzelnidipine is acalcium blocker that attenuates liver fibrosis and may increaseantioxidant defencerdquo British Journal of Pharmacology vol 165no 4 pp 1173ndash1187 2012
[230] L A Calo F Zaghetto E Pagnin P A Davis A Sempliciniand A C Pessina ldquoEffect of manidipine on gene expressionand protein level of oxidative stress-related proteins p22phoxand HO-1 Relevance for antihypertensive and anti-remodelingeffectsrdquo Journal of Cardiovascular Pharmacology vol 43 no 4pp 531ndash538 2004
[231] R Ghyasi G Sepehri M Mohammadi R Badalzadeh and AGhyasi ldquoEffect of mebudipine on oxidative stress and lipid per-oxidation in myocardial ischemic-reperfusion injury in maleratrdquo Journal of Research in Medical Sciences vol 17 no 12 pp1150ndash1155 2012
Oxidative Medicine and Cellular Longevity 35
[232] DCAndersson J Fauconnier T Yamada et al ldquoMitochondrialproduction of reactive oxygen species contributes to the 120573-adrenergic stimulation of mouse cardiomycytesrdquoThe Journal ofPhysiology vol 589 no 7 pp 1791ndash1801 2011
[233] A F Ceylan-Isik N Ari M Stefek et al ldquoEffects of a long-term treatment with an antioxidant pyridoindole on vascularresponsiveness in diabetes-induced aging ratsrdquo Current AgingScience vol 4 no 2 pp 150ndash157 2011
[234] S Saponara G Sgaragli and F Fusi ldquoQuercetin antagonismof Bay K 8644 effects on rat tail artery L-type Ca2+ channelsrdquoEuropean Journal of Pharmacology vol 598 no 1ndash3 pp 75ndash802008
[235] D A Sica ldquoInteraction of grapefruit juice and calcium channelblockersrdquo American Journal of Hypertension vol 19 no 7 pp768ndash773 2006
[236] P Mulder G Litwinienko S Lin P D MacLean L R CBarclay and K U Ingold ldquoThe L-type calcium channel block-ers Hantzsch 14-dihydropyridines are not peroxyl radical-trapping chain-breaking antioxidantsrdquo Chemical Research inToxicology vol 19 no 1 pp 79ndash85 2006
[237] L J Nunez-Vergara R Salazar C Camargo et al ldquoOxidation ofC4-hydroxyphenyl 14-dihydropyridines in dimethylsulfoxideand its reactivity towards alkylperoxyl radicals in aqueousmediumrdquo Bioorganic and Medicinal Chemistry vol 15 no 12pp 4318ndash4326 2007
[238] M E Ortiz L J Nunez-Vergara and J A Squella ldquoRelativereactivity of dihydropyridine derivatives to electrogeneratedsuperoxide ion in DMSO solutions a voltammetric approachrdquoPharmaceutical Research vol 20 no 2 pp 292ndash296 2003
[239] M E Ortiz L J Nunez-Vergara C Camargo and J A SquellaldquoOxidation of Hantzsch 14-dihydropyridines of pharmacolog-ical significance by electrogenerated superoxiderdquo Pharmaceuti-cal Research vol 21 no 3 pp 428ndash435 2004
[240] R S Raghuvanshi and K N Singh ldquoSuperoxide induced oxida-tive aromatization of Hantzsch 14-dihydropyridinesrdquo IndianJournal of Chemistry Section B Organic and Medicinal Chem-istry vol 47 no 11 pp 1735ndash1738 2008
[241] I Kruk A Kladna K Lichszteld et al ldquoAntioxidant activityof 4-flavonil-14-dihydropyridine derivativesrdquo Biopolymers vol62 no 3 pp 163ndash167 2001
[242] G D Tirzit I M Byteva K I Salokhiddinov G P Gurinovichand G Y Dubur ldquo14-Dihydropyridine derivatives as deactiva-tors of singlet oxygenrdquo Chemistry of Heterocyclic Compoundsvol 17 no 7 pp 682ndash684 1981
[243] G D Tirzit E Y Kazush and G Y Dubur ldquoInfluence of14-dihydropyridine derivatives on the generation of hydroxylradicalsrdquo Chemistry of Heterocyclic Compounds vol 28 no 4pp 435ndash437 1992
[244] N A Pizarro-Urzua and L J Nunez-Vergara ldquoNifedipine andnitrendipine reactivity toward singlet oxygenrdquo Journal of Photo-chemistry and Photobiology A Chemistry vol 175 no 2-3 pp129ndash137 2005
[245] L-F Wang H-Y Zhang L Konga Z-W Chena and J-G ShildquoDFT calculations indicate that 14-dihydropyridine is a promis-ing lead antioxidantrdquo Helvetica Chimica Acta vol 87 no 6 pp1515ndash1521 2004
[246] P Mulder H-G Korth and K U Ingold ldquoWhy quantum-thermochemical calculations must be used with caution toindicate lsquoa promising lead antioxidantrsquordquoHelvetica Chimica Actavol 88 no 2 pp 370ndash374 2005
[247] K Yao Y Ina K Nagashima K Ohmori and T Ohno ldquoAntiox-idant effects of calcium antagonists in rat brain homogenatesrdquo
Biological and Pharmaceutical Bulletin vol 23 no 6 pp 766ndash769 2000
[248] T Matsui S-I Yamagishi K Nakamura and H Inoue ldquoBayw 9798 a dihydropyridine structurally related to nifedipinewith no calcium channel-blocking properties inhibits tumournecrosis factor-120572-induced vascular cell adhesion molecule-1expression in endothelial cells by suppressing reactive oxygenspecies generationrdquo Journal of International Medical Researchvol 35 no 6 pp 886ndash891 2007
[249] K AMitrega B VargheseM Porc and T F Krzeminski ldquoAnti-arrhythmic and hemodynamic effects of oxy nifedipine oxynimodipine oxy nitrendipine and oxy nisoldipinerdquo Pharmaco-logical Research vol 66 no 4 pp 300ndash308 2012
[250] V Herbert ldquoSymposium prooxidant effects of antioxidantvitamins Introductionrdquo The Journal of Nutrition vol 126 no4 supplement pp 1197Sndash1200S 1996 httpjnnutritionorgcontent1264 Suppl1197Sfullpdf
[251] B Halliwell ldquoAre polyphenols antioxidants or pro-oxidantsWhat do we learn from cell culture and in vivo studiesrdquoArchives of Biochemistry and Biophysics vol 476 no 2 pp 107ndash112 2008
[252] C Winterbourn Pro-Oxidants or Antioxidants ChristchurchSchool of Medicine Depatment of Pathology Free RadicalSchool SFRBMUniversity of Otago San Francisco Calif USA2009 httpwwwsfrbmorgfrsWinterbournpdf
[253] A Morakinyo B Iranloye and O Adegoke ldquoCalcium antag-onists modulate oxidative stress and acrosomal reaction in ratspermatozoardquo Archives of Medical Science vol 7 no 4 pp 613ndash618 2011
[254] The Alpha-Tocopherol Beta Carotene Cancer Prevention StudyGroup ldquoThe effect of vitamin E and beta carotene on theincidence of lung cancer and other cancers in male smokersrdquoTheNew England Journal of Medicine vol 330 no 15 pp 1029ndash1035 1994
[255] B Poljsak ldquoStrategies for reducing or preventing the generationof oxidative stressrdquo Oxidative Medicine and Cellular Longevityvol 2011 Article ID 194586 15 pages 2011
[256] B Poljsak and I Milisav ldquoThe neglected significance of lsquoanti-oxidative stressrsquordquoOxidativeMedicine and Cellular Longevity vol2012 Article ID 480895 12 pages 2012
[257] T Godfraind and S Salomone ldquoAmbiguities in dietary antiox-idant supplementation compared to calcium channel blockerstherapyrdquo Frontiers in Pharmacology vol 6 article 10 2015
[258] H Wagner H Norr and H Winterhoff ldquoDrugs with adap-togenic effects for strengthening the powers of resistancerdquoZeitschrift fur Phytotherapie vol 13 no 2 pp 42ndash54 1992
Oxidative Medicine and Cellular Longevity 15
14-DHPs as well as stages of chain reactions Accordinglymitochondrial swelling may be prolonged (retarded) accel-erated (promoted) or inhibited (Velena et al [112])
Therefore there is a ground for 14-dihydropyridineseither Ca2+ antagonists or antioxidants to be nominated asuseful tools in development of ldquomitochondrial drugsrdquo relatedto the control of OS
(c) DHPs as AOs in Endoplasmic Reticulum (Inhibition ofNADPH-Dependent LP System) Inhibition of NADPH Oxi-dase by DHPs Elevated level of NADPH oxidase 4- (NOX4-)derived hydrogen peroxide (H
2O2) joined with concomitant
decrease of nitric oxide (NO) mediated signaling and reac-tive oxygen species scavengers are considered to be centralfactor in molecular pathogenesis of fibrosis (Sampson etal [150]) Inhibition of microsomal NADPH-dependent LPwith particular focus on NADPH oxidases (NOX1ndash5 andDUOX1) may be very important for neuro- cardio- andhepatoprotection (Velena et al [112] Leto and Geiszt [151]Griendling et al [152] and Chen et al [153]) Endoplasmicreticulum may be an important target as this is where 14-DHPs could display their antioxidative properties (Velena etal [112] Leto and Geiszt [151] Griendling et al [152] andChen et al [153])
However the initiation of LP in the NADPH-dependentmicrosomal system does not appear to involve either super-oxide or hydrogen peroxide since neither SOD nor cata-lase can inhibit it On the other hand reduced iron playsan important role in both the initiation and propaga-tion of NADPH-dependent microsomal lipid peroxidation(Hochstein and Ernster [154] and Repetto et al [111])
Many DHPs possess inhibitory activity not only towardsAsA-dependent LP in mitochondria but also towardsNADPH-dependent LP as shown in isolated rat liver micro-somes (Velena et al [112]) This means that these compoundsinteract with the shared parts (nonenzymatic and enzymatic)of LP pathways
Microcalorimetry and fluorescent probes procedureswere used for studying the interaction of alpha-tocopheroland 14-DHPs with endoplasmic reticulum membranes andmodel systems human serum albumin and phospholipidbilayers [155] Modification of microviscosity of the endo-plasmatic reticular membranes depends on localization ofantioxidants within the protein structures or phospholipidphase Increase of membrane structuralization under theinfluence of 14-DHPs blocked their antioxidant action inspontaneous and induced lipid peroxidation
Inhibition of rat heart and liver microsomal lipid perox-idation by nifedipine was observed [156] while Goncalves etal [157] found antioxidant effect of calcium antagonists onmicrosomal membranes isolated from different brain areas
Nitroaryl-14-DHPs are both calcium channel antagonistsand antioxidant agents (Letelier et al [158 159]) commonlyused for treatment of cardiovascular diseases These drugsmust be metabolized through cytochrome P450 oxidativesystem (NADPH-cytochrome P450 reductase) mainly local-ized in the hepatic endoplasmic reticulum Several lipophilicdrugs generate OS while being metabolized by this cellularsystem Thus DHP antioxidant properties may prevent the
OS associated with hepatic biotransformation of drugs Var-ious commercial and new nitro-phenyl-DHPs were studiedagainst LP using rat liver microsomes under oxidative stress[159]
Incubation of rat liver microsomes with the 41015840-nitro-4-phenyl-14-DHP compounds (26-dimethyl-4-(41015840-nitro-phenyl)-14-dihydropyridin-35-diethyl-dicarboxylate andN-ethyl-26-dimethyl-4-(41015840-nitrophenyl)-14-dihydropyri-din-35-dimethyl-dicarboxylate) results in an inhibitionof LP the UDPGT (UDP-glucuronyltransferase) oxidativeactivation and the microsomal thiol oxidation induced byFe3+ascorbate a generator system of ROS This effect wasalso produced by nitrofurantoin and naphthalene in thepresence of NADPH
Interestingly IC50
ofDHPs obtained frommicrosomal LPassays decreased to the same extent as the microsomal thiolsoxidation provoked by Fe3+ascorbate [159] Neverthelessthe AO effects of a nitrophenyl-DHP compound in whichhydrogen at position one of the DHP ring was replaced bythe ethyl groupwere significantlyweaker Authors speculatedthat DHPs can resemble NADH transferring one hydrogenatom of 4-position (Hminus) to anion superoxide and another ofthe 1-position (H+) by way of a cationic radical intermediateto generate pyridine derivatives and water [159]
The AO effects of various tested DHP derivatives (m- andp-NO
2phenyl as well as methyl or ethyl and isopropyl-DHP
35-dicarboxylate derivatives) were not significantly differentThe authors assumed that the -NH- group of the dihydropy-ridine ring could contribute both to the development ofthe calcium channel antagonism and to the antioxidativeproperties of DHPs [159]
Prevention of the membrane LP seemingly depends onthe concentration of potential antioxidants such as vitaminE or even 14-DHP in lipids However only the differencesin synthetic DHPs lipophilicity cannot explain significantvariations of DHPs concentration in microsomal membraneand cannot clarify the strength of their antioxidative activityThis work [159] has further demonstrated that 14-DHPsmay prevent the OS induced by biotransformation of somedrugs for example antibiotic nitrofurantoin Simultaneousadministration of DHPs and nitrofurantoinmay be beneficialin reducing nitrofurantoin side effects
While most of Ca antagonist 14-DHPs are metabolizedby CYP3A4 (Guengerich et al [160]) not all of them are goodinhibitors of its activity Thus nicardipine but not nifedipineand nitrendipine inhibits CYP3A4 in vitro [53] Interactionof different DHPs with various types of cytochrome P450 wasdescribed by Carosati et al [53] It was also reported thatDHP class calcium channel blockers reduce the antiplateleteffect of clopidogrel (Park et al [161])This implies themutualinteractions of both drugs with CYP3A4
(3) In Vivo Evaluation of nifedipine effects on Saccharomycescerevisiaewas recently published (Asma andReda [162]) Sur-prisingly nifedipine exercised a toxic effect on Saccharomycescerevisiae shown through measuring cellular proliferationrespiratory activity and the level of some biomarkers (CATand MDA)
16 Oxidative Medicine and Cellular Longevity
However majority of data obtained on various animalcells and tissues by other authors show the protective role ofDHPs against both LP and oxidative stress [113 163 164]
The AOA attributed to many 14-DHPs Ca2+ antag-onists and other compounds reflecting on catalytic LDLperoxidation (see Section 331 (2) and Section 35) shouldencourage their testing for treating cardiovascular diseasesandor alterations of lipid metabolism
The possibility that 14-DHP-based calcium antagonistsexert an antiatherosclerotic action (via inhibition of LDLoxidation and other mechanisms) has been proved by manyexperimental data [165] and several clinical trials Besidesantihypertensive effect nicardipine was shown to possessantioxidative and antielastase activity [165 166] These prop-erties may be useful for prevention of inflammatory reactionwhich is relevant for hypertension pathogenesis
14-DHPs administration inhibits LDL oxidation medi-ated by oxygen radicals leading to decreased carotid inti-mal media thickness and reduced progression of coronaryatherosclerosis [130] It additionally preserves Apo B-100integrity against ROS Of importance antiatherogenic mech-anisms differ between animals and humans (primarily inthe stage of conversion of aldehydes to carboxylic acids)(Parthasarathy et al [167])
For example furyl-DHP compound (FDP-1 diethyl 26-dimethyl-4-(furyl)-14-dihydropyridine-35-dicarboxylate)was shown to act as an antioxidant (decreasing MDA GOTand FFA release of ischemic myocardium and inhibiting Ca-ATPase of erythrocyte membranes) preventing against heartmyocardium ischemia-reperfusion injury and arrhythmiawhen applied (in rats) at 10mgkg (Liu et al [168])
Similarly antioxidative effects of azelnidipine andamlodipine prevented neuronal damage by CCBs aftertransient focal ischemia in rats (Lukic-Panin et al [169])
Allanore et al [170] found that both nifedipine andnicardipine significantly decrease the mean level of plasmamarkers for oxidative stress in patients suffering from sys-temic sclerosis
Antioxidants may be considered as promising neuropro-tective compounds Still while experimental data demon-strate neuroprotective effect in vitro and in animal mod-els clinical evidence is still unsatisfactory and insufficient[171]
(a) Role of Metabolism of DHPs in Their AOA Metabolicpathways and ldquobioavailabilityrdquo of the probable AOA com-pound determine antioxidant activity in vivo Antioxidantmetabolites may vary in stability and activity leading to twoopposite scenarios lack or presence of activity substantiallycontributing to the overall AOA [172] Metabolic biotransfor-mation of DHPs includes oxidation (heteroaromatization)side chain ester group cleavage (deesterification) and 4-substituent abstraction ao [160] None of the DHPs metabo-lites was shown to be more toxic than original reduced formof the compound The commonly detected metabolites ofthe DHPs do not seem to possess the AO activity (withsome exceptions as in the case of metabolites of nifedipineand its analogues including nitrosonifedipine [173 174]) (seefurther in Section 35) Due to DHPs intrinsic instability
achieving andmaintaining an adequate concentrationmay beproblematic both in vitro and in vivo
(b) Role of Concentration and Lipophilicity (MembraneWateror LipidWater Partition Coefficients) of DHPs inTheir Actionas AOs and Antiradical Compounds Antioxidative effects ofany antioxidant depend on its concentration at the site ofaction This parameter is hardly measurable especially intwo-phase systems representing one of obstacles in com-parison to AOA upon applying various compounds [172]It is often incorrectly assumed that the concentrations inthe aqueous solution and at the site of action are the sameHowever even when the concentration in the aqueous phasemay be well controlled the concentration at the site ofaction in the lipid matrix of the membranes might fluctuatebetween different test compounds depending on a differencein lipophilicity [175] The prevention of the membrane LPalso seems to be dependent on the DHP concentration in thelipidmatrix (Mason andTrumbore [46]) and its amphiphilic-ity For example AOA of diludine is associated with itslipophilicity and consequential ability to be incorporatedinto liposomes (Panasenko et al [176]) It was also foundthat diludine easily incorporates into the outer monolayer oferythrocyte membranes [176]
Membranebuffer partition coefficients (lambda) weredirectly measured in the sarcolemma and sarcoplasmicreticulum membranes for three CA DHPs The obtainedvalues were in a broad range between 5000 and 150000(Herbette et al [177])These drugs interact primarily with themembrane bilayer component but may also bind to proteinsboth nonreceptors and receptors The intrinsic forward rateconstants for DHP binding to sarcolemmal calcium channelreceptors were apparently not strongly dependent on theirmembrane partition coefficients For example nimodipine(lambda = 6300) had a forward rate constant of 68 plusmn 06 times106Ms whereas the forward rate constant for Bay P 8857
(lambda = 149000) was 14plusmn08times107Ms Since these DHPsare highly liposoluble model calculations for this bindingreaction demonstrated that these rates on lipid solubilitywould probably not be reflected in the experimental forwardrate constants In addition the intrinsic forward rate constantfor nimodipine binding to sarcolemmal calcium channelreceptors was found not to be linearly dependent on theviscosity of the buffer medium over a fivefold range The rateof drug nonspecific binding to nonreceptor protein present inhighly purified sarcoplasmic reticulum membranes appearsto be extremely fast at least 103 times faster than specificdrug binding to the receptor in the sarcolemma Authorsconcluded that partitioning into the lipid bilayer matrix ofthe sarcolemma could be a general property of CA DHPsand may be a prerequisite for their binding to sarcolemmalmembrane receptors (Herbette et al [177])
The binding of DHP calcium channel agonists and antag-onists (including those with AO properties) to receptors incardiac sarcolemmal membranes is a complex reaction thatmay involve an interaction with the lipid bilayer matrix ofthe sarcolemma (Herbette et al [178]) Belevitch et al [179]studied the binding of DHP CCBs (riodipine and nifedip-ine) and verapamil to model and biological membranes by
Oxidative Medicine and Cellular Longevity 17
fluorescence analysis The consistent location of Ca agonistBay K 8644 was determined to be within the region ofthe first few methylene segments of the fatty acyl chains ofthe membranes (Mason et al [180]) This position is nearto that observed for the DHP calcium channel antagonistsnimodipine and Bay P 8857
Themajority of studies onOSwere performedwithDHPswith various lipophilicity but only a few studies reportedamphiphilicity ofDHPderivatives AmphiphilicDHPderiva-tive K-2-11 reduced the cellular generation of ROS It alsorevealed complete reversal of multidrug resistance (MDR) ofthe resistant cells K-2-11 was more efficient than well-knownMDR inhibitor verapamil Cytotoxic effects of anticancerdrug doxorubicin were enhanced by K-2-11 in bothMDR andparental nonresistant cell line (Cindric et al [181]) K-2-11suppresses increase of ROS and consequentially prevents NF-120581B activation leading to decreased expression of MDR1 andincreased expression of antiapoptotic genes This signalingswitch is necessary for restoring the chemosensitivity ofcancer cells This phenomenon is characteristic both for14-DHPs [182] (18 novel asymmetrical DHPs bearing 3-pyridyl methyl carboxylate and alkyl carboxylate moietiesat C3 and C5 positions resp as well as nitrophenyl orheteroaromatic rings at C4) and for their oxidized formspyridine compounds (Zhou et al [183])
34 Dependence of AOA of DHPs on the Experimental SystemAO effect of DHPs depends on their structure and theexperimental system used (in vitromodel system subcellularorganelle and cells ex vivo and in vivo) Ideally for theevaluation of the profile and value of DHPs AO propertieseach compound should be tested in as many systems aspossible (Dubur et al [45])
Lipidomics studies have been traditionally explored forstudying AOA of DHPs Proteomics methods are less rep-resented and are mostly focused on the properties of DHPsrelated to scavenging of protein free radicals So far there areno studies on the role of DHPs in scavenging nitrosoperoxy-carbonate the reactive species formed out of peroxynitrite inthe presence of carbon dioxide Although it was shown thatalbumin binds diludine no studies revealed the relevance ofthis effect for the AOA of diludine
There are findings showing that dihydropyridine calciumantagonists (DHPs CA) could indirectly play a beneficialprotective role during development of atherosclerosisNamely Berkels et al [184] have studied antioxidativeproperties of four substances the DHP prototype CAnifedipine the long-acting CA lacidipine the DHP calciumchannel agonist BayK8644 and the bulkyDHPderivate BayO 5572 in three different models (1) in an in vitro superoxideanion generating system (hypoxanthinexanthine oxidase)for testing the ldquopurerdquo antioxidative effect (2) in an artificialmembrane preparation (dimyristoylphosphatidylcholine) formimicking a more physiological environment and (3) underconditions of stimulated ROS release (hyperglycemia) fromnative endothelial cells derived from porcine coronary arter-ies
The study also revealed the potential correlation betweenlipophilic and AO properties of DHPs In the first model
Bay K 8644 was significantly more effective in scavengingsuperoxide anions than lacidipine Bay O 5572 or nifedipine(micro- to millimolar concentration range) Addition of anartificial membrane preparation resulted in an enhancedAO effect with lacidipine being the most effective DHP inquenching radicals (low micromolar concentration range)In the third model mimicking hyperglycemia (30mmolL)nifedipine was significantly more potent antioxidant (ther-apeutical nanomolar concentration range) than the otherDHPs Calculated lipophilicity of these four substances(lacidipine gt Bay O 5572 gt Bay K 8644 gt nifedipine) waspositively correlated with antioxidative potential only in thesecond experimental model It has been concluded that AOproperties of DHP substances need to be tested in variousmodels for demonstrating that nifedipine exhibits ROS-quenching properties in a therapeutic concentration range[184]
341 AOA of DHPs in Isolated Cells and Cell Cultures(Comparison with Other Simplest Systems) Although DHPspossess neuromodulatory andor antimutagenic propertiesthe mechanisms of action related to these phenomena arenot entirely elucidated Borovic et al [185] have studied 14-dihydroisonicotinic acid (14-DHINA) derivatives of 14-DHP water-soluble analogues of a well-known AO diludine(diethone) 26-dimethyl-35-diethoxycarbonyl-14-dihydro-isonicotinic acid sodium 2-(26-dimethyl-35-diethoxycar-bonyl-14-dihydropyridine-4-carboxamido)glutamate gluta-pyrone and sodium 2-(26-dimethyl-35-diethoxycarbonyl-14-dihydropyridine-4-carboxamido)ethane-sulphate tauro-pyrone as AO and bioprotectors (Figure 4)
14-DHINArsquos activities were studied in comparison toTrolox by NN-diphenyl-N1015840-picrylhydrazyl (DPPH∙) deoxy-ribose degradation ABTS∙ radical scavenging and AOA(antioxidative capacity method) assays copper-induced LPof cultured rat liver cells (MDA determination by HPLCand 4-hydroxynonenal-protein conjugates by dot-blot) 3H-thymidine incorporation and trypan blue assay for liver cellsgrowth and viability Ic decreased the amount of 4-HNE-protein adducts In all assays Ia was the most potent AOable to completely abolish copper induced LP of liver cellswhile Ic only slightly decreased it Thus AOA is importantactivity principle of Ia which was even superior to Trolox intreated cell cultures Ia (and its analogues) are easily oxidizedin the Fenton system (Rubene et al [186]) exerting ARA too
35 Peculiarities Related to Antioxidative and AntiradicalActivity of Some 14-DHPs Ca Antagonists Nine commer-cialized structurally and functionally different DHPs CAwill be discussed further Their common feature is ability toprevent OS This also counts for some of their metabolitesas already discussed The comparative effects of some DHPsCA on oxidative stress-induced modification of LDL werealready reviewed in Section 331 (2)-(a) AOA of CA DHPswas discussed in Sections 331 (2)-(b) and 331 (2)-(c)
351 Nifedipine and Its Close Analogues Nifedipine vera-pamil and antiarrhythmic-antihypoxic drug stobadin wereshown to depress lipid peroxidation of phosphatidylcholine
18 Oxidative Medicine and Cellular Longevity
NH
COOH
NH
COONa
Glutapyrone
NH
Gammapyrone
NH
C 2H5OOC COOC2H5
Tauropyrone
14-DHINA
H3C H3C
H3C
H3CCH3 CH3
CH3
CH3
COOC2H5COOC2H5
COOC2H5 C2H5OOCC2H5OOCC2H5OOC
CONHCH(CH2)2COONa CONH(CH2)3COONa
CONH(CH2)2SO3Na
Figure 4 Derivatives of 14-dihydroisonicotinic acid (14-DHINA)
liposomes (Ondrias et al [187]) However data obtained insome other experimental systems are conflicting
In an in vitromodel of sarcolemmal membrane lipid per-oxidation three calcium blockers (nifedipine verapamil anddiltiazem) exhibited concentration-dependent (10ndash400 120583M)inhibitory effects [188 189] Nifedipine the most effectivecalcium blocker was more than two-fold potent compared topropranolol achieving significant effect at 10 120583M Nifedipineprotective role on LP using reduced glutathione as modelmarker was recently described (Ray et al [190]) Antiper-oxidative properties of CA nifedipine and its analogueswere explored in different systemspathogenic processesatherogenesis (Henry [165]) brain focal ischemia (Yamatoet al [191]) nephroprotection related to cyclosporine intake(Chander and Chopra [192]) and hepatoprotection relatedto intake of diethyldithiocarbamate (Gaafa et al [193])Recent data suggest that nifedipine action as protector forendothelial cells proceeds independently from its CA proper-ties
The absence of antioxidant effects of nifedipine anddiltiazemonmyocardialmembrane lipid peroxidation oppo-site to nisoldipine and propranolol was also described[194] Nisoldipine and propranolol were shown to havea concentration-dependent antiperoxidant effect with IC
50
values of 282 and 501 120583M respectively Finally nisol-dipine appeared to possess dual antiperoxidant mecha-nisms involving both preventive and chain-breaking proper-ties
These findings were confirmed in some other studiesincluding reports on the lack of antioxidative activity ofnifedipine and nicardipine even at 500120583M concentrationin heart membrane lipid peroxidation tests [134] SimilarlyROS formation in bovine aorta smooth muscle cells was notaffected by addition of amlodipine nimodipine and nife-dipine [123]
(1) Metabolites of Nifedipine and Its Analogues as Antioxidantsand Regulators of OS Antioxidant activity of nifedipine35-dimethoxycarbonyl-26-dimethyl-4-(2-nitrophenyl)-14-dihydropyridine was originally studied in vitro by Kirule etal [195] and Tirzit et al [196] According to the kinetic dataof peroxide accumulation and the ESR spectra (inhibition ofthe autoxidation of methyl oleate in presence of nifedipine)AO action was exerted by the formation of nitroso analogueof the oxidized nifedipine nitroso nifedipine 26-dimethyl-4-(2-nitrosophenyl)-35-pyridine dicarboxylate (NO-NIF)This nitroso aromatic derivative can form nitroxyl radicalsexhibiting remarkable AOA in the presence of unsaturatedfatty acids and lipids [196]
The primary species of free radicals that have beenobtained and identified were ion radicals of the nitrophenyltype (Ogle et al [76]) Such a mechanism coincides withmechanisms proposed afterwards by Nunez-Vergara et al[96] Lopez-Alarcon et al [103] Valenzuela et al [104]Fukuhara et al [174] and Yanez et al [197]
There are also data showing that nitroso compounds mayinhibit LP by direct radical trapping and subsequent forma-tion of stable nitroxide radicals It was further found that thereactivity between the synthesized 14-DHP derivatives withalkylperoxyl radicals involves electron transfer reactionsThisis documented by the presence of pyridine as a final productof the reaction and complete oxidation of the nitroso groupin the case of the nitrosoaryl 14-dihydropyridine derivatives(Valenzuela et al [104]) Tested compounds reacted fastertoward alkylperoxyl radicals and ABTS radical cation thanalkyl ones (Lopez-Alarcon et al [103])
Nitrosonifedipine a photodegradation product of nifedi-pine significantly recovers cellular damage induced by tumornecrosis factor-alpha It also prevents toxic effects of cumeneperoxide which hampers integrity of cell membranes throughoxidative stress Its positive effects are equal to Trolox-C
Oxidative Medicine and Cellular Longevity 19
As a result nitrosonifedipine was already a long time agoclaimed as a candidate for a new class of antioxidative drugs(Kirule et al [195]) cellular protectors against oxidative stressin glomerular endothelial cells [174]
Moreover Misik et al [198] Ondrias et al [199] andStasko et al [200] studied AOA of nifedipine and its oxidizednitroso analogue NO-NIF prevents the progression of type2 diabetic nephropathy associated with endothelial dysfunc-tion through selective AO effects (Ishizawa et al [201]) NO-NIF administration reduces albuminuria and proteinuriaas well as glomerular expansion without affecting glucosemetabolism or systolic blood pressure NO-NIF also sup-presses renal and systemic OS and decreases the expressionof intercellular adhesion molecule-1 (ICAM-1) a marker ofendothelial cell injury in the glomeruli of the KKAy miceSimilar effects were achieved in endothelial nitric oxide syn-thase (eNOS) knockout mice Moreover NO-NIF suppressesurinary angiotensinogen (AGT) excretion and intrarenalAGT protein expression in proximal tubular cells in theKKAy mice On the other hand hyperglycemia-inducedmitochondrial superoxide production was not attenuated byNO-NIF in cultured endothelial cells
Fujii and Berliner found EPR evidence for free radicaladducts of nifedipine in vivo [202] The nature of these rad-icals was surmised by comparing the reaction of illuminatednitrosonifedipine with polyunsaturated fatty acids Surpris-ingly identical radical spectra were detected from excisedliver doped with nonilluminated nifedipine suggesting thatthis drug can be enzymatically converted in vivo to its nitrosoanalogue without the requirement for illumination This isone of the first reports of in vivo EPR evidence for a class ofunsaturated fatty acid radical conjugates resulting from thenormal metabolism of a common drug
Dıaz-Araya et al [173] studied some 4-nitrophenyl-DHPson Fe3+ initiated LP in rat brain slices LP as measuredby MDA formation was inhibited by all the tested nitro-aryl derivatives of 14-DHP over a wide range of concen-trations On the basis of both time course and IC
50experi-
ments the tentative order of AOA on rat brain slices wasnicardipine gt nisoldipine gt (RSSR)-furnidipine gt (RRSS)-furnidipine gt nitrendipine gt nimodipine gt nifedipine14-DHP derivatives that lack a nitro group in the mole-cule (isradipine and amlodipine) also inhibited LP in ratbrain slices but at higher concentrations than that of nitro-substituted derivatives All tested compounds reduced andoxidized nitrosoaryl derivatives (26-dimethyl-4-(2-nitro-sophenyl)-35-pyridinedicarboxylic acid dimethyl ester (pho-tooxidation product of nifedipine ndash NTP) ao) and weremore potent inhibitors of LP than their parent molecules(Valenzuela et al [104])
The electrooxidation process of 4-nitrosoaromatic DHPsis a strongly pH-dependent (two-electron two-proton mech-anism) ECEC type of mechanism that is the sequenceeminusH+eminusH+ at pH gt 85 ECCE mechanism (eminusH+H+eminus)at pH lt 85 dominates Reduction reaction of nitroso groupis as follows R-NO + 2eminus + 2H+ rarr RNHOH (Bollo et al[203])
352 Lacidipine It is a generic DHP type antihypertensiveCA 35-diethyl 4-2-[(1E)-3-(tert-butoxy)-3-oxoprop-1-en-1-yl]phenyl-26-dimethyl-14-dihydropyridine-35-dicarboxy-late
Ursini [204] described redox behaviour of lacidipine andshowed its tissue protective features Cristofori et al studiedantiatherosclerotic activity in addition to lacidipinersquos CAand AO properties [205] Lacidipine reduced the extent ofatherosclerotic area in hypercholesterolemic apoE-deficientmice (these mice show widespread vascular lesions whichclosely resemble the inflammatory fibrous plaques seen inhumans in atherosclerosis) The reduction may be associatedwith the capacity of the drug to maintain endothelial NOlevels at concentrations useful to protect against vasculardamage This work suggested that DHPs modulate vascularrelaxation via increased release of NO
Herbette et al [178] remarked optimal hydrophobicity oflacidipine due to cinnamic acid substituent so membraneinteractions and facilitation of the treatment of atherosclero-sis could proceed (see also Section 331 (2)-(a))
353 Amlodipine Amlodipine (Norvasc) (RS)-3-ethyl5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-14-dihydropyridine-35-dicarboxylate (AML) hasan antioxidant effect on vessels in vitro and is a 3rd genera-tion of charged dihydropyridine CCB that is widely used forthe treatment of hypertensive patients
Amlodipine was shown to have the highest affinity(amlodipine gt verapamil ≫ diltiazem) for the membranebilayer (119870
119901= 104) It produced the significant changes in
membrane thermodynamic properties including a reductionin the thermal phase transition temperature (minus11) enthalpy(minus14) and cooperative unit size (minus59) relative to thecontrol phosphatidylcholine liposomes (Mason et al [49])
Amlodipine AOA is related to its reductant nature orhydrogen donor properties respectively Its ability for donat-ing protons and electrons to the lipid peroxide moleculesblocks the LP process
Amlodipine and even its enantiomers (Zhang et al [206])act as ROS andNOS effectors in several model systems of OSAntioxidant properties of amlodipine were recently reviewedby Vitolina et al [32] Both in vitro and in vivo studiesof amlodipine AO properties revealed inhibition of lipidsoxidative damage primarily those associated with cellularmembranes and lipoprotein particles (LDL) (Mason et al[50])
Under controlled experimental conditions in vitro amlo-dipine showed AOA and ARA by inhibition of lipid peroxideformation and trapping ROS Its scavenging activity forhydroxyl and peroxyl radicals at concentrations as low as100 nmolL (which is remarkably less compared to the classi-cal antioxidants GSH uric acid and Trolox) was shown to beindependent of the calcium channel modulation (Franzoni etal [207])
AML showed efficiency as scavenger of peroxyl radicals(TOSC assay 5945 plusmn 544 unitsmg) significantly stronger(gt50 119875 lt 0001) than GSH (2733plusmn 636 unitsmg) and 70weaker (119875 lt 00001) than uric acid (18144 plusmn 696 unitsmg)and Trolox (17522 plusmn 734 unitsmg)
20 Oxidative Medicine and Cellular Longevity
Of interest the scavenging capacity of AML towardshydroxyl radicals (1455 plusmn 154 unitsmg) was 320 higher(119875 lt 000001) than that of GSH (358 plusmn 112 unitsmg) 20higher than that of uric acid (1198plusmn121 unitsmg) and 100higher than that of Trolox (759 plusmn 143 unitsmg)
Amlodipine was shown to increase enzyme activity ofparaoxonase (PON) and glutathione peroxidase (GSH-Px)However it also decreases glutathione reductase (GSSG-R)activity and diminishes the concentration of the endogenousantioxidant 120572-tocopherol (vitamin E) Moreover AML in aconcentration of 2 ngmL decreased the content of malonicdialdehyde and activity of superoxide dismutase in the blood(Gatsura [208])
Verapamil and amlodipine produced a potent anti-ischemic effect and reduced area of myocardial infarction inrats The observed changes were accompanied by inhibitionof LP In contrast to verapamil in vitro application of AML ina dose of 50 ngmL decreased hemoglobin affinity for oxygenWhen present in a concentration of 2 ngmLAMDdecreasedthe content of MDA and activity of SOD in the blood
On the other hand amlodipine shows no activity relatedto inhibition of macrophage superoxide release and cellmigration which occurs as a consequence of decreasedTNF120572induced O
2
∙ releaseAmlodipine-induced reduction of OS in the brain is
associated with sympathoinhibitory effects in stroke-pronespontaneously hypertensive rats (SHRSP) (Hirooka et al[209]) Antihypertensive treatment with amlodipine reducedOS in all examined areas of the brain and decreased bloodpressure without a reflex increase in sympathetic nerveactivity Nicardipine another CA DHP surprisingly wassignificantly less active than amlodipine
354 Lercanidipine Tomlinson and Benzie reported AOeffect of lercanidipine [210] which is well known as anti-hypertensive drug Zanidip 2[(33-diphenylpropyl)(methyl)-amino]-11-dimethylethyl methyl 26-dimethyl-4-(3-nitro-phenyl)-14-dihydropyridine-35-dicarboxylate Compara-tive data about this drug AOA were presented in parts of thispaper about other individual CA DHPs and in the part aboutthe ex vivo DHPs effects on LDL
355 Nimodipine Nimodipine (ND) commercially knownas Nimotop is 3-(2-methoxyethyl) 5-propan-2-yl 26-dim-ethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxy-late It is centrally active CA
Treatment with glutathione blocked andwith nimodipineattenuated neuronal cell death caused by prolonged exposureof cell culture to 4-HNE (Faraqui [211])
Nascimento et al [212] found AO effect of nimodipine inyoung rats after pilocarpine- (PIL-) induced (in 400mgkg)seizures The PIL administration increased the striatal cata-lase (CAT) activity The administration of ND 30mgkg30min before PIL preserved normal value of CAT activityOn the other hand no difference was detected in the animalstreated with lower dose 10mgkg These results confirmthe neuroprotectiveantiepileptic effect of ND in young ratssuggesting that this drug acts positively on lipid peroxidation
(in both doses) Nimodipine cannot induce these effects viablockade of Ca2+ channel
Ismailoglu et al [213] studied the therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjury These beneficial effects in rats after cerebral corticalinjury seemed to be related to AOA of nimodipine
356 Benidipine Licensed in Japan and South Asia as CA(CCB) benidipine possesses AO properties Chemically it is5-methyl 3-[(3R)-1-(phenylmethyl)piperidin-3-yl] 26-dim-ethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxy-late (or its hydrochloride (4R)-rel-35-pyridinedicarboxylicacid 14-dihydro-26-dimethyl-4-(3-nitrophenyl)- 3-methyl5-[(3R)-1-(phenylmethyl)-3-piperidinyl] ester hydrochloride(1 1))
Benidipine influences processes connected with OS inseveral ways It prevents lysophosphatidylcholine- (lysoPC)-induced injury and ROS production in human aorticendothelial cells (HAECs) (Matsubara and Hasegawa [214])Matsubara et al [215] explained this effect based on stimula-tion of nitric oxide release
LysoPC is a component of oxidized low-density lipopro-teins (oxLDLs) which plays an important role in the patho-genesis of atherosclerosis Pretreatmentwith benidipine (03ndash3 120583molL) for 24 h protected against lysoPC-induced cyto-toxicity in the HAECs through inhibition of both lysoPC-stimulated ROS production and caspase-37-like activationwith a similar potency Since caspase-37 is involved inexecuting the apoptotic process the reduction of the activityof this enzyme by benidipine may explain the antiapoptoticeffect of the drug However benidipine did not suppresslysoPC-induced phosphorylation of mitogen-activated pro-tein kinases and Ca2+ influx in HAECs These results suggestthat the antioxidant properties of benidipine may be respon-sible for its ability to inhibit ROS production a possiblereason for reduced activation of caspase-37 In conclusionbenidipine suppresses lysoPC-induced endothelial dysfunc-tion through inhibition of ROS production which is due atleast in part to its antioxidant effect and not through theinhibition of L-type voltage-dependent calcium channels
Matsubara and Hasegawa [216] examined the effectsof benidipine on cytokine-induced expression of adhesionmolecules and chemokines (chemoattractants) which areimportant for the adhesion of monocytes to endotheliumPretreatment of HAECs with benidipine (03ndash10 120583molL)for 24 h significantly suppressed cytokine-induced vascularcell adhesion molecule-1 (VCAM-1) and intracellular celladhesion molecule-1 (ICAM-1) mRNA and protein expres-sion resulting in reduced adhesion of THP-1 monocytesBenidipine also suppressed induction of monocyte chemoat-tractant protein-1 (MCP-1) and interleukin-8 Benidipinealso inhibited redox-sensitive transcriptional nuclear factor-120581B (NF-120581B) pathway as determined by Western blotting ofinhibitory 120581B (I120581B) phosphorylation and luciferase reporterassay Results of analysis using optical isomers of benidip-ine and antioxidants suggest that these inhibitory effectswere dependent on pharmacological effects other than Ca2+antagonism Benidipine may thus have anti-inflammatoryproperties and benefits for the treatment of atherosclerosis
Oxidative Medicine and Cellular Longevity 21
Benidipine was also shown to inhibit ROS production inpolymorphonuclear leukocytes and oxidative stress in salt-loaded stroke-prone spontaneously hypertensive rats (Mat-subara et al [217])
It should be mentioned that other DHPs also haveendothelial AO actions [218]
357 Azelnidipine (AZL) Azelnidipine 3-[1-[di(phen-yl)methyl]azetidin-3-yl] 5-propan-2-yl 2-amino-6-methyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate(AZL) CAS number 123524-52-7 is commercially available4-nitroaryl-DHP type calcium antagonist with long-actingantihypertensive action (long-acting CA (CCB)) and a lowreported incidence of tachycardia It additionally possessesbeneficial effects in OS and diabetic conditions
Azelnidipine prevents cardiac dysfunction in strepto-zotocin-diabetic rats by reducing intracellular calcium accu-mulation (altering intracellular Ca2+ handling proteins) OSand apoptosis (Kain et al [219]) AZL can reduce the superox-ide production It exerts its protective effects by targeting theNADPH oxidase and mitochondrial redox enzymes AZL-treated diabetic rats express enhanced level of bcl-2 in thelysates of heart muscle indicating that AZL plays protectiverole in cardiac apoptosis
It has been previously observed that azelnidipine inhibitstumor necrosis factor-alpha-induced endothelial cell (EC)oxidative stress through its AO properties (Nakamura etal [220]) Azelnidipine but not nitrendipine completelyinhibits the Ang II-induced ROS generation in ECs (Matsuiet al [221])
Furthermore azelnidipine but not nitrendipine wasfound to partially restore decreased pigment epithelium-derived factor (PEDF) mRNA levels in Ang II-exposed ECsThis study suggests that AZL influence depends on its antiox-idative properties Authors concluded that upregulation ofPEDF by azelnidipine may become a therapeutic targetfor the treatment of diabetic retinopathy associated withhypertension
Antihypertensive agents with AO effects are potentiallyuseful for diabetic patients with hypertension While DHPtypeCAare among themost frequently used antihypertensivedrugs azelnidipine has been reported to have a unique AOeffect in vitro and in vivo in experimental animals (Ohmuraet al [222]) In hypertensive diabetic patients azelnidipinetreatment for 12 weeks induced a more significant decreasein erythrocyte LOOH level than amlodipine although thevalues related to blood pressure during each treatmentremained comparable These data confirm the usefulness ofLOOH level in erythrocyte membrane as a marker of OS invivo and indicate that azelnidipine has a unique antioxidativeproperty in humans
Daikuhara et al [223] reported the results of the OLCAstudy based on combination of (1) olmesartan and a calciumchannel blocker (azelnidipine) or (2) candesartan and a CCBamlodipine in two groups of diabetic hypertensive patientsPatients treated with the first combination presented highlypersistent early morning antihypertensive effect and strongerdecrease in heart rate fasting blood glucose andHbA1c levels
and microalbuminuria when compared to patients treatedwith the combination (2) Because diabetes is associated withsevere chronic OS the observed results might be at least in apart due to the AOA of azelnidipine
In favor of this are findings of Abe et al [224] who foundadditive antioxidative effects of azelnidipine on angiotensinreceptor blocker olmesartan treatment for type 2 diabeticpatients with albuminuria
Similarly the AOA of thiazolidinediones (insulin sensi-tizer) and their effect on cardiovascular function in type 2diabetic model rats and also those of some DHPs (nifedipineamlodipine or AZL commonly used antianginal and anti-hypertensive agents) in cultured human endothelial cells LPwere examined (Mizushige [225]) The AOA was evaluatedby measuring 8-iso-prostaglandine F
2120572concentration and
azelnidipine exhibited potent AOAInsulin (INS) resistance combined with hyperinsuline-
mia is involved in the generation of OS A relation-ship exists between increased production of ROS and thediverse pathogenic mechanisms involved in diabetic vascularcomplications including nephropathy Manabe et al [226]revealed that high doses of INS augmented mesangial cellproliferation through generation of intracellular ROS andactivation of redox signaling pathways Cell proliferation wasincreased in a dose-dependent manner by high doses of INS(01ndash10 120583M) but was inhibited by 01120583M AZL Namely theINS-increased phosphorylation of mitogen activated proteinkinaseextracellular signal-regulated kinase 12 (MAPKERK12) was inhibited by 01 120583MAZL The same AZL concen-tration blocked intracellular ROS production more effec-tively than 01 120583M nifedipine The NADPH oxidase inhibitorapocynin (001ndash01120583M) prevented INS-induced mesangialcell proliferation So azelnidipine inhibits insulin-inducedmesangial cell proliferation by inhibiting the productionof ROS Therefore azelnidipine may have the potential toprotect against the onset of diabetic nephropathy and slowits progression
Azelnidipine inhibited H2O2-induced cell death in
neonatal rat cardiomyocytes (Koyama et al [227]) Azelnidip-ine and nifedipine did not affect theH
2O2-induced activation
of extracellular signal-regulated protein kinases (ERK) andp38 MAPK (mitogen-activated protein kinase) In contrastazelnidipine but not nifedipine inhibited H
2O2-induced c-
Jun NH2-terminal kinases (JNK) activation Authors con-
cluded that azelnidipine has inhibited theH2O2-induced JNK
activation and cardiac cell death Therefore azelnidipine mayhave cardioprotective effects against OS
A specific atheroprotection activity of azelnidipine relatesto inhibition of TNF-120572-induced activator protein-1 activa-tion and interleukin-8 expression in human umbilical veinendothelial cells (HUVEC) through suppression of NADPHoxidase-mediated reactive oxygen species generation (Naka-mura et al [220]) TNF-120572 could play a central role in patho-genesis of insulin resistance and accelerated atherosclerosis inthe metabolic syndrome The concentration of AZL found tobe effective in these in vitro experiments is within therapeuticrange As EC do not possess voltage-operated L-type calciumchannels it is suggested that the beneficial effects of azelni-dipine are not likely due to CA property but to its unique AO
22 Oxidative Medicine and Cellular Longevity
ability Furthermore it has been recently found that serumlevels of monocyte chemoattractant protein-1 a biomarkerfor subclinical atherosclerosis were significantly decreased bythe AZL treatment in patients with essential hypertension Inthis paper [220] authors hypothesize that due to its uniqueTNF-120572 signalmodulatory activity and antioxidative propertyazelnidipine may be a promising DHP for targeting diabetesand cardiovascular diseases in hypertensive patients withmetabolic syndrome
Shinomiya et al [228] evaluated its AOA in culturedhuman arterial EC under OS Azelnidipine has shown apotent antioxidative effect that could be of significant clinicalbenefit when combined with its long-lasting antihypertensiveaction and low incidence of tachycardia
Azelnidipine inhibited TGF-1205731 and angiotensin II- (AngII-) activated 1205721(I) collagen mRNA expression in hepaticstellate cells (HSCs) (Ohyama et al [229]) FurthermoreTGF-1205731- and Ang II-induced OS and TGF-1205731-induced p38and JNK phosphorylation were reduced inHSCs treated withAZL Azelnidipine significantly decreased inflammatory cellinfiltration profibrotic genes expression HSC activation LPoxidative DNA damage and fibrosis in liver of CCl
4- or
TAA-treated mice Finally AZL prevented decrease of theexpression of some AO enzymes and accelerated regressionof liver fibrosis in CCl
4-treated mice Hence the antifibrotic
mechanism of AZL against CCl4-induced liver fibrosis in
mice may have been due to an increased level of AO defenseAs azelnidipine is widely used in clinical practice withoutserious adverse effects it may provide an effective newstrategy for antifibrotic therapy
358 Manidipine Manidipine (2-[4-(diphenylmethyl)pip-erazin-1-yl]ethyl methyl 26-dimethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate) is a DHP CCB withreported nephroprotective properties Calo et al [230] stud-ied effect of manidipine on gene expression and proteinlevel of OS related proteins p22(phox) (human neutrophilcytochrome b light chain (CYBA)) and heme oxygenase-1HO-1 Relevance for antihypertensive effects was revealedThe study assessed the effect of manidipine on normalsubjectsrsquo monocyte gene and protein expression of OS relatedproteins such as p22phox a NADPH oxidase system subunitcritical in generating O
2
∙minus and HO-1 induced by and pro-tective against OS Manidipine was compared with the ACEinhibitor captopril and the CCB nifedipine in the presenceand in the absence of sodiumarsenite (NaAsO
2) as an inducer
of OS Monocyte p22phox (CYBA) mRNA production wasreduced by both manidipine and captopril while no changeswere induced by nifedipine Manidipine increased monocyteHO-1 mRNA production while nifedipine and captoprilshowed no effect The effects of manidipine on p22phoxand HO-1 gene expression in the presence of OS were alsoconfirmed at the protein level Thus manidipine seems tosuppress p22phox and to increase the HO-1 mRNA produc-tion and protein level The manidipine-induced increase ofHO-1 gene and protein expression seems to be a peculiareffect of this drug since it is not observed with captopriland nifedipine This effect together with the reduction of
p22phoxmRNAproduction could play a role in its protectivemechanism against OS
359 Mebudipine The protective effect of mebudipine (14-dihydro-26-dimethyl-4-(3-nitrophenyl)-35-pyridinedicar-boxylic acid 3-methyl-5-tert-butyl ester BAY-n-6391) wasrevealed on OS and LP (MDA decrease SOD GPX andcatalase increase) in myocardial ischemic-reperfusion injuryin male rats (Ghyasi et al [231])
There are articles about other commercial and experi-mental DHPs on OS but we have reviewed only the mostcommonly studied compounds Effects of other commercialCA DHPs on OS are also mentioned in several parts of thisreview
36 14-DHPs Ca Agonists andTheir AOA and ARA For themost popular calcium agonist DHP Bay K 8644 no reactionwith peroxyl radicals was registered (Toniolo et al [114])However interactionwith other compounds possessing AOAand ARA (quercetin) was found
Opposite to that AON-acetylcysteine (NAC) diminishedincrease in Ca2+ transient amplitude and cell shorteninginduced by ISO and forskolin whereas NAC had no effecton the (S)-(minus)-methyl-14-dihydro-26-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylatemdash(minus)-BayK 8644-induced increases (Andersson et al [232])
Increased vasoconstriction responses to Bay K 8644 (3 times10minus7ndash3times 10minus5M)were significantly decreased by pyridoindoleantioxidant stobadine treatment in diabetes (Ceylan-Isik etal [233])
The functional interaction between two L-type Ca2+channel activators quercetin and Bay K 8644 has beeninvestigated in vascular smooth muscle cells Biological ARAcompound quercetin at nutritionally meaningful concen-trations limited the responsiveness of vascular L-type Ca2+channels to the pharmacological stimulation operated by BayK 8644 These data contribute to a better understanding ofquercetin effects on experimental in vivo cardioprotection(Saponara et al [234]) Thus these findings indicated thatalthough Bay K 8644 does not exert potent and direct AOAyet acting as calcium agonist it may affect efficiency of AOsubstances and vice versa
Interaction of grapefruit juice (containing quercetin andits analogues) with DHPs CA diminished effectiveness of CAaction of DHPs (Sica [235])
37 Interpretations of the Mechanism(s) of RadicalScavenging and AOA by DHPs
371 Molecular Mechanism(s) of Radical Scavenging andAOA of DHPs in the Model Systems 35-Dicarbonyl-14-di-hydropyridine derivatives possess powerful bis-120573-carbony-lvinyl-amino conjugation and for that reason cannot be con-sidered as ordinary amino antioxidants The electron andorH donation from DHPs ensures their reductant role andresults in AOA and ARA Oxidation reaction from DHPsresults in production of corresponding heteroaromatic pyri-dine derivatives
Oxidative Medicine and Cellular Longevity 23
Detailed studies were made about substituent in DHPring positions 14- namely 4-unsubstituted- 4-substituted4-alkyl- 4-aryl- 4-alkylaryl- ao 26- 35- (diacetyl ordialkoxycarbonyl chain ao) electronic and steric effects onAOA and ARA of DHPs [44 45 51] see Sections 331and 35 The bell-shaped dependence of DHPs AOA onthe 35-dialkoxycarbonyl- chain length was observed [4445 107 109 112] with the maximum activity at C
2H5ndash
C4H9 Decrease of AOA and incorporation into liposomes for
DHPs with alkyl chains longer than R gt C4H9further were
clarified as probable tendency to self-aggregation of thesecompounds ([51] and citation number 245 therein) Electronacceptorelectron donor properties are relevant for expres-sion of AOA or ARA of 35-disubstituted DHPs 35-Diacyl-substituted and 35-dicarbanilido- and 35-dipyridylamido-substituted DHPs are more active as AOs as their 35-dicyano-substituted analogues which have electron acceptorproperties [186]
Dubur et al [89] observed overwhelming steric influenceof substituents in position 4 of the DHP ring Gaviraghiet al [163 164] proposed that AO activity of DHPs ispartly dependent on capacity of the 14-DHP ring to donateelectrons to the propagating radical (ROO∙ or RO∙) and toreduce it to a less reactive form The abstraction (donation)of electron andor H in the oxidation and LP reactionstakes place from all 35-dicarbonyl-14-DHP systems andresults in the formation of corresponding pyridine derivatives(Augustyniak et al [51]) The physicochemical mechanism ofARA and AOA of 14-DHP has been extensively studied anddiscussed (Mulder et al [236]) but precise mechanisms oftheir activity need further clarification
The reactivity of C-4 substituted 14-DHPs possessingeither secondary or tertiary nitrogen atom in the DHP ringtoward alkyl alkylperoxyl radicals and ABTS radical cationwas determined in aqueous media at pH 74 [103] Thesecompounds reacted faster toward alkylperoxyl radicals andABTS radical cation than alkyl ones N-Ethyl-substitutedDHPs showed the lowest reactivity
The 4-methyl substituted DHP was the most reac-tive compound in previously mentioned reactions (Lopez-Alarcon et al [103]) However it was less active (068versus 10) than Trolox-C DHPs having electron-donatingsubstituents (4-Me-DHP and p-MeO-Phe-DHP) showed thehighest kinetic rate constants toward ABTS radical cation p-nitro-Phe-DHP a compound with an electron-withdrawingsubstituent showed a lower kinetic rate constant and N-alkyl-DHP compounds show kinetic rate constants lowerthan the -NH-DHP
Hydrogen at the 1-position of the DHP ring was revealedaccording to the deuteriumkinetic isotope effect studies to beinvolved in the proposedARAmechanismThis fact ismostlynoticeable in the case of alkyl radicals N-Ethyl-substitutedDHPs show the lowest reactivity when compared to Troloxor nisoldipine In all cases the respective pyridine derivativewas detected as the main product of the reaction (Lopez-Alarcon et al [103]) Authors indicate that the kinetic rateconstants toward alkyl alkylperoxyl andABTS radical cationdepend on the nature of the substituents in the C-4 positionof DHP and the presence of the secondary amine group in the
dihydropyridine ring that is the presence of the hydrogen in1-position
Yanez et al [197] have studied the reactivity of 11derivatives of 14-DHPs (including commercial CA) withalkylperoxyl radicals and ABTS radical cation The tested14-DHPs were 83-fold more reactive towards alkylperoxylradicals than to the ABTS cation radical All commercial14-DHP type CCBs were weaker than Trolox-C The par-ticipation of the hydrogen atom in the 1-position appearsto be very relevant for exhibited reactivity Hantzsch ester(diludine)was again found to be themost active compound inthe reaction with alkylperoxyl radicals 23-fold more activethan Trolox The photodegradation product of nifedipine(nitrosophenyl derivative of pyridine) also showed a highactivity Kinetic rate constants for the reaction between 14-DHP compounds and alkylperoxyl radicals exhibited a fairlygood linear correlation with the oxidation peak potentialof DHP derivatives However the activity of tested 14-DHPs towards ABTS radical cation showed an independencebetween kinetic rate constants and oxidation peak potentials
Kirule et al [195] andTirzit et al [196] studiedmechanismof AOA of 4-nitrophenyl-14-DHPs nifedipine and its ana-logues involving formation of 4-(21015840-nitrosophenyl)-pyridinederivative (as active principle) as a result of intramolecularredox reaction using chemical electrochemical and bio-chemical approaches (see Sections 331 and 351)
Nunez-Vergara et al [237] reported the electrochemicaloxidation of C4-hydroxyphenyl-substituted 14-DHP deriva-tives The oxidation proceeds via formation of the unstabledihydropyridyl radical as confirmed by controlled-potentialelectrolysis (CPE) and ESR experiments This type of 14-DHPs has significant activity towards the radicals even whencompared with commercial 14-DHP drugs with well-knownantioxidant ability
It was observed that nicardipine preferentially targets RO∙radicals and is inactive against ROO∙ Lacidipine on theother hand is equally active towards both types of radicals(Gaviraghi et al [164]) The cytoprotective effect againstexposure to H
2O2was more significant for lacidipine (ID
50=
14 nM its log119875 = 54 membrane partition = 136000 assumesposition located 7 A near to the membrane center otherless lipophilic DHPs located 12ndash16 A far from the center)as compared to amlodipine nifedipine and nicardipine insmooth muscle cell culture (Gaviraghi et al [164]) Oxidativeeffect of H
2O2shifts the Ca channel toward an open state
Thus the redox property of CCBs DHPs may augment theirCCB properties
Oxidation of pharmacologically active Hantzsch 14-dihydropyridines was found by electrogenerated superoxideusing a voltammetric approach in DMSO solutions (Ortiz etal [238] and Ortiz et al [239]) Raghuvanshi and Singh [240]have also reported oxidative aromatization of these DHPsinduced by superoxide
Chemiluminescence (CL) was used in the studies ana-lyzing the antioxidant activity of 12 various 4-flavonil-14-dihydropyridine derivatives (Kruk et al [241]) on a chemicalsystem involving a superoxide radical anion These deriva-tives showed structural similarity to flavonoids with respectto the presence of rings A B and C The results obtained in
24 Oxidative Medicine and Cellular Longevity
this study indicate that the tested derivatives may catalyzeconversion of superoxide radicals through mimicking theactivity of superoxide dismutase by delivering H+ for reac-tion
O2
minus∙+O2
minus∙+ 2H+ 997888rarr H
2O2+1O2
(3)
The enhanced emission of the light in the presence oftested compounds was significant and related to stimulatedproduction ofH
2O2and 1O
2fromO
2
∙The latter specieswereremoved from the reactionmixture by the following sequenceof reactions
H+
O2
minus∙997888rarr HO
2
∙
HO2
∙+O2
∙minus997888rarr HO
2
minus+1O2
2HO2
∙997888rarr H
2O2+1O2
2 (1O2) 997888rarr (O
2)2+ h]lowast
(4)
or to take part in spontaneous dismutation of H2O2
2H2O2997888rarr 2H
2O + 1O
2(5)
The authors have offered an original concept of action for 4-flavonil-14-dihydropyridine derivatives unrelated to that ofO2
∙ radical-trapping chain-breaking antioxidants Insteadthey showed that these compounds act similar to superoxidedismutases converting O
2
∙ to H2O2 Hydrogen peroxide
is less toxic for cells than O2
∙ because it is predominantlyremoved by peroxidases and catalases Finally AO effect ofthese DHPs differed from those mediated by flavonoids witha catechol structure of ring B which are well-known 1O
2
quenchersMulder and collaborators came to similar conclusions
especially related to molecular mechanisms of antioxidativeactivity of DHPs [236]TheAOproperties of Hantzsch 14-di-hydropyridine esters and two dibenzo-14-dihydropyridines910-dihydroacridine (DHAC) and N-methyl-910-dihydro-acridine (N-Me-DHAC) have been explored by determin-ing the autoxidation of styrene or cumene at 30∘C Theseexperiments showed that Hantzsch esters are virtually inac-tive as chain-breaking antioxidants (CB-AOs) contrary tothe findings observed by Lopez-Alarcon et al [103] whoused CB-AOA in aqueous media at pH 74 Their reactivitytoward peroxyl radicals was shown to be some 5 orders ofmagnitude lower than that of the excellent CB-AO 22578-pentamethyl-6-hydroxy-chroman (PMHC)
DHAC was found to be sim10 times less reactive thanPMHC kinetic measurements using DHAC N-deuterio-DHAC and N-Me-DHAC pointing out the abstraction ofN-H hydrogen in DHAC by peroxyl radicals despite the factthat the calculated C-H bond dissociation enthalpy (BDE) inDHAC is about 11 kcalmol lower than the N-H BDE Therates of hydrogen atom abstraction by the 22-diphenyl-1-picrylhydrazyl radical (DPPH∙) have also been determined
for the same series of compounds The trends in the peroxyl∙and DPPH∙ rate constants were found to be similar [236]
Tirzit et al [242] have observed quenching of singletoxygen by DHPs This observation paved the ground forfurther research related to reactions of DHPs with hydroxylradicals (Tirzit et al [243]) singlet oxygen (Kazush etal [94]) and mechanisms of action A series of 14-DHPderivatives in NAD-H-Cu2+-H
2O2system inhibited forming
of the hydroxyl radical (HO∙) while 14-DHP derivativeswith electron donor substituents in the molecule were shownto be capable themselves of generating HO∙ in the presenceof Cu2+ and H
2O2 Rubene et al [186] also described
interaction of 14-DHP derivatives with Fentonrsquos reagentwhich produces hydroxyl radical (HO∙) Rate constants ofthe DHPs reaction (1st order) with HO∙ radical were highin the range 109 L times mol times secminus1 close to that of NADHcysteine and thiourea 35-Diacetyl- derivatives reacted fastercompared to 35-dialkoxycarbonyl- ones The reaction ratedecrease was observed in the case of substitution at position4 as compared to 4-unsubstituted DHPs Some DHPs havingelectron donor -COOminus groups in the 35- or 26- positionsof DHP ring reacted immediately (having rate constantshigher as 109 L times mol times secminus1) Rate constants with HO
2
∙
and O2
∙minus radicals were of lower degree Thus DHPs actingas oxygen radical scavengers could effectively inhibit ROSrelated reactions of LP initiation stage
Nifedipine and nitrendipine reactivity toward singletoxygen was also studied [244] Nifedipine was shown tobe a good scavenger of excited oxygen mainly via physicaldeactivation with values of the total rate constant rangingfrom 208 times 105Mminus1 sminus1 (in dioxane) to 930 times 105Mminus1 sminus1(in propylene carbonate)The less reactive pathway generateda photooxidation product For that reason a mechanisminvolving a perepoxide-like encounter complex in the firststep of the reaction path was proposed (see [244] Figures8 and 9 therein) The dependence was observed on solventmicroscopic parameters of the total rate constant for the reac-tion between singlet oxygen and 14-DHPs These findingsshow that nifedipine possesses stronger protective activity inbiological systems than nitrendipine
Density-functional-theory (DFT) calculations made byWang et al [245] confirmed the former experimental obser-vations that Hantzsch ester diludine is potent antioxi-dant with high H atom-donating ability and relatively lowprooxidant activity Possible reaction pathways for radicalsderived from 14-dihydropyridine and the resonance modesfor radical species were given [245]
Moreover two ethoxycarbonyl (EtOCO) substituentsat C(2) and C(6) should further enhance Hantzsch esterdiludine H-atom-donating ability due to resonance effectsHowever DHPs should be used in nonpolar rather than inpolar solvents since in the latter not H-atom but electrontransfer is preferred in the radical scavenging process [245]
Mulder et al [246] proposed that quantum-thermochem-ical calculations must be used with caution to indicate ldquoapromising lead antioxidantrdquo as they criticized the density-functional-theory (DFT) calculations made by Wang et al[245]
Oxidative Medicine and Cellular Longevity 25
372 Possible Mechanisms of DHPs ARA and AOA in the Bio-logical Systems Interaction with Other OSModifiers Some ofthese mechanisms were already described (Sections 331 (2)-(b) 331 (2)-(c) 331 (3)-(b) 35)
Enzymatic sources of ROSwith confirmed functional rolein hypertension are NADPH oxidase NO synthase (NOS)xanthine oxidase and cyclooxygenase Godfraind [3] hasreviewed AO effects and protective action of calcium channelblockers (CCBs) Yao et al [247] observed antioxidant effects(as inhibition of LP) for cardio- and neuroprotective CCBs(3ndash300 120583molL) including 7 DHPs in homogenates of ratbrain IC
50values (120583M) were as follows nifedipine (515) gt
barnidipine (586) gt benidipine (712) gt nicardipine (1293)gt amlodipine (1355) gt nilvadipine (1673) gt nitrendipine(2521) gt diltiazem (gt300) = verapamil (gt300) There arealso research articles describing the AO properties of CCBsthrough direct scavenging effect or through preservationof the endogenous SOD activity These findings indicatethat CCBs may also act by reducing the production ofvasoconstrictors angiotensin and endothelin
When present in concentrations that can be achievedin plasma CCBs may inhibit LP formation [3] This AOactivity seems to be typical for high lipophilic CCBs becausetheir chemical structure facilitates proton-donating andresonance-stabilization mechanisms that quench the freeradical reaction Their insertion in the membrane nearpolyunsaturated fatty acids at relatively high concentrationspotentiates proton donation (or atomary H) to lipid peroxidemolecules thereby blocking the peroxidation process Theremaining unpaired free electron associated with the CCBmolecule can be stabilized in well-defined resonance struc-tures associated with the DHP ring (Mason et al [48])
The radical reaction (according to Godfraind [3]) thatdescribes the AO effects of a DHP CCBs is LOOlowast + DHPrarr LOOH + DHPlowast (where LOOlowast is lipid peroxide radical)which in general is reaction (7) of the LP reaction cascadeconsisting of sim10 reactions (Scheme 2) [89]
As the rate constants of in vitro interaction of 4-substituted DHPs with peroxyl radicals are three ordersof magnitude lower than that of the vitamin E derivativethese DHPs must be considered as weak AO (Ursini [204])However due to partition coefficient of DHPs in membranesand in case of specific binding high local concentration ofDHPs may be obtained
DHPs without CCB properties for instance Bay w 9798although structurally related to nifedipine inhibit TNF-120572-induced vascular cell adhesion molecule-1 expression inendothelial cells by suppressing reactive oxygen speciesgeneration [248]
Mitrega et al [249] have discovered that antiarrhythmicand hemodynamic effects of oxidized heteroaromatic DHPsoxy nifedipine oxy nimodipine oxy nitrendipine and oxynisoldipine suggest that CCB DHPs and their metabolitescould act at least in two ways targeting OS related eventsas reductants (see Section 351 (1)) andor bypassing OSrelatedmetabolic routes Authors postulated that contrary tocurrent belief NIF metabolites are pharmacologically activeATP sensitive potassium channels were mentioned as a tar-get
38 DHPs Anti- or Prooxidants Several substances (ascorbicacid being the most commonly studied) can serve either asantioxidants or as prooxidants depending on given condi-tions (Herbert [250]) Therefore Halliwell [251] has reporteddilemma related to polyphenols as possible antioxidantsand prooxidants causing experimental artifacts (about 25)by oxidation of antioxidant compounds in the cell culturemedia Nevertheless it is generally accepted opinion thatpolyphenols act as antioxidants in vivo Studies on DHPs alsoface such a dilemmaThe exact roles (anti- or prooxidative) ofany specific DHP depend on its structure appliedachievedconcentration and specificity of the targetexperimentaltesting system
This situation resembles the case of antioxidative effectsof tocopherol which depends on the fate of the secondaryradical as proposed by Winterbourn [252] The question wasldquoVitamin E - Pro- or Antioxidantrdquo
997888rarr chain termination of lipid peroxidation
(6)
Prooxidant
Toc∙ + Lipid-H 997888rarr Lipid∙ (in LDL particles) (7)
This example shows that generally speaking any AO mustfulfil several criteria to be considered as an effective com-pound physiologically
(i) It must be able to functionally interact with endoge-nous scavengers even at low concentrations
(ii) It must affect endogenous pathways of OS(iii) It should not have undesirable adverse effect(iv) It should manifest the antioxidant efficacy dependent
on the oxidant(v) It must discriminate among different strategies
needed for 1-electron and 2-electron processes(vi) Radical scavengers can be prooxidant unless linked to
a radical sink (Winterbourn [252])
According to these statements DHPs could be effective asAO under physiological conditions in vivo (Godfraind [3]and others [30 31 38]) and in vitro in various experimentalsystems (cell and tissue) (see Sections 33 34 35)
Hence calcium antagonists appeared to disrupt thefine balance between the production and scavenging ofROS Nifedipine verapamil and diltiazem were shown toinduce significant oxidative stress in the epididymal sperm(increased MDA and decreased catalase and superoxidedismutase activity) This may be the reason for the inductionof male infertility [253]
The dualism of 14-DHP effects has been recorded asinhibition or promotion of LP as quenching or initiating
26 Oxidative Medicine and Cellular Longevity
oxygen and nitrogen free radical chain reactions radiopro-tecting or radiosensitizing antagonizing or synergizing Ca2+in electromechanical coupling as well as in the membranestabilization or labilization
39 Could DHPs Be Involved in Antioxidative Stress Beforebeing applied in vivo the optimal dose and optimal timeintervals forDHPs applicationmust be knownNamely whileROS have been traditionally considered as toxic byproductsof aerobic metabolism we know nowadays that ROS may actas essential signaling molecules needed for the control ofmany different physiological processes Whether the role ofROS will be damaging protective or signaling depends onthe delicate equilibrium between time- and location-specificROS production and scavenging Accordingly the imbalanceof the increased AO potential so-called antioxidative stresscould be dangerous similar to chronic OS in particular incase of extended exposure Inappropriate interventions inthe oxidative homeostasis by excessive antioxidants especiallyin case of chronic exposure to antioxidants might havevery negative effects as was published in the ATBC studyshowing an increased cancer incidence in smokers treatedby excessive beta-carotene [254] Therefore overconsump-tion of any natural or synthetic AO including DHPs asdietary supplements or drugs must be avoided in order tosuppress oxidative damage and must not disrupt the well-integrated antioxidant defense network (Poljsak [255] andPoljsak and Milisav [256]) This is especially important whenadministrating lipid-soluble antioxidants that can be storedin biomembranes thus not only attenuating or preventing LPbut also affecting physiological effects of the natural antiox-idants in particular tocopherol The interrelationship withthe status of endogenous antioxidantsprooxidants should befollowed
DHPs primarily suppress the initiation stages of LPprocessThey do not entirely stop the LP propagation Actingsynergistically with tocopherol diludine may prevent patho-logical excess of ROS production within the lipid moiety ofthe cellular membranes and LDL However due to its lowsolubility and fast metabolism its concentration in the cellsis low For that reason it cannot cause antioxidative stresseven if used for an extended period of time Thus diludine(diethone) could be only a mild antioxidant it has potentialfor restoring the pool of natural antioxidants (as synergist of120572-tocopherol and polyphenols) in the cells
Moreover DHPs CA used for cardioprotection andvasodilatation as commercial drugs in low concentrationsare fast metabolized via CYP3A4 and for that reason theirapplication does not induce cellular AO stress [53 160]However Godfraind and Salomone [257] have postulated noevidence that allows recommending dietary supplementationwith antioxidants for the primary or secondary prevention ofcardiovascular disease
So far there are no reports on antioxidative stress causedby some DHPs diludine and its analogues Diludine andits analogues therefore could act as adaptogens supportinghormetic effects of mild oxidative stress These compoundsmay act as potential multisided modulators of Yin-Yang
cycles of redox and cell functions (the electroplasmic cycle)(Wagner et al [258])
4 Conclusions
14-Dihydropyridines (14-DHPs) have broad spectrum ofOS modulating activities DHPs have reducing and lipidperoxidation inhibitor properties act as reductants in simplechemical systems and stabilize various biological systems(LDL mitochondria microsomes cells and tissues) againstOS Examples and peculiarities and mechanisms of antiox-idant activity (AOA) and antiradical activity (ARA) as wellas stress-protective effect of DHPs including commercialcalcium antagonists (CA) were highlighted These activitiesdepend on various structural parameters related to DHPs(presence and character of substituents) lipophilicity anddepth of the incorporation in the biologicalmembranesTheyalso depend on the experimental model system for exploringthe lipid peroxidation or oxidative stress Stress-protectiveeffect of some metabolites of CA (nifedipine) is reviewedAlthough some DHPs including CA have prooxidant prop-erties (on epididymal sperm cells) they can generally beconsidered as potent antioxidants Therefore comparisonof the AOA and ARA of different DHPs (mutually andwith other AOs) was described in detail According to thedata presented the DHPs might be considered as bellwetheramong synthetic compounds targeting OS and as a kind ofpharmacological measure for respective field of organic andmedicinal chemistry
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
Authors from Latvian IOS acknowledge ESF 201300021DP1112013APIAVIAA011 and National Research Pro-gramme PUBLIC HEALTHBiomedicine of the Republicof Latvia for financial support administration of the Insti-tute for technical support and Rufus Smits PhD for con-sultations in English The support of Cooperation in Euro-pean System of Science and Technology (COST) Domain ofChemistry Molecular Sciences and Technologies (CMST)was of highest importance for preparation of this paper
[2] D J Triggle ldquo14-Dihydropyridines as calcium channel ligandsand privileged structuresrdquoCellular andMolecular Neurobiologyvol 23 no 3 pp 293ndash303 2003
[3] T Godfraind ldquoAntioxidant effects and the therapeutic modeof action of calcium channel blockers in hypertension andatherosclerosisrdquo Philosophical Transactions of the Royal SocietyB Biological Sciences vol 360 no 1464 pp 2259ndash2272 2005
[4] E Cadenas ldquoMitochondrial free radical production and cellsignalingrdquoMolecular Aspects of Medicine vol 25 no 1-2 pp 17ndash26 2004
[5] E Cadenas ldquoFree radicals oxidative stress and diseasesrdquo inLecture PSC 616 p 38 Missouri University of Science andTechnology Rolla Mo USA httpwwwcarnicominstituteorgarticlesenrique cadenaspdf
[6] K Rahman ldquoStudies on free radicals antioxidants and co-fac-torsrdquo Clinical Interventions in Aging vol 2 no 2 pp 219ndash2362007
[7] V Bocci and G Valacchi ldquoFree radicals and antioxidants howto reestablish redox homeostasis in chronic diseasesrdquo CurrentMedicinal Chemistry vol 20 no 27 pp 3397ndash3415 2013
[8] M Valko C J Rhodes J Moncol M Izakovic and M MazurldquoFree radicals metals and antioxidants in oxidative stress-induced cancerrdquo Chemico-Biological Interactions vol 160 no 1pp 1ndash40 2006
[9] G Bartosz ldquoReactive oxygen species destroyers or messen-gersrdquo Biochemical Pharmacology vol 77 no 8 pp 1303ndash13152009
[10] R Visconti and D Grieco ldquoNew insights on oxidative stress incancerrdquo Current Opinion in Drug Discovery and Developmentvol 12 no 2 pp 240ndash245 2009
[11] R N Kujundzic N Zarkovic and K G Troselj ldquoPyridinenucleotides in regulation of cell death and survival by redoxand non-redox reactionsrdquo Critical Reviews in Eukaryotic GeneExpression vol 24 no 4 pp 287ndash309 2014
[12] B Halliwell and J M C Gutteridge ldquoThe definition and mea-surement of antioxidants in biological systemsrdquo Free RadicalBiology and Medicine vol 18 no 1 pp 125ndash126 1995
[13] V D Kancheva and O T Kasaikina ldquoBio-antioxidantsmdashachemical base of their antioxidant activity and beneficial effect
on human healthrdquo Current Medicinal Chemistry vol 20 no 37pp 4784ndash4805 2013
[14] H V Panglossi Ed Frontiers in Antioxidants Research NovaScience Publishers New York NY USA 2006
[15] E B Burlakova E M Molochkina and G A NikiforovldquoHybrid antioxidantsrdquo Oxidation Communications vol 31 no4 pp 739ndash757 2008 httpmembraneustceducnpaperpdfHybrid20Antioxidantspdf
[16] A Bast and G R M M Haenen ldquoTen misconceptions aboutantioxidantsrdquo Trends in Pharmacological Sciences vol 34 no 8pp 430ndash436 2013
[17] E B Burlakova A V 0lesenko E M Molochkina N PPalmina and N G Khrapova Bioantioxidants for RadiationDamage and Malignant Growth Nauka Moscow Russia 1975(Russian)
[18] J Fang T Seki and H Maeda ldquoTherapeutic strategies by mod-ulating oxygen stress in cancer and inflammationrdquo AdvancedDrug Delivery Reviews vol 61 no 4 pp 290ndash302 2009
[19] M Valko D Leibfritz J Moncol M T D Cronin M Mazurand J Telser ldquoFree radicals and antioxidants in normal physi-ological functions and human diseaserdquo International Journal ofBiochemistry and Cell Biology vol 39 no 1 pp 44ndash84 2007
[20] M Jimenez-Del-Rio and C Velez-Pardo ldquoThe bad the goodand the ugly about oxidative stressrdquo Oxidative Medicine andCellular Longevity vol 2012 Article ID 163913 13 pages 2012
[21] C D Kamat S Gadal M Mhatre K S Williamson Q N Pyeand K Hensley ldquoAntioxidants in central nervous system dis-eases preclinical promise and translational challengesrdquo Journalof Alzheimerrsquos Disease vol 15 no 3 pp 473ndash493 2008
[22] A Pompella H Sies R Wacker et al ldquoThe use of totalantioxidant capacity as surrogate marker for food quality andits effect on health is to be discouragedrdquo Nutrition vol 30 no7-8 pp 791ndash793 2014
[23] Z Ye and H Song ldquoAntioxidant vitamins intake and the risk ofcoronary heart disease meta-analysis of cohort studiesrdquo Euro-pean Journal of Cardiovascular Prevention and Rehabilitationvol 15 no 1 pp 26ndash34 2008
[24] P Knekt J Ritz M A Pereira et al ldquoAntioxidant vitamins andcoronary heart disease risk a pooled analysis of 9 cohortsrdquoTheAmerican Journal of Clinical Nutrition vol 80 no 6 pp 1508ndash1520 2004
[25] A C Carr and M C M Vissers ldquoSynthetic or food-derivedvitamin Cmdashare they equally bioavailablerdquo Nutrients vol 5 no11 pp 4284ndash4304 2013
[26] R Tabrizchi ldquoEdaravoneMitsubishi-TokyordquoCurrentOpinion inInvestigational Drugs vol 1 no 3 pp 347ndash354 2000
[27] K Kikuchi S Tancharoen N Takeshige et al ldquoThe efficacy ofedaravone (radicut) a free radical scavenger for cardiovasculardiseaserdquo International Journal of Molecular Sciences vol 14 no7 pp 13909ndash13930 2013
[28] D Mauzerall and F H Westheimer ldquo1-Benzyldihydronicoti-namidemdasha model for reduced DPNrdquo Journal of the AmericanChemical Society vol 77 no 8 pp 2261ndash2264 1955 ChemicalAbstracts vol 50 Article ID 2588i 1956
[29] F Bossert and W Vater ldquo14-Dihydropyridinesmdasha basis fordeveloping new drugsrdquo Medicinal Research Reviews vol 9 no3 pp 291ndash324 1989
[30] G Swarnalatha G Prasanthi N Sirisha and CMadhusudhanaChetty ldquo14-Dihydropyridines a multtifunctional moleculemdash areviewrdquo International Journal of ChemTech Research vol 3 no1 pp 75ndash89 2011
28 Oxidative Medicine and Cellular Longevity
[31] M Cataldi and F Bruno ldquo14-Dihydropyridines the multiplepersonalities of a blockbuster drug familyrdquo Translational Medi-cine UniSa vol 4 no 2 pp 12ndash26 2012 httpwwwncbinlmnihgovpmcarticlesPMC3728803
[32] R Vitolina A Krauze G Duburs and A Velena ldquoAspects ofthe amlodipine pleiotropy in biochemistry pharmacology andclinicsrdquo International Journal of Pharmaceutical Sciences andResearch vol 3 no 5 pp 1215ndash1232 2012
[33] D Grover S N Mokale and M T Shete ldquoDihydropyridinea novel pharmacophorerdquo International Journal of Pharmaceu-tical Erudition vol 1 no 2 pp 16ndash29 2011 httppharmaeru-ditionorgContentPaper20111-RV-320Final2016-29pdf
[34] A M Vijesh A M Isloor S K Peethambar K N ShivanandaT Arulmoli and N A Isloor ldquoHantzsch reaction synthesis andcharacterization of somenew 14-dihydropyridine derivatives aspotent antimicrobial and antioxidant agentsrdquo European Journalof Medicinal Chemistry vol 46 no 11 pp 5591ndash5597 2011
[35] P Mehta and P Verma ldquoAntimicrobial activity of some deriva-tives of 14-dihydropyridinesrdquo Journal of Chemistry vol 2013Article ID 865128 4 pages 2013
[36] P Olejnıkova L Svorc D Olsovska et al ldquoAntimicrobialactivity of novel C2-substituted 14-dihydropyridine analoguesrdquoScientia Pharmaceutica vol 82 no 2 pp 221ndash232 2014
[37] S Sepehri H Perez Sanchez and A Fassihi ldquoHantzsch-typedihydropyridines and biginelli-type tetra-hydropyrimidinesa review of their chemotherapeutic activitiesrdquo Journal of Phar-macy amp Pharmaceutical Sciences vol 18 no 1 pp 1ndash52 2015httpsejournalslibraryualbertacaindexphpJPPSarticleview2383617863
[38] S A Khedkar and P B Auti ldquo14-Dihydropyridines a classof pharmacologically important moleculesrdquo Mini-Reviews inMedicinal Chemistry vol 14 no 3 pp 282ndash290 2014
[39] G D Tirzit and G Ya Duburs ldquo14-dihydropyridines as inhi-bitors of free-radical reactionsrdquo Chemistry of Heterocyclic Com-pounds vol 8 no 1 pp 126ndash127 1972 Translated from KhimiyaGeterotsiklicheskikh Soedinenii no1 pp 133ndash134 1972 (Rus-sian)
[40] I Bogeski R Kappl C Kummerow R Gulaboski M Hothand B A Niemeyer ldquoRedox regulation of calcium ion channelschemical and physiological aspectsrdquoCell Calcium vol 50 no 5pp 407ndash423 2011
[41] S A Giller G Y Dubur Y R Uldrikis et al ldquoDiludine [Themethod to obtain 35-dicarbonylderivatives of 26-dimethyl-14-dihydropyridines]rdquo Authors certificate of USSR no 3004651971 [Byull Izobret no13 p 95 1971] and following patentsPatent of England no 1294650 1973 Patent of France no2055458 1971 Patent of Japan no 702883 1973 Patent ofHolland no 149787 1976 Patent of Italy no 969022 1974 Patentof FRG no 2036403 1978 US Patent no 3883673 1975 USPatent no 3948924 1976
[42] S A Giller G Y Dubur Y R Uldrikis et al ldquoImprovementsin or relating to the stabilization of carotenerdquo GB Patent no1294650 1972
[43] S A Giller G Y Dubur Y R Uldrikis et al ldquoStabilization ofcarotenerdquo US Patent no 3883673 1975 Chemical Abstracts vol83 Article ID 95193 1975
[44] Yu A Zilber G Ya Dubur K K Kumsar and A Kh VelenaldquoThe effect of antioxidants on the peroxidation of bimole-cular phospholipid membranesrdquo Latvijas PSR ZA Vestis Izves-tia Akademii Nauk Latviyskoy SSR vol 6 pp 80ndash82 1971(Russian) translated from the original Russian Doc Accesion
No AD0771751 distributed by NTIS US Department of Com-merce httpwwwdticmildtictrfulltextu2771751pdf
[45] G Ya Dubur Yu A Zilbers A Kh Velena A O Kumerovaand G D Tirzitis ldquoMultistage study of regulation of peroxida-tion processes in biological membranes by antioxidants of 14-dihydropyridine grouprdquo Izvestiya Akademii Nauk LatviyskoySSR vol 336 no 7 pp 65ndash68 1975 (Russian)
[46] R P Mason and M W Trumbore ldquoDifferential membraneinteractions of calcium channel blockers Implications forantioxidant activityrdquo Biochemical Pharmacology vol 51 no 5pp 653ndash660 1996
[47] R P Mason M F Walter M W Trumbore E G Olmstead Jrand P E Mason ldquoMembrane antioxidant effects of the chargeddihydropyridine calcium antagonist amlodipinerdquo Journal ofMolecular and Cellular Cardiology vol 31 no 1 pp 275ndash2811999
[48] R PMason I T MakMW Trumbore and P EMason ldquoAnti-oxidant properties of calcium antagonists related to membranebiophysical interactionsrdquo American Journal of Cardiology vol84 no 4 pp 16ndash22 1999
[49] R PMasonMW Trumbore and P EMason ldquoMembrane bio-physical interaction of amlodipine and antioxidant propertiesrdquoDrugs vol 59 no 2 pp 9ndash16 2000 (French)
[50] R P Mason P Marche and T H Hintze ldquoNovel vascularbiology of third-generation L-type calcium channel antagonistsAncillary actions of amlodipinerdquo Arteriosclerosis Thrombosisand Vascular Biology vol 23 no 12 pp 2155ndash2163 2003
[51] A Augustyniak G Bartosz A Cipak et al ldquoNatural andsynthetic antioxidants an updated overviewrdquo Free RadicalResearch vol 44 no 10 pp 1216ndash1262 2010
[52] T Grune N Zarkovic and K Kostelidou ldquoLipid peroxidationresearch in Europe and the COST B35 action lsquoLipid Peroxida-tion Associated Disordersrsquordquo Free Radical Research vol 44 no10 pp 1095ndash1097 2010
[53] E Carosati P Ioan M Micucci et al ldquo14-Dihydropyridinescaffold in medicinal chemistry the story so far and perspec-tives (part 2) action in other targets and antitargetsrdquo CurrentMedicinal Chemistry vol 19 no 25 pp 4306ndash4323 2012
[54] U Eisner and J Kuthan ldquoThe chemistry of dihydropyridinesrdquoChemical Reviews vol 72 no 1 pp 1ndash42 1972 httpwwwsci-encemadnessorgtalkfilesphppid=138742ampaid=6475
[55] J Kuthan and A Kurfurst ldquoDevelopment in dihydropyri-dine chemistryrdquo Industrial amp Engineering Chemistry ProductResearch and Development vol 21 no 2 pp 191ndash261 1982
[56] A Sausins and G Duburs ldquoSynthesis of 14-dihydropyridinesby cyclocondensation reactionsrdquo Heterocycles vol 27 no 1 pp269ndash289 1988
[57] A E Sausins and G Y Duburs ldquoSynthesis of 14-dihydro-pyridines in cyclocondensation reactions (review)rdquo Chemistryof Heterocyclic Compounds vol 28 no 4 pp 363ndash391 1992Translated from Khimiya Geterotsiklicheskikh Soedinenii no 4pp 435ndash467 1992 (Russian)
[58] S Kazda ldquoTwenty years of dihydropyridinesrdquo in Dihydropy-ridines Progress in Pharmacology and Therapy W-D Busse BGarthoff and F Seuter Eds pp 1ndash12 Springer Verlag BerlinGermany 1993
[59] J-P Wan and Y Liu ldquoRecent advances in new multicomponentsynthesis of structurally diversified 14-dihydropyridinesrdquo RSCAdvances vol 2 no 26 pp 9763ndash9777 2012
[61] Reaxys Database[62] J Tuttle ldquoStructure mechanism and reactivity of hantzsch
estersrdquo in MacMillan Lab Group Meeting (082504) p 332004 httpwwwprincetoneduchemistrymacmillangroup-meetingsJBT20Hantzschpdf
[63] A Saini S Kumar and J S Sandhu ldquoHantzsch reaction recentadvances in Hantzsch 14-dihydropyridinesrdquo Journal of Sci-entific amp Industrial Research vol 67 pp 95ndash111 2008
[64] L LW Cheung S A Styler and A P Dicks ldquoRapid and conve-nient synthesis of the 14-dihydropyridine privileged structurerdquoJournal of Chemical Education vol 87 no 6 pp 628ndash630 2010
[65] A Kumar R A Maurya S Sharma M Kumar and G BhatialdquoSynthesis and biological evaluation of N-aryl-14-dihydro-pyridines as novel antidyslipidemic and antioxidant agentsrdquoEuropean Journal of Medicinal Chemistry vol 45 no 2 pp 501ndash509 2010
[66] R S Kumar A Idhayadhulla A J Abdul Nasser and J SelvinldquoSynthesis and anticoagulant activity of a new series of 14-dihydropyridine derivativesrdquo European Journal of MedicinalChemistry vol 46 no 2 pp 804ndash810 2011
[67] H A Stefani C B Oliveira R B Almeida et al ldquoDihydro-pyrimidin-(2H)-ones obtained by ultrasound irradiation anew class of potential antioxidant agentsrdquo European Journal ofMedicinal Chemistry vol 41 no 4 pp 513ndash518 2006
[68] H Sun C Shang L Jin and J Zhang ldquoSynthesis and antiox-idant activity of a series of novel 3-chalcone-substituted 14-dihydropyridine derivativesrdquoHeterocyclic Communications vol18 no 5-6 pp 239ndash243 2012
[69] D B Tikhonov and B S Zhorov ldquoStructural model for dihy-dropyridine binding to L-type calcium channelsrdquo The Journalof Biological Chemistry vol 284 no 28 pp 19006ndash19017 2009
[70] G Y Dubur and Y R Uldrikis ldquoThe oxidation of 14-dihydro-pyridinesrdquo Chemistry of Heterocyclic Compounds vol 6 no 1pp 80ndash84 1970 Translated from Khimiya GeterotsiklicheskikhSoedinenii no 1 pp 83ndash88 1970 (Russian)
[71] G Ya Duburs A O Kumerova and Ya R Uldrikis ldquoEnzymicoxidation of hydrogenated pyridines with peroxidase-hydrogenperoxide systemrdquoLatvijas PSRZAVestis vol 73 no 7 pp 73ndash771970 (Russian) Chemical Abstracts vol 73 Article ID 94913g1970
[72] K Xie Y-C Liu Y Cui J-GWang Y Fu andT CWMak ldquoN-methyl-(R)-3-(tert-butyl)-sulfinyl-14-dihydropyridine a novelNADHmodel compoundrdquoMolecules vol 12 no 3 pp 415ndash4222007
[73] S Tamagaki T Mimura and W Tagaki ldquoMetal-ion-facilitatedoxidations of dihydropyridines with molecular oxygen andhydrogen peroxiderdquo Journal of the Chemical Society PerkinTransactions 2 no 10 pp 1645ndash1650 1990
[74] D Tirzite G Tirzitis andD Antipova ldquoReductive ability of 14-dihydropyridine derivatives in relation to ions of trivalent ironrdquoChemistry of Heterocyclic Compounds vol 35 no 5 pp 592ndash594 1999
[76] J Ogle J Stradins and L Baumane ldquoFormation and decay offree cation-radicals in the course of electro-oxidation of 12- and14-dihydropyridines (Hantzsch esters)rdquo Electrochimica Actavol 39 no 1 pp 73ndash79 1994
[77] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for the
synthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts C Wittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Berlin Germany 2010
[78] WDu and Zh Yu ldquoBiomimetic in situ regeneration of cofactorsNAD(P)+ and NAD(P)H models hantzsch esters and dihy-drophenanthridinerdquo Synlett vol 23 no 9 pp 1300ndash1304 2012
[79] H K Chenault and G M Whitesides ldquoRegeneration ofnicotinamide cofactors for use in organic synthesisrdquo AppliedBiochemistry and Biotechnology vol 14 no 2 pp 147ndash197 1987
[80] Y R Uldrikis A A Zidermane E A Biseniex I E Preisa GY Dubur and G D Tirzit ldquoEsters of 26-dimethyl-14-dihydro-pyridine-35-dicarboxylic acid and method of obtainingthereofrdquo WO 8000345 A1 1978 httpworldwideespacenetcompublicationDetailsbiblioDB=EPODOCampII=1ampND=3ampadjacent=trueamplocale=en EPampFT=Dampdate=19800306ampCC=WOampNR=8000345A1ampKC=A1
[81] Y Sambongi H Nitta K Ichihashi M Futai and I Ueda ldquoAnovel water-soluble Hantzsch 14-dihydropyridine compoundthat functions in biological processes through NADH regener-ationrdquo Journal of Organic Chemistry vol 67 no 10 pp 3499ndash3501 2002
[82] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for thesynthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts ChWittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Verlag Berlin Germany 2010
[83] T Okamura T Kikuchi A Nagamine et al ldquoAn approach formeasuring in vivo cerebral redox states using the oxidative con-version of dihydropyridine to pyridinium ion and themetabolictrapping principlerdquo Free Radical Biology and Medicine vol 38no 9 pp 1197ndash1205 2005
[84] K A Schellenberg and F H Westheimer ldquoA free-radicaloxidation of a dihydropyridine1ardquo The Journal of OrganicChemistry vol 30 no 6 pp 1859ndash1862 1965
[85] K A Schellenberg ldquoReaction of hydroxyl radical with thymi-dine Scavenging by a dihydropyridinerdquo Federation Proceedingsvol 38 no 3 I p 1433 1979
[86] E S Huyser J A K Harmony and F L McMillian ldquoPeroxideoxidations of dihydropyridine derivativesrdquo Journal of the Amer-ican Chemical Society vol 94 no 9 pp 3176ndash3180 1972
[87] A Sakamoto S T Ohnishi and R Ogawa ldquoInhibition of lipidperoxidation by some dihydropyridine derivativesrdquo Journal ofAnesthesia vol 7 no 2 pp 193ndash197 1993
[88] R Hardeland ldquoReview Neuroprotection by radical avoidancesearch for suitable agentsrdquo Molecules vol 14 no 12 pp 5054ndash5102 2009
[89] G Ya Dubur A Kh Velena V M Gukasov and Yu AVladimirov ldquoRegulation of peroxidation of mitochondrialmembrane lipids initiated by Fe2+ ions by antoxidants of the14-dihydropyridine series in experiments in vitrordquo Biomed-itsinskaya Khimiya vol 22 no 5 pp 665ndash673 1976 (Russian)Chemical Abstracts vol 88 Article ID 2640 1977
[90] G RMMHaenenM J T J Arts A Bast andMD ColemanldquoStructure and activity in assessing antioxidant activity in vitroand in vivo a critical appraisal illustrated with the flavonoidsrdquoEnvironmental Toxicology and Pharmacology vol 21 no 2 pp191ndash198 2006
[91] G Tirzitis and G Bartosz ldquoDetermination of antiradical andantioxidant activity basic principles and new insightsrdquo ActaBiochimica Polonica vol 57 no 2 pp 139ndash142 2010
30 Oxidative Medicine and Cellular Longevity
[92] G R Buettner and R P Mason ldquoSpin-trapping methods fordetecting superoxide and hydroxyl free radicals in vitro and invivordquo inCritical Reviews of Oxidative Stress and Aging Advancesin Basic Science Diagnostics and Intervention R G Cutler andH Rodriguez Eds vol 1 chapter 2 pp 27ndash38World ScientificLondon UK 2003
[93] M M Tarpey and I Fridovich ldquoMethods of detection ofvascular reactive species Nitric oxide superoxide hydrogenperoxide and peroxynitriterdquo Circulation Research vol 89 no3 pp 224ndash236 2001
[94] E Y Kazush E I Sagun G D Tirzit and G Y DaburldquoQuenching of singlet oxygen by electron donating derivativesof 14-dihydropyridinerdquo Chemistry of Heterocyclic Compoundsvol 30 no 5 pp 562ndash563 1994
[95] G Tirzitis E Kazush and G Duburs ldquoReaction of 14-dihydropyridine derivatives with peroxynitrite anionrdquo Chem-istry of Heterocyclic Compounds vol 34 no 3 pp 321ndash3231998 (Russian) Translated from Khimiya GeterotsiklicheskikhSoedinenii no 3 pp 355ndash357 1998
[96] L J Nunez-Vergara C Lopez-Alarcon P A Navarrete-EncinaA M Atria C Camargo and J A Squella ldquoElectrochemicaland EPR characterization of 14-dihydropyridines Reactivitytowards alkyl radicalsrdquo Free Radical Research vol 37 no 1 pp109ndash120 2003
[97] D Tirzite A Krauze A Zubareva G Tirzitis and G DubursldquoSynthesis and antiradical activity of 5-acetyl-2-alkylthio-4-aryl-6-methyl-14-dihydropyridine-3-carboxylic acid nitrilesrdquoChemistry of Heterocyclic Compounds vol 38 no 7 pp 795ndash800 2002
[98] H Ohkawa N Ohishi and K Yagi ldquoAssay for lipid peroxidesin animal tissues by thiobarbituric acid reactionrdquo AnalyticalBiochemistry vol 95 no 2 pp 351ndash358 1979
[99] N Zarkovic ldquo4-Hydroxynonenal as a bioactive marker ofpathophysiological processesrdquo Molecular Aspects of Medicinevol 24 no 4-5 pp 281ndash291 2003
[100] M Parola G Bellomo G Robino G Barrera and M UDianzani ldquo4-Hydroxynonenal as a biological signal molecularbasis and pathophysiological implicationsrdquo Antioxidants andRedox Signaling vol 1 no 3 pp 255ndash284 1999
[101] T Lovakovic M Poljak-Blazi G Duburs et al ldquoGrowthmodulation of human cells in vitro by mild oxidative stressand 14-dihydropyridine derivative antioxidantsrdquo CollegiumAntropologicum vol 35 no 1 pp 137ndash141 2011
[102] R van den Berg G R M M Haenen H van den Bergand A Bast ldquoApplicability of an improved Trolox equivalentantioxidant capacity (TEAC) assay for evaluation of antioxidantcapacity measurements of mixturesrdquo Food Chemistry vol 66no 4 pp 511ndash517 1999
[103] C Lopez-Alarcon P Navarrete C Camargo J A Squella andL J Nunez-Vergara ldquoReactivity of 14-dihydropyridines towardalkyl alkylperoxyl radicals and ABTS radical cationrdquo ChemicalResearch in Toxicology vol 16 no 2 pp 208ndash215 2003
[104] V Valenzuela P Santander C Camargo J A Squella C Lopez-Alarcon and L J Nunez-Vergara ldquo14-Dihydropyridines reac-tivity of nitrosoaryl and nitroaryl derivatives with alkylperoxylradicals andABTS radical cationrdquo Free Radical Research vol 38no 7 pp 715ndash727 2004
[105] L G Tsetlin N A Chebotareva B I Kurganov A K VelenaG Y Dubur and V Z Lankin ldquoStudy of 14-dihydropyridinesas lipoxygenase inhibitors with the use of hydrated reversedmicellesrdquo Pharmaceutical Chemistry Journal vol 22 no 6 pp425ndash428 1988 (Russian)
[106] J Panek Z Reblova L Kocirkova et al ldquoAntioxidant activityof dihydropyridine derivativesrdquo Czech Journal of Food Sciencesvol 18 pp 144ndash145 2000
[107] G Tirzitis I Kirule and G Duburs ldquoAntioxidationsaktivitatder 35-dicarbonylderivate des 26-demethyl-14-dihydropyri-dinsrdquo Fett Wissenschaft TechnologieFat Science Technology vol90 no 10 pp 411ndash413 1988
[108] M Plotniece G Tirzitis Y Uldrikis et al ldquoSynthesis of 14-dihydropyridine derivatives having an oxy- alkoxy- or dimeth-ylaminophenyl substituent in the 4 position their antioxidantactivity and their binding to phospholipid membranesrdquo Chem-istry of Heterocyclic Compounds vol 32 no 10 pp 1166ndash11721996 Translated from Khimiya Geterotsiklicheskikh Soedineniino 10(352) pp 1358ndash1365 1996 (Russian)
[109] D Y Rubene V S Sharov V I Olenev G D Tirzit G Y Duburand Y A Vladimirov ldquoUse of chemiluminescent method forthe evaluation of antioxidant activity of some derivatives of 14-dihydropyridinerdquo Russian Journal of Physical Chemistry A vol55 no 2 pp 511ndash512 1981 (Russian)
[110] M C R Symons and JM C Gutteridge Free Radicals and IronChemistry Biology and Medicine Oxford Science PublicationsOxford University Press Oxford UK 1998
[111] M Repetto J Semprine and A Boveris ldquoLipid peroxidationchemical mechanism biological implications and analyticaldeterminationrdquo in Lipid Peroxidation A Catala Ed Section ILipid Peroxidation Chemical Mechanisms Antioxidants Bio-logical Implications of Biochemistry Genetics and MolecularBiology chapter 1 pp 3ndash30 InTech Rijeka Croatia 2012
[112] A Velena J Zilbers and G Duburs ldquoDerivatives of 14-dihydropyridines asmodulators of ascorbate-induced lipid per-oxidation and high-amplitude swelling ofmitochondria causedby ascorbate sodium linoleate and sodiumpyrophosphaterdquoCellBiochemistry and Function vol 17 no 4 pp 237ndash252 1999
[113] M V Bilenko L N Shelenkova G Y Dubur and A K VelenaldquoUse of antioxidants to prevent renal damage during acuteischemia and reperfusionrdquo Bulletin of Experimental Biology andMedicine vol 96 no 3 pp 1195ndash1198 1983 Translated fromByulletenrsquo Eksperimentalrsquonoi Biologii i Meditsiny vol 96 no 9pp 8ndash11 1983 (Russian)
[114] R Toniolo F Tubaro F Ursini and G Bontempelli ldquoAn elec-troanalytical investigation on the redox properties of calciumantagonist dihydropyridinesrdquo Electroanalysis vol 15 no 10 pp855ndash861 2003
[115] L Kourimska J Pokorny and G Tirzitis ldquoThe antioxidant aci-tivity of 26-dimethyl-35-diethoxycarbonyl-14-dihydropyri-dine in edible oilsrdquo Nahrung vol 37 no 1 pp 91ndash93 1993
[116] C Lopez-Alarcon H Speisky J A Squella C Olea-Azar CCamargo and L J Nunez-Vergara ldquoReactivity of 14-dihydro-pyridines toward SIN-1-derived peroxynitriterdquo PharmaceuticalResearch vol 21 no 10 pp 1750ndash1757 2004
[117] R A Olek W Ziolkowski J J Kaczor L Greci J Popinigisand J Antosiewicz ldquoAntioxidant activity of NADH and its ana-loguemdashan in vitro studyrdquo Journal of Biochemistry andMolecularBiology vol 37 no 4 pp 416ndash421 2004
[118] E Niki N Noguchi and N Gotoh ldquoInhibition of oxidativemodification of low density lipoprotein by antioxidantsrdquo Jour-nal of Nutritional Science andVitaminology vol 39 supplementpp S1ndashS8 1993
[119] N Rojstaczer and D J Triggle ldquoStructure-function relation-ships of calcium antagonists effect on oxidative modificationof low density lipoproteinrdquo Biochemical Pharmacology vol 51no 2 pp 141ndash150 1996
Oxidative Medicine and Cellular Longevity 31
[120] A Sevanian L Shen and FUrsini ldquoInhibition of LDLoxidationand oxidized LDL-induced cytotoxicity by dihydropyridinecalcium antagonistsrdquo Pharmaceutical Research vol 17 no 8 pp999ndash1006 2000
[121] A Negre-Salvayre and R Salvayre ldquoProtection by Ca2+ channelblockers (nifedipine diltiazem and verapamil) against the tox-icity of oxidized low density lipoprotein to cultured lymphoidcellsrdquo British Journal of Pharmacology vol 107 no 3 pp 738ndash744 1992
[122] A Negre-Salvayre G FitoussiM Troly and R Salvayre ldquoCom-parative cytoprotective effect of dihydropyridine calcium chan-nel blockers against the toxicity of oxidized low density lipopro-tein for cultured lymphoid cellsrdquo Biochemical Pharmacologyvol 44 no 12 pp 2379ndash2386 1992
[123] L Cominacini A F Pasini U Garbin et al ldquoAntioxidant activ-ity of different dihydropyridinesrdquo Biochemical and BiophysicalResearch Communications vol 302 no 4 pp 679ndash684 2003
[124] L Cominacini U Garbin A Fratta Pasini et al ldquoOxidized low-density lipoprotein increases the production of intracellularreactive oxygen species in endothelial cells inhibitory effect oflacidipinerdquo Journal of Hypertension vol 16 no 12 part 2 pp1913ndash1919 1998
[125] H M Lander ldquoAn essential role for free radicals and derivedspecies in signal transductionrdquo The FASEB Journal vol 11 no2 pp 118ndash124 1997
[126] M L L Martinez E Rizzi M M Castro et al ldquoLercanidipinedecreases vascular matrix metalloproteinase-2 activity andprotects against vascular dysfunction in diabetic ratsrdquo EuropeanJournal of Pharmacology vol 599 no 1ndash3 pp 110ndash116 2008
[127] P Lesnik C Dachet L Petit et al ldquoImpact of a combinationof a calcium antagonist and a 120573-blocker on cell- and copper-mediated oxidation of LDL and on the accumulation and effluxof cholesterol in human macrophages and murine J774 cellsrdquoArteriosclerosis Thrombosis and Vascular Biology vol 17 no 5pp 979ndash988 1997
[128] G Sobal E J Menzel and H Sinzinger ldquoCalcium antagonistsas inhibitors of in vitro low density lipoprotein oxidation andglycationrdquoBiochemical Pharmacology vol 61 no 3 pp 373ndash3792001
[129] E Lupo R Locher B Weisser and W Vetter ldquoIn vitro antiox-idant activity of calcium antagonists against LDL oxidationcompared with 120572-tocopherolrdquo Biochemical and BiophysicalResearch Communications vol 203 no 3 pp 1803ndash1808 1994
[130] J Zou Y Li H-Q Fan and J-G Wang ldquoEffects of dihydropy-ridine calcium channel blockers on oxidized low-density lipo-protein induced proliferation and oxidative stress of vascularsmooth muscle cellsrdquo BMC Research Notes vol 5 article 1682012
[131] C Napoli S Salomone T Godfraind et al ldquo14-Dihydro-pyridine calcium channel blockers inhibit plasma and LDL oxi-dation and formation of oxidation-specific epitopes in the arte-rial wall and prolong survival in stroke-prone spontaneouslyhypertensive ratsrdquo Stroke vol 30 no 9 pp 1907ndash1915 1999
[132] G Zernig I Graziadei T Moshammer C Zech N Reider andH Glossmann ldquoMitochondrial Ca2+ antagonist binding sitesare associated with an inner mitochondrial membrane anionchannelrdquo Molecular Pharmacology vol 38 no 3 pp 362ndash3691990
[133] F E Hunter Jr A Scott P E Hochstein et al ldquoStudies of themechanism of ascorbate-induced swelling and lysis of isolatedliver mitochondriardquo The Journal of Biological Chemistry vol239 pp 604ndash613 1964
[134] D R Janero B Burghardt and R Lopez ldquoProtection of cardiacmembrane phospholipid against oxidative injury by calciumantagonistsrdquoBiochemical Pharmacology vol 37 no 21 pp 4197ndash4203 1988
[135] A Karadag B Ozcelik and S S Saner ldquoReview of methods todetermine antioxidant capacitiesrdquo FoodAnalyticalMethods vol2 no 1 pp 41ndash60 2009
[136] Y I Gubskiı N V Litvinova and E V Shnurko-TabakovaldquoAntioxidant and antiradical activity of various classes of antiox-idantsrdquo Ukrainskiı Biokhimicheskiı Zhurnal vol 66 no 4 pp114ndash116 1994 (Russian)
[137] M Takei M Hiramatsu and A Mori ldquoInhibitory effects ofcalcium antagonists onmitochondrial swelling induced by lipidperoxidation or arachidonic acid in the rat brain in vitrordquoNeurochemical Research vol 19 no 9 pp 1199ndash1206 1994
[138] M Takei M Hiramatsu R Edamatsu and A Mori ldquoFreeradical scavenging by calcium antagonistsrdquo Neurosciences vol20 no 2 pp 75ndash82 1994
[139] Ya P Stradin G Ya Dubur Yu A Beilis Ya R Uldrikis andA F Korotkova ldquoVoltammetry of 14-dihydropyridine deriva-tives I Potentials of electrochemical oxidation of 35-diacyl-and 35-di(alkoxycarbonyl)-14-dihydropyridines in acetoni-trilerdquo Chemistry of Heterocyclic Compounds no 1 pp 84ndash871972 (Russian)
[140] E V Ivanov T V Ponomarjova G N Merkusev et al ldquoEinneuer Haut-Radioprotektor Diethon (experimentelle Unter-suchung)rdquo Radiobiologia Radiotherapia vol 31 no 1 pp 69ndash78 1990
[141] E V Ivanov T V Ponomareva G N Merkushev et al ldquoRadia-tion modulating properties of derivates of 14-dihydropyridineand 12345678910-decahydroacridine-18 dionerdquo Radiat-sionnaia Biologiia Radioecologiia vol 44 no 5 pp 550ndash5592004 (Russian)
[142] R O Vitolinia D A Berzinia A K Velena I A Vutsina A AKimenis and G Y Duburs ldquoThe protective effects of the cal-cium antagonist foridon in acute myocardial ischaemiardquo Kardi-ologiya vol 27 no 3 pp 90ndash93 1987 (Russian)
[143] A H Velena G Ya Duburs R O Vitolina et al ldquoEffect ofryodipine on electromechanical parameters of heart and vesselscAMP phosphodiesterase activity and swelling-contractioncycle of mitochondriardquo Arzneimittelforschung vol 35 no 6 pp907ndash914 1985
[144] L I Utno Z E Lipsberga A A Silova M I Girgensone EA Bisenieks and G I Ia ldquoCardioprotective properties of a 14-dihydropyridine derivative glutapyrone in deep hypothermiardquoBiulletenrsquo Eksperimentalrsquonoı Biologii i Meditsiny vol 108 no 11pp 558ndash561 1989 (Russian)
[145] M A S FernandesM S Santos J A F Vicente et al ldquoEffects of14-dihydropyridine derivatives (cerebrocrast gammapyroneglutapyrone and diethone) onmitochondrial bioenergetics andoxidative stress a comparative studyrdquoMitochondrion vol 3 no1 pp 47ndash59 2003
[146] M A S Fernandes M S Santos A J M Moreno et al ldquoEffectsof 5-acetyl(carbamoyl)-6-methylsulfanyl-14-dihydropyridine-5-carbonitriles on rat liver mitochondrial functionrdquo Toxicologyin Vitro vol 23 no 7 pp 1333ndash1341 2009
[147] L Klimaviciusa A Kalda A Kaasik et al ldquoNeuroprotectiveactivity of 14-dihydropyridine derivatives structure determi-nantsrdquo Proceedings of the Latvian Academy of Sciences BNatural Exact and Applied Sciences vol 61 no 1-2 pp 33ndash372007
32 Oxidative Medicine and Cellular Longevity
[148] L Klimaviciusa M A S Fernandes N Lencberga et alldquoTargeting the mitochondria by novel adamantane-containing14-dihydropyridine compoundsrdquo in Bioenergetics K B ClarkEd pp 257ndash272 InTech 2012
[149] V Klusa L Klimaviciusa G Duburs J Poikans and AZharkovsky ldquoAnti-neurotoxic effects of tauropyrone a taurineanaloguerdquo Advances in Experimental Medicine and Biology vol583 pp 499ndash508 2006
[150] N Sampson P Berger and Ch Zenzmaier ldquoRedox signalingas a therapeutic target to inhibit myofibroblast activation indegenerative fibrotic diseaserdquo BioMed Research Internationalvol 2014 Article ID 131737 14 pages 2014
[151] T L Leto and M Geiszt ldquoRole of Nox family NADPH oxidasesin host defenserdquoAntioxidantsampRedox Signaling vol 8 no 9-10pp 1549ndash1561 2006
[152] K K Griendling D Sorescu and M Ushio-Fukai ldquoNAD(P)Hoxidase role in cardiovascular biology and diseaserdquo CirculationResearch vol 86 no 5 pp 494ndash501 2000
[153] H Chen Y S Song and P H Chan ldquoInhibition of NADPHoxi-dase is neuroprotective after ischemia-reperfusionrdquo Journal ofCerebral Blood Flow and Metabolism vol 29 no 7 pp 1262ndash1272 2009
[154] P Hochstein and L Ernster ldquoADP-activated lipid peroxidationcoupled to the TPNH oxidase system of microsomesrdquo Biochem-ical and Biophysical Research Communications vol 12 no 5 pp388ndash394 1963
[155] I I Gubskiı AGGoriushkoNV Litvinova et al ldquoAntioxidantproperties and membranotropic effect of certain derivatives of14-dihydropyridinerdquo Ukrainskiı Biokhimicheskiı Zhurnal vol71 no 4 pp 35ndash39 1999 (Russian)
[156] F Engineer and R Sridhar ldquoInhibition of rat heart andliver microsomal lipid peroxidation by nifedipinerdquo BiochemicalPharmacology vol 38 no 8 pp 1279ndash1285 1989
[157] T Goncalves A P Carvalho and C R Oliveira ldquoAntioxidanteffect of calcium antagonists on microsomai membranes iso-lated from different brain areasrdquo European Journal of Pharma-cology vol 204 no 3 pp 315ndash322 1991
[158] M E Letelier P Izquierdo L Godoy A M Lepe and MFaundez ldquoLiver microsomal biotransformation of nitro-aryldrugs mechanism for potential oxidative stress inductionrdquoJournal of Applied Toxicology vol 24 no 6 pp 519ndash525 2004
[159] M E Letelier P Entrala C Lopez-Alarcon et al ldquoNitroaryl-14-dihydropyridines as antioxidants against rat liver microsomesoxidation induced by ironascorbate Nitrofurantoin and naph-thalenerdquo Toxicology in Vitro vol 21 no 8 pp 1610ndash1618 2007
[160] F P Guengerich W R Brian M Iwasaki M-A Sari CBaarnhielm and P Berntsson ldquoOxidation of dihydropyridinecalcium channel blockers and analogues by human liver cyto-chrome P-450 IIIA4rdquo Journal of Medicinal Chemistry vol 34no 6 pp 1838ndash1844 1991
[161] S H Park S-W RhaW-Y Shin et al ldquoAS-160 Calcium channelblockers of dihydropyridine class reduce the antiplatelet effectof Clopidogrel what is clinical impactrdquo The American Journalof Cardiology vol 107 no 8 supplement p 47A 2011
[162] C Asma and D M Reda ldquoEvaluation of dihydropyridinecalcium antagonist effects on the stress bioindicator orga-nism Saccharomyces cerevisiaerdquo Annals of Biological Researchvol 4 no 10 pp 40ndash46 2013 httpscholarsresearchlibrarycomABR-vol4-iss10ABR-2013-4-10-40-46pdf
[163] G Gaviraghi A M Pastorino E Ratti and D G TristldquoCalcium channel blockers with antioxidant activityrdquo in Free
Radicals Lipoprotein Oxidation andAtherosclerosis G BellomoG Finardi E Maggi and E Rice-Evans Eds pp 431ndash456Richelieu Press London UK 1995
[164] G Gaviraghi AM Pastorino E Ratti and D G Trist ldquoAntiox-idant dihydropyridines a new and comprehensive therapy forfree radical-induced cardiovascular diseasesrdquo in Free Radicalsin Biology and Environment F Minisci Ed vol 27 of NATOASI Series pp 193ndash221 Springer Dordrecht The Netherlands1997
[165] P D Henry ldquoAntiperoxidative actions of calcium antagonistsand atherogenesisrdquo Journal of Cardiovascular Pharmacologyvol 18 supplement 1 pp S6ndashS10 1991
[166] F Kouoh B Gressier T Dine et al ldquoAntioxidant effects andanti-elastase activity of the calcium antagonist nicardipine onactivated human and rabbit neutrophilsmdasha potential antiath-erosclerotic property of calcium antagonistsrdquo CardiovascularDrugs andTherapy vol 16 no 6 pp 515ndash520 2002
[167] S Parthasarathy D Litvinov K Selvarajan and M GarelnabildquoLipid peroxidation and decompositionmdashconflicting roles inplaque vulnerability and stabilityrdquo Biochimica et BiophysicaActa vol 1781 no 5 pp 221ndash231 2008
[168] D-Q Liu Z-Q Pang D-H Zhao and B-H Sheng ldquoEffects offuryl-dihydropyridines I on lipid peroxides of ischemic myo-cardium and ATPases activity of erythrocyte membranes inratsrdquo Acta Pharmacologica Sinica vol 12 no 3 pp 253ndash2561991
[169] V Lukic-Panin T Kamiya H Zhang et al ldquoPrevention of neu-ronal damage by calcium channel blockers with antioxidativeeffects after transient focal ischemia in ratsrdquo Brain Research vol1176 no 1 pp 143ndash150 2007
[170] Y Allanore D Borderie H Lemarechal O G Ekindjian andA Kahan ldquoAcute and sustained effects of dihydropyridine-typecalcium channel antagonists on oxidative stress in systemicsclerosisrdquo American Journal of Medicine vol 116 no 9 pp 595ndash600 2004
[171] I Casetta V Govoni and E Granieri ldquoOxidative stress antioxi-dants and neurodegenerative diseasesrdquo Current PharmaceuticalDesign vol 11 no 16 pp 2033ndash2052 2005
[172] M J T J Arts Assessing antioxidant activity [PhD the-sis] Maastricht University Maastricht The Netherlands 2007httparnounimaasnlshowcgifid=8676
[173] G Dıaz-Araya L Godoy L Naranjo A Squella M E Letelierand L J Nunez-Vergara ldquoAntioxidant effects of 14-dihydro-pyridine and nitroso aryl derivatives on the Fe+3ascorbate-stimulated lipid peroxidation in rat brain slicesrdquo General Phar-macology The Vascular System vol 31 no 3 pp 385ndash391 1998
[174] Y Fukuhara K Tsuchiya Y Horinouchi et al ldquoProtectiveeffect of photodegradation product of nifedipine against tumornecrosis factor 120572-induced oxidative stress in human glomerularendothelial cellsrdquo Journal of Medical Investigation vol 58 no1-2 pp 118ndash126 2011
[175] W Stengel M Jainz and K Andreas ldquoDifferent potencies ofdihydropyridine derivatives in blocking T-type but not L-typeCa2+ channels in neuroblastoma-glioma hybrid cellsrdquo EuropeanJournal of Pharmacology vol 342 no 2-3 pp 339ndash345 1998
[176] O M Panasenko D J Tirzite G D Tirzitis and G J DubursldquoEffect of some 14-dihydropyridine derivatives on structuralorganization of erythrocyte membranesrdquo Biologicheskie Mem-brany (Biochemistry (Moscow) Series A Membrane and CellBiology) vol 1 pp 919ndash925 1984 (Russian)
[177] L G Herbette Y M H Vant Erve and D G Rhodes ldquoInter-action of 14 dihydropyridine calcium channel antagonists with
Oxidative Medicine and Cellular Longevity 33
biological membranes lipid bilayer partitioning could occurbefore drug binding to receptorsrdquo Journal of Molecular andCellular Cardiology vol 21 no 2 pp 187ndash201 1989
[178] L G Herbette P E Mason G Gaviraghi T N Tulenko andR P Mason ldquoThe molecular basis for lacidipinersquos unique phar-macokinetics optimal hydrophobicity results in membraneinteractions that may facilitate the treatment of atherosclerosisrdquoJournal of Cardiovascular Pharmacology vol 23 supplement 5pp S16ndashS25 1994
[179] G V Belevitch G Y Dubur G E Dobretsov N K Kurek andM M Spirin ldquoCalcium antagonists riodipine nifedipine andverapamil binding to model and biological membranes fluore-scence analysisrdquo Biologicheskie Membrany (Biochemistry(Moscow) Series A Membrane and Cell Biology) vol 5 pp768ndash776 1988 (Russian)
[180] R P Mason G E Gonye D W Chester and L G HerbetteldquoPartitioning and location of Bay K 8644 14-dihydropyridinecalcium channel agonist in model and biological membranesrdquoBiophysical Journal vol 55 no 4 pp 769ndash778 1989
[181] M Cindric A Cipak J Serly et al ldquoReversal of multidrugresistance inmurine lymphoma cells by amphiphilic dihydropy-ridine antioxidant derivativerdquo Anticancer Research vol 30 no10 pp 4063ndash4070 2010
[182] F Shekari H Sadeghpour K Javidnia et al ldquoCytotoxic andmultidrug resistance reversal activities of novel 14-dihydro-pyridines against human cancer cellsrdquo European Journal ofPharmacology vol 746 no 1 pp 233ndash244 2015
[183] X-F Zhou Q Shao R A Coburn and M E Morris ldquoQuanti-tative structure-activity relationship and quantitative structure-pharmacokinetics relationship of 14-dihydropyridines andpyridines as multidrug resistance modulatorsrdquo PharmaceuticalResearch vol 22 no 12 pp 1989ndash1996 2005
[184] R Berkels T Breitenbach H Bartels et al ldquoDifferent antioxida-tive potencies of dihydropyridine calcium channel modulatorsin various modelsrdquo Vascular Pharmacology vol 42 no 4 pp145ndash152 2005
[185] S Borovic G Tirzitis D Tirzite et al ldquoBioactive 14-dihydro-isonicotinic acid derivatives prevent oxidative damage of livercellsrdquo European Journal of Pharmacology vol 537 no 1ndash3 pp12ndash19 2006
[186] D Ya Rubene G D Tirzitis and G Ya Duburs ldquoInteractionof some 14-dihydropyridine derivatives with Fentonrsquos reagentrdquoLatvijas PSRZinatnuAkademijas Vestis Kimijas Serija Proceed-ings of the Latvian SSR Academy of Sciences Chemistry Seriespp 212ndash216 1982 (Russian)
[187] K Ondrias V Misık D Gergel and A Stasko ldquoLipid per-oxidation of phosphatidylcholine liposomes depressed by thecalcium channel blockers nifedipine and verapamil and bythe antiarrhythmic-antihypoxic drug stobadinerdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1003 no 3pp 238ndash245 1989
[188] I T Mak and W B Weglicki ldquoComparative antioxidant acti-vities of propranolol nifedipine verapamil and diltiazemagainst sarcolemmal membrane lipid peroxidationrdquoCirculationResearch vol 66 no 5 pp 1449ndash1452 1990
[189] I T Mak P Boehme and W B Weglicki ldquoProtective effects ofcalcium channel blockers against free radical-impaired endo-thelial cell proliferationrdquo Biochemical Pharmacology vol 50 no9 pp 1531ndash1534 1995
[190] S Ray S Mondal and N Dana ldquoEvaluation of protective roleof nifedipine on lipid peroxidation using reduced glutathione as
model markerrdquo Oxidants and Antioxidants in Medical Sciencevol 1 no 2 pp 97ndash100 2012
[191] M Yamato T Shiba T Ide Y Honda K-I Yamada andH Tsutsui ldquoNifedipine treatment reduces brain damage aftertransient focal ischemia possibly through its antioxidativeeffectsrdquoHypertension Research vol 34 no 7 pp 840ndash845 2011
[192] V Chander and K Chopra ldquoNifedipine attenuates changes innitric oxide levels renal oxidative stress and nephrotoxicityinduced by cyclosporinerdquo Renal Failure vol 27 no 4 pp 441ndash450 2005
[193] K M Gaafa M M Badawy and A A Hamza ldquoThe protectiveeffects of ascorbic acid cimetidine and nifedipine on diethyl-dithiocarbamate-induced hepatic toxicity in albino ratsrdquo Drugand Chemical Toxicology vol 34 no 4 pp 405ndash419 2011
[194] H Sugawara K Tobise and S Onodera ldquoAbsence of antiox-idant effects of nifedipine and diltiazem on myocardial mem-brane lipid peroxidation in contrast with those of nisoldipineand propranololrdquo Biochemical Pharmacology vol 47 no 5 pp887ndash892 1994
[195] I E Kirule D Y Rubene E A Bisenieks G D Tirzit and GY Dubur ldquo4-Nitrophenyl-14-dihydropyridinesmdasha new groupof inhibitors of peroxide oxidationrdquo Chemistry of HeterocyclicCompounds vol 18 no 3 p 316 1982
[196] G D Tirzit I E Kirule L K Baumane R A Gavar Y PStradynrsquo andG YDubur ldquoMechanism of the antioxidant actionof 26-dimethyl-35-dimethoxy-carbonyl-4-(2-nitrophenyl)14-dihydropyridinerdquoChemistry ofHeterocyclic Compounds vol 20no 8 pp 915ndash918 1984
[197] C Yanez C Lopez-Alarcon C Camargo V Valenzuela J ASquella and L J Nunez-Vergara ldquoStructural effects on thereactivity 14-dihydropyridines with alkylperoxyl radicals andABTS radical cationrdquo Bioorganic and Medicinal Chemistry vol12 no 9 pp 2459ndash2468 2004
[198] VMisik A J Stasko D Gergel and K Ondrias ldquoSpin-trappingand antioxidant properties of illuminated and nonilluminatednifedipine and nimodipine in heart homogenate and modelsystemrdquo Molecular Pharmacology vol 40 no 3 pp 435ndash4391991
[199] K Ondrias V Misık A Stasko D Gergelrsquo and M HromadovaldquoComparison of antioxidant properties of nifedipine and illu-minated nifedipine with nitroso spin traps in low densitylipoproteins and phosphatidylcholine liposomesrdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1211 no 1pp 114ndash119 1994
[200] A Stasko V Brezova S Biskupic K Ondrias and V MisıkldquoReactive radical intermediates formed from illuminated nife-dipinerdquoFree Radical Biology andMedicine vol 17 no 6 pp 545ndash556 1994
[201] K Ishizawa Y Izawa-Ishizawa N Yamano et al ldquoNitrosoni-fedipine ameliorates the progression of type 2 diabetic nephro-pathy by exerting antioxidative effectsrdquo PLoS ONE vol 9 no 1Article ID e86335 2014
[202] H Fujii and L J Berliner ldquoIn vivo EPR evidence for free radicaladducts of nifedipinerdquoMagnetic Resonance in Medicine vol 42no 4 pp 691ndash694 1999
[203] S Bollo S Finger J C Sturm L J Nunez-Vergara and JA Squella ldquoCyclic voltammetry and scanning electrochemicalmicroscopy studies of the heterogeneous electron transferreaction of some nitrosoaromatic compoundsrdquo ElectrochimicaActa vol 52 no 15 pp 4892ndash4898 2007
34 Oxidative Medicine and Cellular Longevity
[204] F Ursini ldquoTissue protection by lacidipine insight from redoxbehaviorrdquo Journal of Cardiovascular Pharmacology vol 30supplement 2 pp S28ndashS30 1997
[205] P G Cristofori F A Crivellente I Faustinelli et al ldquoInvolve-ment of the nitric oxide system in the anti-atheroscleroticpotential of lacidipine in the apoE-deficient mouse a mor-phological functional and electrochemical studyrdquo ToxicologicPathology vol 32 no 4 pp 493ndash499 2004
[206] X-P Zhang E L Kit S Mital S Chahwala and T HHintze ldquoParadoxical release of nitric oxide by an L-type calciumchannel antagonist the R+ enantiomer of amlodipinerdquo Journalof Cardiovascular Pharmacology vol 39 no 2 pp 208ndash2142002
[207] F Franzoni G Santoro F Regoli et al ldquoAn in vitro study of theperoxyl and hydroxyl radical scavenging capacity of the calciumantagonist amlodipinerdquo Biomedicine and Pharmacotherapy vol58 no 8 pp 423ndash426 2004
[208] S V Gatsura ldquoOxygen-dependent mechanisms underlying theantiischemic effect of verapamil and amlodipinerdquo Bulletin ofExperimental Biology and Medicine vol 137 no 1 pp 40ndash422004
[209] Y Hirooka Y Kimura M Nozoe Y Sagara K Ito and KSunagawa ldquoAmlodipine-induced reduction of oxidative stressin the brain is associated with sympatho-inhibitory effects instroke-prone spontaneously hypertensive ratsrdquo HypertensionResearch vol 29 no 1 pp 49ndash56 2006
[210] B Tomlinson and I F F Benzie ldquoAntioxidant effect of lercani-dipine (note)rdquo Hypertension vol 42 no 4 pp e10ndashe11 2003
[211] A A Faraqui ldquoNeurochemical aspects of 4-hydroxynonenalrdquoin Lipid Mediators and Their Metabolism in the Brain A AFaraqui Ed chapter 6 pp 159ndash191 Springer New York NYUSA 2011
[212] V S NascimentoM S DrsquoAlva A AOliveira et al ldquoAntioxidanteffect of nimodipine in young rats after pilocarpine-inducedseizuresrdquo Pharmacology Biochemistry and Behavior vol 82 no1 pp 11ndash16 2005
[213] O Ismailoglu P Atilla S Palaoglu et al ldquoThe therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjuryrdquo Turkish Neurosurgery vol 22 no 6 pp 740ndash746 2012
[214] M Matsubara and K Hasegawa ldquoBenidipine a dihydropy-ridine-calcium channel blocker prevents lysophosphatidyl-choline-induced injury and reactive oxygen species productionin human aortic endothelial cellsrdquo Atherosclerosis vol 178 no1 pp 57ndash66 2005
[215] M Matsubara K Yao and K Hasegawa ldquoBenidipine adihydropyridine-calcium channel blocker inhibits lysophos-phatidylcholine-induced endothelial injury via stimulation ofnitric oxide releaserdquo Pharmacological Research vol 53 no 1 pp35ndash43 2006
[216] MMatsubara and K Hasegawa ldquoEffects of benidipine a dihyd-ropyridine-Ca2+ channel blocker on expression of cytokine-induced adhesion molecules and chemoattractants in humanaortic endothelial cellsrdquo European Journal of Pharmacology vol498 no 1ndash3 pp 303ndash314 2004
[217] M Matsubara O Akizuki J-I Ikeda K Saeki K Yao and KSasaki ldquoBenidipine an anti-hypertensive drug inhibits reactiveoxygen species production in polymorphonuclear leukocytesand oxidative stress in salt-loaded stroke-prone spontaneouslyhypertensive ratsrdquo European Journal of Pharmacology vol 580no 1-2 pp 201ndash213 2008
[218] A C Rosenkranz H Lob T Breitenbach R Berkels and RRoesen ldquoEndothelial antioxidant actions of dihydropyridines
and angiotensin converting enzyme inhibitorsrdquo European Jour-nal of Pharmacology vol 529 no 1ndash3 pp 55ndash62 2006
[219] V Kain S Kumar and S L Sitasawad ldquoAzelnidipine preventscardiac dysfunction in streptozotocin-diabetic rats by reducingintracellular calcium accumulation oxidative stress and apop-tosisrdquo Cardiovascular Diabetology vol 10 article 97 2011
[220] K Nakamura S Yamagishi and H Inoue ldquoUnique atheropro-tective property of azelnidipine a dihydropyridine-based cal-cium antagonistrdquoMedical Hypotheses vol 65 no 1 pp 155ndash1572005
[221] TMatsui S Yamagishi K Nakamura S Kikuchi andH InoueldquoAzelnidipine a dihydropyridine-based calcium antagonistinhibits angiotensin II-induced oxidative stress generation anddownregulation of pigment epithelium-derived factor mRNAlevels in microvascular endothelial cellsrdquo Drugs under Experi-mental and Clinical Research vol 31 no 5-6 pp 215ndash219 2005
[222] C Ohmura H Watada T Shimizu et al ldquoCalcium channelblocker azelnidipine reduces lipid hydroperoxides in patientswith type 2 diabetes independent of blood pressurerdquo EndocrineJournal vol 54 no 5 pp 805ndash811 2007
[223] H Daikuhara F Kikuchi and T Ishida ldquoThe combination ofOLmesartan and a CAlcium channel blocker (azelnidipine) orcandesartan and a calcium channel blocker (amlodipine) intype 2 diabetic hypertensive patients theOLCA studyrdquoDiabetesand Vascular Disease Research vol 9 no 4 pp 280ndash286 2012
[224] MAbe NMaruyama KOkada SMatsumoto KMatsumotoand M Soma ldquoAdditive antioxidative effects of azelnidipine onangiotensin receptor blocker olmesartan treatment for type 2diabetic patients with albuminuriardquoHypertension Research vol34 no 8 pp 935ndash941 2011
[225] K Mizushige ldquoAntioxidative activities of thiazolidinedionesand dihydropyridine-type calcium antagonistsrdquo IRYOmdashJapa-nese Journal of National Medical Services vol 59 no 11 pp 581ndash592 2005
[226] S Manabe T Okura T Fukuoka and J Higaki ldquoAntioxidativeeffects of azelnidipine on mesangial cell proliferation inducedby highly concentrated insulinrdquo European Journal of Pharma-cology vol 567 no 3 pp 252ndash257 2007
[227] Y Koyama Y Takeishi H Takahashi et al ldquoAzelnidipine inhi-bits H
2O2-induced cell death in neonatal rat cardiomyocytesrdquo
CardiovascularDrugs andTherapy vol 21 no 1 pp 69ndash72 2007[228] K Shinomiya K Mizushige M Fukunaga et al ldquoAntioxidant
effect of a new calcium antagonist azelnipidine in culturedhuman arterial endothelial cellsrdquo Journal of International Med-ical Research vol 32 no 2 pp 170ndash175 2004
[229] T Ohyama K Sato K Kishimoto et al ldquoAzelnidipine is acalcium blocker that attenuates liver fibrosis and may increaseantioxidant defencerdquo British Journal of Pharmacology vol 165no 4 pp 1173ndash1187 2012
[230] L A Calo F Zaghetto E Pagnin P A Davis A Sempliciniand A C Pessina ldquoEffect of manidipine on gene expressionand protein level of oxidative stress-related proteins p22phoxand HO-1 Relevance for antihypertensive and anti-remodelingeffectsrdquo Journal of Cardiovascular Pharmacology vol 43 no 4pp 531ndash538 2004
[231] R Ghyasi G Sepehri M Mohammadi R Badalzadeh and AGhyasi ldquoEffect of mebudipine on oxidative stress and lipid per-oxidation in myocardial ischemic-reperfusion injury in maleratrdquo Journal of Research in Medical Sciences vol 17 no 12 pp1150ndash1155 2012
Oxidative Medicine and Cellular Longevity 35
[232] DCAndersson J Fauconnier T Yamada et al ldquoMitochondrialproduction of reactive oxygen species contributes to the 120573-adrenergic stimulation of mouse cardiomycytesrdquoThe Journal ofPhysiology vol 589 no 7 pp 1791ndash1801 2011
[233] A F Ceylan-Isik N Ari M Stefek et al ldquoEffects of a long-term treatment with an antioxidant pyridoindole on vascularresponsiveness in diabetes-induced aging ratsrdquo Current AgingScience vol 4 no 2 pp 150ndash157 2011
[234] S Saponara G Sgaragli and F Fusi ldquoQuercetin antagonismof Bay K 8644 effects on rat tail artery L-type Ca2+ channelsrdquoEuropean Journal of Pharmacology vol 598 no 1ndash3 pp 75ndash802008
[235] D A Sica ldquoInteraction of grapefruit juice and calcium channelblockersrdquo American Journal of Hypertension vol 19 no 7 pp768ndash773 2006
[236] P Mulder G Litwinienko S Lin P D MacLean L R CBarclay and K U Ingold ldquoThe L-type calcium channel block-ers Hantzsch 14-dihydropyridines are not peroxyl radical-trapping chain-breaking antioxidantsrdquo Chemical Research inToxicology vol 19 no 1 pp 79ndash85 2006
[237] L J Nunez-Vergara R Salazar C Camargo et al ldquoOxidation ofC4-hydroxyphenyl 14-dihydropyridines in dimethylsulfoxideand its reactivity towards alkylperoxyl radicals in aqueousmediumrdquo Bioorganic and Medicinal Chemistry vol 15 no 12pp 4318ndash4326 2007
[238] M E Ortiz L J Nunez-Vergara and J A Squella ldquoRelativereactivity of dihydropyridine derivatives to electrogeneratedsuperoxide ion in DMSO solutions a voltammetric approachrdquoPharmaceutical Research vol 20 no 2 pp 292ndash296 2003
[239] M E Ortiz L J Nunez-Vergara C Camargo and J A SquellaldquoOxidation of Hantzsch 14-dihydropyridines of pharmacolog-ical significance by electrogenerated superoxiderdquo Pharmaceuti-cal Research vol 21 no 3 pp 428ndash435 2004
[240] R S Raghuvanshi and K N Singh ldquoSuperoxide induced oxida-tive aromatization of Hantzsch 14-dihydropyridinesrdquo IndianJournal of Chemistry Section B Organic and Medicinal Chem-istry vol 47 no 11 pp 1735ndash1738 2008
[241] I Kruk A Kladna K Lichszteld et al ldquoAntioxidant activityof 4-flavonil-14-dihydropyridine derivativesrdquo Biopolymers vol62 no 3 pp 163ndash167 2001
[242] G D Tirzit I M Byteva K I Salokhiddinov G P Gurinovichand G Y Dubur ldquo14-Dihydropyridine derivatives as deactiva-tors of singlet oxygenrdquo Chemistry of Heterocyclic Compoundsvol 17 no 7 pp 682ndash684 1981
[243] G D Tirzit E Y Kazush and G Y Dubur ldquoInfluence of14-dihydropyridine derivatives on the generation of hydroxylradicalsrdquo Chemistry of Heterocyclic Compounds vol 28 no 4pp 435ndash437 1992
[244] N A Pizarro-Urzua and L J Nunez-Vergara ldquoNifedipine andnitrendipine reactivity toward singlet oxygenrdquo Journal of Photo-chemistry and Photobiology A Chemistry vol 175 no 2-3 pp129ndash137 2005
[245] L-F Wang H-Y Zhang L Konga Z-W Chena and J-G ShildquoDFT calculations indicate that 14-dihydropyridine is a promis-ing lead antioxidantrdquo Helvetica Chimica Acta vol 87 no 6 pp1515ndash1521 2004
[246] P Mulder H-G Korth and K U Ingold ldquoWhy quantum-thermochemical calculations must be used with caution toindicate lsquoa promising lead antioxidantrsquordquoHelvetica Chimica Actavol 88 no 2 pp 370ndash374 2005
[247] K Yao Y Ina K Nagashima K Ohmori and T Ohno ldquoAntiox-idant effects of calcium antagonists in rat brain homogenatesrdquo
Biological and Pharmaceutical Bulletin vol 23 no 6 pp 766ndash769 2000
[248] T Matsui S-I Yamagishi K Nakamura and H Inoue ldquoBayw 9798 a dihydropyridine structurally related to nifedipinewith no calcium channel-blocking properties inhibits tumournecrosis factor-120572-induced vascular cell adhesion molecule-1expression in endothelial cells by suppressing reactive oxygenspecies generationrdquo Journal of International Medical Researchvol 35 no 6 pp 886ndash891 2007
[249] K AMitrega B VargheseM Porc and T F Krzeminski ldquoAnti-arrhythmic and hemodynamic effects of oxy nifedipine oxynimodipine oxy nitrendipine and oxy nisoldipinerdquo Pharmaco-logical Research vol 66 no 4 pp 300ndash308 2012
[250] V Herbert ldquoSymposium prooxidant effects of antioxidantvitamins Introductionrdquo The Journal of Nutrition vol 126 no4 supplement pp 1197Sndash1200S 1996 httpjnnutritionorgcontent1264 Suppl1197Sfullpdf
[251] B Halliwell ldquoAre polyphenols antioxidants or pro-oxidantsWhat do we learn from cell culture and in vivo studiesrdquoArchives of Biochemistry and Biophysics vol 476 no 2 pp 107ndash112 2008
[252] C Winterbourn Pro-Oxidants or Antioxidants ChristchurchSchool of Medicine Depatment of Pathology Free RadicalSchool SFRBMUniversity of Otago San Francisco Calif USA2009 httpwwwsfrbmorgfrsWinterbournpdf
[253] A Morakinyo B Iranloye and O Adegoke ldquoCalcium antag-onists modulate oxidative stress and acrosomal reaction in ratspermatozoardquo Archives of Medical Science vol 7 no 4 pp 613ndash618 2011
[254] The Alpha-Tocopherol Beta Carotene Cancer Prevention StudyGroup ldquoThe effect of vitamin E and beta carotene on theincidence of lung cancer and other cancers in male smokersrdquoTheNew England Journal of Medicine vol 330 no 15 pp 1029ndash1035 1994
[255] B Poljsak ldquoStrategies for reducing or preventing the generationof oxidative stressrdquo Oxidative Medicine and Cellular Longevityvol 2011 Article ID 194586 15 pages 2011
[256] B Poljsak and I Milisav ldquoThe neglected significance of lsquoanti-oxidative stressrsquordquoOxidativeMedicine and Cellular Longevity vol2012 Article ID 480895 12 pages 2012
[257] T Godfraind and S Salomone ldquoAmbiguities in dietary antiox-idant supplementation compared to calcium channel blockerstherapyrdquo Frontiers in Pharmacology vol 6 article 10 2015
[258] H Wagner H Norr and H Winterhoff ldquoDrugs with adap-togenic effects for strengthening the powers of resistancerdquoZeitschrift fur Phytotherapie vol 13 no 2 pp 42ndash54 1992
16 Oxidative Medicine and Cellular Longevity
However majority of data obtained on various animalcells and tissues by other authors show the protective role ofDHPs against both LP and oxidative stress [113 163 164]
The AOA attributed to many 14-DHPs Ca2+ antag-onists and other compounds reflecting on catalytic LDLperoxidation (see Section 331 (2) and Section 35) shouldencourage their testing for treating cardiovascular diseasesandor alterations of lipid metabolism
The possibility that 14-DHP-based calcium antagonistsexert an antiatherosclerotic action (via inhibition of LDLoxidation and other mechanisms) has been proved by manyexperimental data [165] and several clinical trials Besidesantihypertensive effect nicardipine was shown to possessantioxidative and antielastase activity [165 166] These prop-erties may be useful for prevention of inflammatory reactionwhich is relevant for hypertension pathogenesis
14-DHPs administration inhibits LDL oxidation medi-ated by oxygen radicals leading to decreased carotid inti-mal media thickness and reduced progression of coronaryatherosclerosis [130] It additionally preserves Apo B-100integrity against ROS Of importance antiatherogenic mech-anisms differ between animals and humans (primarily inthe stage of conversion of aldehydes to carboxylic acids)(Parthasarathy et al [167])
For example furyl-DHP compound (FDP-1 diethyl 26-dimethyl-4-(furyl)-14-dihydropyridine-35-dicarboxylate)was shown to act as an antioxidant (decreasing MDA GOTand FFA release of ischemic myocardium and inhibiting Ca-ATPase of erythrocyte membranes) preventing against heartmyocardium ischemia-reperfusion injury and arrhythmiawhen applied (in rats) at 10mgkg (Liu et al [168])
Similarly antioxidative effects of azelnidipine andamlodipine prevented neuronal damage by CCBs aftertransient focal ischemia in rats (Lukic-Panin et al [169])
Allanore et al [170] found that both nifedipine andnicardipine significantly decrease the mean level of plasmamarkers for oxidative stress in patients suffering from sys-temic sclerosis
Antioxidants may be considered as promising neuropro-tective compounds Still while experimental data demon-strate neuroprotective effect in vitro and in animal mod-els clinical evidence is still unsatisfactory and insufficient[171]
(a) Role of Metabolism of DHPs in Their AOA Metabolicpathways and ldquobioavailabilityrdquo of the probable AOA com-pound determine antioxidant activity in vivo Antioxidantmetabolites may vary in stability and activity leading to twoopposite scenarios lack or presence of activity substantiallycontributing to the overall AOA [172] Metabolic biotransfor-mation of DHPs includes oxidation (heteroaromatization)side chain ester group cleavage (deesterification) and 4-substituent abstraction ao [160] None of the DHPs metabo-lites was shown to be more toxic than original reduced formof the compound The commonly detected metabolites ofthe DHPs do not seem to possess the AO activity (withsome exceptions as in the case of metabolites of nifedipineand its analogues including nitrosonifedipine [173 174]) (seefurther in Section 35) Due to DHPs intrinsic instability
achieving andmaintaining an adequate concentrationmay beproblematic both in vitro and in vivo
(b) Role of Concentration and Lipophilicity (MembraneWateror LipidWater Partition Coefficients) of DHPs inTheir Actionas AOs and Antiradical Compounds Antioxidative effects ofany antioxidant depend on its concentration at the site ofaction This parameter is hardly measurable especially intwo-phase systems representing one of obstacles in com-parison to AOA upon applying various compounds [172]It is often incorrectly assumed that the concentrations inthe aqueous solution and at the site of action are the sameHowever even when the concentration in the aqueous phasemay be well controlled the concentration at the site ofaction in the lipid matrix of the membranes might fluctuatebetween different test compounds depending on a differencein lipophilicity [175] The prevention of the membrane LPalso seems to be dependent on the DHP concentration in thelipidmatrix (Mason andTrumbore [46]) and its amphiphilic-ity For example AOA of diludine is associated with itslipophilicity and consequential ability to be incorporatedinto liposomes (Panasenko et al [176]) It was also foundthat diludine easily incorporates into the outer monolayer oferythrocyte membranes [176]
Membranebuffer partition coefficients (lambda) weredirectly measured in the sarcolemma and sarcoplasmicreticulum membranes for three CA DHPs The obtainedvalues were in a broad range between 5000 and 150000(Herbette et al [177])These drugs interact primarily with themembrane bilayer component but may also bind to proteinsboth nonreceptors and receptors The intrinsic forward rateconstants for DHP binding to sarcolemmal calcium channelreceptors were apparently not strongly dependent on theirmembrane partition coefficients For example nimodipine(lambda = 6300) had a forward rate constant of 68 plusmn 06 times106Ms whereas the forward rate constant for Bay P 8857
(lambda = 149000) was 14plusmn08times107Ms Since these DHPsare highly liposoluble model calculations for this bindingreaction demonstrated that these rates on lipid solubilitywould probably not be reflected in the experimental forwardrate constants In addition the intrinsic forward rate constantfor nimodipine binding to sarcolemmal calcium channelreceptors was found not to be linearly dependent on theviscosity of the buffer medium over a fivefold range The rateof drug nonspecific binding to nonreceptor protein present inhighly purified sarcoplasmic reticulum membranes appearsto be extremely fast at least 103 times faster than specificdrug binding to the receptor in the sarcolemma Authorsconcluded that partitioning into the lipid bilayer matrix ofthe sarcolemma could be a general property of CA DHPsand may be a prerequisite for their binding to sarcolemmalmembrane receptors (Herbette et al [177])
The binding of DHP calcium channel agonists and antag-onists (including those with AO properties) to receptors incardiac sarcolemmal membranes is a complex reaction thatmay involve an interaction with the lipid bilayer matrix ofthe sarcolemma (Herbette et al [178]) Belevitch et al [179]studied the binding of DHP CCBs (riodipine and nifedip-ine) and verapamil to model and biological membranes by
Oxidative Medicine and Cellular Longevity 17
fluorescence analysis The consistent location of Ca agonistBay K 8644 was determined to be within the region ofthe first few methylene segments of the fatty acyl chains ofthe membranes (Mason et al [180]) This position is nearto that observed for the DHP calcium channel antagonistsnimodipine and Bay P 8857
Themajority of studies onOSwere performedwithDHPswith various lipophilicity but only a few studies reportedamphiphilicity ofDHPderivatives AmphiphilicDHPderiva-tive K-2-11 reduced the cellular generation of ROS It alsorevealed complete reversal of multidrug resistance (MDR) ofthe resistant cells K-2-11 was more efficient than well-knownMDR inhibitor verapamil Cytotoxic effects of anticancerdrug doxorubicin were enhanced by K-2-11 in bothMDR andparental nonresistant cell line (Cindric et al [181]) K-2-11suppresses increase of ROS and consequentially prevents NF-120581B activation leading to decreased expression of MDR1 andincreased expression of antiapoptotic genes This signalingswitch is necessary for restoring the chemosensitivity ofcancer cells This phenomenon is characteristic both for14-DHPs [182] (18 novel asymmetrical DHPs bearing 3-pyridyl methyl carboxylate and alkyl carboxylate moietiesat C3 and C5 positions resp as well as nitrophenyl orheteroaromatic rings at C4) and for their oxidized formspyridine compounds (Zhou et al [183])
34 Dependence of AOA of DHPs on the Experimental SystemAO effect of DHPs depends on their structure and theexperimental system used (in vitromodel system subcellularorganelle and cells ex vivo and in vivo) Ideally for theevaluation of the profile and value of DHPs AO propertieseach compound should be tested in as many systems aspossible (Dubur et al [45])
Lipidomics studies have been traditionally explored forstudying AOA of DHPs Proteomics methods are less rep-resented and are mostly focused on the properties of DHPsrelated to scavenging of protein free radicals So far there areno studies on the role of DHPs in scavenging nitrosoperoxy-carbonate the reactive species formed out of peroxynitrite inthe presence of carbon dioxide Although it was shown thatalbumin binds diludine no studies revealed the relevance ofthis effect for the AOA of diludine
There are findings showing that dihydropyridine calciumantagonists (DHPs CA) could indirectly play a beneficialprotective role during development of atherosclerosisNamely Berkels et al [184] have studied antioxidativeproperties of four substances the DHP prototype CAnifedipine the long-acting CA lacidipine the DHP calciumchannel agonist BayK8644 and the bulkyDHPderivate BayO 5572 in three different models (1) in an in vitro superoxideanion generating system (hypoxanthinexanthine oxidase)for testing the ldquopurerdquo antioxidative effect (2) in an artificialmembrane preparation (dimyristoylphosphatidylcholine) formimicking a more physiological environment and (3) underconditions of stimulated ROS release (hyperglycemia) fromnative endothelial cells derived from porcine coronary arter-ies
The study also revealed the potential correlation betweenlipophilic and AO properties of DHPs In the first model
Bay K 8644 was significantly more effective in scavengingsuperoxide anions than lacidipine Bay O 5572 or nifedipine(micro- to millimolar concentration range) Addition of anartificial membrane preparation resulted in an enhancedAO effect with lacidipine being the most effective DHP inquenching radicals (low micromolar concentration range)In the third model mimicking hyperglycemia (30mmolL)nifedipine was significantly more potent antioxidant (ther-apeutical nanomolar concentration range) than the otherDHPs Calculated lipophilicity of these four substances(lacidipine gt Bay O 5572 gt Bay K 8644 gt nifedipine) waspositively correlated with antioxidative potential only in thesecond experimental model It has been concluded that AOproperties of DHP substances need to be tested in variousmodels for demonstrating that nifedipine exhibits ROS-quenching properties in a therapeutic concentration range[184]
341 AOA of DHPs in Isolated Cells and Cell Cultures(Comparison with Other Simplest Systems) Although DHPspossess neuromodulatory andor antimutagenic propertiesthe mechanisms of action related to these phenomena arenot entirely elucidated Borovic et al [185] have studied 14-dihydroisonicotinic acid (14-DHINA) derivatives of 14-DHP water-soluble analogues of a well-known AO diludine(diethone) 26-dimethyl-35-diethoxycarbonyl-14-dihydro-isonicotinic acid sodium 2-(26-dimethyl-35-diethoxycar-bonyl-14-dihydropyridine-4-carboxamido)glutamate gluta-pyrone and sodium 2-(26-dimethyl-35-diethoxycarbonyl-14-dihydropyridine-4-carboxamido)ethane-sulphate tauro-pyrone as AO and bioprotectors (Figure 4)
14-DHINArsquos activities were studied in comparison toTrolox by NN-diphenyl-N1015840-picrylhydrazyl (DPPH∙) deoxy-ribose degradation ABTS∙ radical scavenging and AOA(antioxidative capacity method) assays copper-induced LPof cultured rat liver cells (MDA determination by HPLCand 4-hydroxynonenal-protein conjugates by dot-blot) 3H-thymidine incorporation and trypan blue assay for liver cellsgrowth and viability Ic decreased the amount of 4-HNE-protein adducts In all assays Ia was the most potent AOable to completely abolish copper induced LP of liver cellswhile Ic only slightly decreased it Thus AOA is importantactivity principle of Ia which was even superior to Trolox intreated cell cultures Ia (and its analogues) are easily oxidizedin the Fenton system (Rubene et al [186]) exerting ARA too
35 Peculiarities Related to Antioxidative and AntiradicalActivity of Some 14-DHPs Ca Antagonists Nine commer-cialized structurally and functionally different DHPs CAwill be discussed further Their common feature is ability toprevent OS This also counts for some of their metabolitesas already discussed The comparative effects of some DHPsCA on oxidative stress-induced modification of LDL werealready reviewed in Section 331 (2)-(a) AOA of CA DHPswas discussed in Sections 331 (2)-(b) and 331 (2)-(c)
351 Nifedipine and Its Close Analogues Nifedipine vera-pamil and antiarrhythmic-antihypoxic drug stobadin wereshown to depress lipid peroxidation of phosphatidylcholine
18 Oxidative Medicine and Cellular Longevity
NH
COOH
NH
COONa
Glutapyrone
NH
Gammapyrone
NH
C 2H5OOC COOC2H5
Tauropyrone
14-DHINA
H3C H3C
H3C
H3CCH3 CH3
CH3
CH3
COOC2H5COOC2H5
COOC2H5 C2H5OOCC2H5OOCC2H5OOC
CONHCH(CH2)2COONa CONH(CH2)3COONa
CONH(CH2)2SO3Na
Figure 4 Derivatives of 14-dihydroisonicotinic acid (14-DHINA)
liposomes (Ondrias et al [187]) However data obtained insome other experimental systems are conflicting
In an in vitromodel of sarcolemmal membrane lipid per-oxidation three calcium blockers (nifedipine verapamil anddiltiazem) exhibited concentration-dependent (10ndash400 120583M)inhibitory effects [188 189] Nifedipine the most effectivecalcium blocker was more than two-fold potent compared topropranolol achieving significant effect at 10 120583M Nifedipineprotective role on LP using reduced glutathione as modelmarker was recently described (Ray et al [190]) Antiper-oxidative properties of CA nifedipine and its analogueswere explored in different systemspathogenic processesatherogenesis (Henry [165]) brain focal ischemia (Yamatoet al [191]) nephroprotection related to cyclosporine intake(Chander and Chopra [192]) and hepatoprotection relatedto intake of diethyldithiocarbamate (Gaafa et al [193])Recent data suggest that nifedipine action as protector forendothelial cells proceeds independently from its CA proper-ties
The absence of antioxidant effects of nifedipine anddiltiazemonmyocardialmembrane lipid peroxidation oppo-site to nisoldipine and propranolol was also described[194] Nisoldipine and propranolol were shown to havea concentration-dependent antiperoxidant effect with IC
50
values of 282 and 501 120583M respectively Finally nisol-dipine appeared to possess dual antiperoxidant mecha-nisms involving both preventive and chain-breaking proper-ties
These findings were confirmed in some other studiesincluding reports on the lack of antioxidative activity ofnifedipine and nicardipine even at 500120583M concentrationin heart membrane lipid peroxidation tests [134] SimilarlyROS formation in bovine aorta smooth muscle cells was notaffected by addition of amlodipine nimodipine and nife-dipine [123]
(1) Metabolites of Nifedipine and Its Analogues as Antioxidantsand Regulators of OS Antioxidant activity of nifedipine35-dimethoxycarbonyl-26-dimethyl-4-(2-nitrophenyl)-14-dihydropyridine was originally studied in vitro by Kirule etal [195] and Tirzit et al [196] According to the kinetic dataof peroxide accumulation and the ESR spectra (inhibition ofthe autoxidation of methyl oleate in presence of nifedipine)AO action was exerted by the formation of nitroso analogueof the oxidized nifedipine nitroso nifedipine 26-dimethyl-4-(2-nitrosophenyl)-35-pyridine dicarboxylate (NO-NIF)This nitroso aromatic derivative can form nitroxyl radicalsexhibiting remarkable AOA in the presence of unsaturatedfatty acids and lipids [196]
The primary species of free radicals that have beenobtained and identified were ion radicals of the nitrophenyltype (Ogle et al [76]) Such a mechanism coincides withmechanisms proposed afterwards by Nunez-Vergara et al[96] Lopez-Alarcon et al [103] Valenzuela et al [104]Fukuhara et al [174] and Yanez et al [197]
There are also data showing that nitroso compounds mayinhibit LP by direct radical trapping and subsequent forma-tion of stable nitroxide radicals It was further found that thereactivity between the synthesized 14-DHP derivatives withalkylperoxyl radicals involves electron transfer reactionsThisis documented by the presence of pyridine as a final productof the reaction and complete oxidation of the nitroso groupin the case of the nitrosoaryl 14-dihydropyridine derivatives(Valenzuela et al [104]) Tested compounds reacted fastertoward alkylperoxyl radicals and ABTS radical cation thanalkyl ones (Lopez-Alarcon et al [103])
Nitrosonifedipine a photodegradation product of nifedi-pine significantly recovers cellular damage induced by tumornecrosis factor-alpha It also prevents toxic effects of cumeneperoxide which hampers integrity of cell membranes throughoxidative stress Its positive effects are equal to Trolox-C
Oxidative Medicine and Cellular Longevity 19
As a result nitrosonifedipine was already a long time agoclaimed as a candidate for a new class of antioxidative drugs(Kirule et al [195]) cellular protectors against oxidative stressin glomerular endothelial cells [174]
Moreover Misik et al [198] Ondrias et al [199] andStasko et al [200] studied AOA of nifedipine and its oxidizednitroso analogue NO-NIF prevents the progression of type2 diabetic nephropathy associated with endothelial dysfunc-tion through selective AO effects (Ishizawa et al [201]) NO-NIF administration reduces albuminuria and proteinuriaas well as glomerular expansion without affecting glucosemetabolism or systolic blood pressure NO-NIF also sup-presses renal and systemic OS and decreases the expressionof intercellular adhesion molecule-1 (ICAM-1) a marker ofendothelial cell injury in the glomeruli of the KKAy miceSimilar effects were achieved in endothelial nitric oxide syn-thase (eNOS) knockout mice Moreover NO-NIF suppressesurinary angiotensinogen (AGT) excretion and intrarenalAGT protein expression in proximal tubular cells in theKKAy mice On the other hand hyperglycemia-inducedmitochondrial superoxide production was not attenuated byNO-NIF in cultured endothelial cells
Fujii and Berliner found EPR evidence for free radicaladducts of nifedipine in vivo [202] The nature of these rad-icals was surmised by comparing the reaction of illuminatednitrosonifedipine with polyunsaturated fatty acids Surpris-ingly identical radical spectra were detected from excisedliver doped with nonilluminated nifedipine suggesting thatthis drug can be enzymatically converted in vivo to its nitrosoanalogue without the requirement for illumination This isone of the first reports of in vivo EPR evidence for a class ofunsaturated fatty acid radical conjugates resulting from thenormal metabolism of a common drug
Dıaz-Araya et al [173] studied some 4-nitrophenyl-DHPson Fe3+ initiated LP in rat brain slices LP as measuredby MDA formation was inhibited by all the tested nitro-aryl derivatives of 14-DHP over a wide range of concen-trations On the basis of both time course and IC
50experi-
ments the tentative order of AOA on rat brain slices wasnicardipine gt nisoldipine gt (RSSR)-furnidipine gt (RRSS)-furnidipine gt nitrendipine gt nimodipine gt nifedipine14-DHP derivatives that lack a nitro group in the mole-cule (isradipine and amlodipine) also inhibited LP in ratbrain slices but at higher concentrations than that of nitro-substituted derivatives All tested compounds reduced andoxidized nitrosoaryl derivatives (26-dimethyl-4-(2-nitro-sophenyl)-35-pyridinedicarboxylic acid dimethyl ester (pho-tooxidation product of nifedipine ndash NTP) ao) and weremore potent inhibitors of LP than their parent molecules(Valenzuela et al [104])
The electrooxidation process of 4-nitrosoaromatic DHPsis a strongly pH-dependent (two-electron two-proton mech-anism) ECEC type of mechanism that is the sequenceeminusH+eminusH+ at pH gt 85 ECCE mechanism (eminusH+H+eminus)at pH lt 85 dominates Reduction reaction of nitroso groupis as follows R-NO + 2eminus + 2H+ rarr RNHOH (Bollo et al[203])
352 Lacidipine It is a generic DHP type antihypertensiveCA 35-diethyl 4-2-[(1E)-3-(tert-butoxy)-3-oxoprop-1-en-1-yl]phenyl-26-dimethyl-14-dihydropyridine-35-dicarboxy-late
Ursini [204] described redox behaviour of lacidipine andshowed its tissue protective features Cristofori et al studiedantiatherosclerotic activity in addition to lacidipinersquos CAand AO properties [205] Lacidipine reduced the extent ofatherosclerotic area in hypercholesterolemic apoE-deficientmice (these mice show widespread vascular lesions whichclosely resemble the inflammatory fibrous plaques seen inhumans in atherosclerosis) The reduction may be associatedwith the capacity of the drug to maintain endothelial NOlevels at concentrations useful to protect against vasculardamage This work suggested that DHPs modulate vascularrelaxation via increased release of NO
Herbette et al [178] remarked optimal hydrophobicity oflacidipine due to cinnamic acid substituent so membraneinteractions and facilitation of the treatment of atherosclero-sis could proceed (see also Section 331 (2)-(a))
353 Amlodipine Amlodipine (Norvasc) (RS)-3-ethyl5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-14-dihydropyridine-35-dicarboxylate (AML) hasan antioxidant effect on vessels in vitro and is a 3rd genera-tion of charged dihydropyridine CCB that is widely used forthe treatment of hypertensive patients
Amlodipine was shown to have the highest affinity(amlodipine gt verapamil ≫ diltiazem) for the membranebilayer (119870
119901= 104) It produced the significant changes in
membrane thermodynamic properties including a reductionin the thermal phase transition temperature (minus11) enthalpy(minus14) and cooperative unit size (minus59) relative to thecontrol phosphatidylcholine liposomes (Mason et al [49])
Amlodipine AOA is related to its reductant nature orhydrogen donor properties respectively Its ability for donat-ing protons and electrons to the lipid peroxide moleculesblocks the LP process
Amlodipine and even its enantiomers (Zhang et al [206])act as ROS andNOS effectors in several model systems of OSAntioxidant properties of amlodipine were recently reviewedby Vitolina et al [32] Both in vitro and in vivo studiesof amlodipine AO properties revealed inhibition of lipidsoxidative damage primarily those associated with cellularmembranes and lipoprotein particles (LDL) (Mason et al[50])
Under controlled experimental conditions in vitro amlo-dipine showed AOA and ARA by inhibition of lipid peroxideformation and trapping ROS Its scavenging activity forhydroxyl and peroxyl radicals at concentrations as low as100 nmolL (which is remarkably less compared to the classi-cal antioxidants GSH uric acid and Trolox) was shown to beindependent of the calcium channel modulation (Franzoni etal [207])
AML showed efficiency as scavenger of peroxyl radicals(TOSC assay 5945 plusmn 544 unitsmg) significantly stronger(gt50 119875 lt 0001) than GSH (2733plusmn 636 unitsmg) and 70weaker (119875 lt 00001) than uric acid (18144 plusmn 696 unitsmg)and Trolox (17522 plusmn 734 unitsmg)
20 Oxidative Medicine and Cellular Longevity
Of interest the scavenging capacity of AML towardshydroxyl radicals (1455 plusmn 154 unitsmg) was 320 higher(119875 lt 000001) than that of GSH (358 plusmn 112 unitsmg) 20higher than that of uric acid (1198plusmn121 unitsmg) and 100higher than that of Trolox (759 plusmn 143 unitsmg)
Amlodipine was shown to increase enzyme activity ofparaoxonase (PON) and glutathione peroxidase (GSH-Px)However it also decreases glutathione reductase (GSSG-R)activity and diminishes the concentration of the endogenousantioxidant 120572-tocopherol (vitamin E) Moreover AML in aconcentration of 2 ngmL decreased the content of malonicdialdehyde and activity of superoxide dismutase in the blood(Gatsura [208])
Verapamil and amlodipine produced a potent anti-ischemic effect and reduced area of myocardial infarction inrats The observed changes were accompanied by inhibitionof LP In contrast to verapamil in vitro application of AML ina dose of 50 ngmL decreased hemoglobin affinity for oxygenWhen present in a concentration of 2 ngmLAMDdecreasedthe content of MDA and activity of SOD in the blood
On the other hand amlodipine shows no activity relatedto inhibition of macrophage superoxide release and cellmigration which occurs as a consequence of decreasedTNF120572induced O
2
∙ releaseAmlodipine-induced reduction of OS in the brain is
associated with sympathoinhibitory effects in stroke-pronespontaneously hypertensive rats (SHRSP) (Hirooka et al[209]) Antihypertensive treatment with amlodipine reducedOS in all examined areas of the brain and decreased bloodpressure without a reflex increase in sympathetic nerveactivity Nicardipine another CA DHP surprisingly wassignificantly less active than amlodipine
354 Lercanidipine Tomlinson and Benzie reported AOeffect of lercanidipine [210] which is well known as anti-hypertensive drug Zanidip 2[(33-diphenylpropyl)(methyl)-amino]-11-dimethylethyl methyl 26-dimethyl-4-(3-nitro-phenyl)-14-dihydropyridine-35-dicarboxylate Compara-tive data about this drug AOA were presented in parts of thispaper about other individual CA DHPs and in the part aboutthe ex vivo DHPs effects on LDL
355 Nimodipine Nimodipine (ND) commercially knownas Nimotop is 3-(2-methoxyethyl) 5-propan-2-yl 26-dim-ethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxy-late It is centrally active CA
Treatment with glutathione blocked andwith nimodipineattenuated neuronal cell death caused by prolonged exposureof cell culture to 4-HNE (Faraqui [211])
Nascimento et al [212] found AO effect of nimodipine inyoung rats after pilocarpine- (PIL-) induced (in 400mgkg)seizures The PIL administration increased the striatal cata-lase (CAT) activity The administration of ND 30mgkg30min before PIL preserved normal value of CAT activityOn the other hand no difference was detected in the animalstreated with lower dose 10mgkg These results confirmthe neuroprotectiveantiepileptic effect of ND in young ratssuggesting that this drug acts positively on lipid peroxidation
(in both doses) Nimodipine cannot induce these effects viablockade of Ca2+ channel
Ismailoglu et al [213] studied the therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjury These beneficial effects in rats after cerebral corticalinjury seemed to be related to AOA of nimodipine
356 Benidipine Licensed in Japan and South Asia as CA(CCB) benidipine possesses AO properties Chemically it is5-methyl 3-[(3R)-1-(phenylmethyl)piperidin-3-yl] 26-dim-ethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxy-late (or its hydrochloride (4R)-rel-35-pyridinedicarboxylicacid 14-dihydro-26-dimethyl-4-(3-nitrophenyl)- 3-methyl5-[(3R)-1-(phenylmethyl)-3-piperidinyl] ester hydrochloride(1 1))
Benidipine influences processes connected with OS inseveral ways It prevents lysophosphatidylcholine- (lysoPC)-induced injury and ROS production in human aorticendothelial cells (HAECs) (Matsubara and Hasegawa [214])Matsubara et al [215] explained this effect based on stimula-tion of nitric oxide release
LysoPC is a component of oxidized low-density lipopro-teins (oxLDLs) which plays an important role in the patho-genesis of atherosclerosis Pretreatmentwith benidipine (03ndash3 120583molL) for 24 h protected against lysoPC-induced cyto-toxicity in the HAECs through inhibition of both lysoPC-stimulated ROS production and caspase-37-like activationwith a similar potency Since caspase-37 is involved inexecuting the apoptotic process the reduction of the activityof this enzyme by benidipine may explain the antiapoptoticeffect of the drug However benidipine did not suppresslysoPC-induced phosphorylation of mitogen-activated pro-tein kinases and Ca2+ influx in HAECs These results suggestthat the antioxidant properties of benidipine may be respon-sible for its ability to inhibit ROS production a possiblereason for reduced activation of caspase-37 In conclusionbenidipine suppresses lysoPC-induced endothelial dysfunc-tion through inhibition of ROS production which is due atleast in part to its antioxidant effect and not through theinhibition of L-type voltage-dependent calcium channels
Matsubara and Hasegawa [216] examined the effectsof benidipine on cytokine-induced expression of adhesionmolecules and chemokines (chemoattractants) which areimportant for the adhesion of monocytes to endotheliumPretreatment of HAECs with benidipine (03ndash10 120583molL)for 24 h significantly suppressed cytokine-induced vascularcell adhesion molecule-1 (VCAM-1) and intracellular celladhesion molecule-1 (ICAM-1) mRNA and protein expres-sion resulting in reduced adhesion of THP-1 monocytesBenidipine also suppressed induction of monocyte chemoat-tractant protein-1 (MCP-1) and interleukin-8 Benidipinealso inhibited redox-sensitive transcriptional nuclear factor-120581B (NF-120581B) pathway as determined by Western blotting ofinhibitory 120581B (I120581B) phosphorylation and luciferase reporterassay Results of analysis using optical isomers of benidip-ine and antioxidants suggest that these inhibitory effectswere dependent on pharmacological effects other than Ca2+antagonism Benidipine may thus have anti-inflammatoryproperties and benefits for the treatment of atherosclerosis
Oxidative Medicine and Cellular Longevity 21
Benidipine was also shown to inhibit ROS production inpolymorphonuclear leukocytes and oxidative stress in salt-loaded stroke-prone spontaneously hypertensive rats (Mat-subara et al [217])
It should be mentioned that other DHPs also haveendothelial AO actions [218]
357 Azelnidipine (AZL) Azelnidipine 3-[1-[di(phen-yl)methyl]azetidin-3-yl] 5-propan-2-yl 2-amino-6-methyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate(AZL) CAS number 123524-52-7 is commercially available4-nitroaryl-DHP type calcium antagonist with long-actingantihypertensive action (long-acting CA (CCB)) and a lowreported incidence of tachycardia It additionally possessesbeneficial effects in OS and diabetic conditions
Azelnidipine prevents cardiac dysfunction in strepto-zotocin-diabetic rats by reducing intracellular calcium accu-mulation (altering intracellular Ca2+ handling proteins) OSand apoptosis (Kain et al [219]) AZL can reduce the superox-ide production It exerts its protective effects by targeting theNADPH oxidase and mitochondrial redox enzymes AZL-treated diabetic rats express enhanced level of bcl-2 in thelysates of heart muscle indicating that AZL plays protectiverole in cardiac apoptosis
It has been previously observed that azelnidipine inhibitstumor necrosis factor-alpha-induced endothelial cell (EC)oxidative stress through its AO properties (Nakamura etal [220]) Azelnidipine but not nitrendipine completelyinhibits the Ang II-induced ROS generation in ECs (Matsuiet al [221])
Furthermore azelnidipine but not nitrendipine wasfound to partially restore decreased pigment epithelium-derived factor (PEDF) mRNA levels in Ang II-exposed ECsThis study suggests that AZL influence depends on its antiox-idative properties Authors concluded that upregulation ofPEDF by azelnidipine may become a therapeutic targetfor the treatment of diabetic retinopathy associated withhypertension
Antihypertensive agents with AO effects are potentiallyuseful for diabetic patients with hypertension While DHPtypeCAare among themost frequently used antihypertensivedrugs azelnidipine has been reported to have a unique AOeffect in vitro and in vivo in experimental animals (Ohmuraet al [222]) In hypertensive diabetic patients azelnidipinetreatment for 12 weeks induced a more significant decreasein erythrocyte LOOH level than amlodipine although thevalues related to blood pressure during each treatmentremained comparable These data confirm the usefulness ofLOOH level in erythrocyte membrane as a marker of OS invivo and indicate that azelnidipine has a unique antioxidativeproperty in humans
Daikuhara et al [223] reported the results of the OLCAstudy based on combination of (1) olmesartan and a calciumchannel blocker (azelnidipine) or (2) candesartan and a CCBamlodipine in two groups of diabetic hypertensive patientsPatients treated with the first combination presented highlypersistent early morning antihypertensive effect and strongerdecrease in heart rate fasting blood glucose andHbA1c levels
and microalbuminuria when compared to patients treatedwith the combination (2) Because diabetes is associated withsevere chronic OS the observed results might be at least in apart due to the AOA of azelnidipine
In favor of this are findings of Abe et al [224] who foundadditive antioxidative effects of azelnidipine on angiotensinreceptor blocker olmesartan treatment for type 2 diabeticpatients with albuminuria
Similarly the AOA of thiazolidinediones (insulin sensi-tizer) and their effect on cardiovascular function in type 2diabetic model rats and also those of some DHPs (nifedipineamlodipine or AZL commonly used antianginal and anti-hypertensive agents) in cultured human endothelial cells LPwere examined (Mizushige [225]) The AOA was evaluatedby measuring 8-iso-prostaglandine F
2120572concentration and
azelnidipine exhibited potent AOAInsulin (INS) resistance combined with hyperinsuline-
mia is involved in the generation of OS A relation-ship exists between increased production of ROS and thediverse pathogenic mechanisms involved in diabetic vascularcomplications including nephropathy Manabe et al [226]revealed that high doses of INS augmented mesangial cellproliferation through generation of intracellular ROS andactivation of redox signaling pathways Cell proliferation wasincreased in a dose-dependent manner by high doses of INS(01ndash10 120583M) but was inhibited by 01120583M AZL Namely theINS-increased phosphorylation of mitogen activated proteinkinaseextracellular signal-regulated kinase 12 (MAPKERK12) was inhibited by 01 120583MAZL The same AZL concen-tration blocked intracellular ROS production more effec-tively than 01 120583M nifedipine The NADPH oxidase inhibitorapocynin (001ndash01120583M) prevented INS-induced mesangialcell proliferation So azelnidipine inhibits insulin-inducedmesangial cell proliferation by inhibiting the productionof ROS Therefore azelnidipine may have the potential toprotect against the onset of diabetic nephropathy and slowits progression
Azelnidipine inhibited H2O2-induced cell death in
neonatal rat cardiomyocytes (Koyama et al [227]) Azelnidip-ine and nifedipine did not affect theH
2O2-induced activation
of extracellular signal-regulated protein kinases (ERK) andp38 MAPK (mitogen-activated protein kinase) In contrastazelnidipine but not nifedipine inhibited H
2O2-induced c-
Jun NH2-terminal kinases (JNK) activation Authors con-
cluded that azelnidipine has inhibited theH2O2-induced JNK
activation and cardiac cell death Therefore azelnidipine mayhave cardioprotective effects against OS
A specific atheroprotection activity of azelnidipine relatesto inhibition of TNF-120572-induced activator protein-1 activa-tion and interleukin-8 expression in human umbilical veinendothelial cells (HUVEC) through suppression of NADPHoxidase-mediated reactive oxygen species generation (Naka-mura et al [220]) TNF-120572 could play a central role in patho-genesis of insulin resistance and accelerated atherosclerosis inthe metabolic syndrome The concentration of AZL found tobe effective in these in vitro experiments is within therapeuticrange As EC do not possess voltage-operated L-type calciumchannels it is suggested that the beneficial effects of azelni-dipine are not likely due to CA property but to its unique AO
22 Oxidative Medicine and Cellular Longevity
ability Furthermore it has been recently found that serumlevels of monocyte chemoattractant protein-1 a biomarkerfor subclinical atherosclerosis were significantly decreased bythe AZL treatment in patients with essential hypertension Inthis paper [220] authors hypothesize that due to its uniqueTNF-120572 signalmodulatory activity and antioxidative propertyazelnidipine may be a promising DHP for targeting diabetesand cardiovascular diseases in hypertensive patients withmetabolic syndrome
Shinomiya et al [228] evaluated its AOA in culturedhuman arterial EC under OS Azelnidipine has shown apotent antioxidative effect that could be of significant clinicalbenefit when combined with its long-lasting antihypertensiveaction and low incidence of tachycardia
Azelnidipine inhibited TGF-1205731 and angiotensin II- (AngII-) activated 1205721(I) collagen mRNA expression in hepaticstellate cells (HSCs) (Ohyama et al [229]) FurthermoreTGF-1205731- and Ang II-induced OS and TGF-1205731-induced p38and JNK phosphorylation were reduced inHSCs treated withAZL Azelnidipine significantly decreased inflammatory cellinfiltration profibrotic genes expression HSC activation LPoxidative DNA damage and fibrosis in liver of CCl
4- or
TAA-treated mice Finally AZL prevented decrease of theexpression of some AO enzymes and accelerated regressionof liver fibrosis in CCl
4-treated mice Hence the antifibrotic
mechanism of AZL against CCl4-induced liver fibrosis in
mice may have been due to an increased level of AO defenseAs azelnidipine is widely used in clinical practice withoutserious adverse effects it may provide an effective newstrategy for antifibrotic therapy
358 Manidipine Manidipine (2-[4-(diphenylmethyl)pip-erazin-1-yl]ethyl methyl 26-dimethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate) is a DHP CCB withreported nephroprotective properties Calo et al [230] stud-ied effect of manidipine on gene expression and proteinlevel of OS related proteins p22(phox) (human neutrophilcytochrome b light chain (CYBA)) and heme oxygenase-1HO-1 Relevance for antihypertensive effects was revealedThe study assessed the effect of manidipine on normalsubjectsrsquo monocyte gene and protein expression of OS relatedproteins such as p22phox a NADPH oxidase system subunitcritical in generating O
2
∙minus and HO-1 induced by and pro-tective against OS Manidipine was compared with the ACEinhibitor captopril and the CCB nifedipine in the presenceand in the absence of sodiumarsenite (NaAsO
2) as an inducer
of OS Monocyte p22phox (CYBA) mRNA production wasreduced by both manidipine and captopril while no changeswere induced by nifedipine Manidipine increased monocyteHO-1 mRNA production while nifedipine and captoprilshowed no effect The effects of manidipine on p22phoxand HO-1 gene expression in the presence of OS were alsoconfirmed at the protein level Thus manidipine seems tosuppress p22phox and to increase the HO-1 mRNA produc-tion and protein level The manidipine-induced increase ofHO-1 gene and protein expression seems to be a peculiareffect of this drug since it is not observed with captopriland nifedipine This effect together with the reduction of
p22phoxmRNAproduction could play a role in its protectivemechanism against OS
359 Mebudipine The protective effect of mebudipine (14-dihydro-26-dimethyl-4-(3-nitrophenyl)-35-pyridinedicar-boxylic acid 3-methyl-5-tert-butyl ester BAY-n-6391) wasrevealed on OS and LP (MDA decrease SOD GPX andcatalase increase) in myocardial ischemic-reperfusion injuryin male rats (Ghyasi et al [231])
There are articles about other commercial and experi-mental DHPs on OS but we have reviewed only the mostcommonly studied compounds Effects of other commercialCA DHPs on OS are also mentioned in several parts of thisreview
36 14-DHPs Ca Agonists andTheir AOA and ARA For themost popular calcium agonist DHP Bay K 8644 no reactionwith peroxyl radicals was registered (Toniolo et al [114])However interactionwith other compounds possessing AOAand ARA (quercetin) was found
Opposite to that AON-acetylcysteine (NAC) diminishedincrease in Ca2+ transient amplitude and cell shorteninginduced by ISO and forskolin whereas NAC had no effecton the (S)-(minus)-methyl-14-dihydro-26-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylatemdash(minus)-BayK 8644-induced increases (Andersson et al [232])
Increased vasoconstriction responses to Bay K 8644 (3 times10minus7ndash3times 10minus5M)were significantly decreased by pyridoindoleantioxidant stobadine treatment in diabetes (Ceylan-Isik etal [233])
The functional interaction between two L-type Ca2+channel activators quercetin and Bay K 8644 has beeninvestigated in vascular smooth muscle cells Biological ARAcompound quercetin at nutritionally meaningful concen-trations limited the responsiveness of vascular L-type Ca2+channels to the pharmacological stimulation operated by BayK 8644 These data contribute to a better understanding ofquercetin effects on experimental in vivo cardioprotection(Saponara et al [234]) Thus these findings indicated thatalthough Bay K 8644 does not exert potent and direct AOAyet acting as calcium agonist it may affect efficiency of AOsubstances and vice versa
Interaction of grapefruit juice (containing quercetin andits analogues) with DHPs CA diminished effectiveness of CAaction of DHPs (Sica [235])
37 Interpretations of the Mechanism(s) of RadicalScavenging and AOA by DHPs
371 Molecular Mechanism(s) of Radical Scavenging andAOA of DHPs in the Model Systems 35-Dicarbonyl-14-di-hydropyridine derivatives possess powerful bis-120573-carbony-lvinyl-amino conjugation and for that reason cannot be con-sidered as ordinary amino antioxidants The electron andorH donation from DHPs ensures their reductant role andresults in AOA and ARA Oxidation reaction from DHPsresults in production of corresponding heteroaromatic pyri-dine derivatives
Oxidative Medicine and Cellular Longevity 23
Detailed studies were made about substituent in DHPring positions 14- namely 4-unsubstituted- 4-substituted4-alkyl- 4-aryl- 4-alkylaryl- ao 26- 35- (diacetyl ordialkoxycarbonyl chain ao) electronic and steric effects onAOA and ARA of DHPs [44 45 51] see Sections 331and 35 The bell-shaped dependence of DHPs AOA onthe 35-dialkoxycarbonyl- chain length was observed [4445 107 109 112] with the maximum activity at C
2H5ndash
C4H9 Decrease of AOA and incorporation into liposomes for
DHPs with alkyl chains longer than R gt C4H9further were
clarified as probable tendency to self-aggregation of thesecompounds ([51] and citation number 245 therein) Electronacceptorelectron donor properties are relevant for expres-sion of AOA or ARA of 35-disubstituted DHPs 35-Diacyl-substituted and 35-dicarbanilido- and 35-dipyridylamido-substituted DHPs are more active as AOs as their 35-dicyano-substituted analogues which have electron acceptorproperties [186]
Dubur et al [89] observed overwhelming steric influenceof substituents in position 4 of the DHP ring Gaviraghiet al [163 164] proposed that AO activity of DHPs ispartly dependent on capacity of the 14-DHP ring to donateelectrons to the propagating radical (ROO∙ or RO∙) and toreduce it to a less reactive form The abstraction (donation)of electron andor H in the oxidation and LP reactionstakes place from all 35-dicarbonyl-14-DHP systems andresults in the formation of corresponding pyridine derivatives(Augustyniak et al [51]) The physicochemical mechanism ofARA and AOA of 14-DHP has been extensively studied anddiscussed (Mulder et al [236]) but precise mechanisms oftheir activity need further clarification
The reactivity of C-4 substituted 14-DHPs possessingeither secondary or tertiary nitrogen atom in the DHP ringtoward alkyl alkylperoxyl radicals and ABTS radical cationwas determined in aqueous media at pH 74 [103] Thesecompounds reacted faster toward alkylperoxyl radicals andABTS radical cation than alkyl ones N-Ethyl-substitutedDHPs showed the lowest reactivity
The 4-methyl substituted DHP was the most reac-tive compound in previously mentioned reactions (Lopez-Alarcon et al [103]) However it was less active (068versus 10) than Trolox-C DHPs having electron-donatingsubstituents (4-Me-DHP and p-MeO-Phe-DHP) showed thehighest kinetic rate constants toward ABTS radical cation p-nitro-Phe-DHP a compound with an electron-withdrawingsubstituent showed a lower kinetic rate constant and N-alkyl-DHP compounds show kinetic rate constants lowerthan the -NH-DHP
Hydrogen at the 1-position of the DHP ring was revealedaccording to the deuteriumkinetic isotope effect studies to beinvolved in the proposedARAmechanismThis fact ismostlynoticeable in the case of alkyl radicals N-Ethyl-substitutedDHPs show the lowest reactivity when compared to Troloxor nisoldipine In all cases the respective pyridine derivativewas detected as the main product of the reaction (Lopez-Alarcon et al [103]) Authors indicate that the kinetic rateconstants toward alkyl alkylperoxyl andABTS radical cationdepend on the nature of the substituents in the C-4 positionof DHP and the presence of the secondary amine group in the
dihydropyridine ring that is the presence of the hydrogen in1-position
Yanez et al [197] have studied the reactivity of 11derivatives of 14-DHPs (including commercial CA) withalkylperoxyl radicals and ABTS radical cation The tested14-DHPs were 83-fold more reactive towards alkylperoxylradicals than to the ABTS cation radical All commercial14-DHP type CCBs were weaker than Trolox-C The par-ticipation of the hydrogen atom in the 1-position appearsto be very relevant for exhibited reactivity Hantzsch ester(diludine)was again found to be themost active compound inthe reaction with alkylperoxyl radicals 23-fold more activethan Trolox The photodegradation product of nifedipine(nitrosophenyl derivative of pyridine) also showed a highactivity Kinetic rate constants for the reaction between 14-DHP compounds and alkylperoxyl radicals exhibited a fairlygood linear correlation with the oxidation peak potentialof DHP derivatives However the activity of tested 14-DHPs towards ABTS radical cation showed an independencebetween kinetic rate constants and oxidation peak potentials
Kirule et al [195] andTirzit et al [196] studiedmechanismof AOA of 4-nitrophenyl-14-DHPs nifedipine and its ana-logues involving formation of 4-(21015840-nitrosophenyl)-pyridinederivative (as active principle) as a result of intramolecularredox reaction using chemical electrochemical and bio-chemical approaches (see Sections 331 and 351)
Nunez-Vergara et al [237] reported the electrochemicaloxidation of C4-hydroxyphenyl-substituted 14-DHP deriva-tives The oxidation proceeds via formation of the unstabledihydropyridyl radical as confirmed by controlled-potentialelectrolysis (CPE) and ESR experiments This type of 14-DHPs has significant activity towards the radicals even whencompared with commercial 14-DHP drugs with well-knownantioxidant ability
It was observed that nicardipine preferentially targets RO∙radicals and is inactive against ROO∙ Lacidipine on theother hand is equally active towards both types of radicals(Gaviraghi et al [164]) The cytoprotective effect againstexposure to H
2O2was more significant for lacidipine (ID
50=
14 nM its log119875 = 54 membrane partition = 136000 assumesposition located 7 A near to the membrane center otherless lipophilic DHPs located 12ndash16 A far from the center)as compared to amlodipine nifedipine and nicardipine insmooth muscle cell culture (Gaviraghi et al [164]) Oxidativeeffect of H
2O2shifts the Ca channel toward an open state
Thus the redox property of CCBs DHPs may augment theirCCB properties
Oxidation of pharmacologically active Hantzsch 14-dihydropyridines was found by electrogenerated superoxideusing a voltammetric approach in DMSO solutions (Ortiz etal [238] and Ortiz et al [239]) Raghuvanshi and Singh [240]have also reported oxidative aromatization of these DHPsinduced by superoxide
Chemiluminescence (CL) was used in the studies ana-lyzing the antioxidant activity of 12 various 4-flavonil-14-dihydropyridine derivatives (Kruk et al [241]) on a chemicalsystem involving a superoxide radical anion These deriva-tives showed structural similarity to flavonoids with respectto the presence of rings A B and C The results obtained in
24 Oxidative Medicine and Cellular Longevity
this study indicate that the tested derivatives may catalyzeconversion of superoxide radicals through mimicking theactivity of superoxide dismutase by delivering H+ for reac-tion
O2
minus∙+O2
minus∙+ 2H+ 997888rarr H
2O2+1O2
(3)
The enhanced emission of the light in the presence oftested compounds was significant and related to stimulatedproduction ofH
2O2and 1O
2fromO
2
∙The latter specieswereremoved from the reactionmixture by the following sequenceof reactions
H+
O2
minus∙997888rarr HO
2
∙
HO2
∙+O2
∙minus997888rarr HO
2
minus+1O2
2HO2
∙997888rarr H
2O2+1O2
2 (1O2) 997888rarr (O
2)2+ h]lowast
(4)
or to take part in spontaneous dismutation of H2O2
2H2O2997888rarr 2H
2O + 1O
2(5)
The authors have offered an original concept of action for 4-flavonil-14-dihydropyridine derivatives unrelated to that ofO2
∙ radical-trapping chain-breaking antioxidants Insteadthey showed that these compounds act similar to superoxidedismutases converting O
2
∙ to H2O2 Hydrogen peroxide
is less toxic for cells than O2
∙ because it is predominantlyremoved by peroxidases and catalases Finally AO effect ofthese DHPs differed from those mediated by flavonoids witha catechol structure of ring B which are well-known 1O
2
quenchersMulder and collaborators came to similar conclusions
especially related to molecular mechanisms of antioxidativeactivity of DHPs [236]TheAOproperties of Hantzsch 14-di-hydropyridine esters and two dibenzo-14-dihydropyridines910-dihydroacridine (DHAC) and N-methyl-910-dihydro-acridine (N-Me-DHAC) have been explored by determin-ing the autoxidation of styrene or cumene at 30∘C Theseexperiments showed that Hantzsch esters are virtually inac-tive as chain-breaking antioxidants (CB-AOs) contrary tothe findings observed by Lopez-Alarcon et al [103] whoused CB-AOA in aqueous media at pH 74 Their reactivitytoward peroxyl radicals was shown to be some 5 orders ofmagnitude lower than that of the excellent CB-AO 22578-pentamethyl-6-hydroxy-chroman (PMHC)
DHAC was found to be sim10 times less reactive thanPMHC kinetic measurements using DHAC N-deuterio-DHAC and N-Me-DHAC pointing out the abstraction ofN-H hydrogen in DHAC by peroxyl radicals despite the factthat the calculated C-H bond dissociation enthalpy (BDE) inDHAC is about 11 kcalmol lower than the N-H BDE Therates of hydrogen atom abstraction by the 22-diphenyl-1-picrylhydrazyl radical (DPPH∙) have also been determined
for the same series of compounds The trends in the peroxyl∙and DPPH∙ rate constants were found to be similar [236]
Tirzit et al [242] have observed quenching of singletoxygen by DHPs This observation paved the ground forfurther research related to reactions of DHPs with hydroxylradicals (Tirzit et al [243]) singlet oxygen (Kazush etal [94]) and mechanisms of action A series of 14-DHPderivatives in NAD-H-Cu2+-H
2O2system inhibited forming
of the hydroxyl radical (HO∙) while 14-DHP derivativeswith electron donor substituents in the molecule were shownto be capable themselves of generating HO∙ in the presenceof Cu2+ and H
2O2 Rubene et al [186] also described
interaction of 14-DHP derivatives with Fentonrsquos reagentwhich produces hydroxyl radical (HO∙) Rate constants ofthe DHPs reaction (1st order) with HO∙ radical were highin the range 109 L times mol times secminus1 close to that of NADHcysteine and thiourea 35-Diacetyl- derivatives reacted fastercompared to 35-dialkoxycarbonyl- ones The reaction ratedecrease was observed in the case of substitution at position4 as compared to 4-unsubstituted DHPs Some DHPs havingelectron donor -COOminus groups in the 35- or 26- positionsof DHP ring reacted immediately (having rate constantshigher as 109 L times mol times secminus1) Rate constants with HO
2
∙
and O2
∙minus radicals were of lower degree Thus DHPs actingas oxygen radical scavengers could effectively inhibit ROSrelated reactions of LP initiation stage
Nifedipine and nitrendipine reactivity toward singletoxygen was also studied [244] Nifedipine was shown tobe a good scavenger of excited oxygen mainly via physicaldeactivation with values of the total rate constant rangingfrom 208 times 105Mminus1 sminus1 (in dioxane) to 930 times 105Mminus1 sminus1(in propylene carbonate)The less reactive pathway generateda photooxidation product For that reason a mechanisminvolving a perepoxide-like encounter complex in the firststep of the reaction path was proposed (see [244] Figures8 and 9 therein) The dependence was observed on solventmicroscopic parameters of the total rate constant for the reac-tion between singlet oxygen and 14-DHPs These findingsshow that nifedipine possesses stronger protective activity inbiological systems than nitrendipine
Density-functional-theory (DFT) calculations made byWang et al [245] confirmed the former experimental obser-vations that Hantzsch ester diludine is potent antioxi-dant with high H atom-donating ability and relatively lowprooxidant activity Possible reaction pathways for radicalsderived from 14-dihydropyridine and the resonance modesfor radical species were given [245]
Moreover two ethoxycarbonyl (EtOCO) substituentsat C(2) and C(6) should further enhance Hantzsch esterdiludine H-atom-donating ability due to resonance effectsHowever DHPs should be used in nonpolar rather than inpolar solvents since in the latter not H-atom but electrontransfer is preferred in the radical scavenging process [245]
Mulder et al [246] proposed that quantum-thermochem-ical calculations must be used with caution to indicate ldquoapromising lead antioxidantrdquo as they criticized the density-functional-theory (DFT) calculations made by Wang et al[245]
Oxidative Medicine and Cellular Longevity 25
372 Possible Mechanisms of DHPs ARA and AOA in the Bio-logical Systems Interaction with Other OSModifiers Some ofthese mechanisms were already described (Sections 331 (2)-(b) 331 (2)-(c) 331 (3)-(b) 35)
Enzymatic sources of ROSwith confirmed functional rolein hypertension are NADPH oxidase NO synthase (NOS)xanthine oxidase and cyclooxygenase Godfraind [3] hasreviewed AO effects and protective action of calcium channelblockers (CCBs) Yao et al [247] observed antioxidant effects(as inhibition of LP) for cardio- and neuroprotective CCBs(3ndash300 120583molL) including 7 DHPs in homogenates of ratbrain IC
50values (120583M) were as follows nifedipine (515) gt
barnidipine (586) gt benidipine (712) gt nicardipine (1293)gt amlodipine (1355) gt nilvadipine (1673) gt nitrendipine(2521) gt diltiazem (gt300) = verapamil (gt300) There arealso research articles describing the AO properties of CCBsthrough direct scavenging effect or through preservationof the endogenous SOD activity These findings indicatethat CCBs may also act by reducing the production ofvasoconstrictors angiotensin and endothelin
When present in concentrations that can be achievedin plasma CCBs may inhibit LP formation [3] This AOactivity seems to be typical for high lipophilic CCBs becausetheir chemical structure facilitates proton-donating andresonance-stabilization mechanisms that quench the freeradical reaction Their insertion in the membrane nearpolyunsaturated fatty acids at relatively high concentrationspotentiates proton donation (or atomary H) to lipid peroxidemolecules thereby blocking the peroxidation process Theremaining unpaired free electron associated with the CCBmolecule can be stabilized in well-defined resonance struc-tures associated with the DHP ring (Mason et al [48])
The radical reaction (according to Godfraind [3]) thatdescribes the AO effects of a DHP CCBs is LOOlowast + DHPrarr LOOH + DHPlowast (where LOOlowast is lipid peroxide radical)which in general is reaction (7) of the LP reaction cascadeconsisting of sim10 reactions (Scheme 2) [89]
As the rate constants of in vitro interaction of 4-substituted DHPs with peroxyl radicals are three ordersof magnitude lower than that of the vitamin E derivativethese DHPs must be considered as weak AO (Ursini [204])However due to partition coefficient of DHPs in membranesand in case of specific binding high local concentration ofDHPs may be obtained
DHPs without CCB properties for instance Bay w 9798although structurally related to nifedipine inhibit TNF-120572-induced vascular cell adhesion molecule-1 expression inendothelial cells by suppressing reactive oxygen speciesgeneration [248]
Mitrega et al [249] have discovered that antiarrhythmicand hemodynamic effects of oxidized heteroaromatic DHPsoxy nifedipine oxy nimodipine oxy nitrendipine and oxynisoldipine suggest that CCB DHPs and their metabolitescould act at least in two ways targeting OS related eventsas reductants (see Section 351 (1)) andor bypassing OSrelatedmetabolic routes Authors postulated that contrary tocurrent belief NIF metabolites are pharmacologically activeATP sensitive potassium channels were mentioned as a tar-get
38 DHPs Anti- or Prooxidants Several substances (ascorbicacid being the most commonly studied) can serve either asantioxidants or as prooxidants depending on given condi-tions (Herbert [250]) Therefore Halliwell [251] has reporteddilemma related to polyphenols as possible antioxidantsand prooxidants causing experimental artifacts (about 25)by oxidation of antioxidant compounds in the cell culturemedia Nevertheless it is generally accepted opinion thatpolyphenols act as antioxidants in vivo Studies on DHPs alsoface such a dilemmaThe exact roles (anti- or prooxidative) ofany specific DHP depend on its structure appliedachievedconcentration and specificity of the targetexperimentaltesting system
This situation resembles the case of antioxidative effectsof tocopherol which depends on the fate of the secondaryradical as proposed by Winterbourn [252] The question wasldquoVitamin E - Pro- or Antioxidantrdquo
997888rarr chain termination of lipid peroxidation
(6)
Prooxidant
Toc∙ + Lipid-H 997888rarr Lipid∙ (in LDL particles) (7)
This example shows that generally speaking any AO mustfulfil several criteria to be considered as an effective com-pound physiologically
(i) It must be able to functionally interact with endoge-nous scavengers even at low concentrations
(ii) It must affect endogenous pathways of OS(iii) It should not have undesirable adverse effect(iv) It should manifest the antioxidant efficacy dependent
on the oxidant(v) It must discriminate among different strategies
needed for 1-electron and 2-electron processes(vi) Radical scavengers can be prooxidant unless linked to
a radical sink (Winterbourn [252])
According to these statements DHPs could be effective asAO under physiological conditions in vivo (Godfraind [3]and others [30 31 38]) and in vitro in various experimentalsystems (cell and tissue) (see Sections 33 34 35)
Hence calcium antagonists appeared to disrupt thefine balance between the production and scavenging ofROS Nifedipine verapamil and diltiazem were shown toinduce significant oxidative stress in the epididymal sperm(increased MDA and decreased catalase and superoxidedismutase activity) This may be the reason for the inductionof male infertility [253]
The dualism of 14-DHP effects has been recorded asinhibition or promotion of LP as quenching or initiating
26 Oxidative Medicine and Cellular Longevity
oxygen and nitrogen free radical chain reactions radiopro-tecting or radiosensitizing antagonizing or synergizing Ca2+in electromechanical coupling as well as in the membranestabilization or labilization
39 Could DHPs Be Involved in Antioxidative Stress Beforebeing applied in vivo the optimal dose and optimal timeintervals forDHPs applicationmust be knownNamely whileROS have been traditionally considered as toxic byproductsof aerobic metabolism we know nowadays that ROS may actas essential signaling molecules needed for the control ofmany different physiological processes Whether the role ofROS will be damaging protective or signaling depends onthe delicate equilibrium between time- and location-specificROS production and scavenging Accordingly the imbalanceof the increased AO potential so-called antioxidative stresscould be dangerous similar to chronic OS in particular incase of extended exposure Inappropriate interventions inthe oxidative homeostasis by excessive antioxidants especiallyin case of chronic exposure to antioxidants might havevery negative effects as was published in the ATBC studyshowing an increased cancer incidence in smokers treatedby excessive beta-carotene [254] Therefore overconsump-tion of any natural or synthetic AO including DHPs asdietary supplements or drugs must be avoided in order tosuppress oxidative damage and must not disrupt the well-integrated antioxidant defense network (Poljsak [255] andPoljsak and Milisav [256]) This is especially important whenadministrating lipid-soluble antioxidants that can be storedin biomembranes thus not only attenuating or preventing LPbut also affecting physiological effects of the natural antiox-idants in particular tocopherol The interrelationship withthe status of endogenous antioxidantsprooxidants should befollowed
DHPs primarily suppress the initiation stages of LPprocessThey do not entirely stop the LP propagation Actingsynergistically with tocopherol diludine may prevent patho-logical excess of ROS production within the lipid moiety ofthe cellular membranes and LDL However due to its lowsolubility and fast metabolism its concentration in the cellsis low For that reason it cannot cause antioxidative stresseven if used for an extended period of time Thus diludine(diethone) could be only a mild antioxidant it has potentialfor restoring the pool of natural antioxidants (as synergist of120572-tocopherol and polyphenols) in the cells
Moreover DHPs CA used for cardioprotection andvasodilatation as commercial drugs in low concentrationsare fast metabolized via CYP3A4 and for that reason theirapplication does not induce cellular AO stress [53 160]However Godfraind and Salomone [257] have postulated noevidence that allows recommending dietary supplementationwith antioxidants for the primary or secondary prevention ofcardiovascular disease
So far there are no reports on antioxidative stress causedby some DHPs diludine and its analogues Diludine andits analogues therefore could act as adaptogens supportinghormetic effects of mild oxidative stress These compoundsmay act as potential multisided modulators of Yin-Yang
cycles of redox and cell functions (the electroplasmic cycle)(Wagner et al [258])
4 Conclusions
14-Dihydropyridines (14-DHPs) have broad spectrum ofOS modulating activities DHPs have reducing and lipidperoxidation inhibitor properties act as reductants in simplechemical systems and stabilize various biological systems(LDL mitochondria microsomes cells and tissues) againstOS Examples and peculiarities and mechanisms of antiox-idant activity (AOA) and antiradical activity (ARA) as wellas stress-protective effect of DHPs including commercialcalcium antagonists (CA) were highlighted These activitiesdepend on various structural parameters related to DHPs(presence and character of substituents) lipophilicity anddepth of the incorporation in the biologicalmembranesTheyalso depend on the experimental model system for exploringthe lipid peroxidation or oxidative stress Stress-protectiveeffect of some metabolites of CA (nifedipine) is reviewedAlthough some DHPs including CA have prooxidant prop-erties (on epididymal sperm cells) they can generally beconsidered as potent antioxidants Therefore comparisonof the AOA and ARA of different DHPs (mutually andwith other AOs) was described in detail According to thedata presented the DHPs might be considered as bellwetheramong synthetic compounds targeting OS and as a kind ofpharmacological measure for respective field of organic andmedicinal chemistry
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
Authors from Latvian IOS acknowledge ESF 201300021DP1112013APIAVIAA011 and National Research Pro-gramme PUBLIC HEALTHBiomedicine of the Republicof Latvia for financial support administration of the Insti-tute for technical support and Rufus Smits PhD for con-sultations in English The support of Cooperation in Euro-pean System of Science and Technology (COST) Domain ofChemistry Molecular Sciences and Technologies (CMST)was of highest importance for preparation of this paper
[2] D J Triggle ldquo14-Dihydropyridines as calcium channel ligandsand privileged structuresrdquoCellular andMolecular Neurobiologyvol 23 no 3 pp 293ndash303 2003
[3] T Godfraind ldquoAntioxidant effects and the therapeutic modeof action of calcium channel blockers in hypertension andatherosclerosisrdquo Philosophical Transactions of the Royal SocietyB Biological Sciences vol 360 no 1464 pp 2259ndash2272 2005
[4] E Cadenas ldquoMitochondrial free radical production and cellsignalingrdquoMolecular Aspects of Medicine vol 25 no 1-2 pp 17ndash26 2004
[5] E Cadenas ldquoFree radicals oxidative stress and diseasesrdquo inLecture PSC 616 p 38 Missouri University of Science andTechnology Rolla Mo USA httpwwwcarnicominstituteorgarticlesenrique cadenaspdf
[6] K Rahman ldquoStudies on free radicals antioxidants and co-fac-torsrdquo Clinical Interventions in Aging vol 2 no 2 pp 219ndash2362007
[7] V Bocci and G Valacchi ldquoFree radicals and antioxidants howto reestablish redox homeostasis in chronic diseasesrdquo CurrentMedicinal Chemistry vol 20 no 27 pp 3397ndash3415 2013
[8] M Valko C J Rhodes J Moncol M Izakovic and M MazurldquoFree radicals metals and antioxidants in oxidative stress-induced cancerrdquo Chemico-Biological Interactions vol 160 no 1pp 1ndash40 2006
[9] G Bartosz ldquoReactive oxygen species destroyers or messen-gersrdquo Biochemical Pharmacology vol 77 no 8 pp 1303ndash13152009
[10] R Visconti and D Grieco ldquoNew insights on oxidative stress incancerrdquo Current Opinion in Drug Discovery and Developmentvol 12 no 2 pp 240ndash245 2009
[11] R N Kujundzic N Zarkovic and K G Troselj ldquoPyridinenucleotides in regulation of cell death and survival by redoxand non-redox reactionsrdquo Critical Reviews in Eukaryotic GeneExpression vol 24 no 4 pp 287ndash309 2014
[12] B Halliwell and J M C Gutteridge ldquoThe definition and mea-surement of antioxidants in biological systemsrdquo Free RadicalBiology and Medicine vol 18 no 1 pp 125ndash126 1995
[13] V D Kancheva and O T Kasaikina ldquoBio-antioxidantsmdashachemical base of their antioxidant activity and beneficial effect
on human healthrdquo Current Medicinal Chemistry vol 20 no 37pp 4784ndash4805 2013
[14] H V Panglossi Ed Frontiers in Antioxidants Research NovaScience Publishers New York NY USA 2006
[15] E B Burlakova E M Molochkina and G A NikiforovldquoHybrid antioxidantsrdquo Oxidation Communications vol 31 no4 pp 739ndash757 2008 httpmembraneustceducnpaperpdfHybrid20Antioxidantspdf
[16] A Bast and G R M M Haenen ldquoTen misconceptions aboutantioxidantsrdquo Trends in Pharmacological Sciences vol 34 no 8pp 430ndash436 2013
[17] E B Burlakova A V 0lesenko E M Molochkina N PPalmina and N G Khrapova Bioantioxidants for RadiationDamage and Malignant Growth Nauka Moscow Russia 1975(Russian)
[18] J Fang T Seki and H Maeda ldquoTherapeutic strategies by mod-ulating oxygen stress in cancer and inflammationrdquo AdvancedDrug Delivery Reviews vol 61 no 4 pp 290ndash302 2009
[19] M Valko D Leibfritz J Moncol M T D Cronin M Mazurand J Telser ldquoFree radicals and antioxidants in normal physi-ological functions and human diseaserdquo International Journal ofBiochemistry and Cell Biology vol 39 no 1 pp 44ndash84 2007
[20] M Jimenez-Del-Rio and C Velez-Pardo ldquoThe bad the goodand the ugly about oxidative stressrdquo Oxidative Medicine andCellular Longevity vol 2012 Article ID 163913 13 pages 2012
[21] C D Kamat S Gadal M Mhatre K S Williamson Q N Pyeand K Hensley ldquoAntioxidants in central nervous system dis-eases preclinical promise and translational challengesrdquo Journalof Alzheimerrsquos Disease vol 15 no 3 pp 473ndash493 2008
[22] A Pompella H Sies R Wacker et al ldquoThe use of totalantioxidant capacity as surrogate marker for food quality andits effect on health is to be discouragedrdquo Nutrition vol 30 no7-8 pp 791ndash793 2014
[23] Z Ye and H Song ldquoAntioxidant vitamins intake and the risk ofcoronary heart disease meta-analysis of cohort studiesrdquo Euro-pean Journal of Cardiovascular Prevention and Rehabilitationvol 15 no 1 pp 26ndash34 2008
[24] P Knekt J Ritz M A Pereira et al ldquoAntioxidant vitamins andcoronary heart disease risk a pooled analysis of 9 cohortsrdquoTheAmerican Journal of Clinical Nutrition vol 80 no 6 pp 1508ndash1520 2004
[25] A C Carr and M C M Vissers ldquoSynthetic or food-derivedvitamin Cmdashare they equally bioavailablerdquo Nutrients vol 5 no11 pp 4284ndash4304 2013
[26] R Tabrizchi ldquoEdaravoneMitsubishi-TokyordquoCurrentOpinion inInvestigational Drugs vol 1 no 3 pp 347ndash354 2000
[27] K Kikuchi S Tancharoen N Takeshige et al ldquoThe efficacy ofedaravone (radicut) a free radical scavenger for cardiovasculardiseaserdquo International Journal of Molecular Sciences vol 14 no7 pp 13909ndash13930 2013
[28] D Mauzerall and F H Westheimer ldquo1-Benzyldihydronicoti-namidemdasha model for reduced DPNrdquo Journal of the AmericanChemical Society vol 77 no 8 pp 2261ndash2264 1955 ChemicalAbstracts vol 50 Article ID 2588i 1956
[29] F Bossert and W Vater ldquo14-Dihydropyridinesmdasha basis fordeveloping new drugsrdquo Medicinal Research Reviews vol 9 no3 pp 291ndash324 1989
[30] G Swarnalatha G Prasanthi N Sirisha and CMadhusudhanaChetty ldquo14-Dihydropyridines a multtifunctional moleculemdash areviewrdquo International Journal of ChemTech Research vol 3 no1 pp 75ndash89 2011
28 Oxidative Medicine and Cellular Longevity
[31] M Cataldi and F Bruno ldquo14-Dihydropyridines the multiplepersonalities of a blockbuster drug familyrdquo Translational Medi-cine UniSa vol 4 no 2 pp 12ndash26 2012 httpwwwncbinlmnihgovpmcarticlesPMC3728803
[32] R Vitolina A Krauze G Duburs and A Velena ldquoAspects ofthe amlodipine pleiotropy in biochemistry pharmacology andclinicsrdquo International Journal of Pharmaceutical Sciences andResearch vol 3 no 5 pp 1215ndash1232 2012
[33] D Grover S N Mokale and M T Shete ldquoDihydropyridinea novel pharmacophorerdquo International Journal of Pharmaceu-tical Erudition vol 1 no 2 pp 16ndash29 2011 httppharmaeru-ditionorgContentPaper20111-RV-320Final2016-29pdf
[34] A M Vijesh A M Isloor S K Peethambar K N ShivanandaT Arulmoli and N A Isloor ldquoHantzsch reaction synthesis andcharacterization of somenew 14-dihydropyridine derivatives aspotent antimicrobial and antioxidant agentsrdquo European Journalof Medicinal Chemistry vol 46 no 11 pp 5591ndash5597 2011
[35] P Mehta and P Verma ldquoAntimicrobial activity of some deriva-tives of 14-dihydropyridinesrdquo Journal of Chemistry vol 2013Article ID 865128 4 pages 2013
[36] P Olejnıkova L Svorc D Olsovska et al ldquoAntimicrobialactivity of novel C2-substituted 14-dihydropyridine analoguesrdquoScientia Pharmaceutica vol 82 no 2 pp 221ndash232 2014
[37] S Sepehri H Perez Sanchez and A Fassihi ldquoHantzsch-typedihydropyridines and biginelli-type tetra-hydropyrimidinesa review of their chemotherapeutic activitiesrdquo Journal of Phar-macy amp Pharmaceutical Sciences vol 18 no 1 pp 1ndash52 2015httpsejournalslibraryualbertacaindexphpJPPSarticleview2383617863
[38] S A Khedkar and P B Auti ldquo14-Dihydropyridines a classof pharmacologically important moleculesrdquo Mini-Reviews inMedicinal Chemistry vol 14 no 3 pp 282ndash290 2014
[39] G D Tirzit and G Ya Duburs ldquo14-dihydropyridines as inhi-bitors of free-radical reactionsrdquo Chemistry of Heterocyclic Com-pounds vol 8 no 1 pp 126ndash127 1972 Translated from KhimiyaGeterotsiklicheskikh Soedinenii no1 pp 133ndash134 1972 (Rus-sian)
[40] I Bogeski R Kappl C Kummerow R Gulaboski M Hothand B A Niemeyer ldquoRedox regulation of calcium ion channelschemical and physiological aspectsrdquoCell Calcium vol 50 no 5pp 407ndash423 2011
[41] S A Giller G Y Dubur Y R Uldrikis et al ldquoDiludine [Themethod to obtain 35-dicarbonylderivatives of 26-dimethyl-14-dihydropyridines]rdquo Authors certificate of USSR no 3004651971 [Byull Izobret no13 p 95 1971] and following patentsPatent of England no 1294650 1973 Patent of France no2055458 1971 Patent of Japan no 702883 1973 Patent ofHolland no 149787 1976 Patent of Italy no 969022 1974 Patentof FRG no 2036403 1978 US Patent no 3883673 1975 USPatent no 3948924 1976
[42] S A Giller G Y Dubur Y R Uldrikis et al ldquoImprovementsin or relating to the stabilization of carotenerdquo GB Patent no1294650 1972
[43] S A Giller G Y Dubur Y R Uldrikis et al ldquoStabilization ofcarotenerdquo US Patent no 3883673 1975 Chemical Abstracts vol83 Article ID 95193 1975
[44] Yu A Zilber G Ya Dubur K K Kumsar and A Kh VelenaldquoThe effect of antioxidants on the peroxidation of bimole-cular phospholipid membranesrdquo Latvijas PSR ZA Vestis Izves-tia Akademii Nauk Latviyskoy SSR vol 6 pp 80ndash82 1971(Russian) translated from the original Russian Doc Accesion
No AD0771751 distributed by NTIS US Department of Com-merce httpwwwdticmildtictrfulltextu2771751pdf
[45] G Ya Dubur Yu A Zilbers A Kh Velena A O Kumerovaand G D Tirzitis ldquoMultistage study of regulation of peroxida-tion processes in biological membranes by antioxidants of 14-dihydropyridine grouprdquo Izvestiya Akademii Nauk LatviyskoySSR vol 336 no 7 pp 65ndash68 1975 (Russian)
[46] R P Mason and M W Trumbore ldquoDifferential membraneinteractions of calcium channel blockers Implications forantioxidant activityrdquo Biochemical Pharmacology vol 51 no 5pp 653ndash660 1996
[47] R P Mason M F Walter M W Trumbore E G Olmstead Jrand P E Mason ldquoMembrane antioxidant effects of the chargeddihydropyridine calcium antagonist amlodipinerdquo Journal ofMolecular and Cellular Cardiology vol 31 no 1 pp 275ndash2811999
[48] R PMason I T MakMW Trumbore and P EMason ldquoAnti-oxidant properties of calcium antagonists related to membranebiophysical interactionsrdquo American Journal of Cardiology vol84 no 4 pp 16ndash22 1999
[49] R PMasonMW Trumbore and P EMason ldquoMembrane bio-physical interaction of amlodipine and antioxidant propertiesrdquoDrugs vol 59 no 2 pp 9ndash16 2000 (French)
[50] R P Mason P Marche and T H Hintze ldquoNovel vascularbiology of third-generation L-type calcium channel antagonistsAncillary actions of amlodipinerdquo Arteriosclerosis Thrombosisand Vascular Biology vol 23 no 12 pp 2155ndash2163 2003
[51] A Augustyniak G Bartosz A Cipak et al ldquoNatural andsynthetic antioxidants an updated overviewrdquo Free RadicalResearch vol 44 no 10 pp 1216ndash1262 2010
[52] T Grune N Zarkovic and K Kostelidou ldquoLipid peroxidationresearch in Europe and the COST B35 action lsquoLipid Peroxida-tion Associated Disordersrsquordquo Free Radical Research vol 44 no10 pp 1095ndash1097 2010
[53] E Carosati P Ioan M Micucci et al ldquo14-Dihydropyridinescaffold in medicinal chemistry the story so far and perspec-tives (part 2) action in other targets and antitargetsrdquo CurrentMedicinal Chemistry vol 19 no 25 pp 4306ndash4323 2012
[54] U Eisner and J Kuthan ldquoThe chemistry of dihydropyridinesrdquoChemical Reviews vol 72 no 1 pp 1ndash42 1972 httpwwwsci-encemadnessorgtalkfilesphppid=138742ampaid=6475
[55] J Kuthan and A Kurfurst ldquoDevelopment in dihydropyri-dine chemistryrdquo Industrial amp Engineering Chemistry ProductResearch and Development vol 21 no 2 pp 191ndash261 1982
[56] A Sausins and G Duburs ldquoSynthesis of 14-dihydropyridinesby cyclocondensation reactionsrdquo Heterocycles vol 27 no 1 pp269ndash289 1988
[57] A E Sausins and G Y Duburs ldquoSynthesis of 14-dihydro-pyridines in cyclocondensation reactions (review)rdquo Chemistryof Heterocyclic Compounds vol 28 no 4 pp 363ndash391 1992Translated from Khimiya Geterotsiklicheskikh Soedinenii no 4pp 435ndash467 1992 (Russian)
[58] S Kazda ldquoTwenty years of dihydropyridinesrdquo in Dihydropy-ridines Progress in Pharmacology and Therapy W-D Busse BGarthoff and F Seuter Eds pp 1ndash12 Springer Verlag BerlinGermany 1993
[59] J-P Wan and Y Liu ldquoRecent advances in new multicomponentsynthesis of structurally diversified 14-dihydropyridinesrdquo RSCAdvances vol 2 no 26 pp 9763ndash9777 2012
[61] Reaxys Database[62] J Tuttle ldquoStructure mechanism and reactivity of hantzsch
estersrdquo in MacMillan Lab Group Meeting (082504) p 332004 httpwwwprincetoneduchemistrymacmillangroup-meetingsJBT20Hantzschpdf
[63] A Saini S Kumar and J S Sandhu ldquoHantzsch reaction recentadvances in Hantzsch 14-dihydropyridinesrdquo Journal of Sci-entific amp Industrial Research vol 67 pp 95ndash111 2008
[64] L LW Cheung S A Styler and A P Dicks ldquoRapid and conve-nient synthesis of the 14-dihydropyridine privileged structurerdquoJournal of Chemical Education vol 87 no 6 pp 628ndash630 2010
[65] A Kumar R A Maurya S Sharma M Kumar and G BhatialdquoSynthesis and biological evaluation of N-aryl-14-dihydro-pyridines as novel antidyslipidemic and antioxidant agentsrdquoEuropean Journal of Medicinal Chemistry vol 45 no 2 pp 501ndash509 2010
[66] R S Kumar A Idhayadhulla A J Abdul Nasser and J SelvinldquoSynthesis and anticoagulant activity of a new series of 14-dihydropyridine derivativesrdquo European Journal of MedicinalChemistry vol 46 no 2 pp 804ndash810 2011
[67] H A Stefani C B Oliveira R B Almeida et al ldquoDihydro-pyrimidin-(2H)-ones obtained by ultrasound irradiation anew class of potential antioxidant agentsrdquo European Journal ofMedicinal Chemistry vol 41 no 4 pp 513ndash518 2006
[68] H Sun C Shang L Jin and J Zhang ldquoSynthesis and antiox-idant activity of a series of novel 3-chalcone-substituted 14-dihydropyridine derivativesrdquoHeterocyclic Communications vol18 no 5-6 pp 239ndash243 2012
[69] D B Tikhonov and B S Zhorov ldquoStructural model for dihy-dropyridine binding to L-type calcium channelsrdquo The Journalof Biological Chemistry vol 284 no 28 pp 19006ndash19017 2009
[70] G Y Dubur and Y R Uldrikis ldquoThe oxidation of 14-dihydro-pyridinesrdquo Chemistry of Heterocyclic Compounds vol 6 no 1pp 80ndash84 1970 Translated from Khimiya GeterotsiklicheskikhSoedinenii no 1 pp 83ndash88 1970 (Russian)
[71] G Ya Duburs A O Kumerova and Ya R Uldrikis ldquoEnzymicoxidation of hydrogenated pyridines with peroxidase-hydrogenperoxide systemrdquoLatvijas PSRZAVestis vol 73 no 7 pp 73ndash771970 (Russian) Chemical Abstracts vol 73 Article ID 94913g1970
[72] K Xie Y-C Liu Y Cui J-GWang Y Fu andT CWMak ldquoN-methyl-(R)-3-(tert-butyl)-sulfinyl-14-dihydropyridine a novelNADHmodel compoundrdquoMolecules vol 12 no 3 pp 415ndash4222007
[73] S Tamagaki T Mimura and W Tagaki ldquoMetal-ion-facilitatedoxidations of dihydropyridines with molecular oxygen andhydrogen peroxiderdquo Journal of the Chemical Society PerkinTransactions 2 no 10 pp 1645ndash1650 1990
[74] D Tirzite G Tirzitis andD Antipova ldquoReductive ability of 14-dihydropyridine derivatives in relation to ions of trivalent ironrdquoChemistry of Heterocyclic Compounds vol 35 no 5 pp 592ndash594 1999
[76] J Ogle J Stradins and L Baumane ldquoFormation and decay offree cation-radicals in the course of electro-oxidation of 12- and14-dihydropyridines (Hantzsch esters)rdquo Electrochimica Actavol 39 no 1 pp 73ndash79 1994
[77] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for the
synthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts C Wittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Berlin Germany 2010
[78] WDu and Zh Yu ldquoBiomimetic in situ regeneration of cofactorsNAD(P)+ and NAD(P)H models hantzsch esters and dihy-drophenanthridinerdquo Synlett vol 23 no 9 pp 1300ndash1304 2012
[79] H K Chenault and G M Whitesides ldquoRegeneration ofnicotinamide cofactors for use in organic synthesisrdquo AppliedBiochemistry and Biotechnology vol 14 no 2 pp 147ndash197 1987
[80] Y R Uldrikis A A Zidermane E A Biseniex I E Preisa GY Dubur and G D Tirzit ldquoEsters of 26-dimethyl-14-dihydro-pyridine-35-dicarboxylic acid and method of obtainingthereofrdquo WO 8000345 A1 1978 httpworldwideespacenetcompublicationDetailsbiblioDB=EPODOCampII=1ampND=3ampadjacent=trueamplocale=en EPampFT=Dampdate=19800306ampCC=WOampNR=8000345A1ampKC=A1
[81] Y Sambongi H Nitta K Ichihashi M Futai and I Ueda ldquoAnovel water-soluble Hantzsch 14-dihydropyridine compoundthat functions in biological processes through NADH regener-ationrdquo Journal of Organic Chemistry vol 67 no 10 pp 3499ndash3501 2002
[82] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for thesynthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts ChWittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Verlag Berlin Germany 2010
[83] T Okamura T Kikuchi A Nagamine et al ldquoAn approach formeasuring in vivo cerebral redox states using the oxidative con-version of dihydropyridine to pyridinium ion and themetabolictrapping principlerdquo Free Radical Biology and Medicine vol 38no 9 pp 1197ndash1205 2005
[84] K A Schellenberg and F H Westheimer ldquoA free-radicaloxidation of a dihydropyridine1ardquo The Journal of OrganicChemistry vol 30 no 6 pp 1859ndash1862 1965
[85] K A Schellenberg ldquoReaction of hydroxyl radical with thymi-dine Scavenging by a dihydropyridinerdquo Federation Proceedingsvol 38 no 3 I p 1433 1979
[86] E S Huyser J A K Harmony and F L McMillian ldquoPeroxideoxidations of dihydropyridine derivativesrdquo Journal of the Amer-ican Chemical Society vol 94 no 9 pp 3176ndash3180 1972
[87] A Sakamoto S T Ohnishi and R Ogawa ldquoInhibition of lipidperoxidation by some dihydropyridine derivativesrdquo Journal ofAnesthesia vol 7 no 2 pp 193ndash197 1993
[88] R Hardeland ldquoReview Neuroprotection by radical avoidancesearch for suitable agentsrdquo Molecules vol 14 no 12 pp 5054ndash5102 2009
[89] G Ya Dubur A Kh Velena V M Gukasov and Yu AVladimirov ldquoRegulation of peroxidation of mitochondrialmembrane lipids initiated by Fe2+ ions by antoxidants of the14-dihydropyridine series in experiments in vitrordquo Biomed-itsinskaya Khimiya vol 22 no 5 pp 665ndash673 1976 (Russian)Chemical Abstracts vol 88 Article ID 2640 1977
[90] G RMMHaenenM J T J Arts A Bast andMD ColemanldquoStructure and activity in assessing antioxidant activity in vitroand in vivo a critical appraisal illustrated with the flavonoidsrdquoEnvironmental Toxicology and Pharmacology vol 21 no 2 pp191ndash198 2006
[91] G Tirzitis and G Bartosz ldquoDetermination of antiradical andantioxidant activity basic principles and new insightsrdquo ActaBiochimica Polonica vol 57 no 2 pp 139ndash142 2010
30 Oxidative Medicine and Cellular Longevity
[92] G R Buettner and R P Mason ldquoSpin-trapping methods fordetecting superoxide and hydroxyl free radicals in vitro and invivordquo inCritical Reviews of Oxidative Stress and Aging Advancesin Basic Science Diagnostics and Intervention R G Cutler andH Rodriguez Eds vol 1 chapter 2 pp 27ndash38World ScientificLondon UK 2003
[93] M M Tarpey and I Fridovich ldquoMethods of detection ofvascular reactive species Nitric oxide superoxide hydrogenperoxide and peroxynitriterdquo Circulation Research vol 89 no3 pp 224ndash236 2001
[94] E Y Kazush E I Sagun G D Tirzit and G Y DaburldquoQuenching of singlet oxygen by electron donating derivativesof 14-dihydropyridinerdquo Chemistry of Heterocyclic Compoundsvol 30 no 5 pp 562ndash563 1994
[95] G Tirzitis E Kazush and G Duburs ldquoReaction of 14-dihydropyridine derivatives with peroxynitrite anionrdquo Chem-istry of Heterocyclic Compounds vol 34 no 3 pp 321ndash3231998 (Russian) Translated from Khimiya GeterotsiklicheskikhSoedinenii no 3 pp 355ndash357 1998
[96] L J Nunez-Vergara C Lopez-Alarcon P A Navarrete-EncinaA M Atria C Camargo and J A Squella ldquoElectrochemicaland EPR characterization of 14-dihydropyridines Reactivitytowards alkyl radicalsrdquo Free Radical Research vol 37 no 1 pp109ndash120 2003
[97] D Tirzite A Krauze A Zubareva G Tirzitis and G DubursldquoSynthesis and antiradical activity of 5-acetyl-2-alkylthio-4-aryl-6-methyl-14-dihydropyridine-3-carboxylic acid nitrilesrdquoChemistry of Heterocyclic Compounds vol 38 no 7 pp 795ndash800 2002
[98] H Ohkawa N Ohishi and K Yagi ldquoAssay for lipid peroxidesin animal tissues by thiobarbituric acid reactionrdquo AnalyticalBiochemistry vol 95 no 2 pp 351ndash358 1979
[99] N Zarkovic ldquo4-Hydroxynonenal as a bioactive marker ofpathophysiological processesrdquo Molecular Aspects of Medicinevol 24 no 4-5 pp 281ndash291 2003
[100] M Parola G Bellomo G Robino G Barrera and M UDianzani ldquo4-Hydroxynonenal as a biological signal molecularbasis and pathophysiological implicationsrdquo Antioxidants andRedox Signaling vol 1 no 3 pp 255ndash284 1999
[101] T Lovakovic M Poljak-Blazi G Duburs et al ldquoGrowthmodulation of human cells in vitro by mild oxidative stressand 14-dihydropyridine derivative antioxidantsrdquo CollegiumAntropologicum vol 35 no 1 pp 137ndash141 2011
[102] R van den Berg G R M M Haenen H van den Bergand A Bast ldquoApplicability of an improved Trolox equivalentantioxidant capacity (TEAC) assay for evaluation of antioxidantcapacity measurements of mixturesrdquo Food Chemistry vol 66no 4 pp 511ndash517 1999
[103] C Lopez-Alarcon P Navarrete C Camargo J A Squella andL J Nunez-Vergara ldquoReactivity of 14-dihydropyridines towardalkyl alkylperoxyl radicals and ABTS radical cationrdquo ChemicalResearch in Toxicology vol 16 no 2 pp 208ndash215 2003
[104] V Valenzuela P Santander C Camargo J A Squella C Lopez-Alarcon and L J Nunez-Vergara ldquo14-Dihydropyridines reac-tivity of nitrosoaryl and nitroaryl derivatives with alkylperoxylradicals andABTS radical cationrdquo Free Radical Research vol 38no 7 pp 715ndash727 2004
[105] L G Tsetlin N A Chebotareva B I Kurganov A K VelenaG Y Dubur and V Z Lankin ldquoStudy of 14-dihydropyridinesas lipoxygenase inhibitors with the use of hydrated reversedmicellesrdquo Pharmaceutical Chemistry Journal vol 22 no 6 pp425ndash428 1988 (Russian)
[106] J Panek Z Reblova L Kocirkova et al ldquoAntioxidant activityof dihydropyridine derivativesrdquo Czech Journal of Food Sciencesvol 18 pp 144ndash145 2000
[107] G Tirzitis I Kirule and G Duburs ldquoAntioxidationsaktivitatder 35-dicarbonylderivate des 26-demethyl-14-dihydropyri-dinsrdquo Fett Wissenschaft TechnologieFat Science Technology vol90 no 10 pp 411ndash413 1988
[108] M Plotniece G Tirzitis Y Uldrikis et al ldquoSynthesis of 14-dihydropyridine derivatives having an oxy- alkoxy- or dimeth-ylaminophenyl substituent in the 4 position their antioxidantactivity and their binding to phospholipid membranesrdquo Chem-istry of Heterocyclic Compounds vol 32 no 10 pp 1166ndash11721996 Translated from Khimiya Geterotsiklicheskikh Soedineniino 10(352) pp 1358ndash1365 1996 (Russian)
[109] D Y Rubene V S Sharov V I Olenev G D Tirzit G Y Duburand Y A Vladimirov ldquoUse of chemiluminescent method forthe evaluation of antioxidant activity of some derivatives of 14-dihydropyridinerdquo Russian Journal of Physical Chemistry A vol55 no 2 pp 511ndash512 1981 (Russian)
[110] M C R Symons and JM C Gutteridge Free Radicals and IronChemistry Biology and Medicine Oxford Science PublicationsOxford University Press Oxford UK 1998
[111] M Repetto J Semprine and A Boveris ldquoLipid peroxidationchemical mechanism biological implications and analyticaldeterminationrdquo in Lipid Peroxidation A Catala Ed Section ILipid Peroxidation Chemical Mechanisms Antioxidants Bio-logical Implications of Biochemistry Genetics and MolecularBiology chapter 1 pp 3ndash30 InTech Rijeka Croatia 2012
[112] A Velena J Zilbers and G Duburs ldquoDerivatives of 14-dihydropyridines asmodulators of ascorbate-induced lipid per-oxidation and high-amplitude swelling ofmitochondria causedby ascorbate sodium linoleate and sodiumpyrophosphaterdquoCellBiochemistry and Function vol 17 no 4 pp 237ndash252 1999
[113] M V Bilenko L N Shelenkova G Y Dubur and A K VelenaldquoUse of antioxidants to prevent renal damage during acuteischemia and reperfusionrdquo Bulletin of Experimental Biology andMedicine vol 96 no 3 pp 1195ndash1198 1983 Translated fromByulletenrsquo Eksperimentalrsquonoi Biologii i Meditsiny vol 96 no 9pp 8ndash11 1983 (Russian)
[114] R Toniolo F Tubaro F Ursini and G Bontempelli ldquoAn elec-troanalytical investigation on the redox properties of calciumantagonist dihydropyridinesrdquo Electroanalysis vol 15 no 10 pp855ndash861 2003
[115] L Kourimska J Pokorny and G Tirzitis ldquoThe antioxidant aci-tivity of 26-dimethyl-35-diethoxycarbonyl-14-dihydropyri-dine in edible oilsrdquo Nahrung vol 37 no 1 pp 91ndash93 1993
[116] C Lopez-Alarcon H Speisky J A Squella C Olea-Azar CCamargo and L J Nunez-Vergara ldquoReactivity of 14-dihydro-pyridines toward SIN-1-derived peroxynitriterdquo PharmaceuticalResearch vol 21 no 10 pp 1750ndash1757 2004
[117] R A Olek W Ziolkowski J J Kaczor L Greci J Popinigisand J Antosiewicz ldquoAntioxidant activity of NADH and its ana-loguemdashan in vitro studyrdquo Journal of Biochemistry andMolecularBiology vol 37 no 4 pp 416ndash421 2004
[118] E Niki N Noguchi and N Gotoh ldquoInhibition of oxidativemodification of low density lipoprotein by antioxidantsrdquo Jour-nal of Nutritional Science andVitaminology vol 39 supplementpp S1ndashS8 1993
[119] N Rojstaczer and D J Triggle ldquoStructure-function relation-ships of calcium antagonists effect on oxidative modificationof low density lipoproteinrdquo Biochemical Pharmacology vol 51no 2 pp 141ndash150 1996
Oxidative Medicine and Cellular Longevity 31
[120] A Sevanian L Shen and FUrsini ldquoInhibition of LDLoxidationand oxidized LDL-induced cytotoxicity by dihydropyridinecalcium antagonistsrdquo Pharmaceutical Research vol 17 no 8 pp999ndash1006 2000
[121] A Negre-Salvayre and R Salvayre ldquoProtection by Ca2+ channelblockers (nifedipine diltiazem and verapamil) against the tox-icity of oxidized low density lipoprotein to cultured lymphoidcellsrdquo British Journal of Pharmacology vol 107 no 3 pp 738ndash744 1992
[122] A Negre-Salvayre G FitoussiM Troly and R Salvayre ldquoCom-parative cytoprotective effect of dihydropyridine calcium chan-nel blockers against the toxicity of oxidized low density lipopro-tein for cultured lymphoid cellsrdquo Biochemical Pharmacologyvol 44 no 12 pp 2379ndash2386 1992
[123] L Cominacini A F Pasini U Garbin et al ldquoAntioxidant activ-ity of different dihydropyridinesrdquo Biochemical and BiophysicalResearch Communications vol 302 no 4 pp 679ndash684 2003
[124] L Cominacini U Garbin A Fratta Pasini et al ldquoOxidized low-density lipoprotein increases the production of intracellularreactive oxygen species in endothelial cells inhibitory effect oflacidipinerdquo Journal of Hypertension vol 16 no 12 part 2 pp1913ndash1919 1998
[125] H M Lander ldquoAn essential role for free radicals and derivedspecies in signal transductionrdquo The FASEB Journal vol 11 no2 pp 118ndash124 1997
[126] M L L Martinez E Rizzi M M Castro et al ldquoLercanidipinedecreases vascular matrix metalloproteinase-2 activity andprotects against vascular dysfunction in diabetic ratsrdquo EuropeanJournal of Pharmacology vol 599 no 1ndash3 pp 110ndash116 2008
[127] P Lesnik C Dachet L Petit et al ldquoImpact of a combinationof a calcium antagonist and a 120573-blocker on cell- and copper-mediated oxidation of LDL and on the accumulation and effluxof cholesterol in human macrophages and murine J774 cellsrdquoArteriosclerosis Thrombosis and Vascular Biology vol 17 no 5pp 979ndash988 1997
[128] G Sobal E J Menzel and H Sinzinger ldquoCalcium antagonistsas inhibitors of in vitro low density lipoprotein oxidation andglycationrdquoBiochemical Pharmacology vol 61 no 3 pp 373ndash3792001
[129] E Lupo R Locher B Weisser and W Vetter ldquoIn vitro antiox-idant activity of calcium antagonists against LDL oxidationcompared with 120572-tocopherolrdquo Biochemical and BiophysicalResearch Communications vol 203 no 3 pp 1803ndash1808 1994
[130] J Zou Y Li H-Q Fan and J-G Wang ldquoEffects of dihydropy-ridine calcium channel blockers on oxidized low-density lipo-protein induced proliferation and oxidative stress of vascularsmooth muscle cellsrdquo BMC Research Notes vol 5 article 1682012
[131] C Napoli S Salomone T Godfraind et al ldquo14-Dihydro-pyridine calcium channel blockers inhibit plasma and LDL oxi-dation and formation of oxidation-specific epitopes in the arte-rial wall and prolong survival in stroke-prone spontaneouslyhypertensive ratsrdquo Stroke vol 30 no 9 pp 1907ndash1915 1999
[132] G Zernig I Graziadei T Moshammer C Zech N Reider andH Glossmann ldquoMitochondrial Ca2+ antagonist binding sitesare associated with an inner mitochondrial membrane anionchannelrdquo Molecular Pharmacology vol 38 no 3 pp 362ndash3691990
[133] F E Hunter Jr A Scott P E Hochstein et al ldquoStudies of themechanism of ascorbate-induced swelling and lysis of isolatedliver mitochondriardquo The Journal of Biological Chemistry vol239 pp 604ndash613 1964
[134] D R Janero B Burghardt and R Lopez ldquoProtection of cardiacmembrane phospholipid against oxidative injury by calciumantagonistsrdquoBiochemical Pharmacology vol 37 no 21 pp 4197ndash4203 1988
[135] A Karadag B Ozcelik and S S Saner ldquoReview of methods todetermine antioxidant capacitiesrdquo FoodAnalyticalMethods vol2 no 1 pp 41ndash60 2009
[136] Y I Gubskiı N V Litvinova and E V Shnurko-TabakovaldquoAntioxidant and antiradical activity of various classes of antiox-idantsrdquo Ukrainskiı Biokhimicheskiı Zhurnal vol 66 no 4 pp114ndash116 1994 (Russian)
[137] M Takei M Hiramatsu and A Mori ldquoInhibitory effects ofcalcium antagonists onmitochondrial swelling induced by lipidperoxidation or arachidonic acid in the rat brain in vitrordquoNeurochemical Research vol 19 no 9 pp 1199ndash1206 1994
[138] M Takei M Hiramatsu R Edamatsu and A Mori ldquoFreeradical scavenging by calcium antagonistsrdquo Neurosciences vol20 no 2 pp 75ndash82 1994
[139] Ya P Stradin G Ya Dubur Yu A Beilis Ya R Uldrikis andA F Korotkova ldquoVoltammetry of 14-dihydropyridine deriva-tives I Potentials of electrochemical oxidation of 35-diacyl-and 35-di(alkoxycarbonyl)-14-dihydropyridines in acetoni-trilerdquo Chemistry of Heterocyclic Compounds no 1 pp 84ndash871972 (Russian)
[140] E V Ivanov T V Ponomarjova G N Merkusev et al ldquoEinneuer Haut-Radioprotektor Diethon (experimentelle Unter-suchung)rdquo Radiobiologia Radiotherapia vol 31 no 1 pp 69ndash78 1990
[141] E V Ivanov T V Ponomareva G N Merkushev et al ldquoRadia-tion modulating properties of derivates of 14-dihydropyridineand 12345678910-decahydroacridine-18 dionerdquo Radiat-sionnaia Biologiia Radioecologiia vol 44 no 5 pp 550ndash5592004 (Russian)
[142] R O Vitolinia D A Berzinia A K Velena I A Vutsina A AKimenis and G Y Duburs ldquoThe protective effects of the cal-cium antagonist foridon in acute myocardial ischaemiardquo Kardi-ologiya vol 27 no 3 pp 90ndash93 1987 (Russian)
[143] A H Velena G Ya Duburs R O Vitolina et al ldquoEffect ofryodipine on electromechanical parameters of heart and vesselscAMP phosphodiesterase activity and swelling-contractioncycle of mitochondriardquo Arzneimittelforschung vol 35 no 6 pp907ndash914 1985
[144] L I Utno Z E Lipsberga A A Silova M I Girgensone EA Bisenieks and G I Ia ldquoCardioprotective properties of a 14-dihydropyridine derivative glutapyrone in deep hypothermiardquoBiulletenrsquo Eksperimentalrsquonoı Biologii i Meditsiny vol 108 no 11pp 558ndash561 1989 (Russian)
[145] M A S FernandesM S Santos J A F Vicente et al ldquoEffects of14-dihydropyridine derivatives (cerebrocrast gammapyroneglutapyrone and diethone) onmitochondrial bioenergetics andoxidative stress a comparative studyrdquoMitochondrion vol 3 no1 pp 47ndash59 2003
[146] M A S Fernandes M S Santos A J M Moreno et al ldquoEffectsof 5-acetyl(carbamoyl)-6-methylsulfanyl-14-dihydropyridine-5-carbonitriles on rat liver mitochondrial functionrdquo Toxicologyin Vitro vol 23 no 7 pp 1333ndash1341 2009
[147] L Klimaviciusa A Kalda A Kaasik et al ldquoNeuroprotectiveactivity of 14-dihydropyridine derivatives structure determi-nantsrdquo Proceedings of the Latvian Academy of Sciences BNatural Exact and Applied Sciences vol 61 no 1-2 pp 33ndash372007
32 Oxidative Medicine and Cellular Longevity
[148] L Klimaviciusa M A S Fernandes N Lencberga et alldquoTargeting the mitochondria by novel adamantane-containing14-dihydropyridine compoundsrdquo in Bioenergetics K B ClarkEd pp 257ndash272 InTech 2012
[149] V Klusa L Klimaviciusa G Duburs J Poikans and AZharkovsky ldquoAnti-neurotoxic effects of tauropyrone a taurineanaloguerdquo Advances in Experimental Medicine and Biology vol583 pp 499ndash508 2006
[150] N Sampson P Berger and Ch Zenzmaier ldquoRedox signalingas a therapeutic target to inhibit myofibroblast activation indegenerative fibrotic diseaserdquo BioMed Research Internationalvol 2014 Article ID 131737 14 pages 2014
[151] T L Leto and M Geiszt ldquoRole of Nox family NADPH oxidasesin host defenserdquoAntioxidantsampRedox Signaling vol 8 no 9-10pp 1549ndash1561 2006
[152] K K Griendling D Sorescu and M Ushio-Fukai ldquoNAD(P)Hoxidase role in cardiovascular biology and diseaserdquo CirculationResearch vol 86 no 5 pp 494ndash501 2000
[153] H Chen Y S Song and P H Chan ldquoInhibition of NADPHoxi-dase is neuroprotective after ischemia-reperfusionrdquo Journal ofCerebral Blood Flow and Metabolism vol 29 no 7 pp 1262ndash1272 2009
[154] P Hochstein and L Ernster ldquoADP-activated lipid peroxidationcoupled to the TPNH oxidase system of microsomesrdquo Biochem-ical and Biophysical Research Communications vol 12 no 5 pp388ndash394 1963
[155] I I Gubskiı AGGoriushkoNV Litvinova et al ldquoAntioxidantproperties and membranotropic effect of certain derivatives of14-dihydropyridinerdquo Ukrainskiı Biokhimicheskiı Zhurnal vol71 no 4 pp 35ndash39 1999 (Russian)
[156] F Engineer and R Sridhar ldquoInhibition of rat heart andliver microsomal lipid peroxidation by nifedipinerdquo BiochemicalPharmacology vol 38 no 8 pp 1279ndash1285 1989
[157] T Goncalves A P Carvalho and C R Oliveira ldquoAntioxidanteffect of calcium antagonists on microsomai membranes iso-lated from different brain areasrdquo European Journal of Pharma-cology vol 204 no 3 pp 315ndash322 1991
[158] M E Letelier P Izquierdo L Godoy A M Lepe and MFaundez ldquoLiver microsomal biotransformation of nitro-aryldrugs mechanism for potential oxidative stress inductionrdquoJournal of Applied Toxicology vol 24 no 6 pp 519ndash525 2004
[159] M E Letelier P Entrala C Lopez-Alarcon et al ldquoNitroaryl-14-dihydropyridines as antioxidants against rat liver microsomesoxidation induced by ironascorbate Nitrofurantoin and naph-thalenerdquo Toxicology in Vitro vol 21 no 8 pp 1610ndash1618 2007
[160] F P Guengerich W R Brian M Iwasaki M-A Sari CBaarnhielm and P Berntsson ldquoOxidation of dihydropyridinecalcium channel blockers and analogues by human liver cyto-chrome P-450 IIIA4rdquo Journal of Medicinal Chemistry vol 34no 6 pp 1838ndash1844 1991
[161] S H Park S-W RhaW-Y Shin et al ldquoAS-160 Calcium channelblockers of dihydropyridine class reduce the antiplatelet effectof Clopidogrel what is clinical impactrdquo The American Journalof Cardiology vol 107 no 8 supplement p 47A 2011
[162] C Asma and D M Reda ldquoEvaluation of dihydropyridinecalcium antagonist effects on the stress bioindicator orga-nism Saccharomyces cerevisiaerdquo Annals of Biological Researchvol 4 no 10 pp 40ndash46 2013 httpscholarsresearchlibrarycomABR-vol4-iss10ABR-2013-4-10-40-46pdf
[163] G Gaviraghi A M Pastorino E Ratti and D G TristldquoCalcium channel blockers with antioxidant activityrdquo in Free
Radicals Lipoprotein Oxidation andAtherosclerosis G BellomoG Finardi E Maggi and E Rice-Evans Eds pp 431ndash456Richelieu Press London UK 1995
[164] G Gaviraghi AM Pastorino E Ratti and D G Trist ldquoAntiox-idant dihydropyridines a new and comprehensive therapy forfree radical-induced cardiovascular diseasesrdquo in Free Radicalsin Biology and Environment F Minisci Ed vol 27 of NATOASI Series pp 193ndash221 Springer Dordrecht The Netherlands1997
[165] P D Henry ldquoAntiperoxidative actions of calcium antagonistsand atherogenesisrdquo Journal of Cardiovascular Pharmacologyvol 18 supplement 1 pp S6ndashS10 1991
[166] F Kouoh B Gressier T Dine et al ldquoAntioxidant effects andanti-elastase activity of the calcium antagonist nicardipine onactivated human and rabbit neutrophilsmdasha potential antiath-erosclerotic property of calcium antagonistsrdquo CardiovascularDrugs andTherapy vol 16 no 6 pp 515ndash520 2002
[167] S Parthasarathy D Litvinov K Selvarajan and M GarelnabildquoLipid peroxidation and decompositionmdashconflicting roles inplaque vulnerability and stabilityrdquo Biochimica et BiophysicaActa vol 1781 no 5 pp 221ndash231 2008
[168] D-Q Liu Z-Q Pang D-H Zhao and B-H Sheng ldquoEffects offuryl-dihydropyridines I on lipid peroxides of ischemic myo-cardium and ATPases activity of erythrocyte membranes inratsrdquo Acta Pharmacologica Sinica vol 12 no 3 pp 253ndash2561991
[169] V Lukic-Panin T Kamiya H Zhang et al ldquoPrevention of neu-ronal damage by calcium channel blockers with antioxidativeeffects after transient focal ischemia in ratsrdquo Brain Research vol1176 no 1 pp 143ndash150 2007
[170] Y Allanore D Borderie H Lemarechal O G Ekindjian andA Kahan ldquoAcute and sustained effects of dihydropyridine-typecalcium channel antagonists on oxidative stress in systemicsclerosisrdquo American Journal of Medicine vol 116 no 9 pp 595ndash600 2004
[171] I Casetta V Govoni and E Granieri ldquoOxidative stress antioxi-dants and neurodegenerative diseasesrdquo Current PharmaceuticalDesign vol 11 no 16 pp 2033ndash2052 2005
[172] M J T J Arts Assessing antioxidant activity [PhD the-sis] Maastricht University Maastricht The Netherlands 2007httparnounimaasnlshowcgifid=8676
[173] G Dıaz-Araya L Godoy L Naranjo A Squella M E Letelierand L J Nunez-Vergara ldquoAntioxidant effects of 14-dihydro-pyridine and nitroso aryl derivatives on the Fe+3ascorbate-stimulated lipid peroxidation in rat brain slicesrdquo General Phar-macology The Vascular System vol 31 no 3 pp 385ndash391 1998
[174] Y Fukuhara K Tsuchiya Y Horinouchi et al ldquoProtectiveeffect of photodegradation product of nifedipine against tumornecrosis factor 120572-induced oxidative stress in human glomerularendothelial cellsrdquo Journal of Medical Investigation vol 58 no1-2 pp 118ndash126 2011
[175] W Stengel M Jainz and K Andreas ldquoDifferent potencies ofdihydropyridine derivatives in blocking T-type but not L-typeCa2+ channels in neuroblastoma-glioma hybrid cellsrdquo EuropeanJournal of Pharmacology vol 342 no 2-3 pp 339ndash345 1998
[176] O M Panasenko D J Tirzite G D Tirzitis and G J DubursldquoEffect of some 14-dihydropyridine derivatives on structuralorganization of erythrocyte membranesrdquo Biologicheskie Mem-brany (Biochemistry (Moscow) Series A Membrane and CellBiology) vol 1 pp 919ndash925 1984 (Russian)
[177] L G Herbette Y M H Vant Erve and D G Rhodes ldquoInter-action of 14 dihydropyridine calcium channel antagonists with
Oxidative Medicine and Cellular Longevity 33
biological membranes lipid bilayer partitioning could occurbefore drug binding to receptorsrdquo Journal of Molecular andCellular Cardiology vol 21 no 2 pp 187ndash201 1989
[178] L G Herbette P E Mason G Gaviraghi T N Tulenko andR P Mason ldquoThe molecular basis for lacidipinersquos unique phar-macokinetics optimal hydrophobicity results in membraneinteractions that may facilitate the treatment of atherosclerosisrdquoJournal of Cardiovascular Pharmacology vol 23 supplement 5pp S16ndashS25 1994
[179] G V Belevitch G Y Dubur G E Dobretsov N K Kurek andM M Spirin ldquoCalcium antagonists riodipine nifedipine andverapamil binding to model and biological membranes fluore-scence analysisrdquo Biologicheskie Membrany (Biochemistry(Moscow) Series A Membrane and Cell Biology) vol 5 pp768ndash776 1988 (Russian)
[180] R P Mason G E Gonye D W Chester and L G HerbetteldquoPartitioning and location of Bay K 8644 14-dihydropyridinecalcium channel agonist in model and biological membranesrdquoBiophysical Journal vol 55 no 4 pp 769ndash778 1989
[181] M Cindric A Cipak J Serly et al ldquoReversal of multidrugresistance inmurine lymphoma cells by amphiphilic dihydropy-ridine antioxidant derivativerdquo Anticancer Research vol 30 no10 pp 4063ndash4070 2010
[182] F Shekari H Sadeghpour K Javidnia et al ldquoCytotoxic andmultidrug resistance reversal activities of novel 14-dihydro-pyridines against human cancer cellsrdquo European Journal ofPharmacology vol 746 no 1 pp 233ndash244 2015
[183] X-F Zhou Q Shao R A Coburn and M E Morris ldquoQuanti-tative structure-activity relationship and quantitative structure-pharmacokinetics relationship of 14-dihydropyridines andpyridines as multidrug resistance modulatorsrdquo PharmaceuticalResearch vol 22 no 12 pp 1989ndash1996 2005
[184] R Berkels T Breitenbach H Bartels et al ldquoDifferent antioxida-tive potencies of dihydropyridine calcium channel modulatorsin various modelsrdquo Vascular Pharmacology vol 42 no 4 pp145ndash152 2005
[185] S Borovic G Tirzitis D Tirzite et al ldquoBioactive 14-dihydro-isonicotinic acid derivatives prevent oxidative damage of livercellsrdquo European Journal of Pharmacology vol 537 no 1ndash3 pp12ndash19 2006
[186] D Ya Rubene G D Tirzitis and G Ya Duburs ldquoInteractionof some 14-dihydropyridine derivatives with Fentonrsquos reagentrdquoLatvijas PSRZinatnuAkademijas Vestis Kimijas Serija Proceed-ings of the Latvian SSR Academy of Sciences Chemistry Seriespp 212ndash216 1982 (Russian)
[187] K Ondrias V Misık D Gergel and A Stasko ldquoLipid per-oxidation of phosphatidylcholine liposomes depressed by thecalcium channel blockers nifedipine and verapamil and bythe antiarrhythmic-antihypoxic drug stobadinerdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1003 no 3pp 238ndash245 1989
[188] I T Mak and W B Weglicki ldquoComparative antioxidant acti-vities of propranolol nifedipine verapamil and diltiazemagainst sarcolemmal membrane lipid peroxidationrdquoCirculationResearch vol 66 no 5 pp 1449ndash1452 1990
[189] I T Mak P Boehme and W B Weglicki ldquoProtective effects ofcalcium channel blockers against free radical-impaired endo-thelial cell proliferationrdquo Biochemical Pharmacology vol 50 no9 pp 1531ndash1534 1995
[190] S Ray S Mondal and N Dana ldquoEvaluation of protective roleof nifedipine on lipid peroxidation using reduced glutathione as
model markerrdquo Oxidants and Antioxidants in Medical Sciencevol 1 no 2 pp 97ndash100 2012
[191] M Yamato T Shiba T Ide Y Honda K-I Yamada andH Tsutsui ldquoNifedipine treatment reduces brain damage aftertransient focal ischemia possibly through its antioxidativeeffectsrdquoHypertension Research vol 34 no 7 pp 840ndash845 2011
[192] V Chander and K Chopra ldquoNifedipine attenuates changes innitric oxide levels renal oxidative stress and nephrotoxicityinduced by cyclosporinerdquo Renal Failure vol 27 no 4 pp 441ndash450 2005
[193] K M Gaafa M M Badawy and A A Hamza ldquoThe protectiveeffects of ascorbic acid cimetidine and nifedipine on diethyl-dithiocarbamate-induced hepatic toxicity in albino ratsrdquo Drugand Chemical Toxicology vol 34 no 4 pp 405ndash419 2011
[194] H Sugawara K Tobise and S Onodera ldquoAbsence of antiox-idant effects of nifedipine and diltiazem on myocardial mem-brane lipid peroxidation in contrast with those of nisoldipineand propranololrdquo Biochemical Pharmacology vol 47 no 5 pp887ndash892 1994
[195] I E Kirule D Y Rubene E A Bisenieks G D Tirzit and GY Dubur ldquo4-Nitrophenyl-14-dihydropyridinesmdasha new groupof inhibitors of peroxide oxidationrdquo Chemistry of HeterocyclicCompounds vol 18 no 3 p 316 1982
[196] G D Tirzit I E Kirule L K Baumane R A Gavar Y PStradynrsquo andG YDubur ldquoMechanism of the antioxidant actionof 26-dimethyl-35-dimethoxy-carbonyl-4-(2-nitrophenyl)14-dihydropyridinerdquoChemistry ofHeterocyclic Compounds vol 20no 8 pp 915ndash918 1984
[197] C Yanez C Lopez-Alarcon C Camargo V Valenzuela J ASquella and L J Nunez-Vergara ldquoStructural effects on thereactivity 14-dihydropyridines with alkylperoxyl radicals andABTS radical cationrdquo Bioorganic and Medicinal Chemistry vol12 no 9 pp 2459ndash2468 2004
[198] VMisik A J Stasko D Gergel and K Ondrias ldquoSpin-trappingand antioxidant properties of illuminated and nonilluminatednifedipine and nimodipine in heart homogenate and modelsystemrdquo Molecular Pharmacology vol 40 no 3 pp 435ndash4391991
[199] K Ondrias V Misık A Stasko D Gergelrsquo and M HromadovaldquoComparison of antioxidant properties of nifedipine and illu-minated nifedipine with nitroso spin traps in low densitylipoproteins and phosphatidylcholine liposomesrdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1211 no 1pp 114ndash119 1994
[200] A Stasko V Brezova S Biskupic K Ondrias and V MisıkldquoReactive radical intermediates formed from illuminated nife-dipinerdquoFree Radical Biology andMedicine vol 17 no 6 pp 545ndash556 1994
[201] K Ishizawa Y Izawa-Ishizawa N Yamano et al ldquoNitrosoni-fedipine ameliorates the progression of type 2 diabetic nephro-pathy by exerting antioxidative effectsrdquo PLoS ONE vol 9 no 1Article ID e86335 2014
[202] H Fujii and L J Berliner ldquoIn vivo EPR evidence for free radicaladducts of nifedipinerdquoMagnetic Resonance in Medicine vol 42no 4 pp 691ndash694 1999
[203] S Bollo S Finger J C Sturm L J Nunez-Vergara and JA Squella ldquoCyclic voltammetry and scanning electrochemicalmicroscopy studies of the heterogeneous electron transferreaction of some nitrosoaromatic compoundsrdquo ElectrochimicaActa vol 52 no 15 pp 4892ndash4898 2007
34 Oxidative Medicine and Cellular Longevity
[204] F Ursini ldquoTissue protection by lacidipine insight from redoxbehaviorrdquo Journal of Cardiovascular Pharmacology vol 30supplement 2 pp S28ndashS30 1997
[205] P G Cristofori F A Crivellente I Faustinelli et al ldquoInvolve-ment of the nitric oxide system in the anti-atheroscleroticpotential of lacidipine in the apoE-deficient mouse a mor-phological functional and electrochemical studyrdquo ToxicologicPathology vol 32 no 4 pp 493ndash499 2004
[206] X-P Zhang E L Kit S Mital S Chahwala and T HHintze ldquoParadoxical release of nitric oxide by an L-type calciumchannel antagonist the R+ enantiomer of amlodipinerdquo Journalof Cardiovascular Pharmacology vol 39 no 2 pp 208ndash2142002
[207] F Franzoni G Santoro F Regoli et al ldquoAn in vitro study of theperoxyl and hydroxyl radical scavenging capacity of the calciumantagonist amlodipinerdquo Biomedicine and Pharmacotherapy vol58 no 8 pp 423ndash426 2004
[208] S V Gatsura ldquoOxygen-dependent mechanisms underlying theantiischemic effect of verapamil and amlodipinerdquo Bulletin ofExperimental Biology and Medicine vol 137 no 1 pp 40ndash422004
[209] Y Hirooka Y Kimura M Nozoe Y Sagara K Ito and KSunagawa ldquoAmlodipine-induced reduction of oxidative stressin the brain is associated with sympatho-inhibitory effects instroke-prone spontaneously hypertensive ratsrdquo HypertensionResearch vol 29 no 1 pp 49ndash56 2006
[210] B Tomlinson and I F F Benzie ldquoAntioxidant effect of lercani-dipine (note)rdquo Hypertension vol 42 no 4 pp e10ndashe11 2003
[211] A A Faraqui ldquoNeurochemical aspects of 4-hydroxynonenalrdquoin Lipid Mediators and Their Metabolism in the Brain A AFaraqui Ed chapter 6 pp 159ndash191 Springer New York NYUSA 2011
[212] V S NascimentoM S DrsquoAlva A AOliveira et al ldquoAntioxidanteffect of nimodipine in young rats after pilocarpine-inducedseizuresrdquo Pharmacology Biochemistry and Behavior vol 82 no1 pp 11ndash16 2005
[213] O Ismailoglu P Atilla S Palaoglu et al ldquoThe therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjuryrdquo Turkish Neurosurgery vol 22 no 6 pp 740ndash746 2012
[214] M Matsubara and K Hasegawa ldquoBenidipine a dihydropy-ridine-calcium channel blocker prevents lysophosphatidyl-choline-induced injury and reactive oxygen species productionin human aortic endothelial cellsrdquo Atherosclerosis vol 178 no1 pp 57ndash66 2005
[215] M Matsubara K Yao and K Hasegawa ldquoBenidipine adihydropyridine-calcium channel blocker inhibits lysophos-phatidylcholine-induced endothelial injury via stimulation ofnitric oxide releaserdquo Pharmacological Research vol 53 no 1 pp35ndash43 2006
[216] MMatsubara and K Hasegawa ldquoEffects of benidipine a dihyd-ropyridine-Ca2+ channel blocker on expression of cytokine-induced adhesion molecules and chemoattractants in humanaortic endothelial cellsrdquo European Journal of Pharmacology vol498 no 1ndash3 pp 303ndash314 2004
[217] M Matsubara O Akizuki J-I Ikeda K Saeki K Yao and KSasaki ldquoBenidipine an anti-hypertensive drug inhibits reactiveoxygen species production in polymorphonuclear leukocytesand oxidative stress in salt-loaded stroke-prone spontaneouslyhypertensive ratsrdquo European Journal of Pharmacology vol 580no 1-2 pp 201ndash213 2008
[218] A C Rosenkranz H Lob T Breitenbach R Berkels and RRoesen ldquoEndothelial antioxidant actions of dihydropyridines
and angiotensin converting enzyme inhibitorsrdquo European Jour-nal of Pharmacology vol 529 no 1ndash3 pp 55ndash62 2006
[219] V Kain S Kumar and S L Sitasawad ldquoAzelnidipine preventscardiac dysfunction in streptozotocin-diabetic rats by reducingintracellular calcium accumulation oxidative stress and apop-tosisrdquo Cardiovascular Diabetology vol 10 article 97 2011
[220] K Nakamura S Yamagishi and H Inoue ldquoUnique atheropro-tective property of azelnidipine a dihydropyridine-based cal-cium antagonistrdquoMedical Hypotheses vol 65 no 1 pp 155ndash1572005
[221] TMatsui S Yamagishi K Nakamura S Kikuchi andH InoueldquoAzelnidipine a dihydropyridine-based calcium antagonistinhibits angiotensin II-induced oxidative stress generation anddownregulation of pigment epithelium-derived factor mRNAlevels in microvascular endothelial cellsrdquo Drugs under Experi-mental and Clinical Research vol 31 no 5-6 pp 215ndash219 2005
[222] C Ohmura H Watada T Shimizu et al ldquoCalcium channelblocker azelnidipine reduces lipid hydroperoxides in patientswith type 2 diabetes independent of blood pressurerdquo EndocrineJournal vol 54 no 5 pp 805ndash811 2007
[223] H Daikuhara F Kikuchi and T Ishida ldquoThe combination ofOLmesartan and a CAlcium channel blocker (azelnidipine) orcandesartan and a calcium channel blocker (amlodipine) intype 2 diabetic hypertensive patients theOLCA studyrdquoDiabetesand Vascular Disease Research vol 9 no 4 pp 280ndash286 2012
[224] MAbe NMaruyama KOkada SMatsumoto KMatsumotoand M Soma ldquoAdditive antioxidative effects of azelnidipine onangiotensin receptor blocker olmesartan treatment for type 2diabetic patients with albuminuriardquoHypertension Research vol34 no 8 pp 935ndash941 2011
[225] K Mizushige ldquoAntioxidative activities of thiazolidinedionesand dihydropyridine-type calcium antagonistsrdquo IRYOmdashJapa-nese Journal of National Medical Services vol 59 no 11 pp 581ndash592 2005
[226] S Manabe T Okura T Fukuoka and J Higaki ldquoAntioxidativeeffects of azelnidipine on mesangial cell proliferation inducedby highly concentrated insulinrdquo European Journal of Pharma-cology vol 567 no 3 pp 252ndash257 2007
[227] Y Koyama Y Takeishi H Takahashi et al ldquoAzelnidipine inhi-bits H
2O2-induced cell death in neonatal rat cardiomyocytesrdquo
CardiovascularDrugs andTherapy vol 21 no 1 pp 69ndash72 2007[228] K Shinomiya K Mizushige M Fukunaga et al ldquoAntioxidant
effect of a new calcium antagonist azelnipidine in culturedhuman arterial endothelial cellsrdquo Journal of International Med-ical Research vol 32 no 2 pp 170ndash175 2004
[229] T Ohyama K Sato K Kishimoto et al ldquoAzelnidipine is acalcium blocker that attenuates liver fibrosis and may increaseantioxidant defencerdquo British Journal of Pharmacology vol 165no 4 pp 1173ndash1187 2012
[230] L A Calo F Zaghetto E Pagnin P A Davis A Sempliciniand A C Pessina ldquoEffect of manidipine on gene expressionand protein level of oxidative stress-related proteins p22phoxand HO-1 Relevance for antihypertensive and anti-remodelingeffectsrdquo Journal of Cardiovascular Pharmacology vol 43 no 4pp 531ndash538 2004
[231] R Ghyasi G Sepehri M Mohammadi R Badalzadeh and AGhyasi ldquoEffect of mebudipine on oxidative stress and lipid per-oxidation in myocardial ischemic-reperfusion injury in maleratrdquo Journal of Research in Medical Sciences vol 17 no 12 pp1150ndash1155 2012
Oxidative Medicine and Cellular Longevity 35
[232] DCAndersson J Fauconnier T Yamada et al ldquoMitochondrialproduction of reactive oxygen species contributes to the 120573-adrenergic stimulation of mouse cardiomycytesrdquoThe Journal ofPhysiology vol 589 no 7 pp 1791ndash1801 2011
[233] A F Ceylan-Isik N Ari M Stefek et al ldquoEffects of a long-term treatment with an antioxidant pyridoindole on vascularresponsiveness in diabetes-induced aging ratsrdquo Current AgingScience vol 4 no 2 pp 150ndash157 2011
[234] S Saponara G Sgaragli and F Fusi ldquoQuercetin antagonismof Bay K 8644 effects on rat tail artery L-type Ca2+ channelsrdquoEuropean Journal of Pharmacology vol 598 no 1ndash3 pp 75ndash802008
[235] D A Sica ldquoInteraction of grapefruit juice and calcium channelblockersrdquo American Journal of Hypertension vol 19 no 7 pp768ndash773 2006
[236] P Mulder G Litwinienko S Lin P D MacLean L R CBarclay and K U Ingold ldquoThe L-type calcium channel block-ers Hantzsch 14-dihydropyridines are not peroxyl radical-trapping chain-breaking antioxidantsrdquo Chemical Research inToxicology vol 19 no 1 pp 79ndash85 2006
[237] L J Nunez-Vergara R Salazar C Camargo et al ldquoOxidation ofC4-hydroxyphenyl 14-dihydropyridines in dimethylsulfoxideand its reactivity towards alkylperoxyl radicals in aqueousmediumrdquo Bioorganic and Medicinal Chemistry vol 15 no 12pp 4318ndash4326 2007
[238] M E Ortiz L J Nunez-Vergara and J A Squella ldquoRelativereactivity of dihydropyridine derivatives to electrogeneratedsuperoxide ion in DMSO solutions a voltammetric approachrdquoPharmaceutical Research vol 20 no 2 pp 292ndash296 2003
[239] M E Ortiz L J Nunez-Vergara C Camargo and J A SquellaldquoOxidation of Hantzsch 14-dihydropyridines of pharmacolog-ical significance by electrogenerated superoxiderdquo Pharmaceuti-cal Research vol 21 no 3 pp 428ndash435 2004
[240] R S Raghuvanshi and K N Singh ldquoSuperoxide induced oxida-tive aromatization of Hantzsch 14-dihydropyridinesrdquo IndianJournal of Chemistry Section B Organic and Medicinal Chem-istry vol 47 no 11 pp 1735ndash1738 2008
[241] I Kruk A Kladna K Lichszteld et al ldquoAntioxidant activityof 4-flavonil-14-dihydropyridine derivativesrdquo Biopolymers vol62 no 3 pp 163ndash167 2001
[242] G D Tirzit I M Byteva K I Salokhiddinov G P Gurinovichand G Y Dubur ldquo14-Dihydropyridine derivatives as deactiva-tors of singlet oxygenrdquo Chemistry of Heterocyclic Compoundsvol 17 no 7 pp 682ndash684 1981
[243] G D Tirzit E Y Kazush and G Y Dubur ldquoInfluence of14-dihydropyridine derivatives on the generation of hydroxylradicalsrdquo Chemistry of Heterocyclic Compounds vol 28 no 4pp 435ndash437 1992
[244] N A Pizarro-Urzua and L J Nunez-Vergara ldquoNifedipine andnitrendipine reactivity toward singlet oxygenrdquo Journal of Photo-chemistry and Photobiology A Chemistry vol 175 no 2-3 pp129ndash137 2005
[245] L-F Wang H-Y Zhang L Konga Z-W Chena and J-G ShildquoDFT calculations indicate that 14-dihydropyridine is a promis-ing lead antioxidantrdquo Helvetica Chimica Acta vol 87 no 6 pp1515ndash1521 2004
[246] P Mulder H-G Korth and K U Ingold ldquoWhy quantum-thermochemical calculations must be used with caution toindicate lsquoa promising lead antioxidantrsquordquoHelvetica Chimica Actavol 88 no 2 pp 370ndash374 2005
[247] K Yao Y Ina K Nagashima K Ohmori and T Ohno ldquoAntiox-idant effects of calcium antagonists in rat brain homogenatesrdquo
Biological and Pharmaceutical Bulletin vol 23 no 6 pp 766ndash769 2000
[248] T Matsui S-I Yamagishi K Nakamura and H Inoue ldquoBayw 9798 a dihydropyridine structurally related to nifedipinewith no calcium channel-blocking properties inhibits tumournecrosis factor-120572-induced vascular cell adhesion molecule-1expression in endothelial cells by suppressing reactive oxygenspecies generationrdquo Journal of International Medical Researchvol 35 no 6 pp 886ndash891 2007
[249] K AMitrega B VargheseM Porc and T F Krzeminski ldquoAnti-arrhythmic and hemodynamic effects of oxy nifedipine oxynimodipine oxy nitrendipine and oxy nisoldipinerdquo Pharmaco-logical Research vol 66 no 4 pp 300ndash308 2012
[250] V Herbert ldquoSymposium prooxidant effects of antioxidantvitamins Introductionrdquo The Journal of Nutrition vol 126 no4 supplement pp 1197Sndash1200S 1996 httpjnnutritionorgcontent1264 Suppl1197Sfullpdf
[251] B Halliwell ldquoAre polyphenols antioxidants or pro-oxidantsWhat do we learn from cell culture and in vivo studiesrdquoArchives of Biochemistry and Biophysics vol 476 no 2 pp 107ndash112 2008
[252] C Winterbourn Pro-Oxidants or Antioxidants ChristchurchSchool of Medicine Depatment of Pathology Free RadicalSchool SFRBMUniversity of Otago San Francisco Calif USA2009 httpwwwsfrbmorgfrsWinterbournpdf
[253] A Morakinyo B Iranloye and O Adegoke ldquoCalcium antag-onists modulate oxidative stress and acrosomal reaction in ratspermatozoardquo Archives of Medical Science vol 7 no 4 pp 613ndash618 2011
[254] The Alpha-Tocopherol Beta Carotene Cancer Prevention StudyGroup ldquoThe effect of vitamin E and beta carotene on theincidence of lung cancer and other cancers in male smokersrdquoTheNew England Journal of Medicine vol 330 no 15 pp 1029ndash1035 1994
[255] B Poljsak ldquoStrategies for reducing or preventing the generationof oxidative stressrdquo Oxidative Medicine and Cellular Longevityvol 2011 Article ID 194586 15 pages 2011
[256] B Poljsak and I Milisav ldquoThe neglected significance of lsquoanti-oxidative stressrsquordquoOxidativeMedicine and Cellular Longevity vol2012 Article ID 480895 12 pages 2012
[257] T Godfraind and S Salomone ldquoAmbiguities in dietary antiox-idant supplementation compared to calcium channel blockerstherapyrdquo Frontiers in Pharmacology vol 6 article 10 2015
[258] H Wagner H Norr and H Winterhoff ldquoDrugs with adap-togenic effects for strengthening the powers of resistancerdquoZeitschrift fur Phytotherapie vol 13 no 2 pp 42ndash54 1992
Oxidative Medicine and Cellular Longevity 17
fluorescence analysis The consistent location of Ca agonistBay K 8644 was determined to be within the region ofthe first few methylene segments of the fatty acyl chains ofthe membranes (Mason et al [180]) This position is nearto that observed for the DHP calcium channel antagonistsnimodipine and Bay P 8857
Themajority of studies onOSwere performedwithDHPswith various lipophilicity but only a few studies reportedamphiphilicity ofDHPderivatives AmphiphilicDHPderiva-tive K-2-11 reduced the cellular generation of ROS It alsorevealed complete reversal of multidrug resistance (MDR) ofthe resistant cells K-2-11 was more efficient than well-knownMDR inhibitor verapamil Cytotoxic effects of anticancerdrug doxorubicin were enhanced by K-2-11 in bothMDR andparental nonresistant cell line (Cindric et al [181]) K-2-11suppresses increase of ROS and consequentially prevents NF-120581B activation leading to decreased expression of MDR1 andincreased expression of antiapoptotic genes This signalingswitch is necessary for restoring the chemosensitivity ofcancer cells This phenomenon is characteristic both for14-DHPs [182] (18 novel asymmetrical DHPs bearing 3-pyridyl methyl carboxylate and alkyl carboxylate moietiesat C3 and C5 positions resp as well as nitrophenyl orheteroaromatic rings at C4) and for their oxidized formspyridine compounds (Zhou et al [183])
34 Dependence of AOA of DHPs on the Experimental SystemAO effect of DHPs depends on their structure and theexperimental system used (in vitromodel system subcellularorganelle and cells ex vivo and in vivo) Ideally for theevaluation of the profile and value of DHPs AO propertieseach compound should be tested in as many systems aspossible (Dubur et al [45])
Lipidomics studies have been traditionally explored forstudying AOA of DHPs Proteomics methods are less rep-resented and are mostly focused on the properties of DHPsrelated to scavenging of protein free radicals So far there areno studies on the role of DHPs in scavenging nitrosoperoxy-carbonate the reactive species formed out of peroxynitrite inthe presence of carbon dioxide Although it was shown thatalbumin binds diludine no studies revealed the relevance ofthis effect for the AOA of diludine
There are findings showing that dihydropyridine calciumantagonists (DHPs CA) could indirectly play a beneficialprotective role during development of atherosclerosisNamely Berkels et al [184] have studied antioxidativeproperties of four substances the DHP prototype CAnifedipine the long-acting CA lacidipine the DHP calciumchannel agonist BayK8644 and the bulkyDHPderivate BayO 5572 in three different models (1) in an in vitro superoxideanion generating system (hypoxanthinexanthine oxidase)for testing the ldquopurerdquo antioxidative effect (2) in an artificialmembrane preparation (dimyristoylphosphatidylcholine) formimicking a more physiological environment and (3) underconditions of stimulated ROS release (hyperglycemia) fromnative endothelial cells derived from porcine coronary arter-ies
The study also revealed the potential correlation betweenlipophilic and AO properties of DHPs In the first model
Bay K 8644 was significantly more effective in scavengingsuperoxide anions than lacidipine Bay O 5572 or nifedipine(micro- to millimolar concentration range) Addition of anartificial membrane preparation resulted in an enhancedAO effect with lacidipine being the most effective DHP inquenching radicals (low micromolar concentration range)In the third model mimicking hyperglycemia (30mmolL)nifedipine was significantly more potent antioxidant (ther-apeutical nanomolar concentration range) than the otherDHPs Calculated lipophilicity of these four substances(lacidipine gt Bay O 5572 gt Bay K 8644 gt nifedipine) waspositively correlated with antioxidative potential only in thesecond experimental model It has been concluded that AOproperties of DHP substances need to be tested in variousmodels for demonstrating that nifedipine exhibits ROS-quenching properties in a therapeutic concentration range[184]
341 AOA of DHPs in Isolated Cells and Cell Cultures(Comparison with Other Simplest Systems) Although DHPspossess neuromodulatory andor antimutagenic propertiesthe mechanisms of action related to these phenomena arenot entirely elucidated Borovic et al [185] have studied 14-dihydroisonicotinic acid (14-DHINA) derivatives of 14-DHP water-soluble analogues of a well-known AO diludine(diethone) 26-dimethyl-35-diethoxycarbonyl-14-dihydro-isonicotinic acid sodium 2-(26-dimethyl-35-diethoxycar-bonyl-14-dihydropyridine-4-carboxamido)glutamate gluta-pyrone and sodium 2-(26-dimethyl-35-diethoxycarbonyl-14-dihydropyridine-4-carboxamido)ethane-sulphate tauro-pyrone as AO and bioprotectors (Figure 4)
14-DHINArsquos activities were studied in comparison toTrolox by NN-diphenyl-N1015840-picrylhydrazyl (DPPH∙) deoxy-ribose degradation ABTS∙ radical scavenging and AOA(antioxidative capacity method) assays copper-induced LPof cultured rat liver cells (MDA determination by HPLCand 4-hydroxynonenal-protein conjugates by dot-blot) 3H-thymidine incorporation and trypan blue assay for liver cellsgrowth and viability Ic decreased the amount of 4-HNE-protein adducts In all assays Ia was the most potent AOable to completely abolish copper induced LP of liver cellswhile Ic only slightly decreased it Thus AOA is importantactivity principle of Ia which was even superior to Trolox intreated cell cultures Ia (and its analogues) are easily oxidizedin the Fenton system (Rubene et al [186]) exerting ARA too
35 Peculiarities Related to Antioxidative and AntiradicalActivity of Some 14-DHPs Ca Antagonists Nine commer-cialized structurally and functionally different DHPs CAwill be discussed further Their common feature is ability toprevent OS This also counts for some of their metabolitesas already discussed The comparative effects of some DHPsCA on oxidative stress-induced modification of LDL werealready reviewed in Section 331 (2)-(a) AOA of CA DHPswas discussed in Sections 331 (2)-(b) and 331 (2)-(c)
351 Nifedipine and Its Close Analogues Nifedipine vera-pamil and antiarrhythmic-antihypoxic drug stobadin wereshown to depress lipid peroxidation of phosphatidylcholine
18 Oxidative Medicine and Cellular Longevity
NH
COOH
NH
COONa
Glutapyrone
NH
Gammapyrone
NH
C 2H5OOC COOC2H5
Tauropyrone
14-DHINA
H3C H3C
H3C
H3CCH3 CH3
CH3
CH3
COOC2H5COOC2H5
COOC2H5 C2H5OOCC2H5OOCC2H5OOC
CONHCH(CH2)2COONa CONH(CH2)3COONa
CONH(CH2)2SO3Na
Figure 4 Derivatives of 14-dihydroisonicotinic acid (14-DHINA)
liposomes (Ondrias et al [187]) However data obtained insome other experimental systems are conflicting
In an in vitromodel of sarcolemmal membrane lipid per-oxidation three calcium blockers (nifedipine verapamil anddiltiazem) exhibited concentration-dependent (10ndash400 120583M)inhibitory effects [188 189] Nifedipine the most effectivecalcium blocker was more than two-fold potent compared topropranolol achieving significant effect at 10 120583M Nifedipineprotective role on LP using reduced glutathione as modelmarker was recently described (Ray et al [190]) Antiper-oxidative properties of CA nifedipine and its analogueswere explored in different systemspathogenic processesatherogenesis (Henry [165]) brain focal ischemia (Yamatoet al [191]) nephroprotection related to cyclosporine intake(Chander and Chopra [192]) and hepatoprotection relatedto intake of diethyldithiocarbamate (Gaafa et al [193])Recent data suggest that nifedipine action as protector forendothelial cells proceeds independently from its CA proper-ties
The absence of antioxidant effects of nifedipine anddiltiazemonmyocardialmembrane lipid peroxidation oppo-site to nisoldipine and propranolol was also described[194] Nisoldipine and propranolol were shown to havea concentration-dependent antiperoxidant effect with IC
50
values of 282 and 501 120583M respectively Finally nisol-dipine appeared to possess dual antiperoxidant mecha-nisms involving both preventive and chain-breaking proper-ties
These findings were confirmed in some other studiesincluding reports on the lack of antioxidative activity ofnifedipine and nicardipine even at 500120583M concentrationin heart membrane lipid peroxidation tests [134] SimilarlyROS formation in bovine aorta smooth muscle cells was notaffected by addition of amlodipine nimodipine and nife-dipine [123]
(1) Metabolites of Nifedipine and Its Analogues as Antioxidantsand Regulators of OS Antioxidant activity of nifedipine35-dimethoxycarbonyl-26-dimethyl-4-(2-nitrophenyl)-14-dihydropyridine was originally studied in vitro by Kirule etal [195] and Tirzit et al [196] According to the kinetic dataof peroxide accumulation and the ESR spectra (inhibition ofthe autoxidation of methyl oleate in presence of nifedipine)AO action was exerted by the formation of nitroso analogueof the oxidized nifedipine nitroso nifedipine 26-dimethyl-4-(2-nitrosophenyl)-35-pyridine dicarboxylate (NO-NIF)This nitroso aromatic derivative can form nitroxyl radicalsexhibiting remarkable AOA in the presence of unsaturatedfatty acids and lipids [196]
The primary species of free radicals that have beenobtained and identified were ion radicals of the nitrophenyltype (Ogle et al [76]) Such a mechanism coincides withmechanisms proposed afterwards by Nunez-Vergara et al[96] Lopez-Alarcon et al [103] Valenzuela et al [104]Fukuhara et al [174] and Yanez et al [197]
There are also data showing that nitroso compounds mayinhibit LP by direct radical trapping and subsequent forma-tion of stable nitroxide radicals It was further found that thereactivity between the synthesized 14-DHP derivatives withalkylperoxyl radicals involves electron transfer reactionsThisis documented by the presence of pyridine as a final productof the reaction and complete oxidation of the nitroso groupin the case of the nitrosoaryl 14-dihydropyridine derivatives(Valenzuela et al [104]) Tested compounds reacted fastertoward alkylperoxyl radicals and ABTS radical cation thanalkyl ones (Lopez-Alarcon et al [103])
Nitrosonifedipine a photodegradation product of nifedi-pine significantly recovers cellular damage induced by tumornecrosis factor-alpha It also prevents toxic effects of cumeneperoxide which hampers integrity of cell membranes throughoxidative stress Its positive effects are equal to Trolox-C
Oxidative Medicine and Cellular Longevity 19
As a result nitrosonifedipine was already a long time agoclaimed as a candidate for a new class of antioxidative drugs(Kirule et al [195]) cellular protectors against oxidative stressin glomerular endothelial cells [174]
Moreover Misik et al [198] Ondrias et al [199] andStasko et al [200] studied AOA of nifedipine and its oxidizednitroso analogue NO-NIF prevents the progression of type2 diabetic nephropathy associated with endothelial dysfunc-tion through selective AO effects (Ishizawa et al [201]) NO-NIF administration reduces albuminuria and proteinuriaas well as glomerular expansion without affecting glucosemetabolism or systolic blood pressure NO-NIF also sup-presses renal and systemic OS and decreases the expressionof intercellular adhesion molecule-1 (ICAM-1) a marker ofendothelial cell injury in the glomeruli of the KKAy miceSimilar effects were achieved in endothelial nitric oxide syn-thase (eNOS) knockout mice Moreover NO-NIF suppressesurinary angiotensinogen (AGT) excretion and intrarenalAGT protein expression in proximal tubular cells in theKKAy mice On the other hand hyperglycemia-inducedmitochondrial superoxide production was not attenuated byNO-NIF in cultured endothelial cells
Fujii and Berliner found EPR evidence for free radicaladducts of nifedipine in vivo [202] The nature of these rad-icals was surmised by comparing the reaction of illuminatednitrosonifedipine with polyunsaturated fatty acids Surpris-ingly identical radical spectra were detected from excisedliver doped with nonilluminated nifedipine suggesting thatthis drug can be enzymatically converted in vivo to its nitrosoanalogue without the requirement for illumination This isone of the first reports of in vivo EPR evidence for a class ofunsaturated fatty acid radical conjugates resulting from thenormal metabolism of a common drug
Dıaz-Araya et al [173] studied some 4-nitrophenyl-DHPson Fe3+ initiated LP in rat brain slices LP as measuredby MDA formation was inhibited by all the tested nitro-aryl derivatives of 14-DHP over a wide range of concen-trations On the basis of both time course and IC
50experi-
ments the tentative order of AOA on rat brain slices wasnicardipine gt nisoldipine gt (RSSR)-furnidipine gt (RRSS)-furnidipine gt nitrendipine gt nimodipine gt nifedipine14-DHP derivatives that lack a nitro group in the mole-cule (isradipine and amlodipine) also inhibited LP in ratbrain slices but at higher concentrations than that of nitro-substituted derivatives All tested compounds reduced andoxidized nitrosoaryl derivatives (26-dimethyl-4-(2-nitro-sophenyl)-35-pyridinedicarboxylic acid dimethyl ester (pho-tooxidation product of nifedipine ndash NTP) ao) and weremore potent inhibitors of LP than their parent molecules(Valenzuela et al [104])
The electrooxidation process of 4-nitrosoaromatic DHPsis a strongly pH-dependent (two-electron two-proton mech-anism) ECEC type of mechanism that is the sequenceeminusH+eminusH+ at pH gt 85 ECCE mechanism (eminusH+H+eminus)at pH lt 85 dominates Reduction reaction of nitroso groupis as follows R-NO + 2eminus + 2H+ rarr RNHOH (Bollo et al[203])
352 Lacidipine It is a generic DHP type antihypertensiveCA 35-diethyl 4-2-[(1E)-3-(tert-butoxy)-3-oxoprop-1-en-1-yl]phenyl-26-dimethyl-14-dihydropyridine-35-dicarboxy-late
Ursini [204] described redox behaviour of lacidipine andshowed its tissue protective features Cristofori et al studiedantiatherosclerotic activity in addition to lacidipinersquos CAand AO properties [205] Lacidipine reduced the extent ofatherosclerotic area in hypercholesterolemic apoE-deficientmice (these mice show widespread vascular lesions whichclosely resemble the inflammatory fibrous plaques seen inhumans in atherosclerosis) The reduction may be associatedwith the capacity of the drug to maintain endothelial NOlevels at concentrations useful to protect against vasculardamage This work suggested that DHPs modulate vascularrelaxation via increased release of NO
Herbette et al [178] remarked optimal hydrophobicity oflacidipine due to cinnamic acid substituent so membraneinteractions and facilitation of the treatment of atherosclero-sis could proceed (see also Section 331 (2)-(a))
353 Amlodipine Amlodipine (Norvasc) (RS)-3-ethyl5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-14-dihydropyridine-35-dicarboxylate (AML) hasan antioxidant effect on vessels in vitro and is a 3rd genera-tion of charged dihydropyridine CCB that is widely used forthe treatment of hypertensive patients
Amlodipine was shown to have the highest affinity(amlodipine gt verapamil ≫ diltiazem) for the membranebilayer (119870
119901= 104) It produced the significant changes in
membrane thermodynamic properties including a reductionin the thermal phase transition temperature (minus11) enthalpy(minus14) and cooperative unit size (minus59) relative to thecontrol phosphatidylcholine liposomes (Mason et al [49])
Amlodipine AOA is related to its reductant nature orhydrogen donor properties respectively Its ability for donat-ing protons and electrons to the lipid peroxide moleculesblocks the LP process
Amlodipine and even its enantiomers (Zhang et al [206])act as ROS andNOS effectors in several model systems of OSAntioxidant properties of amlodipine were recently reviewedby Vitolina et al [32] Both in vitro and in vivo studiesof amlodipine AO properties revealed inhibition of lipidsoxidative damage primarily those associated with cellularmembranes and lipoprotein particles (LDL) (Mason et al[50])
Under controlled experimental conditions in vitro amlo-dipine showed AOA and ARA by inhibition of lipid peroxideformation and trapping ROS Its scavenging activity forhydroxyl and peroxyl radicals at concentrations as low as100 nmolL (which is remarkably less compared to the classi-cal antioxidants GSH uric acid and Trolox) was shown to beindependent of the calcium channel modulation (Franzoni etal [207])
AML showed efficiency as scavenger of peroxyl radicals(TOSC assay 5945 plusmn 544 unitsmg) significantly stronger(gt50 119875 lt 0001) than GSH (2733plusmn 636 unitsmg) and 70weaker (119875 lt 00001) than uric acid (18144 plusmn 696 unitsmg)and Trolox (17522 plusmn 734 unitsmg)
20 Oxidative Medicine and Cellular Longevity
Of interest the scavenging capacity of AML towardshydroxyl radicals (1455 plusmn 154 unitsmg) was 320 higher(119875 lt 000001) than that of GSH (358 plusmn 112 unitsmg) 20higher than that of uric acid (1198plusmn121 unitsmg) and 100higher than that of Trolox (759 plusmn 143 unitsmg)
Amlodipine was shown to increase enzyme activity ofparaoxonase (PON) and glutathione peroxidase (GSH-Px)However it also decreases glutathione reductase (GSSG-R)activity and diminishes the concentration of the endogenousantioxidant 120572-tocopherol (vitamin E) Moreover AML in aconcentration of 2 ngmL decreased the content of malonicdialdehyde and activity of superoxide dismutase in the blood(Gatsura [208])
Verapamil and amlodipine produced a potent anti-ischemic effect and reduced area of myocardial infarction inrats The observed changes were accompanied by inhibitionof LP In contrast to verapamil in vitro application of AML ina dose of 50 ngmL decreased hemoglobin affinity for oxygenWhen present in a concentration of 2 ngmLAMDdecreasedthe content of MDA and activity of SOD in the blood
On the other hand amlodipine shows no activity relatedto inhibition of macrophage superoxide release and cellmigration which occurs as a consequence of decreasedTNF120572induced O
2
∙ releaseAmlodipine-induced reduction of OS in the brain is
associated with sympathoinhibitory effects in stroke-pronespontaneously hypertensive rats (SHRSP) (Hirooka et al[209]) Antihypertensive treatment with amlodipine reducedOS in all examined areas of the brain and decreased bloodpressure without a reflex increase in sympathetic nerveactivity Nicardipine another CA DHP surprisingly wassignificantly less active than amlodipine
354 Lercanidipine Tomlinson and Benzie reported AOeffect of lercanidipine [210] which is well known as anti-hypertensive drug Zanidip 2[(33-diphenylpropyl)(methyl)-amino]-11-dimethylethyl methyl 26-dimethyl-4-(3-nitro-phenyl)-14-dihydropyridine-35-dicarboxylate Compara-tive data about this drug AOA were presented in parts of thispaper about other individual CA DHPs and in the part aboutthe ex vivo DHPs effects on LDL
355 Nimodipine Nimodipine (ND) commercially knownas Nimotop is 3-(2-methoxyethyl) 5-propan-2-yl 26-dim-ethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxy-late It is centrally active CA
Treatment with glutathione blocked andwith nimodipineattenuated neuronal cell death caused by prolonged exposureof cell culture to 4-HNE (Faraqui [211])
Nascimento et al [212] found AO effect of nimodipine inyoung rats after pilocarpine- (PIL-) induced (in 400mgkg)seizures The PIL administration increased the striatal cata-lase (CAT) activity The administration of ND 30mgkg30min before PIL preserved normal value of CAT activityOn the other hand no difference was detected in the animalstreated with lower dose 10mgkg These results confirmthe neuroprotectiveantiepileptic effect of ND in young ratssuggesting that this drug acts positively on lipid peroxidation
(in both doses) Nimodipine cannot induce these effects viablockade of Ca2+ channel
Ismailoglu et al [213] studied the therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjury These beneficial effects in rats after cerebral corticalinjury seemed to be related to AOA of nimodipine
356 Benidipine Licensed in Japan and South Asia as CA(CCB) benidipine possesses AO properties Chemically it is5-methyl 3-[(3R)-1-(phenylmethyl)piperidin-3-yl] 26-dim-ethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxy-late (or its hydrochloride (4R)-rel-35-pyridinedicarboxylicacid 14-dihydro-26-dimethyl-4-(3-nitrophenyl)- 3-methyl5-[(3R)-1-(phenylmethyl)-3-piperidinyl] ester hydrochloride(1 1))
Benidipine influences processes connected with OS inseveral ways It prevents lysophosphatidylcholine- (lysoPC)-induced injury and ROS production in human aorticendothelial cells (HAECs) (Matsubara and Hasegawa [214])Matsubara et al [215] explained this effect based on stimula-tion of nitric oxide release
LysoPC is a component of oxidized low-density lipopro-teins (oxLDLs) which plays an important role in the patho-genesis of atherosclerosis Pretreatmentwith benidipine (03ndash3 120583molL) for 24 h protected against lysoPC-induced cyto-toxicity in the HAECs through inhibition of both lysoPC-stimulated ROS production and caspase-37-like activationwith a similar potency Since caspase-37 is involved inexecuting the apoptotic process the reduction of the activityof this enzyme by benidipine may explain the antiapoptoticeffect of the drug However benidipine did not suppresslysoPC-induced phosphorylation of mitogen-activated pro-tein kinases and Ca2+ influx in HAECs These results suggestthat the antioxidant properties of benidipine may be respon-sible for its ability to inhibit ROS production a possiblereason for reduced activation of caspase-37 In conclusionbenidipine suppresses lysoPC-induced endothelial dysfunc-tion through inhibition of ROS production which is due atleast in part to its antioxidant effect and not through theinhibition of L-type voltage-dependent calcium channels
Matsubara and Hasegawa [216] examined the effectsof benidipine on cytokine-induced expression of adhesionmolecules and chemokines (chemoattractants) which areimportant for the adhesion of monocytes to endotheliumPretreatment of HAECs with benidipine (03ndash10 120583molL)for 24 h significantly suppressed cytokine-induced vascularcell adhesion molecule-1 (VCAM-1) and intracellular celladhesion molecule-1 (ICAM-1) mRNA and protein expres-sion resulting in reduced adhesion of THP-1 monocytesBenidipine also suppressed induction of monocyte chemoat-tractant protein-1 (MCP-1) and interleukin-8 Benidipinealso inhibited redox-sensitive transcriptional nuclear factor-120581B (NF-120581B) pathway as determined by Western blotting ofinhibitory 120581B (I120581B) phosphorylation and luciferase reporterassay Results of analysis using optical isomers of benidip-ine and antioxidants suggest that these inhibitory effectswere dependent on pharmacological effects other than Ca2+antagonism Benidipine may thus have anti-inflammatoryproperties and benefits for the treatment of atherosclerosis
Oxidative Medicine and Cellular Longevity 21
Benidipine was also shown to inhibit ROS production inpolymorphonuclear leukocytes and oxidative stress in salt-loaded stroke-prone spontaneously hypertensive rats (Mat-subara et al [217])
It should be mentioned that other DHPs also haveendothelial AO actions [218]
357 Azelnidipine (AZL) Azelnidipine 3-[1-[di(phen-yl)methyl]azetidin-3-yl] 5-propan-2-yl 2-amino-6-methyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate(AZL) CAS number 123524-52-7 is commercially available4-nitroaryl-DHP type calcium antagonist with long-actingantihypertensive action (long-acting CA (CCB)) and a lowreported incidence of tachycardia It additionally possessesbeneficial effects in OS and diabetic conditions
Azelnidipine prevents cardiac dysfunction in strepto-zotocin-diabetic rats by reducing intracellular calcium accu-mulation (altering intracellular Ca2+ handling proteins) OSand apoptosis (Kain et al [219]) AZL can reduce the superox-ide production It exerts its protective effects by targeting theNADPH oxidase and mitochondrial redox enzymes AZL-treated diabetic rats express enhanced level of bcl-2 in thelysates of heart muscle indicating that AZL plays protectiverole in cardiac apoptosis
It has been previously observed that azelnidipine inhibitstumor necrosis factor-alpha-induced endothelial cell (EC)oxidative stress through its AO properties (Nakamura etal [220]) Azelnidipine but not nitrendipine completelyinhibits the Ang II-induced ROS generation in ECs (Matsuiet al [221])
Furthermore azelnidipine but not nitrendipine wasfound to partially restore decreased pigment epithelium-derived factor (PEDF) mRNA levels in Ang II-exposed ECsThis study suggests that AZL influence depends on its antiox-idative properties Authors concluded that upregulation ofPEDF by azelnidipine may become a therapeutic targetfor the treatment of diabetic retinopathy associated withhypertension
Antihypertensive agents with AO effects are potentiallyuseful for diabetic patients with hypertension While DHPtypeCAare among themost frequently used antihypertensivedrugs azelnidipine has been reported to have a unique AOeffect in vitro and in vivo in experimental animals (Ohmuraet al [222]) In hypertensive diabetic patients azelnidipinetreatment for 12 weeks induced a more significant decreasein erythrocyte LOOH level than amlodipine although thevalues related to blood pressure during each treatmentremained comparable These data confirm the usefulness ofLOOH level in erythrocyte membrane as a marker of OS invivo and indicate that azelnidipine has a unique antioxidativeproperty in humans
Daikuhara et al [223] reported the results of the OLCAstudy based on combination of (1) olmesartan and a calciumchannel blocker (azelnidipine) or (2) candesartan and a CCBamlodipine in two groups of diabetic hypertensive patientsPatients treated with the first combination presented highlypersistent early morning antihypertensive effect and strongerdecrease in heart rate fasting blood glucose andHbA1c levels
and microalbuminuria when compared to patients treatedwith the combination (2) Because diabetes is associated withsevere chronic OS the observed results might be at least in apart due to the AOA of azelnidipine
In favor of this are findings of Abe et al [224] who foundadditive antioxidative effects of azelnidipine on angiotensinreceptor blocker olmesartan treatment for type 2 diabeticpatients with albuminuria
Similarly the AOA of thiazolidinediones (insulin sensi-tizer) and their effect on cardiovascular function in type 2diabetic model rats and also those of some DHPs (nifedipineamlodipine or AZL commonly used antianginal and anti-hypertensive agents) in cultured human endothelial cells LPwere examined (Mizushige [225]) The AOA was evaluatedby measuring 8-iso-prostaglandine F
2120572concentration and
azelnidipine exhibited potent AOAInsulin (INS) resistance combined with hyperinsuline-
mia is involved in the generation of OS A relation-ship exists between increased production of ROS and thediverse pathogenic mechanisms involved in diabetic vascularcomplications including nephropathy Manabe et al [226]revealed that high doses of INS augmented mesangial cellproliferation through generation of intracellular ROS andactivation of redox signaling pathways Cell proliferation wasincreased in a dose-dependent manner by high doses of INS(01ndash10 120583M) but was inhibited by 01120583M AZL Namely theINS-increased phosphorylation of mitogen activated proteinkinaseextracellular signal-regulated kinase 12 (MAPKERK12) was inhibited by 01 120583MAZL The same AZL concen-tration blocked intracellular ROS production more effec-tively than 01 120583M nifedipine The NADPH oxidase inhibitorapocynin (001ndash01120583M) prevented INS-induced mesangialcell proliferation So azelnidipine inhibits insulin-inducedmesangial cell proliferation by inhibiting the productionof ROS Therefore azelnidipine may have the potential toprotect against the onset of diabetic nephropathy and slowits progression
Azelnidipine inhibited H2O2-induced cell death in
neonatal rat cardiomyocytes (Koyama et al [227]) Azelnidip-ine and nifedipine did not affect theH
2O2-induced activation
of extracellular signal-regulated protein kinases (ERK) andp38 MAPK (mitogen-activated protein kinase) In contrastazelnidipine but not nifedipine inhibited H
2O2-induced c-
Jun NH2-terminal kinases (JNK) activation Authors con-
cluded that azelnidipine has inhibited theH2O2-induced JNK
activation and cardiac cell death Therefore azelnidipine mayhave cardioprotective effects against OS
A specific atheroprotection activity of azelnidipine relatesto inhibition of TNF-120572-induced activator protein-1 activa-tion and interleukin-8 expression in human umbilical veinendothelial cells (HUVEC) through suppression of NADPHoxidase-mediated reactive oxygen species generation (Naka-mura et al [220]) TNF-120572 could play a central role in patho-genesis of insulin resistance and accelerated atherosclerosis inthe metabolic syndrome The concentration of AZL found tobe effective in these in vitro experiments is within therapeuticrange As EC do not possess voltage-operated L-type calciumchannels it is suggested that the beneficial effects of azelni-dipine are not likely due to CA property but to its unique AO
22 Oxidative Medicine and Cellular Longevity
ability Furthermore it has been recently found that serumlevels of monocyte chemoattractant protein-1 a biomarkerfor subclinical atherosclerosis were significantly decreased bythe AZL treatment in patients with essential hypertension Inthis paper [220] authors hypothesize that due to its uniqueTNF-120572 signalmodulatory activity and antioxidative propertyazelnidipine may be a promising DHP for targeting diabetesand cardiovascular diseases in hypertensive patients withmetabolic syndrome
Shinomiya et al [228] evaluated its AOA in culturedhuman arterial EC under OS Azelnidipine has shown apotent antioxidative effect that could be of significant clinicalbenefit when combined with its long-lasting antihypertensiveaction and low incidence of tachycardia
Azelnidipine inhibited TGF-1205731 and angiotensin II- (AngII-) activated 1205721(I) collagen mRNA expression in hepaticstellate cells (HSCs) (Ohyama et al [229]) FurthermoreTGF-1205731- and Ang II-induced OS and TGF-1205731-induced p38and JNK phosphorylation were reduced inHSCs treated withAZL Azelnidipine significantly decreased inflammatory cellinfiltration profibrotic genes expression HSC activation LPoxidative DNA damage and fibrosis in liver of CCl
4- or
TAA-treated mice Finally AZL prevented decrease of theexpression of some AO enzymes and accelerated regressionof liver fibrosis in CCl
4-treated mice Hence the antifibrotic
mechanism of AZL against CCl4-induced liver fibrosis in
mice may have been due to an increased level of AO defenseAs azelnidipine is widely used in clinical practice withoutserious adverse effects it may provide an effective newstrategy for antifibrotic therapy
358 Manidipine Manidipine (2-[4-(diphenylmethyl)pip-erazin-1-yl]ethyl methyl 26-dimethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate) is a DHP CCB withreported nephroprotective properties Calo et al [230] stud-ied effect of manidipine on gene expression and proteinlevel of OS related proteins p22(phox) (human neutrophilcytochrome b light chain (CYBA)) and heme oxygenase-1HO-1 Relevance for antihypertensive effects was revealedThe study assessed the effect of manidipine on normalsubjectsrsquo monocyte gene and protein expression of OS relatedproteins such as p22phox a NADPH oxidase system subunitcritical in generating O
2
∙minus and HO-1 induced by and pro-tective against OS Manidipine was compared with the ACEinhibitor captopril and the CCB nifedipine in the presenceand in the absence of sodiumarsenite (NaAsO
2) as an inducer
of OS Monocyte p22phox (CYBA) mRNA production wasreduced by both manidipine and captopril while no changeswere induced by nifedipine Manidipine increased monocyteHO-1 mRNA production while nifedipine and captoprilshowed no effect The effects of manidipine on p22phoxand HO-1 gene expression in the presence of OS were alsoconfirmed at the protein level Thus manidipine seems tosuppress p22phox and to increase the HO-1 mRNA produc-tion and protein level The manidipine-induced increase ofHO-1 gene and protein expression seems to be a peculiareffect of this drug since it is not observed with captopriland nifedipine This effect together with the reduction of
p22phoxmRNAproduction could play a role in its protectivemechanism against OS
359 Mebudipine The protective effect of mebudipine (14-dihydro-26-dimethyl-4-(3-nitrophenyl)-35-pyridinedicar-boxylic acid 3-methyl-5-tert-butyl ester BAY-n-6391) wasrevealed on OS and LP (MDA decrease SOD GPX andcatalase increase) in myocardial ischemic-reperfusion injuryin male rats (Ghyasi et al [231])
There are articles about other commercial and experi-mental DHPs on OS but we have reviewed only the mostcommonly studied compounds Effects of other commercialCA DHPs on OS are also mentioned in several parts of thisreview
36 14-DHPs Ca Agonists andTheir AOA and ARA For themost popular calcium agonist DHP Bay K 8644 no reactionwith peroxyl radicals was registered (Toniolo et al [114])However interactionwith other compounds possessing AOAand ARA (quercetin) was found
Opposite to that AON-acetylcysteine (NAC) diminishedincrease in Ca2+ transient amplitude and cell shorteninginduced by ISO and forskolin whereas NAC had no effecton the (S)-(minus)-methyl-14-dihydro-26-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylatemdash(minus)-BayK 8644-induced increases (Andersson et al [232])
Increased vasoconstriction responses to Bay K 8644 (3 times10minus7ndash3times 10minus5M)were significantly decreased by pyridoindoleantioxidant stobadine treatment in diabetes (Ceylan-Isik etal [233])
The functional interaction between two L-type Ca2+channel activators quercetin and Bay K 8644 has beeninvestigated in vascular smooth muscle cells Biological ARAcompound quercetin at nutritionally meaningful concen-trations limited the responsiveness of vascular L-type Ca2+channels to the pharmacological stimulation operated by BayK 8644 These data contribute to a better understanding ofquercetin effects on experimental in vivo cardioprotection(Saponara et al [234]) Thus these findings indicated thatalthough Bay K 8644 does not exert potent and direct AOAyet acting as calcium agonist it may affect efficiency of AOsubstances and vice versa
Interaction of grapefruit juice (containing quercetin andits analogues) with DHPs CA diminished effectiveness of CAaction of DHPs (Sica [235])
37 Interpretations of the Mechanism(s) of RadicalScavenging and AOA by DHPs
371 Molecular Mechanism(s) of Radical Scavenging andAOA of DHPs in the Model Systems 35-Dicarbonyl-14-di-hydropyridine derivatives possess powerful bis-120573-carbony-lvinyl-amino conjugation and for that reason cannot be con-sidered as ordinary amino antioxidants The electron andorH donation from DHPs ensures their reductant role andresults in AOA and ARA Oxidation reaction from DHPsresults in production of corresponding heteroaromatic pyri-dine derivatives
Oxidative Medicine and Cellular Longevity 23
Detailed studies were made about substituent in DHPring positions 14- namely 4-unsubstituted- 4-substituted4-alkyl- 4-aryl- 4-alkylaryl- ao 26- 35- (diacetyl ordialkoxycarbonyl chain ao) electronic and steric effects onAOA and ARA of DHPs [44 45 51] see Sections 331and 35 The bell-shaped dependence of DHPs AOA onthe 35-dialkoxycarbonyl- chain length was observed [4445 107 109 112] with the maximum activity at C
2H5ndash
C4H9 Decrease of AOA and incorporation into liposomes for
DHPs with alkyl chains longer than R gt C4H9further were
clarified as probable tendency to self-aggregation of thesecompounds ([51] and citation number 245 therein) Electronacceptorelectron donor properties are relevant for expres-sion of AOA or ARA of 35-disubstituted DHPs 35-Diacyl-substituted and 35-dicarbanilido- and 35-dipyridylamido-substituted DHPs are more active as AOs as their 35-dicyano-substituted analogues which have electron acceptorproperties [186]
Dubur et al [89] observed overwhelming steric influenceof substituents in position 4 of the DHP ring Gaviraghiet al [163 164] proposed that AO activity of DHPs ispartly dependent on capacity of the 14-DHP ring to donateelectrons to the propagating radical (ROO∙ or RO∙) and toreduce it to a less reactive form The abstraction (donation)of electron andor H in the oxidation and LP reactionstakes place from all 35-dicarbonyl-14-DHP systems andresults in the formation of corresponding pyridine derivatives(Augustyniak et al [51]) The physicochemical mechanism ofARA and AOA of 14-DHP has been extensively studied anddiscussed (Mulder et al [236]) but precise mechanisms oftheir activity need further clarification
The reactivity of C-4 substituted 14-DHPs possessingeither secondary or tertiary nitrogen atom in the DHP ringtoward alkyl alkylperoxyl radicals and ABTS radical cationwas determined in aqueous media at pH 74 [103] Thesecompounds reacted faster toward alkylperoxyl radicals andABTS radical cation than alkyl ones N-Ethyl-substitutedDHPs showed the lowest reactivity
The 4-methyl substituted DHP was the most reac-tive compound in previously mentioned reactions (Lopez-Alarcon et al [103]) However it was less active (068versus 10) than Trolox-C DHPs having electron-donatingsubstituents (4-Me-DHP and p-MeO-Phe-DHP) showed thehighest kinetic rate constants toward ABTS radical cation p-nitro-Phe-DHP a compound with an electron-withdrawingsubstituent showed a lower kinetic rate constant and N-alkyl-DHP compounds show kinetic rate constants lowerthan the -NH-DHP
Hydrogen at the 1-position of the DHP ring was revealedaccording to the deuteriumkinetic isotope effect studies to beinvolved in the proposedARAmechanismThis fact ismostlynoticeable in the case of alkyl radicals N-Ethyl-substitutedDHPs show the lowest reactivity when compared to Troloxor nisoldipine In all cases the respective pyridine derivativewas detected as the main product of the reaction (Lopez-Alarcon et al [103]) Authors indicate that the kinetic rateconstants toward alkyl alkylperoxyl andABTS radical cationdepend on the nature of the substituents in the C-4 positionof DHP and the presence of the secondary amine group in the
dihydropyridine ring that is the presence of the hydrogen in1-position
Yanez et al [197] have studied the reactivity of 11derivatives of 14-DHPs (including commercial CA) withalkylperoxyl radicals and ABTS radical cation The tested14-DHPs were 83-fold more reactive towards alkylperoxylradicals than to the ABTS cation radical All commercial14-DHP type CCBs were weaker than Trolox-C The par-ticipation of the hydrogen atom in the 1-position appearsto be very relevant for exhibited reactivity Hantzsch ester(diludine)was again found to be themost active compound inthe reaction with alkylperoxyl radicals 23-fold more activethan Trolox The photodegradation product of nifedipine(nitrosophenyl derivative of pyridine) also showed a highactivity Kinetic rate constants for the reaction between 14-DHP compounds and alkylperoxyl radicals exhibited a fairlygood linear correlation with the oxidation peak potentialof DHP derivatives However the activity of tested 14-DHPs towards ABTS radical cation showed an independencebetween kinetic rate constants and oxidation peak potentials
Kirule et al [195] andTirzit et al [196] studiedmechanismof AOA of 4-nitrophenyl-14-DHPs nifedipine and its ana-logues involving formation of 4-(21015840-nitrosophenyl)-pyridinederivative (as active principle) as a result of intramolecularredox reaction using chemical electrochemical and bio-chemical approaches (see Sections 331 and 351)
Nunez-Vergara et al [237] reported the electrochemicaloxidation of C4-hydroxyphenyl-substituted 14-DHP deriva-tives The oxidation proceeds via formation of the unstabledihydropyridyl radical as confirmed by controlled-potentialelectrolysis (CPE) and ESR experiments This type of 14-DHPs has significant activity towards the radicals even whencompared with commercial 14-DHP drugs with well-knownantioxidant ability
It was observed that nicardipine preferentially targets RO∙radicals and is inactive against ROO∙ Lacidipine on theother hand is equally active towards both types of radicals(Gaviraghi et al [164]) The cytoprotective effect againstexposure to H
2O2was more significant for lacidipine (ID
50=
14 nM its log119875 = 54 membrane partition = 136000 assumesposition located 7 A near to the membrane center otherless lipophilic DHPs located 12ndash16 A far from the center)as compared to amlodipine nifedipine and nicardipine insmooth muscle cell culture (Gaviraghi et al [164]) Oxidativeeffect of H
2O2shifts the Ca channel toward an open state
Thus the redox property of CCBs DHPs may augment theirCCB properties
Oxidation of pharmacologically active Hantzsch 14-dihydropyridines was found by electrogenerated superoxideusing a voltammetric approach in DMSO solutions (Ortiz etal [238] and Ortiz et al [239]) Raghuvanshi and Singh [240]have also reported oxidative aromatization of these DHPsinduced by superoxide
Chemiluminescence (CL) was used in the studies ana-lyzing the antioxidant activity of 12 various 4-flavonil-14-dihydropyridine derivatives (Kruk et al [241]) on a chemicalsystem involving a superoxide radical anion These deriva-tives showed structural similarity to flavonoids with respectto the presence of rings A B and C The results obtained in
24 Oxidative Medicine and Cellular Longevity
this study indicate that the tested derivatives may catalyzeconversion of superoxide radicals through mimicking theactivity of superoxide dismutase by delivering H+ for reac-tion
O2
minus∙+O2
minus∙+ 2H+ 997888rarr H
2O2+1O2
(3)
The enhanced emission of the light in the presence oftested compounds was significant and related to stimulatedproduction ofH
2O2and 1O
2fromO
2
∙The latter specieswereremoved from the reactionmixture by the following sequenceof reactions
H+
O2
minus∙997888rarr HO
2
∙
HO2
∙+O2
∙minus997888rarr HO
2
minus+1O2
2HO2
∙997888rarr H
2O2+1O2
2 (1O2) 997888rarr (O
2)2+ h]lowast
(4)
or to take part in spontaneous dismutation of H2O2
2H2O2997888rarr 2H
2O + 1O
2(5)
The authors have offered an original concept of action for 4-flavonil-14-dihydropyridine derivatives unrelated to that ofO2
∙ radical-trapping chain-breaking antioxidants Insteadthey showed that these compounds act similar to superoxidedismutases converting O
2
∙ to H2O2 Hydrogen peroxide
is less toxic for cells than O2
∙ because it is predominantlyremoved by peroxidases and catalases Finally AO effect ofthese DHPs differed from those mediated by flavonoids witha catechol structure of ring B which are well-known 1O
2
quenchersMulder and collaborators came to similar conclusions
especially related to molecular mechanisms of antioxidativeactivity of DHPs [236]TheAOproperties of Hantzsch 14-di-hydropyridine esters and two dibenzo-14-dihydropyridines910-dihydroacridine (DHAC) and N-methyl-910-dihydro-acridine (N-Me-DHAC) have been explored by determin-ing the autoxidation of styrene or cumene at 30∘C Theseexperiments showed that Hantzsch esters are virtually inac-tive as chain-breaking antioxidants (CB-AOs) contrary tothe findings observed by Lopez-Alarcon et al [103] whoused CB-AOA in aqueous media at pH 74 Their reactivitytoward peroxyl radicals was shown to be some 5 orders ofmagnitude lower than that of the excellent CB-AO 22578-pentamethyl-6-hydroxy-chroman (PMHC)
DHAC was found to be sim10 times less reactive thanPMHC kinetic measurements using DHAC N-deuterio-DHAC and N-Me-DHAC pointing out the abstraction ofN-H hydrogen in DHAC by peroxyl radicals despite the factthat the calculated C-H bond dissociation enthalpy (BDE) inDHAC is about 11 kcalmol lower than the N-H BDE Therates of hydrogen atom abstraction by the 22-diphenyl-1-picrylhydrazyl radical (DPPH∙) have also been determined
for the same series of compounds The trends in the peroxyl∙and DPPH∙ rate constants were found to be similar [236]
Tirzit et al [242] have observed quenching of singletoxygen by DHPs This observation paved the ground forfurther research related to reactions of DHPs with hydroxylradicals (Tirzit et al [243]) singlet oxygen (Kazush etal [94]) and mechanisms of action A series of 14-DHPderivatives in NAD-H-Cu2+-H
2O2system inhibited forming
of the hydroxyl radical (HO∙) while 14-DHP derivativeswith electron donor substituents in the molecule were shownto be capable themselves of generating HO∙ in the presenceof Cu2+ and H
2O2 Rubene et al [186] also described
interaction of 14-DHP derivatives with Fentonrsquos reagentwhich produces hydroxyl radical (HO∙) Rate constants ofthe DHPs reaction (1st order) with HO∙ radical were highin the range 109 L times mol times secminus1 close to that of NADHcysteine and thiourea 35-Diacetyl- derivatives reacted fastercompared to 35-dialkoxycarbonyl- ones The reaction ratedecrease was observed in the case of substitution at position4 as compared to 4-unsubstituted DHPs Some DHPs havingelectron donor -COOminus groups in the 35- or 26- positionsof DHP ring reacted immediately (having rate constantshigher as 109 L times mol times secminus1) Rate constants with HO
2
∙
and O2
∙minus radicals were of lower degree Thus DHPs actingas oxygen radical scavengers could effectively inhibit ROSrelated reactions of LP initiation stage
Nifedipine and nitrendipine reactivity toward singletoxygen was also studied [244] Nifedipine was shown tobe a good scavenger of excited oxygen mainly via physicaldeactivation with values of the total rate constant rangingfrom 208 times 105Mminus1 sminus1 (in dioxane) to 930 times 105Mminus1 sminus1(in propylene carbonate)The less reactive pathway generateda photooxidation product For that reason a mechanisminvolving a perepoxide-like encounter complex in the firststep of the reaction path was proposed (see [244] Figures8 and 9 therein) The dependence was observed on solventmicroscopic parameters of the total rate constant for the reac-tion between singlet oxygen and 14-DHPs These findingsshow that nifedipine possesses stronger protective activity inbiological systems than nitrendipine
Density-functional-theory (DFT) calculations made byWang et al [245] confirmed the former experimental obser-vations that Hantzsch ester diludine is potent antioxi-dant with high H atom-donating ability and relatively lowprooxidant activity Possible reaction pathways for radicalsderived from 14-dihydropyridine and the resonance modesfor radical species were given [245]
Moreover two ethoxycarbonyl (EtOCO) substituentsat C(2) and C(6) should further enhance Hantzsch esterdiludine H-atom-donating ability due to resonance effectsHowever DHPs should be used in nonpolar rather than inpolar solvents since in the latter not H-atom but electrontransfer is preferred in the radical scavenging process [245]
Mulder et al [246] proposed that quantum-thermochem-ical calculations must be used with caution to indicate ldquoapromising lead antioxidantrdquo as they criticized the density-functional-theory (DFT) calculations made by Wang et al[245]
Oxidative Medicine and Cellular Longevity 25
372 Possible Mechanisms of DHPs ARA and AOA in the Bio-logical Systems Interaction with Other OSModifiers Some ofthese mechanisms were already described (Sections 331 (2)-(b) 331 (2)-(c) 331 (3)-(b) 35)
Enzymatic sources of ROSwith confirmed functional rolein hypertension are NADPH oxidase NO synthase (NOS)xanthine oxidase and cyclooxygenase Godfraind [3] hasreviewed AO effects and protective action of calcium channelblockers (CCBs) Yao et al [247] observed antioxidant effects(as inhibition of LP) for cardio- and neuroprotective CCBs(3ndash300 120583molL) including 7 DHPs in homogenates of ratbrain IC
50values (120583M) were as follows nifedipine (515) gt
barnidipine (586) gt benidipine (712) gt nicardipine (1293)gt amlodipine (1355) gt nilvadipine (1673) gt nitrendipine(2521) gt diltiazem (gt300) = verapamil (gt300) There arealso research articles describing the AO properties of CCBsthrough direct scavenging effect or through preservationof the endogenous SOD activity These findings indicatethat CCBs may also act by reducing the production ofvasoconstrictors angiotensin and endothelin
When present in concentrations that can be achievedin plasma CCBs may inhibit LP formation [3] This AOactivity seems to be typical for high lipophilic CCBs becausetheir chemical structure facilitates proton-donating andresonance-stabilization mechanisms that quench the freeradical reaction Their insertion in the membrane nearpolyunsaturated fatty acids at relatively high concentrationspotentiates proton donation (or atomary H) to lipid peroxidemolecules thereby blocking the peroxidation process Theremaining unpaired free electron associated with the CCBmolecule can be stabilized in well-defined resonance struc-tures associated with the DHP ring (Mason et al [48])
The radical reaction (according to Godfraind [3]) thatdescribes the AO effects of a DHP CCBs is LOOlowast + DHPrarr LOOH + DHPlowast (where LOOlowast is lipid peroxide radical)which in general is reaction (7) of the LP reaction cascadeconsisting of sim10 reactions (Scheme 2) [89]
As the rate constants of in vitro interaction of 4-substituted DHPs with peroxyl radicals are three ordersof magnitude lower than that of the vitamin E derivativethese DHPs must be considered as weak AO (Ursini [204])However due to partition coefficient of DHPs in membranesand in case of specific binding high local concentration ofDHPs may be obtained
DHPs without CCB properties for instance Bay w 9798although structurally related to nifedipine inhibit TNF-120572-induced vascular cell adhesion molecule-1 expression inendothelial cells by suppressing reactive oxygen speciesgeneration [248]
Mitrega et al [249] have discovered that antiarrhythmicand hemodynamic effects of oxidized heteroaromatic DHPsoxy nifedipine oxy nimodipine oxy nitrendipine and oxynisoldipine suggest that CCB DHPs and their metabolitescould act at least in two ways targeting OS related eventsas reductants (see Section 351 (1)) andor bypassing OSrelatedmetabolic routes Authors postulated that contrary tocurrent belief NIF metabolites are pharmacologically activeATP sensitive potassium channels were mentioned as a tar-get
38 DHPs Anti- or Prooxidants Several substances (ascorbicacid being the most commonly studied) can serve either asantioxidants or as prooxidants depending on given condi-tions (Herbert [250]) Therefore Halliwell [251] has reporteddilemma related to polyphenols as possible antioxidantsand prooxidants causing experimental artifacts (about 25)by oxidation of antioxidant compounds in the cell culturemedia Nevertheless it is generally accepted opinion thatpolyphenols act as antioxidants in vivo Studies on DHPs alsoface such a dilemmaThe exact roles (anti- or prooxidative) ofany specific DHP depend on its structure appliedachievedconcentration and specificity of the targetexperimentaltesting system
This situation resembles the case of antioxidative effectsof tocopherol which depends on the fate of the secondaryradical as proposed by Winterbourn [252] The question wasldquoVitamin E - Pro- or Antioxidantrdquo
997888rarr chain termination of lipid peroxidation
(6)
Prooxidant
Toc∙ + Lipid-H 997888rarr Lipid∙ (in LDL particles) (7)
This example shows that generally speaking any AO mustfulfil several criteria to be considered as an effective com-pound physiologically
(i) It must be able to functionally interact with endoge-nous scavengers even at low concentrations
(ii) It must affect endogenous pathways of OS(iii) It should not have undesirable adverse effect(iv) It should manifest the antioxidant efficacy dependent
on the oxidant(v) It must discriminate among different strategies
needed for 1-electron and 2-electron processes(vi) Radical scavengers can be prooxidant unless linked to
a radical sink (Winterbourn [252])
According to these statements DHPs could be effective asAO under physiological conditions in vivo (Godfraind [3]and others [30 31 38]) and in vitro in various experimentalsystems (cell and tissue) (see Sections 33 34 35)
Hence calcium antagonists appeared to disrupt thefine balance between the production and scavenging ofROS Nifedipine verapamil and diltiazem were shown toinduce significant oxidative stress in the epididymal sperm(increased MDA and decreased catalase and superoxidedismutase activity) This may be the reason for the inductionof male infertility [253]
The dualism of 14-DHP effects has been recorded asinhibition or promotion of LP as quenching or initiating
26 Oxidative Medicine and Cellular Longevity
oxygen and nitrogen free radical chain reactions radiopro-tecting or radiosensitizing antagonizing or synergizing Ca2+in electromechanical coupling as well as in the membranestabilization or labilization
39 Could DHPs Be Involved in Antioxidative Stress Beforebeing applied in vivo the optimal dose and optimal timeintervals forDHPs applicationmust be knownNamely whileROS have been traditionally considered as toxic byproductsof aerobic metabolism we know nowadays that ROS may actas essential signaling molecules needed for the control ofmany different physiological processes Whether the role ofROS will be damaging protective or signaling depends onthe delicate equilibrium between time- and location-specificROS production and scavenging Accordingly the imbalanceof the increased AO potential so-called antioxidative stresscould be dangerous similar to chronic OS in particular incase of extended exposure Inappropriate interventions inthe oxidative homeostasis by excessive antioxidants especiallyin case of chronic exposure to antioxidants might havevery negative effects as was published in the ATBC studyshowing an increased cancer incidence in smokers treatedby excessive beta-carotene [254] Therefore overconsump-tion of any natural or synthetic AO including DHPs asdietary supplements or drugs must be avoided in order tosuppress oxidative damage and must not disrupt the well-integrated antioxidant defense network (Poljsak [255] andPoljsak and Milisav [256]) This is especially important whenadministrating lipid-soluble antioxidants that can be storedin biomembranes thus not only attenuating or preventing LPbut also affecting physiological effects of the natural antiox-idants in particular tocopherol The interrelationship withthe status of endogenous antioxidantsprooxidants should befollowed
DHPs primarily suppress the initiation stages of LPprocessThey do not entirely stop the LP propagation Actingsynergistically with tocopherol diludine may prevent patho-logical excess of ROS production within the lipid moiety ofthe cellular membranes and LDL However due to its lowsolubility and fast metabolism its concentration in the cellsis low For that reason it cannot cause antioxidative stresseven if used for an extended period of time Thus diludine(diethone) could be only a mild antioxidant it has potentialfor restoring the pool of natural antioxidants (as synergist of120572-tocopherol and polyphenols) in the cells
Moreover DHPs CA used for cardioprotection andvasodilatation as commercial drugs in low concentrationsare fast metabolized via CYP3A4 and for that reason theirapplication does not induce cellular AO stress [53 160]However Godfraind and Salomone [257] have postulated noevidence that allows recommending dietary supplementationwith antioxidants for the primary or secondary prevention ofcardiovascular disease
So far there are no reports on antioxidative stress causedby some DHPs diludine and its analogues Diludine andits analogues therefore could act as adaptogens supportinghormetic effects of mild oxidative stress These compoundsmay act as potential multisided modulators of Yin-Yang
cycles of redox and cell functions (the electroplasmic cycle)(Wagner et al [258])
4 Conclusions
14-Dihydropyridines (14-DHPs) have broad spectrum ofOS modulating activities DHPs have reducing and lipidperoxidation inhibitor properties act as reductants in simplechemical systems and stabilize various biological systems(LDL mitochondria microsomes cells and tissues) againstOS Examples and peculiarities and mechanisms of antiox-idant activity (AOA) and antiradical activity (ARA) as wellas stress-protective effect of DHPs including commercialcalcium antagonists (CA) were highlighted These activitiesdepend on various structural parameters related to DHPs(presence and character of substituents) lipophilicity anddepth of the incorporation in the biologicalmembranesTheyalso depend on the experimental model system for exploringthe lipid peroxidation or oxidative stress Stress-protectiveeffect of some metabolites of CA (nifedipine) is reviewedAlthough some DHPs including CA have prooxidant prop-erties (on epididymal sperm cells) they can generally beconsidered as potent antioxidants Therefore comparisonof the AOA and ARA of different DHPs (mutually andwith other AOs) was described in detail According to thedata presented the DHPs might be considered as bellwetheramong synthetic compounds targeting OS and as a kind ofpharmacological measure for respective field of organic andmedicinal chemistry
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
Authors from Latvian IOS acknowledge ESF 201300021DP1112013APIAVIAA011 and National Research Pro-gramme PUBLIC HEALTHBiomedicine of the Republicof Latvia for financial support administration of the Insti-tute for technical support and Rufus Smits PhD for con-sultations in English The support of Cooperation in Euro-pean System of Science and Technology (COST) Domain ofChemistry Molecular Sciences and Technologies (CMST)was of highest importance for preparation of this paper
[2] D J Triggle ldquo14-Dihydropyridines as calcium channel ligandsand privileged structuresrdquoCellular andMolecular Neurobiologyvol 23 no 3 pp 293ndash303 2003
[3] T Godfraind ldquoAntioxidant effects and the therapeutic modeof action of calcium channel blockers in hypertension andatherosclerosisrdquo Philosophical Transactions of the Royal SocietyB Biological Sciences vol 360 no 1464 pp 2259ndash2272 2005
[4] E Cadenas ldquoMitochondrial free radical production and cellsignalingrdquoMolecular Aspects of Medicine vol 25 no 1-2 pp 17ndash26 2004
[5] E Cadenas ldquoFree radicals oxidative stress and diseasesrdquo inLecture PSC 616 p 38 Missouri University of Science andTechnology Rolla Mo USA httpwwwcarnicominstituteorgarticlesenrique cadenaspdf
[6] K Rahman ldquoStudies on free radicals antioxidants and co-fac-torsrdquo Clinical Interventions in Aging vol 2 no 2 pp 219ndash2362007
[7] V Bocci and G Valacchi ldquoFree radicals and antioxidants howto reestablish redox homeostasis in chronic diseasesrdquo CurrentMedicinal Chemistry vol 20 no 27 pp 3397ndash3415 2013
[8] M Valko C J Rhodes J Moncol M Izakovic and M MazurldquoFree radicals metals and antioxidants in oxidative stress-induced cancerrdquo Chemico-Biological Interactions vol 160 no 1pp 1ndash40 2006
[9] G Bartosz ldquoReactive oxygen species destroyers or messen-gersrdquo Biochemical Pharmacology vol 77 no 8 pp 1303ndash13152009
[10] R Visconti and D Grieco ldquoNew insights on oxidative stress incancerrdquo Current Opinion in Drug Discovery and Developmentvol 12 no 2 pp 240ndash245 2009
[11] R N Kujundzic N Zarkovic and K G Troselj ldquoPyridinenucleotides in regulation of cell death and survival by redoxand non-redox reactionsrdquo Critical Reviews in Eukaryotic GeneExpression vol 24 no 4 pp 287ndash309 2014
[12] B Halliwell and J M C Gutteridge ldquoThe definition and mea-surement of antioxidants in biological systemsrdquo Free RadicalBiology and Medicine vol 18 no 1 pp 125ndash126 1995
[13] V D Kancheva and O T Kasaikina ldquoBio-antioxidantsmdashachemical base of their antioxidant activity and beneficial effect
on human healthrdquo Current Medicinal Chemistry vol 20 no 37pp 4784ndash4805 2013
[14] H V Panglossi Ed Frontiers in Antioxidants Research NovaScience Publishers New York NY USA 2006
[15] E B Burlakova E M Molochkina and G A NikiforovldquoHybrid antioxidantsrdquo Oxidation Communications vol 31 no4 pp 739ndash757 2008 httpmembraneustceducnpaperpdfHybrid20Antioxidantspdf
[16] A Bast and G R M M Haenen ldquoTen misconceptions aboutantioxidantsrdquo Trends in Pharmacological Sciences vol 34 no 8pp 430ndash436 2013
[17] E B Burlakova A V 0lesenko E M Molochkina N PPalmina and N G Khrapova Bioantioxidants for RadiationDamage and Malignant Growth Nauka Moscow Russia 1975(Russian)
[18] J Fang T Seki and H Maeda ldquoTherapeutic strategies by mod-ulating oxygen stress in cancer and inflammationrdquo AdvancedDrug Delivery Reviews vol 61 no 4 pp 290ndash302 2009
[19] M Valko D Leibfritz J Moncol M T D Cronin M Mazurand J Telser ldquoFree radicals and antioxidants in normal physi-ological functions and human diseaserdquo International Journal ofBiochemistry and Cell Biology vol 39 no 1 pp 44ndash84 2007
[20] M Jimenez-Del-Rio and C Velez-Pardo ldquoThe bad the goodand the ugly about oxidative stressrdquo Oxidative Medicine andCellular Longevity vol 2012 Article ID 163913 13 pages 2012
[21] C D Kamat S Gadal M Mhatre K S Williamson Q N Pyeand K Hensley ldquoAntioxidants in central nervous system dis-eases preclinical promise and translational challengesrdquo Journalof Alzheimerrsquos Disease vol 15 no 3 pp 473ndash493 2008
[22] A Pompella H Sies R Wacker et al ldquoThe use of totalantioxidant capacity as surrogate marker for food quality andits effect on health is to be discouragedrdquo Nutrition vol 30 no7-8 pp 791ndash793 2014
[23] Z Ye and H Song ldquoAntioxidant vitamins intake and the risk ofcoronary heart disease meta-analysis of cohort studiesrdquo Euro-pean Journal of Cardiovascular Prevention and Rehabilitationvol 15 no 1 pp 26ndash34 2008
[24] P Knekt J Ritz M A Pereira et al ldquoAntioxidant vitamins andcoronary heart disease risk a pooled analysis of 9 cohortsrdquoTheAmerican Journal of Clinical Nutrition vol 80 no 6 pp 1508ndash1520 2004
[25] A C Carr and M C M Vissers ldquoSynthetic or food-derivedvitamin Cmdashare they equally bioavailablerdquo Nutrients vol 5 no11 pp 4284ndash4304 2013
[26] R Tabrizchi ldquoEdaravoneMitsubishi-TokyordquoCurrentOpinion inInvestigational Drugs vol 1 no 3 pp 347ndash354 2000
[27] K Kikuchi S Tancharoen N Takeshige et al ldquoThe efficacy ofedaravone (radicut) a free radical scavenger for cardiovasculardiseaserdquo International Journal of Molecular Sciences vol 14 no7 pp 13909ndash13930 2013
[28] D Mauzerall and F H Westheimer ldquo1-Benzyldihydronicoti-namidemdasha model for reduced DPNrdquo Journal of the AmericanChemical Society vol 77 no 8 pp 2261ndash2264 1955 ChemicalAbstracts vol 50 Article ID 2588i 1956
[29] F Bossert and W Vater ldquo14-Dihydropyridinesmdasha basis fordeveloping new drugsrdquo Medicinal Research Reviews vol 9 no3 pp 291ndash324 1989
[30] G Swarnalatha G Prasanthi N Sirisha and CMadhusudhanaChetty ldquo14-Dihydropyridines a multtifunctional moleculemdash areviewrdquo International Journal of ChemTech Research vol 3 no1 pp 75ndash89 2011
28 Oxidative Medicine and Cellular Longevity
[31] M Cataldi and F Bruno ldquo14-Dihydropyridines the multiplepersonalities of a blockbuster drug familyrdquo Translational Medi-cine UniSa vol 4 no 2 pp 12ndash26 2012 httpwwwncbinlmnihgovpmcarticlesPMC3728803
[32] R Vitolina A Krauze G Duburs and A Velena ldquoAspects ofthe amlodipine pleiotropy in biochemistry pharmacology andclinicsrdquo International Journal of Pharmaceutical Sciences andResearch vol 3 no 5 pp 1215ndash1232 2012
[33] D Grover S N Mokale and M T Shete ldquoDihydropyridinea novel pharmacophorerdquo International Journal of Pharmaceu-tical Erudition vol 1 no 2 pp 16ndash29 2011 httppharmaeru-ditionorgContentPaper20111-RV-320Final2016-29pdf
[34] A M Vijesh A M Isloor S K Peethambar K N ShivanandaT Arulmoli and N A Isloor ldquoHantzsch reaction synthesis andcharacterization of somenew 14-dihydropyridine derivatives aspotent antimicrobial and antioxidant agentsrdquo European Journalof Medicinal Chemistry vol 46 no 11 pp 5591ndash5597 2011
[35] P Mehta and P Verma ldquoAntimicrobial activity of some deriva-tives of 14-dihydropyridinesrdquo Journal of Chemistry vol 2013Article ID 865128 4 pages 2013
[36] P Olejnıkova L Svorc D Olsovska et al ldquoAntimicrobialactivity of novel C2-substituted 14-dihydropyridine analoguesrdquoScientia Pharmaceutica vol 82 no 2 pp 221ndash232 2014
[37] S Sepehri H Perez Sanchez and A Fassihi ldquoHantzsch-typedihydropyridines and biginelli-type tetra-hydropyrimidinesa review of their chemotherapeutic activitiesrdquo Journal of Phar-macy amp Pharmaceutical Sciences vol 18 no 1 pp 1ndash52 2015httpsejournalslibraryualbertacaindexphpJPPSarticleview2383617863
[38] S A Khedkar and P B Auti ldquo14-Dihydropyridines a classof pharmacologically important moleculesrdquo Mini-Reviews inMedicinal Chemistry vol 14 no 3 pp 282ndash290 2014
[39] G D Tirzit and G Ya Duburs ldquo14-dihydropyridines as inhi-bitors of free-radical reactionsrdquo Chemistry of Heterocyclic Com-pounds vol 8 no 1 pp 126ndash127 1972 Translated from KhimiyaGeterotsiklicheskikh Soedinenii no1 pp 133ndash134 1972 (Rus-sian)
[40] I Bogeski R Kappl C Kummerow R Gulaboski M Hothand B A Niemeyer ldquoRedox regulation of calcium ion channelschemical and physiological aspectsrdquoCell Calcium vol 50 no 5pp 407ndash423 2011
[41] S A Giller G Y Dubur Y R Uldrikis et al ldquoDiludine [Themethod to obtain 35-dicarbonylderivatives of 26-dimethyl-14-dihydropyridines]rdquo Authors certificate of USSR no 3004651971 [Byull Izobret no13 p 95 1971] and following patentsPatent of England no 1294650 1973 Patent of France no2055458 1971 Patent of Japan no 702883 1973 Patent ofHolland no 149787 1976 Patent of Italy no 969022 1974 Patentof FRG no 2036403 1978 US Patent no 3883673 1975 USPatent no 3948924 1976
[42] S A Giller G Y Dubur Y R Uldrikis et al ldquoImprovementsin or relating to the stabilization of carotenerdquo GB Patent no1294650 1972
[43] S A Giller G Y Dubur Y R Uldrikis et al ldquoStabilization ofcarotenerdquo US Patent no 3883673 1975 Chemical Abstracts vol83 Article ID 95193 1975
[44] Yu A Zilber G Ya Dubur K K Kumsar and A Kh VelenaldquoThe effect of antioxidants on the peroxidation of bimole-cular phospholipid membranesrdquo Latvijas PSR ZA Vestis Izves-tia Akademii Nauk Latviyskoy SSR vol 6 pp 80ndash82 1971(Russian) translated from the original Russian Doc Accesion
No AD0771751 distributed by NTIS US Department of Com-merce httpwwwdticmildtictrfulltextu2771751pdf
[45] G Ya Dubur Yu A Zilbers A Kh Velena A O Kumerovaand G D Tirzitis ldquoMultistage study of regulation of peroxida-tion processes in biological membranes by antioxidants of 14-dihydropyridine grouprdquo Izvestiya Akademii Nauk LatviyskoySSR vol 336 no 7 pp 65ndash68 1975 (Russian)
[46] R P Mason and M W Trumbore ldquoDifferential membraneinteractions of calcium channel blockers Implications forantioxidant activityrdquo Biochemical Pharmacology vol 51 no 5pp 653ndash660 1996
[47] R P Mason M F Walter M W Trumbore E G Olmstead Jrand P E Mason ldquoMembrane antioxidant effects of the chargeddihydropyridine calcium antagonist amlodipinerdquo Journal ofMolecular and Cellular Cardiology vol 31 no 1 pp 275ndash2811999
[48] R PMason I T MakMW Trumbore and P EMason ldquoAnti-oxidant properties of calcium antagonists related to membranebiophysical interactionsrdquo American Journal of Cardiology vol84 no 4 pp 16ndash22 1999
[49] R PMasonMW Trumbore and P EMason ldquoMembrane bio-physical interaction of amlodipine and antioxidant propertiesrdquoDrugs vol 59 no 2 pp 9ndash16 2000 (French)
[50] R P Mason P Marche and T H Hintze ldquoNovel vascularbiology of third-generation L-type calcium channel antagonistsAncillary actions of amlodipinerdquo Arteriosclerosis Thrombosisand Vascular Biology vol 23 no 12 pp 2155ndash2163 2003
[51] A Augustyniak G Bartosz A Cipak et al ldquoNatural andsynthetic antioxidants an updated overviewrdquo Free RadicalResearch vol 44 no 10 pp 1216ndash1262 2010
[52] T Grune N Zarkovic and K Kostelidou ldquoLipid peroxidationresearch in Europe and the COST B35 action lsquoLipid Peroxida-tion Associated Disordersrsquordquo Free Radical Research vol 44 no10 pp 1095ndash1097 2010
[53] E Carosati P Ioan M Micucci et al ldquo14-Dihydropyridinescaffold in medicinal chemistry the story so far and perspec-tives (part 2) action in other targets and antitargetsrdquo CurrentMedicinal Chemistry vol 19 no 25 pp 4306ndash4323 2012
[54] U Eisner and J Kuthan ldquoThe chemistry of dihydropyridinesrdquoChemical Reviews vol 72 no 1 pp 1ndash42 1972 httpwwwsci-encemadnessorgtalkfilesphppid=138742ampaid=6475
[55] J Kuthan and A Kurfurst ldquoDevelopment in dihydropyri-dine chemistryrdquo Industrial amp Engineering Chemistry ProductResearch and Development vol 21 no 2 pp 191ndash261 1982
[56] A Sausins and G Duburs ldquoSynthesis of 14-dihydropyridinesby cyclocondensation reactionsrdquo Heterocycles vol 27 no 1 pp269ndash289 1988
[57] A E Sausins and G Y Duburs ldquoSynthesis of 14-dihydro-pyridines in cyclocondensation reactions (review)rdquo Chemistryof Heterocyclic Compounds vol 28 no 4 pp 363ndash391 1992Translated from Khimiya Geterotsiklicheskikh Soedinenii no 4pp 435ndash467 1992 (Russian)
[58] S Kazda ldquoTwenty years of dihydropyridinesrdquo in Dihydropy-ridines Progress in Pharmacology and Therapy W-D Busse BGarthoff and F Seuter Eds pp 1ndash12 Springer Verlag BerlinGermany 1993
[59] J-P Wan and Y Liu ldquoRecent advances in new multicomponentsynthesis of structurally diversified 14-dihydropyridinesrdquo RSCAdvances vol 2 no 26 pp 9763ndash9777 2012
[61] Reaxys Database[62] J Tuttle ldquoStructure mechanism and reactivity of hantzsch
estersrdquo in MacMillan Lab Group Meeting (082504) p 332004 httpwwwprincetoneduchemistrymacmillangroup-meetingsJBT20Hantzschpdf
[63] A Saini S Kumar and J S Sandhu ldquoHantzsch reaction recentadvances in Hantzsch 14-dihydropyridinesrdquo Journal of Sci-entific amp Industrial Research vol 67 pp 95ndash111 2008
[64] L LW Cheung S A Styler and A P Dicks ldquoRapid and conve-nient synthesis of the 14-dihydropyridine privileged structurerdquoJournal of Chemical Education vol 87 no 6 pp 628ndash630 2010
[65] A Kumar R A Maurya S Sharma M Kumar and G BhatialdquoSynthesis and biological evaluation of N-aryl-14-dihydro-pyridines as novel antidyslipidemic and antioxidant agentsrdquoEuropean Journal of Medicinal Chemistry vol 45 no 2 pp 501ndash509 2010
[66] R S Kumar A Idhayadhulla A J Abdul Nasser and J SelvinldquoSynthesis and anticoagulant activity of a new series of 14-dihydropyridine derivativesrdquo European Journal of MedicinalChemistry vol 46 no 2 pp 804ndash810 2011
[67] H A Stefani C B Oliveira R B Almeida et al ldquoDihydro-pyrimidin-(2H)-ones obtained by ultrasound irradiation anew class of potential antioxidant agentsrdquo European Journal ofMedicinal Chemistry vol 41 no 4 pp 513ndash518 2006
[68] H Sun C Shang L Jin and J Zhang ldquoSynthesis and antiox-idant activity of a series of novel 3-chalcone-substituted 14-dihydropyridine derivativesrdquoHeterocyclic Communications vol18 no 5-6 pp 239ndash243 2012
[69] D B Tikhonov and B S Zhorov ldquoStructural model for dihy-dropyridine binding to L-type calcium channelsrdquo The Journalof Biological Chemistry vol 284 no 28 pp 19006ndash19017 2009
[70] G Y Dubur and Y R Uldrikis ldquoThe oxidation of 14-dihydro-pyridinesrdquo Chemistry of Heterocyclic Compounds vol 6 no 1pp 80ndash84 1970 Translated from Khimiya GeterotsiklicheskikhSoedinenii no 1 pp 83ndash88 1970 (Russian)
[71] G Ya Duburs A O Kumerova and Ya R Uldrikis ldquoEnzymicoxidation of hydrogenated pyridines with peroxidase-hydrogenperoxide systemrdquoLatvijas PSRZAVestis vol 73 no 7 pp 73ndash771970 (Russian) Chemical Abstracts vol 73 Article ID 94913g1970
[72] K Xie Y-C Liu Y Cui J-GWang Y Fu andT CWMak ldquoN-methyl-(R)-3-(tert-butyl)-sulfinyl-14-dihydropyridine a novelNADHmodel compoundrdquoMolecules vol 12 no 3 pp 415ndash4222007
[73] S Tamagaki T Mimura and W Tagaki ldquoMetal-ion-facilitatedoxidations of dihydropyridines with molecular oxygen andhydrogen peroxiderdquo Journal of the Chemical Society PerkinTransactions 2 no 10 pp 1645ndash1650 1990
[74] D Tirzite G Tirzitis andD Antipova ldquoReductive ability of 14-dihydropyridine derivatives in relation to ions of trivalent ironrdquoChemistry of Heterocyclic Compounds vol 35 no 5 pp 592ndash594 1999
[76] J Ogle J Stradins and L Baumane ldquoFormation and decay offree cation-radicals in the course of electro-oxidation of 12- and14-dihydropyridines (Hantzsch esters)rdquo Electrochimica Actavol 39 no 1 pp 73ndash79 1994
[77] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for the
synthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts C Wittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Berlin Germany 2010
[78] WDu and Zh Yu ldquoBiomimetic in situ regeneration of cofactorsNAD(P)+ and NAD(P)H models hantzsch esters and dihy-drophenanthridinerdquo Synlett vol 23 no 9 pp 1300ndash1304 2012
[79] H K Chenault and G M Whitesides ldquoRegeneration ofnicotinamide cofactors for use in organic synthesisrdquo AppliedBiochemistry and Biotechnology vol 14 no 2 pp 147ndash197 1987
[80] Y R Uldrikis A A Zidermane E A Biseniex I E Preisa GY Dubur and G D Tirzit ldquoEsters of 26-dimethyl-14-dihydro-pyridine-35-dicarboxylic acid and method of obtainingthereofrdquo WO 8000345 A1 1978 httpworldwideespacenetcompublicationDetailsbiblioDB=EPODOCampII=1ampND=3ampadjacent=trueamplocale=en EPampFT=Dampdate=19800306ampCC=WOampNR=8000345A1ampKC=A1
[81] Y Sambongi H Nitta K Ichihashi M Futai and I Ueda ldquoAnovel water-soluble Hantzsch 14-dihydropyridine compoundthat functions in biological processes through NADH regener-ationrdquo Journal of Organic Chemistry vol 67 no 10 pp 3499ndash3501 2002
[82] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for thesynthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts ChWittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Verlag Berlin Germany 2010
[83] T Okamura T Kikuchi A Nagamine et al ldquoAn approach formeasuring in vivo cerebral redox states using the oxidative con-version of dihydropyridine to pyridinium ion and themetabolictrapping principlerdquo Free Radical Biology and Medicine vol 38no 9 pp 1197ndash1205 2005
[84] K A Schellenberg and F H Westheimer ldquoA free-radicaloxidation of a dihydropyridine1ardquo The Journal of OrganicChemistry vol 30 no 6 pp 1859ndash1862 1965
[85] K A Schellenberg ldquoReaction of hydroxyl radical with thymi-dine Scavenging by a dihydropyridinerdquo Federation Proceedingsvol 38 no 3 I p 1433 1979
[86] E S Huyser J A K Harmony and F L McMillian ldquoPeroxideoxidations of dihydropyridine derivativesrdquo Journal of the Amer-ican Chemical Society vol 94 no 9 pp 3176ndash3180 1972
[87] A Sakamoto S T Ohnishi and R Ogawa ldquoInhibition of lipidperoxidation by some dihydropyridine derivativesrdquo Journal ofAnesthesia vol 7 no 2 pp 193ndash197 1993
[88] R Hardeland ldquoReview Neuroprotection by radical avoidancesearch for suitable agentsrdquo Molecules vol 14 no 12 pp 5054ndash5102 2009
[89] G Ya Dubur A Kh Velena V M Gukasov and Yu AVladimirov ldquoRegulation of peroxidation of mitochondrialmembrane lipids initiated by Fe2+ ions by antoxidants of the14-dihydropyridine series in experiments in vitrordquo Biomed-itsinskaya Khimiya vol 22 no 5 pp 665ndash673 1976 (Russian)Chemical Abstracts vol 88 Article ID 2640 1977
[90] G RMMHaenenM J T J Arts A Bast andMD ColemanldquoStructure and activity in assessing antioxidant activity in vitroand in vivo a critical appraisal illustrated with the flavonoidsrdquoEnvironmental Toxicology and Pharmacology vol 21 no 2 pp191ndash198 2006
[91] G Tirzitis and G Bartosz ldquoDetermination of antiradical andantioxidant activity basic principles and new insightsrdquo ActaBiochimica Polonica vol 57 no 2 pp 139ndash142 2010
30 Oxidative Medicine and Cellular Longevity
[92] G R Buettner and R P Mason ldquoSpin-trapping methods fordetecting superoxide and hydroxyl free radicals in vitro and invivordquo inCritical Reviews of Oxidative Stress and Aging Advancesin Basic Science Diagnostics and Intervention R G Cutler andH Rodriguez Eds vol 1 chapter 2 pp 27ndash38World ScientificLondon UK 2003
[93] M M Tarpey and I Fridovich ldquoMethods of detection ofvascular reactive species Nitric oxide superoxide hydrogenperoxide and peroxynitriterdquo Circulation Research vol 89 no3 pp 224ndash236 2001
[94] E Y Kazush E I Sagun G D Tirzit and G Y DaburldquoQuenching of singlet oxygen by electron donating derivativesof 14-dihydropyridinerdquo Chemistry of Heterocyclic Compoundsvol 30 no 5 pp 562ndash563 1994
[95] G Tirzitis E Kazush and G Duburs ldquoReaction of 14-dihydropyridine derivatives with peroxynitrite anionrdquo Chem-istry of Heterocyclic Compounds vol 34 no 3 pp 321ndash3231998 (Russian) Translated from Khimiya GeterotsiklicheskikhSoedinenii no 3 pp 355ndash357 1998
[96] L J Nunez-Vergara C Lopez-Alarcon P A Navarrete-EncinaA M Atria C Camargo and J A Squella ldquoElectrochemicaland EPR characterization of 14-dihydropyridines Reactivitytowards alkyl radicalsrdquo Free Radical Research vol 37 no 1 pp109ndash120 2003
[97] D Tirzite A Krauze A Zubareva G Tirzitis and G DubursldquoSynthesis and antiradical activity of 5-acetyl-2-alkylthio-4-aryl-6-methyl-14-dihydropyridine-3-carboxylic acid nitrilesrdquoChemistry of Heterocyclic Compounds vol 38 no 7 pp 795ndash800 2002
[98] H Ohkawa N Ohishi and K Yagi ldquoAssay for lipid peroxidesin animal tissues by thiobarbituric acid reactionrdquo AnalyticalBiochemistry vol 95 no 2 pp 351ndash358 1979
[99] N Zarkovic ldquo4-Hydroxynonenal as a bioactive marker ofpathophysiological processesrdquo Molecular Aspects of Medicinevol 24 no 4-5 pp 281ndash291 2003
[100] M Parola G Bellomo G Robino G Barrera and M UDianzani ldquo4-Hydroxynonenal as a biological signal molecularbasis and pathophysiological implicationsrdquo Antioxidants andRedox Signaling vol 1 no 3 pp 255ndash284 1999
[101] T Lovakovic M Poljak-Blazi G Duburs et al ldquoGrowthmodulation of human cells in vitro by mild oxidative stressand 14-dihydropyridine derivative antioxidantsrdquo CollegiumAntropologicum vol 35 no 1 pp 137ndash141 2011
[102] R van den Berg G R M M Haenen H van den Bergand A Bast ldquoApplicability of an improved Trolox equivalentantioxidant capacity (TEAC) assay for evaluation of antioxidantcapacity measurements of mixturesrdquo Food Chemistry vol 66no 4 pp 511ndash517 1999
[103] C Lopez-Alarcon P Navarrete C Camargo J A Squella andL J Nunez-Vergara ldquoReactivity of 14-dihydropyridines towardalkyl alkylperoxyl radicals and ABTS radical cationrdquo ChemicalResearch in Toxicology vol 16 no 2 pp 208ndash215 2003
[104] V Valenzuela P Santander C Camargo J A Squella C Lopez-Alarcon and L J Nunez-Vergara ldquo14-Dihydropyridines reac-tivity of nitrosoaryl and nitroaryl derivatives with alkylperoxylradicals andABTS radical cationrdquo Free Radical Research vol 38no 7 pp 715ndash727 2004
[105] L G Tsetlin N A Chebotareva B I Kurganov A K VelenaG Y Dubur and V Z Lankin ldquoStudy of 14-dihydropyridinesas lipoxygenase inhibitors with the use of hydrated reversedmicellesrdquo Pharmaceutical Chemistry Journal vol 22 no 6 pp425ndash428 1988 (Russian)
[106] J Panek Z Reblova L Kocirkova et al ldquoAntioxidant activityof dihydropyridine derivativesrdquo Czech Journal of Food Sciencesvol 18 pp 144ndash145 2000
[107] G Tirzitis I Kirule and G Duburs ldquoAntioxidationsaktivitatder 35-dicarbonylderivate des 26-demethyl-14-dihydropyri-dinsrdquo Fett Wissenschaft TechnologieFat Science Technology vol90 no 10 pp 411ndash413 1988
[108] M Plotniece G Tirzitis Y Uldrikis et al ldquoSynthesis of 14-dihydropyridine derivatives having an oxy- alkoxy- or dimeth-ylaminophenyl substituent in the 4 position their antioxidantactivity and their binding to phospholipid membranesrdquo Chem-istry of Heterocyclic Compounds vol 32 no 10 pp 1166ndash11721996 Translated from Khimiya Geterotsiklicheskikh Soedineniino 10(352) pp 1358ndash1365 1996 (Russian)
[109] D Y Rubene V S Sharov V I Olenev G D Tirzit G Y Duburand Y A Vladimirov ldquoUse of chemiluminescent method forthe evaluation of antioxidant activity of some derivatives of 14-dihydropyridinerdquo Russian Journal of Physical Chemistry A vol55 no 2 pp 511ndash512 1981 (Russian)
[110] M C R Symons and JM C Gutteridge Free Radicals and IronChemistry Biology and Medicine Oxford Science PublicationsOxford University Press Oxford UK 1998
[111] M Repetto J Semprine and A Boveris ldquoLipid peroxidationchemical mechanism biological implications and analyticaldeterminationrdquo in Lipid Peroxidation A Catala Ed Section ILipid Peroxidation Chemical Mechanisms Antioxidants Bio-logical Implications of Biochemistry Genetics and MolecularBiology chapter 1 pp 3ndash30 InTech Rijeka Croatia 2012
[112] A Velena J Zilbers and G Duburs ldquoDerivatives of 14-dihydropyridines asmodulators of ascorbate-induced lipid per-oxidation and high-amplitude swelling ofmitochondria causedby ascorbate sodium linoleate and sodiumpyrophosphaterdquoCellBiochemistry and Function vol 17 no 4 pp 237ndash252 1999
[113] M V Bilenko L N Shelenkova G Y Dubur and A K VelenaldquoUse of antioxidants to prevent renal damage during acuteischemia and reperfusionrdquo Bulletin of Experimental Biology andMedicine vol 96 no 3 pp 1195ndash1198 1983 Translated fromByulletenrsquo Eksperimentalrsquonoi Biologii i Meditsiny vol 96 no 9pp 8ndash11 1983 (Russian)
[114] R Toniolo F Tubaro F Ursini and G Bontempelli ldquoAn elec-troanalytical investigation on the redox properties of calciumantagonist dihydropyridinesrdquo Electroanalysis vol 15 no 10 pp855ndash861 2003
[115] L Kourimska J Pokorny and G Tirzitis ldquoThe antioxidant aci-tivity of 26-dimethyl-35-diethoxycarbonyl-14-dihydropyri-dine in edible oilsrdquo Nahrung vol 37 no 1 pp 91ndash93 1993
[116] C Lopez-Alarcon H Speisky J A Squella C Olea-Azar CCamargo and L J Nunez-Vergara ldquoReactivity of 14-dihydro-pyridines toward SIN-1-derived peroxynitriterdquo PharmaceuticalResearch vol 21 no 10 pp 1750ndash1757 2004
[117] R A Olek W Ziolkowski J J Kaczor L Greci J Popinigisand J Antosiewicz ldquoAntioxidant activity of NADH and its ana-loguemdashan in vitro studyrdquo Journal of Biochemistry andMolecularBiology vol 37 no 4 pp 416ndash421 2004
[118] E Niki N Noguchi and N Gotoh ldquoInhibition of oxidativemodification of low density lipoprotein by antioxidantsrdquo Jour-nal of Nutritional Science andVitaminology vol 39 supplementpp S1ndashS8 1993
[119] N Rojstaczer and D J Triggle ldquoStructure-function relation-ships of calcium antagonists effect on oxidative modificationof low density lipoproteinrdquo Biochemical Pharmacology vol 51no 2 pp 141ndash150 1996
Oxidative Medicine and Cellular Longevity 31
[120] A Sevanian L Shen and FUrsini ldquoInhibition of LDLoxidationand oxidized LDL-induced cytotoxicity by dihydropyridinecalcium antagonistsrdquo Pharmaceutical Research vol 17 no 8 pp999ndash1006 2000
[121] A Negre-Salvayre and R Salvayre ldquoProtection by Ca2+ channelblockers (nifedipine diltiazem and verapamil) against the tox-icity of oxidized low density lipoprotein to cultured lymphoidcellsrdquo British Journal of Pharmacology vol 107 no 3 pp 738ndash744 1992
[122] A Negre-Salvayre G FitoussiM Troly and R Salvayre ldquoCom-parative cytoprotective effect of dihydropyridine calcium chan-nel blockers against the toxicity of oxidized low density lipopro-tein for cultured lymphoid cellsrdquo Biochemical Pharmacologyvol 44 no 12 pp 2379ndash2386 1992
[123] L Cominacini A F Pasini U Garbin et al ldquoAntioxidant activ-ity of different dihydropyridinesrdquo Biochemical and BiophysicalResearch Communications vol 302 no 4 pp 679ndash684 2003
[124] L Cominacini U Garbin A Fratta Pasini et al ldquoOxidized low-density lipoprotein increases the production of intracellularreactive oxygen species in endothelial cells inhibitory effect oflacidipinerdquo Journal of Hypertension vol 16 no 12 part 2 pp1913ndash1919 1998
[125] H M Lander ldquoAn essential role for free radicals and derivedspecies in signal transductionrdquo The FASEB Journal vol 11 no2 pp 118ndash124 1997
[126] M L L Martinez E Rizzi M M Castro et al ldquoLercanidipinedecreases vascular matrix metalloproteinase-2 activity andprotects against vascular dysfunction in diabetic ratsrdquo EuropeanJournal of Pharmacology vol 599 no 1ndash3 pp 110ndash116 2008
[127] P Lesnik C Dachet L Petit et al ldquoImpact of a combinationof a calcium antagonist and a 120573-blocker on cell- and copper-mediated oxidation of LDL and on the accumulation and effluxof cholesterol in human macrophages and murine J774 cellsrdquoArteriosclerosis Thrombosis and Vascular Biology vol 17 no 5pp 979ndash988 1997
[128] G Sobal E J Menzel and H Sinzinger ldquoCalcium antagonistsas inhibitors of in vitro low density lipoprotein oxidation andglycationrdquoBiochemical Pharmacology vol 61 no 3 pp 373ndash3792001
[129] E Lupo R Locher B Weisser and W Vetter ldquoIn vitro antiox-idant activity of calcium antagonists against LDL oxidationcompared with 120572-tocopherolrdquo Biochemical and BiophysicalResearch Communications vol 203 no 3 pp 1803ndash1808 1994
[130] J Zou Y Li H-Q Fan and J-G Wang ldquoEffects of dihydropy-ridine calcium channel blockers on oxidized low-density lipo-protein induced proliferation and oxidative stress of vascularsmooth muscle cellsrdquo BMC Research Notes vol 5 article 1682012
[131] C Napoli S Salomone T Godfraind et al ldquo14-Dihydro-pyridine calcium channel blockers inhibit plasma and LDL oxi-dation and formation of oxidation-specific epitopes in the arte-rial wall and prolong survival in stroke-prone spontaneouslyhypertensive ratsrdquo Stroke vol 30 no 9 pp 1907ndash1915 1999
[132] G Zernig I Graziadei T Moshammer C Zech N Reider andH Glossmann ldquoMitochondrial Ca2+ antagonist binding sitesare associated with an inner mitochondrial membrane anionchannelrdquo Molecular Pharmacology vol 38 no 3 pp 362ndash3691990
[133] F E Hunter Jr A Scott P E Hochstein et al ldquoStudies of themechanism of ascorbate-induced swelling and lysis of isolatedliver mitochondriardquo The Journal of Biological Chemistry vol239 pp 604ndash613 1964
[134] D R Janero B Burghardt and R Lopez ldquoProtection of cardiacmembrane phospholipid against oxidative injury by calciumantagonistsrdquoBiochemical Pharmacology vol 37 no 21 pp 4197ndash4203 1988
[135] A Karadag B Ozcelik and S S Saner ldquoReview of methods todetermine antioxidant capacitiesrdquo FoodAnalyticalMethods vol2 no 1 pp 41ndash60 2009
[136] Y I Gubskiı N V Litvinova and E V Shnurko-TabakovaldquoAntioxidant and antiradical activity of various classes of antiox-idantsrdquo Ukrainskiı Biokhimicheskiı Zhurnal vol 66 no 4 pp114ndash116 1994 (Russian)
[137] M Takei M Hiramatsu and A Mori ldquoInhibitory effects ofcalcium antagonists onmitochondrial swelling induced by lipidperoxidation or arachidonic acid in the rat brain in vitrordquoNeurochemical Research vol 19 no 9 pp 1199ndash1206 1994
[138] M Takei M Hiramatsu R Edamatsu and A Mori ldquoFreeradical scavenging by calcium antagonistsrdquo Neurosciences vol20 no 2 pp 75ndash82 1994
[139] Ya P Stradin G Ya Dubur Yu A Beilis Ya R Uldrikis andA F Korotkova ldquoVoltammetry of 14-dihydropyridine deriva-tives I Potentials of electrochemical oxidation of 35-diacyl-and 35-di(alkoxycarbonyl)-14-dihydropyridines in acetoni-trilerdquo Chemistry of Heterocyclic Compounds no 1 pp 84ndash871972 (Russian)
[140] E V Ivanov T V Ponomarjova G N Merkusev et al ldquoEinneuer Haut-Radioprotektor Diethon (experimentelle Unter-suchung)rdquo Radiobiologia Radiotherapia vol 31 no 1 pp 69ndash78 1990
[141] E V Ivanov T V Ponomareva G N Merkushev et al ldquoRadia-tion modulating properties of derivates of 14-dihydropyridineand 12345678910-decahydroacridine-18 dionerdquo Radiat-sionnaia Biologiia Radioecologiia vol 44 no 5 pp 550ndash5592004 (Russian)
[142] R O Vitolinia D A Berzinia A K Velena I A Vutsina A AKimenis and G Y Duburs ldquoThe protective effects of the cal-cium antagonist foridon in acute myocardial ischaemiardquo Kardi-ologiya vol 27 no 3 pp 90ndash93 1987 (Russian)
[143] A H Velena G Ya Duburs R O Vitolina et al ldquoEffect ofryodipine on electromechanical parameters of heart and vesselscAMP phosphodiesterase activity and swelling-contractioncycle of mitochondriardquo Arzneimittelforschung vol 35 no 6 pp907ndash914 1985
[144] L I Utno Z E Lipsberga A A Silova M I Girgensone EA Bisenieks and G I Ia ldquoCardioprotective properties of a 14-dihydropyridine derivative glutapyrone in deep hypothermiardquoBiulletenrsquo Eksperimentalrsquonoı Biologii i Meditsiny vol 108 no 11pp 558ndash561 1989 (Russian)
[145] M A S FernandesM S Santos J A F Vicente et al ldquoEffects of14-dihydropyridine derivatives (cerebrocrast gammapyroneglutapyrone and diethone) onmitochondrial bioenergetics andoxidative stress a comparative studyrdquoMitochondrion vol 3 no1 pp 47ndash59 2003
[146] M A S Fernandes M S Santos A J M Moreno et al ldquoEffectsof 5-acetyl(carbamoyl)-6-methylsulfanyl-14-dihydropyridine-5-carbonitriles on rat liver mitochondrial functionrdquo Toxicologyin Vitro vol 23 no 7 pp 1333ndash1341 2009
[147] L Klimaviciusa A Kalda A Kaasik et al ldquoNeuroprotectiveactivity of 14-dihydropyridine derivatives structure determi-nantsrdquo Proceedings of the Latvian Academy of Sciences BNatural Exact and Applied Sciences vol 61 no 1-2 pp 33ndash372007
32 Oxidative Medicine and Cellular Longevity
[148] L Klimaviciusa M A S Fernandes N Lencberga et alldquoTargeting the mitochondria by novel adamantane-containing14-dihydropyridine compoundsrdquo in Bioenergetics K B ClarkEd pp 257ndash272 InTech 2012
[149] V Klusa L Klimaviciusa G Duburs J Poikans and AZharkovsky ldquoAnti-neurotoxic effects of tauropyrone a taurineanaloguerdquo Advances in Experimental Medicine and Biology vol583 pp 499ndash508 2006
[150] N Sampson P Berger and Ch Zenzmaier ldquoRedox signalingas a therapeutic target to inhibit myofibroblast activation indegenerative fibrotic diseaserdquo BioMed Research Internationalvol 2014 Article ID 131737 14 pages 2014
[151] T L Leto and M Geiszt ldquoRole of Nox family NADPH oxidasesin host defenserdquoAntioxidantsampRedox Signaling vol 8 no 9-10pp 1549ndash1561 2006
[152] K K Griendling D Sorescu and M Ushio-Fukai ldquoNAD(P)Hoxidase role in cardiovascular biology and diseaserdquo CirculationResearch vol 86 no 5 pp 494ndash501 2000
[153] H Chen Y S Song and P H Chan ldquoInhibition of NADPHoxi-dase is neuroprotective after ischemia-reperfusionrdquo Journal ofCerebral Blood Flow and Metabolism vol 29 no 7 pp 1262ndash1272 2009
[154] P Hochstein and L Ernster ldquoADP-activated lipid peroxidationcoupled to the TPNH oxidase system of microsomesrdquo Biochem-ical and Biophysical Research Communications vol 12 no 5 pp388ndash394 1963
[155] I I Gubskiı AGGoriushkoNV Litvinova et al ldquoAntioxidantproperties and membranotropic effect of certain derivatives of14-dihydropyridinerdquo Ukrainskiı Biokhimicheskiı Zhurnal vol71 no 4 pp 35ndash39 1999 (Russian)
[156] F Engineer and R Sridhar ldquoInhibition of rat heart andliver microsomal lipid peroxidation by nifedipinerdquo BiochemicalPharmacology vol 38 no 8 pp 1279ndash1285 1989
[157] T Goncalves A P Carvalho and C R Oliveira ldquoAntioxidanteffect of calcium antagonists on microsomai membranes iso-lated from different brain areasrdquo European Journal of Pharma-cology vol 204 no 3 pp 315ndash322 1991
[158] M E Letelier P Izquierdo L Godoy A M Lepe and MFaundez ldquoLiver microsomal biotransformation of nitro-aryldrugs mechanism for potential oxidative stress inductionrdquoJournal of Applied Toxicology vol 24 no 6 pp 519ndash525 2004
[159] M E Letelier P Entrala C Lopez-Alarcon et al ldquoNitroaryl-14-dihydropyridines as antioxidants against rat liver microsomesoxidation induced by ironascorbate Nitrofurantoin and naph-thalenerdquo Toxicology in Vitro vol 21 no 8 pp 1610ndash1618 2007
[160] F P Guengerich W R Brian M Iwasaki M-A Sari CBaarnhielm and P Berntsson ldquoOxidation of dihydropyridinecalcium channel blockers and analogues by human liver cyto-chrome P-450 IIIA4rdquo Journal of Medicinal Chemistry vol 34no 6 pp 1838ndash1844 1991
[161] S H Park S-W RhaW-Y Shin et al ldquoAS-160 Calcium channelblockers of dihydropyridine class reduce the antiplatelet effectof Clopidogrel what is clinical impactrdquo The American Journalof Cardiology vol 107 no 8 supplement p 47A 2011
[162] C Asma and D M Reda ldquoEvaluation of dihydropyridinecalcium antagonist effects on the stress bioindicator orga-nism Saccharomyces cerevisiaerdquo Annals of Biological Researchvol 4 no 10 pp 40ndash46 2013 httpscholarsresearchlibrarycomABR-vol4-iss10ABR-2013-4-10-40-46pdf
[163] G Gaviraghi A M Pastorino E Ratti and D G TristldquoCalcium channel blockers with antioxidant activityrdquo in Free
Radicals Lipoprotein Oxidation andAtherosclerosis G BellomoG Finardi E Maggi and E Rice-Evans Eds pp 431ndash456Richelieu Press London UK 1995
[164] G Gaviraghi AM Pastorino E Ratti and D G Trist ldquoAntiox-idant dihydropyridines a new and comprehensive therapy forfree radical-induced cardiovascular diseasesrdquo in Free Radicalsin Biology and Environment F Minisci Ed vol 27 of NATOASI Series pp 193ndash221 Springer Dordrecht The Netherlands1997
[165] P D Henry ldquoAntiperoxidative actions of calcium antagonistsand atherogenesisrdquo Journal of Cardiovascular Pharmacologyvol 18 supplement 1 pp S6ndashS10 1991
[166] F Kouoh B Gressier T Dine et al ldquoAntioxidant effects andanti-elastase activity of the calcium antagonist nicardipine onactivated human and rabbit neutrophilsmdasha potential antiath-erosclerotic property of calcium antagonistsrdquo CardiovascularDrugs andTherapy vol 16 no 6 pp 515ndash520 2002
[167] S Parthasarathy D Litvinov K Selvarajan and M GarelnabildquoLipid peroxidation and decompositionmdashconflicting roles inplaque vulnerability and stabilityrdquo Biochimica et BiophysicaActa vol 1781 no 5 pp 221ndash231 2008
[168] D-Q Liu Z-Q Pang D-H Zhao and B-H Sheng ldquoEffects offuryl-dihydropyridines I on lipid peroxides of ischemic myo-cardium and ATPases activity of erythrocyte membranes inratsrdquo Acta Pharmacologica Sinica vol 12 no 3 pp 253ndash2561991
[169] V Lukic-Panin T Kamiya H Zhang et al ldquoPrevention of neu-ronal damage by calcium channel blockers with antioxidativeeffects after transient focal ischemia in ratsrdquo Brain Research vol1176 no 1 pp 143ndash150 2007
[170] Y Allanore D Borderie H Lemarechal O G Ekindjian andA Kahan ldquoAcute and sustained effects of dihydropyridine-typecalcium channel antagonists on oxidative stress in systemicsclerosisrdquo American Journal of Medicine vol 116 no 9 pp 595ndash600 2004
[171] I Casetta V Govoni and E Granieri ldquoOxidative stress antioxi-dants and neurodegenerative diseasesrdquo Current PharmaceuticalDesign vol 11 no 16 pp 2033ndash2052 2005
[172] M J T J Arts Assessing antioxidant activity [PhD the-sis] Maastricht University Maastricht The Netherlands 2007httparnounimaasnlshowcgifid=8676
[173] G Dıaz-Araya L Godoy L Naranjo A Squella M E Letelierand L J Nunez-Vergara ldquoAntioxidant effects of 14-dihydro-pyridine and nitroso aryl derivatives on the Fe+3ascorbate-stimulated lipid peroxidation in rat brain slicesrdquo General Phar-macology The Vascular System vol 31 no 3 pp 385ndash391 1998
[174] Y Fukuhara K Tsuchiya Y Horinouchi et al ldquoProtectiveeffect of photodegradation product of nifedipine against tumornecrosis factor 120572-induced oxidative stress in human glomerularendothelial cellsrdquo Journal of Medical Investigation vol 58 no1-2 pp 118ndash126 2011
[175] W Stengel M Jainz and K Andreas ldquoDifferent potencies ofdihydropyridine derivatives in blocking T-type but not L-typeCa2+ channels in neuroblastoma-glioma hybrid cellsrdquo EuropeanJournal of Pharmacology vol 342 no 2-3 pp 339ndash345 1998
[176] O M Panasenko D J Tirzite G D Tirzitis and G J DubursldquoEffect of some 14-dihydropyridine derivatives on structuralorganization of erythrocyte membranesrdquo Biologicheskie Mem-brany (Biochemistry (Moscow) Series A Membrane and CellBiology) vol 1 pp 919ndash925 1984 (Russian)
[177] L G Herbette Y M H Vant Erve and D G Rhodes ldquoInter-action of 14 dihydropyridine calcium channel antagonists with
Oxidative Medicine and Cellular Longevity 33
biological membranes lipid bilayer partitioning could occurbefore drug binding to receptorsrdquo Journal of Molecular andCellular Cardiology vol 21 no 2 pp 187ndash201 1989
[178] L G Herbette P E Mason G Gaviraghi T N Tulenko andR P Mason ldquoThe molecular basis for lacidipinersquos unique phar-macokinetics optimal hydrophobicity results in membraneinteractions that may facilitate the treatment of atherosclerosisrdquoJournal of Cardiovascular Pharmacology vol 23 supplement 5pp S16ndashS25 1994
[179] G V Belevitch G Y Dubur G E Dobretsov N K Kurek andM M Spirin ldquoCalcium antagonists riodipine nifedipine andverapamil binding to model and biological membranes fluore-scence analysisrdquo Biologicheskie Membrany (Biochemistry(Moscow) Series A Membrane and Cell Biology) vol 5 pp768ndash776 1988 (Russian)
[180] R P Mason G E Gonye D W Chester and L G HerbetteldquoPartitioning and location of Bay K 8644 14-dihydropyridinecalcium channel agonist in model and biological membranesrdquoBiophysical Journal vol 55 no 4 pp 769ndash778 1989
[181] M Cindric A Cipak J Serly et al ldquoReversal of multidrugresistance inmurine lymphoma cells by amphiphilic dihydropy-ridine antioxidant derivativerdquo Anticancer Research vol 30 no10 pp 4063ndash4070 2010
[182] F Shekari H Sadeghpour K Javidnia et al ldquoCytotoxic andmultidrug resistance reversal activities of novel 14-dihydro-pyridines against human cancer cellsrdquo European Journal ofPharmacology vol 746 no 1 pp 233ndash244 2015
[183] X-F Zhou Q Shao R A Coburn and M E Morris ldquoQuanti-tative structure-activity relationship and quantitative structure-pharmacokinetics relationship of 14-dihydropyridines andpyridines as multidrug resistance modulatorsrdquo PharmaceuticalResearch vol 22 no 12 pp 1989ndash1996 2005
[184] R Berkels T Breitenbach H Bartels et al ldquoDifferent antioxida-tive potencies of dihydropyridine calcium channel modulatorsin various modelsrdquo Vascular Pharmacology vol 42 no 4 pp145ndash152 2005
[185] S Borovic G Tirzitis D Tirzite et al ldquoBioactive 14-dihydro-isonicotinic acid derivatives prevent oxidative damage of livercellsrdquo European Journal of Pharmacology vol 537 no 1ndash3 pp12ndash19 2006
[186] D Ya Rubene G D Tirzitis and G Ya Duburs ldquoInteractionof some 14-dihydropyridine derivatives with Fentonrsquos reagentrdquoLatvijas PSRZinatnuAkademijas Vestis Kimijas Serija Proceed-ings of the Latvian SSR Academy of Sciences Chemistry Seriespp 212ndash216 1982 (Russian)
[187] K Ondrias V Misık D Gergel and A Stasko ldquoLipid per-oxidation of phosphatidylcholine liposomes depressed by thecalcium channel blockers nifedipine and verapamil and bythe antiarrhythmic-antihypoxic drug stobadinerdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1003 no 3pp 238ndash245 1989
[188] I T Mak and W B Weglicki ldquoComparative antioxidant acti-vities of propranolol nifedipine verapamil and diltiazemagainst sarcolemmal membrane lipid peroxidationrdquoCirculationResearch vol 66 no 5 pp 1449ndash1452 1990
[189] I T Mak P Boehme and W B Weglicki ldquoProtective effects ofcalcium channel blockers against free radical-impaired endo-thelial cell proliferationrdquo Biochemical Pharmacology vol 50 no9 pp 1531ndash1534 1995
[190] S Ray S Mondal and N Dana ldquoEvaluation of protective roleof nifedipine on lipid peroxidation using reduced glutathione as
model markerrdquo Oxidants and Antioxidants in Medical Sciencevol 1 no 2 pp 97ndash100 2012
[191] M Yamato T Shiba T Ide Y Honda K-I Yamada andH Tsutsui ldquoNifedipine treatment reduces brain damage aftertransient focal ischemia possibly through its antioxidativeeffectsrdquoHypertension Research vol 34 no 7 pp 840ndash845 2011
[192] V Chander and K Chopra ldquoNifedipine attenuates changes innitric oxide levels renal oxidative stress and nephrotoxicityinduced by cyclosporinerdquo Renal Failure vol 27 no 4 pp 441ndash450 2005
[193] K M Gaafa M M Badawy and A A Hamza ldquoThe protectiveeffects of ascorbic acid cimetidine and nifedipine on diethyl-dithiocarbamate-induced hepatic toxicity in albino ratsrdquo Drugand Chemical Toxicology vol 34 no 4 pp 405ndash419 2011
[194] H Sugawara K Tobise and S Onodera ldquoAbsence of antiox-idant effects of nifedipine and diltiazem on myocardial mem-brane lipid peroxidation in contrast with those of nisoldipineand propranololrdquo Biochemical Pharmacology vol 47 no 5 pp887ndash892 1994
[195] I E Kirule D Y Rubene E A Bisenieks G D Tirzit and GY Dubur ldquo4-Nitrophenyl-14-dihydropyridinesmdasha new groupof inhibitors of peroxide oxidationrdquo Chemistry of HeterocyclicCompounds vol 18 no 3 p 316 1982
[196] G D Tirzit I E Kirule L K Baumane R A Gavar Y PStradynrsquo andG YDubur ldquoMechanism of the antioxidant actionof 26-dimethyl-35-dimethoxy-carbonyl-4-(2-nitrophenyl)14-dihydropyridinerdquoChemistry ofHeterocyclic Compounds vol 20no 8 pp 915ndash918 1984
[197] C Yanez C Lopez-Alarcon C Camargo V Valenzuela J ASquella and L J Nunez-Vergara ldquoStructural effects on thereactivity 14-dihydropyridines with alkylperoxyl radicals andABTS radical cationrdquo Bioorganic and Medicinal Chemistry vol12 no 9 pp 2459ndash2468 2004
[198] VMisik A J Stasko D Gergel and K Ondrias ldquoSpin-trappingand antioxidant properties of illuminated and nonilluminatednifedipine and nimodipine in heart homogenate and modelsystemrdquo Molecular Pharmacology vol 40 no 3 pp 435ndash4391991
[199] K Ondrias V Misık A Stasko D Gergelrsquo and M HromadovaldquoComparison of antioxidant properties of nifedipine and illu-minated nifedipine with nitroso spin traps in low densitylipoproteins and phosphatidylcholine liposomesrdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1211 no 1pp 114ndash119 1994
[200] A Stasko V Brezova S Biskupic K Ondrias and V MisıkldquoReactive radical intermediates formed from illuminated nife-dipinerdquoFree Radical Biology andMedicine vol 17 no 6 pp 545ndash556 1994
[201] K Ishizawa Y Izawa-Ishizawa N Yamano et al ldquoNitrosoni-fedipine ameliorates the progression of type 2 diabetic nephro-pathy by exerting antioxidative effectsrdquo PLoS ONE vol 9 no 1Article ID e86335 2014
[202] H Fujii and L J Berliner ldquoIn vivo EPR evidence for free radicaladducts of nifedipinerdquoMagnetic Resonance in Medicine vol 42no 4 pp 691ndash694 1999
[203] S Bollo S Finger J C Sturm L J Nunez-Vergara and JA Squella ldquoCyclic voltammetry and scanning electrochemicalmicroscopy studies of the heterogeneous electron transferreaction of some nitrosoaromatic compoundsrdquo ElectrochimicaActa vol 52 no 15 pp 4892ndash4898 2007
34 Oxidative Medicine and Cellular Longevity
[204] F Ursini ldquoTissue protection by lacidipine insight from redoxbehaviorrdquo Journal of Cardiovascular Pharmacology vol 30supplement 2 pp S28ndashS30 1997
[205] P G Cristofori F A Crivellente I Faustinelli et al ldquoInvolve-ment of the nitric oxide system in the anti-atheroscleroticpotential of lacidipine in the apoE-deficient mouse a mor-phological functional and electrochemical studyrdquo ToxicologicPathology vol 32 no 4 pp 493ndash499 2004
[206] X-P Zhang E L Kit S Mital S Chahwala and T HHintze ldquoParadoxical release of nitric oxide by an L-type calciumchannel antagonist the R+ enantiomer of amlodipinerdquo Journalof Cardiovascular Pharmacology vol 39 no 2 pp 208ndash2142002
[207] F Franzoni G Santoro F Regoli et al ldquoAn in vitro study of theperoxyl and hydroxyl radical scavenging capacity of the calciumantagonist amlodipinerdquo Biomedicine and Pharmacotherapy vol58 no 8 pp 423ndash426 2004
[208] S V Gatsura ldquoOxygen-dependent mechanisms underlying theantiischemic effect of verapamil and amlodipinerdquo Bulletin ofExperimental Biology and Medicine vol 137 no 1 pp 40ndash422004
[209] Y Hirooka Y Kimura M Nozoe Y Sagara K Ito and KSunagawa ldquoAmlodipine-induced reduction of oxidative stressin the brain is associated with sympatho-inhibitory effects instroke-prone spontaneously hypertensive ratsrdquo HypertensionResearch vol 29 no 1 pp 49ndash56 2006
[210] B Tomlinson and I F F Benzie ldquoAntioxidant effect of lercani-dipine (note)rdquo Hypertension vol 42 no 4 pp e10ndashe11 2003
[211] A A Faraqui ldquoNeurochemical aspects of 4-hydroxynonenalrdquoin Lipid Mediators and Their Metabolism in the Brain A AFaraqui Ed chapter 6 pp 159ndash191 Springer New York NYUSA 2011
[212] V S NascimentoM S DrsquoAlva A AOliveira et al ldquoAntioxidanteffect of nimodipine in young rats after pilocarpine-inducedseizuresrdquo Pharmacology Biochemistry and Behavior vol 82 no1 pp 11ndash16 2005
[213] O Ismailoglu P Atilla S Palaoglu et al ldquoThe therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjuryrdquo Turkish Neurosurgery vol 22 no 6 pp 740ndash746 2012
[214] M Matsubara and K Hasegawa ldquoBenidipine a dihydropy-ridine-calcium channel blocker prevents lysophosphatidyl-choline-induced injury and reactive oxygen species productionin human aortic endothelial cellsrdquo Atherosclerosis vol 178 no1 pp 57ndash66 2005
[215] M Matsubara K Yao and K Hasegawa ldquoBenidipine adihydropyridine-calcium channel blocker inhibits lysophos-phatidylcholine-induced endothelial injury via stimulation ofnitric oxide releaserdquo Pharmacological Research vol 53 no 1 pp35ndash43 2006
[216] MMatsubara and K Hasegawa ldquoEffects of benidipine a dihyd-ropyridine-Ca2+ channel blocker on expression of cytokine-induced adhesion molecules and chemoattractants in humanaortic endothelial cellsrdquo European Journal of Pharmacology vol498 no 1ndash3 pp 303ndash314 2004
[217] M Matsubara O Akizuki J-I Ikeda K Saeki K Yao and KSasaki ldquoBenidipine an anti-hypertensive drug inhibits reactiveoxygen species production in polymorphonuclear leukocytesand oxidative stress in salt-loaded stroke-prone spontaneouslyhypertensive ratsrdquo European Journal of Pharmacology vol 580no 1-2 pp 201ndash213 2008
[218] A C Rosenkranz H Lob T Breitenbach R Berkels and RRoesen ldquoEndothelial antioxidant actions of dihydropyridines
and angiotensin converting enzyme inhibitorsrdquo European Jour-nal of Pharmacology vol 529 no 1ndash3 pp 55ndash62 2006
[219] V Kain S Kumar and S L Sitasawad ldquoAzelnidipine preventscardiac dysfunction in streptozotocin-diabetic rats by reducingintracellular calcium accumulation oxidative stress and apop-tosisrdquo Cardiovascular Diabetology vol 10 article 97 2011
[220] K Nakamura S Yamagishi and H Inoue ldquoUnique atheropro-tective property of azelnidipine a dihydropyridine-based cal-cium antagonistrdquoMedical Hypotheses vol 65 no 1 pp 155ndash1572005
[221] TMatsui S Yamagishi K Nakamura S Kikuchi andH InoueldquoAzelnidipine a dihydropyridine-based calcium antagonistinhibits angiotensin II-induced oxidative stress generation anddownregulation of pigment epithelium-derived factor mRNAlevels in microvascular endothelial cellsrdquo Drugs under Experi-mental and Clinical Research vol 31 no 5-6 pp 215ndash219 2005
[222] C Ohmura H Watada T Shimizu et al ldquoCalcium channelblocker azelnidipine reduces lipid hydroperoxides in patientswith type 2 diabetes independent of blood pressurerdquo EndocrineJournal vol 54 no 5 pp 805ndash811 2007
[223] H Daikuhara F Kikuchi and T Ishida ldquoThe combination ofOLmesartan and a CAlcium channel blocker (azelnidipine) orcandesartan and a calcium channel blocker (amlodipine) intype 2 diabetic hypertensive patients theOLCA studyrdquoDiabetesand Vascular Disease Research vol 9 no 4 pp 280ndash286 2012
[224] MAbe NMaruyama KOkada SMatsumoto KMatsumotoand M Soma ldquoAdditive antioxidative effects of azelnidipine onangiotensin receptor blocker olmesartan treatment for type 2diabetic patients with albuminuriardquoHypertension Research vol34 no 8 pp 935ndash941 2011
[225] K Mizushige ldquoAntioxidative activities of thiazolidinedionesand dihydropyridine-type calcium antagonistsrdquo IRYOmdashJapa-nese Journal of National Medical Services vol 59 no 11 pp 581ndash592 2005
[226] S Manabe T Okura T Fukuoka and J Higaki ldquoAntioxidativeeffects of azelnidipine on mesangial cell proliferation inducedby highly concentrated insulinrdquo European Journal of Pharma-cology vol 567 no 3 pp 252ndash257 2007
[227] Y Koyama Y Takeishi H Takahashi et al ldquoAzelnidipine inhi-bits H
2O2-induced cell death in neonatal rat cardiomyocytesrdquo
CardiovascularDrugs andTherapy vol 21 no 1 pp 69ndash72 2007[228] K Shinomiya K Mizushige M Fukunaga et al ldquoAntioxidant
effect of a new calcium antagonist azelnipidine in culturedhuman arterial endothelial cellsrdquo Journal of International Med-ical Research vol 32 no 2 pp 170ndash175 2004
[229] T Ohyama K Sato K Kishimoto et al ldquoAzelnidipine is acalcium blocker that attenuates liver fibrosis and may increaseantioxidant defencerdquo British Journal of Pharmacology vol 165no 4 pp 1173ndash1187 2012
[230] L A Calo F Zaghetto E Pagnin P A Davis A Sempliciniand A C Pessina ldquoEffect of manidipine on gene expressionand protein level of oxidative stress-related proteins p22phoxand HO-1 Relevance for antihypertensive and anti-remodelingeffectsrdquo Journal of Cardiovascular Pharmacology vol 43 no 4pp 531ndash538 2004
[231] R Ghyasi G Sepehri M Mohammadi R Badalzadeh and AGhyasi ldquoEffect of mebudipine on oxidative stress and lipid per-oxidation in myocardial ischemic-reperfusion injury in maleratrdquo Journal of Research in Medical Sciences vol 17 no 12 pp1150ndash1155 2012
Oxidative Medicine and Cellular Longevity 35
[232] DCAndersson J Fauconnier T Yamada et al ldquoMitochondrialproduction of reactive oxygen species contributes to the 120573-adrenergic stimulation of mouse cardiomycytesrdquoThe Journal ofPhysiology vol 589 no 7 pp 1791ndash1801 2011
[233] A F Ceylan-Isik N Ari M Stefek et al ldquoEffects of a long-term treatment with an antioxidant pyridoindole on vascularresponsiveness in diabetes-induced aging ratsrdquo Current AgingScience vol 4 no 2 pp 150ndash157 2011
[234] S Saponara G Sgaragli and F Fusi ldquoQuercetin antagonismof Bay K 8644 effects on rat tail artery L-type Ca2+ channelsrdquoEuropean Journal of Pharmacology vol 598 no 1ndash3 pp 75ndash802008
[235] D A Sica ldquoInteraction of grapefruit juice and calcium channelblockersrdquo American Journal of Hypertension vol 19 no 7 pp768ndash773 2006
[236] P Mulder G Litwinienko S Lin P D MacLean L R CBarclay and K U Ingold ldquoThe L-type calcium channel block-ers Hantzsch 14-dihydropyridines are not peroxyl radical-trapping chain-breaking antioxidantsrdquo Chemical Research inToxicology vol 19 no 1 pp 79ndash85 2006
[237] L J Nunez-Vergara R Salazar C Camargo et al ldquoOxidation ofC4-hydroxyphenyl 14-dihydropyridines in dimethylsulfoxideand its reactivity towards alkylperoxyl radicals in aqueousmediumrdquo Bioorganic and Medicinal Chemistry vol 15 no 12pp 4318ndash4326 2007
[238] M E Ortiz L J Nunez-Vergara and J A Squella ldquoRelativereactivity of dihydropyridine derivatives to electrogeneratedsuperoxide ion in DMSO solutions a voltammetric approachrdquoPharmaceutical Research vol 20 no 2 pp 292ndash296 2003
[239] M E Ortiz L J Nunez-Vergara C Camargo and J A SquellaldquoOxidation of Hantzsch 14-dihydropyridines of pharmacolog-ical significance by electrogenerated superoxiderdquo Pharmaceuti-cal Research vol 21 no 3 pp 428ndash435 2004
[240] R S Raghuvanshi and K N Singh ldquoSuperoxide induced oxida-tive aromatization of Hantzsch 14-dihydropyridinesrdquo IndianJournal of Chemistry Section B Organic and Medicinal Chem-istry vol 47 no 11 pp 1735ndash1738 2008
[241] I Kruk A Kladna K Lichszteld et al ldquoAntioxidant activityof 4-flavonil-14-dihydropyridine derivativesrdquo Biopolymers vol62 no 3 pp 163ndash167 2001
[242] G D Tirzit I M Byteva K I Salokhiddinov G P Gurinovichand G Y Dubur ldquo14-Dihydropyridine derivatives as deactiva-tors of singlet oxygenrdquo Chemistry of Heterocyclic Compoundsvol 17 no 7 pp 682ndash684 1981
[243] G D Tirzit E Y Kazush and G Y Dubur ldquoInfluence of14-dihydropyridine derivatives on the generation of hydroxylradicalsrdquo Chemistry of Heterocyclic Compounds vol 28 no 4pp 435ndash437 1992
[244] N A Pizarro-Urzua and L J Nunez-Vergara ldquoNifedipine andnitrendipine reactivity toward singlet oxygenrdquo Journal of Photo-chemistry and Photobiology A Chemistry vol 175 no 2-3 pp129ndash137 2005
[245] L-F Wang H-Y Zhang L Konga Z-W Chena and J-G ShildquoDFT calculations indicate that 14-dihydropyridine is a promis-ing lead antioxidantrdquo Helvetica Chimica Acta vol 87 no 6 pp1515ndash1521 2004
[246] P Mulder H-G Korth and K U Ingold ldquoWhy quantum-thermochemical calculations must be used with caution toindicate lsquoa promising lead antioxidantrsquordquoHelvetica Chimica Actavol 88 no 2 pp 370ndash374 2005
[247] K Yao Y Ina K Nagashima K Ohmori and T Ohno ldquoAntiox-idant effects of calcium antagonists in rat brain homogenatesrdquo
Biological and Pharmaceutical Bulletin vol 23 no 6 pp 766ndash769 2000
[248] T Matsui S-I Yamagishi K Nakamura and H Inoue ldquoBayw 9798 a dihydropyridine structurally related to nifedipinewith no calcium channel-blocking properties inhibits tumournecrosis factor-120572-induced vascular cell adhesion molecule-1expression in endothelial cells by suppressing reactive oxygenspecies generationrdquo Journal of International Medical Researchvol 35 no 6 pp 886ndash891 2007
[249] K AMitrega B VargheseM Porc and T F Krzeminski ldquoAnti-arrhythmic and hemodynamic effects of oxy nifedipine oxynimodipine oxy nitrendipine and oxy nisoldipinerdquo Pharmaco-logical Research vol 66 no 4 pp 300ndash308 2012
[250] V Herbert ldquoSymposium prooxidant effects of antioxidantvitamins Introductionrdquo The Journal of Nutrition vol 126 no4 supplement pp 1197Sndash1200S 1996 httpjnnutritionorgcontent1264 Suppl1197Sfullpdf
[251] B Halliwell ldquoAre polyphenols antioxidants or pro-oxidantsWhat do we learn from cell culture and in vivo studiesrdquoArchives of Biochemistry and Biophysics vol 476 no 2 pp 107ndash112 2008
[252] C Winterbourn Pro-Oxidants or Antioxidants ChristchurchSchool of Medicine Depatment of Pathology Free RadicalSchool SFRBMUniversity of Otago San Francisco Calif USA2009 httpwwwsfrbmorgfrsWinterbournpdf
[253] A Morakinyo B Iranloye and O Adegoke ldquoCalcium antag-onists modulate oxidative stress and acrosomal reaction in ratspermatozoardquo Archives of Medical Science vol 7 no 4 pp 613ndash618 2011
[254] The Alpha-Tocopherol Beta Carotene Cancer Prevention StudyGroup ldquoThe effect of vitamin E and beta carotene on theincidence of lung cancer and other cancers in male smokersrdquoTheNew England Journal of Medicine vol 330 no 15 pp 1029ndash1035 1994
[255] B Poljsak ldquoStrategies for reducing or preventing the generationof oxidative stressrdquo Oxidative Medicine and Cellular Longevityvol 2011 Article ID 194586 15 pages 2011
[256] B Poljsak and I Milisav ldquoThe neglected significance of lsquoanti-oxidative stressrsquordquoOxidativeMedicine and Cellular Longevity vol2012 Article ID 480895 12 pages 2012
[257] T Godfraind and S Salomone ldquoAmbiguities in dietary antiox-idant supplementation compared to calcium channel blockerstherapyrdquo Frontiers in Pharmacology vol 6 article 10 2015
[258] H Wagner H Norr and H Winterhoff ldquoDrugs with adap-togenic effects for strengthening the powers of resistancerdquoZeitschrift fur Phytotherapie vol 13 no 2 pp 42ndash54 1992
18 Oxidative Medicine and Cellular Longevity
NH
COOH
NH
COONa
Glutapyrone
NH
Gammapyrone
NH
C 2H5OOC COOC2H5
Tauropyrone
14-DHINA
H3C H3C
H3C
H3CCH3 CH3
CH3
CH3
COOC2H5COOC2H5
COOC2H5 C2H5OOCC2H5OOCC2H5OOC
CONHCH(CH2)2COONa CONH(CH2)3COONa
CONH(CH2)2SO3Na
Figure 4 Derivatives of 14-dihydroisonicotinic acid (14-DHINA)
liposomes (Ondrias et al [187]) However data obtained insome other experimental systems are conflicting
In an in vitromodel of sarcolemmal membrane lipid per-oxidation three calcium blockers (nifedipine verapamil anddiltiazem) exhibited concentration-dependent (10ndash400 120583M)inhibitory effects [188 189] Nifedipine the most effectivecalcium blocker was more than two-fold potent compared topropranolol achieving significant effect at 10 120583M Nifedipineprotective role on LP using reduced glutathione as modelmarker was recently described (Ray et al [190]) Antiper-oxidative properties of CA nifedipine and its analogueswere explored in different systemspathogenic processesatherogenesis (Henry [165]) brain focal ischemia (Yamatoet al [191]) nephroprotection related to cyclosporine intake(Chander and Chopra [192]) and hepatoprotection relatedto intake of diethyldithiocarbamate (Gaafa et al [193])Recent data suggest that nifedipine action as protector forendothelial cells proceeds independently from its CA proper-ties
The absence of antioxidant effects of nifedipine anddiltiazemonmyocardialmembrane lipid peroxidation oppo-site to nisoldipine and propranolol was also described[194] Nisoldipine and propranolol were shown to havea concentration-dependent antiperoxidant effect with IC
50
values of 282 and 501 120583M respectively Finally nisol-dipine appeared to possess dual antiperoxidant mecha-nisms involving both preventive and chain-breaking proper-ties
These findings were confirmed in some other studiesincluding reports on the lack of antioxidative activity ofnifedipine and nicardipine even at 500120583M concentrationin heart membrane lipid peroxidation tests [134] SimilarlyROS formation in bovine aorta smooth muscle cells was notaffected by addition of amlodipine nimodipine and nife-dipine [123]
(1) Metabolites of Nifedipine and Its Analogues as Antioxidantsand Regulators of OS Antioxidant activity of nifedipine35-dimethoxycarbonyl-26-dimethyl-4-(2-nitrophenyl)-14-dihydropyridine was originally studied in vitro by Kirule etal [195] and Tirzit et al [196] According to the kinetic dataof peroxide accumulation and the ESR spectra (inhibition ofthe autoxidation of methyl oleate in presence of nifedipine)AO action was exerted by the formation of nitroso analogueof the oxidized nifedipine nitroso nifedipine 26-dimethyl-4-(2-nitrosophenyl)-35-pyridine dicarboxylate (NO-NIF)This nitroso aromatic derivative can form nitroxyl radicalsexhibiting remarkable AOA in the presence of unsaturatedfatty acids and lipids [196]
The primary species of free radicals that have beenobtained and identified were ion radicals of the nitrophenyltype (Ogle et al [76]) Such a mechanism coincides withmechanisms proposed afterwards by Nunez-Vergara et al[96] Lopez-Alarcon et al [103] Valenzuela et al [104]Fukuhara et al [174] and Yanez et al [197]
There are also data showing that nitroso compounds mayinhibit LP by direct radical trapping and subsequent forma-tion of stable nitroxide radicals It was further found that thereactivity between the synthesized 14-DHP derivatives withalkylperoxyl radicals involves electron transfer reactionsThisis documented by the presence of pyridine as a final productof the reaction and complete oxidation of the nitroso groupin the case of the nitrosoaryl 14-dihydropyridine derivatives(Valenzuela et al [104]) Tested compounds reacted fastertoward alkylperoxyl radicals and ABTS radical cation thanalkyl ones (Lopez-Alarcon et al [103])
Nitrosonifedipine a photodegradation product of nifedi-pine significantly recovers cellular damage induced by tumornecrosis factor-alpha It also prevents toxic effects of cumeneperoxide which hampers integrity of cell membranes throughoxidative stress Its positive effects are equal to Trolox-C
Oxidative Medicine and Cellular Longevity 19
As a result nitrosonifedipine was already a long time agoclaimed as a candidate for a new class of antioxidative drugs(Kirule et al [195]) cellular protectors against oxidative stressin glomerular endothelial cells [174]
Moreover Misik et al [198] Ondrias et al [199] andStasko et al [200] studied AOA of nifedipine and its oxidizednitroso analogue NO-NIF prevents the progression of type2 diabetic nephropathy associated with endothelial dysfunc-tion through selective AO effects (Ishizawa et al [201]) NO-NIF administration reduces albuminuria and proteinuriaas well as glomerular expansion without affecting glucosemetabolism or systolic blood pressure NO-NIF also sup-presses renal and systemic OS and decreases the expressionof intercellular adhesion molecule-1 (ICAM-1) a marker ofendothelial cell injury in the glomeruli of the KKAy miceSimilar effects were achieved in endothelial nitric oxide syn-thase (eNOS) knockout mice Moreover NO-NIF suppressesurinary angiotensinogen (AGT) excretion and intrarenalAGT protein expression in proximal tubular cells in theKKAy mice On the other hand hyperglycemia-inducedmitochondrial superoxide production was not attenuated byNO-NIF in cultured endothelial cells
Fujii and Berliner found EPR evidence for free radicaladducts of nifedipine in vivo [202] The nature of these rad-icals was surmised by comparing the reaction of illuminatednitrosonifedipine with polyunsaturated fatty acids Surpris-ingly identical radical spectra were detected from excisedliver doped with nonilluminated nifedipine suggesting thatthis drug can be enzymatically converted in vivo to its nitrosoanalogue without the requirement for illumination This isone of the first reports of in vivo EPR evidence for a class ofunsaturated fatty acid radical conjugates resulting from thenormal metabolism of a common drug
Dıaz-Araya et al [173] studied some 4-nitrophenyl-DHPson Fe3+ initiated LP in rat brain slices LP as measuredby MDA formation was inhibited by all the tested nitro-aryl derivatives of 14-DHP over a wide range of concen-trations On the basis of both time course and IC
50experi-
ments the tentative order of AOA on rat brain slices wasnicardipine gt nisoldipine gt (RSSR)-furnidipine gt (RRSS)-furnidipine gt nitrendipine gt nimodipine gt nifedipine14-DHP derivatives that lack a nitro group in the mole-cule (isradipine and amlodipine) also inhibited LP in ratbrain slices but at higher concentrations than that of nitro-substituted derivatives All tested compounds reduced andoxidized nitrosoaryl derivatives (26-dimethyl-4-(2-nitro-sophenyl)-35-pyridinedicarboxylic acid dimethyl ester (pho-tooxidation product of nifedipine ndash NTP) ao) and weremore potent inhibitors of LP than their parent molecules(Valenzuela et al [104])
The electrooxidation process of 4-nitrosoaromatic DHPsis a strongly pH-dependent (two-electron two-proton mech-anism) ECEC type of mechanism that is the sequenceeminusH+eminusH+ at pH gt 85 ECCE mechanism (eminusH+H+eminus)at pH lt 85 dominates Reduction reaction of nitroso groupis as follows R-NO + 2eminus + 2H+ rarr RNHOH (Bollo et al[203])
352 Lacidipine It is a generic DHP type antihypertensiveCA 35-diethyl 4-2-[(1E)-3-(tert-butoxy)-3-oxoprop-1-en-1-yl]phenyl-26-dimethyl-14-dihydropyridine-35-dicarboxy-late
Ursini [204] described redox behaviour of lacidipine andshowed its tissue protective features Cristofori et al studiedantiatherosclerotic activity in addition to lacidipinersquos CAand AO properties [205] Lacidipine reduced the extent ofatherosclerotic area in hypercholesterolemic apoE-deficientmice (these mice show widespread vascular lesions whichclosely resemble the inflammatory fibrous plaques seen inhumans in atherosclerosis) The reduction may be associatedwith the capacity of the drug to maintain endothelial NOlevels at concentrations useful to protect against vasculardamage This work suggested that DHPs modulate vascularrelaxation via increased release of NO
Herbette et al [178] remarked optimal hydrophobicity oflacidipine due to cinnamic acid substituent so membraneinteractions and facilitation of the treatment of atherosclero-sis could proceed (see also Section 331 (2)-(a))
353 Amlodipine Amlodipine (Norvasc) (RS)-3-ethyl5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-14-dihydropyridine-35-dicarboxylate (AML) hasan antioxidant effect on vessels in vitro and is a 3rd genera-tion of charged dihydropyridine CCB that is widely used forthe treatment of hypertensive patients
Amlodipine was shown to have the highest affinity(amlodipine gt verapamil ≫ diltiazem) for the membranebilayer (119870
119901= 104) It produced the significant changes in
membrane thermodynamic properties including a reductionin the thermal phase transition temperature (minus11) enthalpy(minus14) and cooperative unit size (minus59) relative to thecontrol phosphatidylcholine liposomes (Mason et al [49])
Amlodipine AOA is related to its reductant nature orhydrogen donor properties respectively Its ability for donat-ing protons and electrons to the lipid peroxide moleculesblocks the LP process
Amlodipine and even its enantiomers (Zhang et al [206])act as ROS andNOS effectors in several model systems of OSAntioxidant properties of amlodipine were recently reviewedby Vitolina et al [32] Both in vitro and in vivo studiesof amlodipine AO properties revealed inhibition of lipidsoxidative damage primarily those associated with cellularmembranes and lipoprotein particles (LDL) (Mason et al[50])
Under controlled experimental conditions in vitro amlo-dipine showed AOA and ARA by inhibition of lipid peroxideformation and trapping ROS Its scavenging activity forhydroxyl and peroxyl radicals at concentrations as low as100 nmolL (which is remarkably less compared to the classi-cal antioxidants GSH uric acid and Trolox) was shown to beindependent of the calcium channel modulation (Franzoni etal [207])
AML showed efficiency as scavenger of peroxyl radicals(TOSC assay 5945 plusmn 544 unitsmg) significantly stronger(gt50 119875 lt 0001) than GSH (2733plusmn 636 unitsmg) and 70weaker (119875 lt 00001) than uric acid (18144 plusmn 696 unitsmg)and Trolox (17522 plusmn 734 unitsmg)
20 Oxidative Medicine and Cellular Longevity
Of interest the scavenging capacity of AML towardshydroxyl radicals (1455 plusmn 154 unitsmg) was 320 higher(119875 lt 000001) than that of GSH (358 plusmn 112 unitsmg) 20higher than that of uric acid (1198plusmn121 unitsmg) and 100higher than that of Trolox (759 plusmn 143 unitsmg)
Amlodipine was shown to increase enzyme activity ofparaoxonase (PON) and glutathione peroxidase (GSH-Px)However it also decreases glutathione reductase (GSSG-R)activity and diminishes the concentration of the endogenousantioxidant 120572-tocopherol (vitamin E) Moreover AML in aconcentration of 2 ngmL decreased the content of malonicdialdehyde and activity of superoxide dismutase in the blood(Gatsura [208])
Verapamil and amlodipine produced a potent anti-ischemic effect and reduced area of myocardial infarction inrats The observed changes were accompanied by inhibitionof LP In contrast to verapamil in vitro application of AML ina dose of 50 ngmL decreased hemoglobin affinity for oxygenWhen present in a concentration of 2 ngmLAMDdecreasedthe content of MDA and activity of SOD in the blood
On the other hand amlodipine shows no activity relatedto inhibition of macrophage superoxide release and cellmigration which occurs as a consequence of decreasedTNF120572induced O
2
∙ releaseAmlodipine-induced reduction of OS in the brain is
associated with sympathoinhibitory effects in stroke-pronespontaneously hypertensive rats (SHRSP) (Hirooka et al[209]) Antihypertensive treatment with amlodipine reducedOS in all examined areas of the brain and decreased bloodpressure without a reflex increase in sympathetic nerveactivity Nicardipine another CA DHP surprisingly wassignificantly less active than amlodipine
354 Lercanidipine Tomlinson and Benzie reported AOeffect of lercanidipine [210] which is well known as anti-hypertensive drug Zanidip 2[(33-diphenylpropyl)(methyl)-amino]-11-dimethylethyl methyl 26-dimethyl-4-(3-nitro-phenyl)-14-dihydropyridine-35-dicarboxylate Compara-tive data about this drug AOA were presented in parts of thispaper about other individual CA DHPs and in the part aboutthe ex vivo DHPs effects on LDL
355 Nimodipine Nimodipine (ND) commercially knownas Nimotop is 3-(2-methoxyethyl) 5-propan-2-yl 26-dim-ethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxy-late It is centrally active CA
Treatment with glutathione blocked andwith nimodipineattenuated neuronal cell death caused by prolonged exposureof cell culture to 4-HNE (Faraqui [211])
Nascimento et al [212] found AO effect of nimodipine inyoung rats after pilocarpine- (PIL-) induced (in 400mgkg)seizures The PIL administration increased the striatal cata-lase (CAT) activity The administration of ND 30mgkg30min before PIL preserved normal value of CAT activityOn the other hand no difference was detected in the animalstreated with lower dose 10mgkg These results confirmthe neuroprotectiveantiepileptic effect of ND in young ratssuggesting that this drug acts positively on lipid peroxidation
(in both doses) Nimodipine cannot induce these effects viablockade of Ca2+ channel
Ismailoglu et al [213] studied the therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjury These beneficial effects in rats after cerebral corticalinjury seemed to be related to AOA of nimodipine
356 Benidipine Licensed in Japan and South Asia as CA(CCB) benidipine possesses AO properties Chemically it is5-methyl 3-[(3R)-1-(phenylmethyl)piperidin-3-yl] 26-dim-ethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxy-late (or its hydrochloride (4R)-rel-35-pyridinedicarboxylicacid 14-dihydro-26-dimethyl-4-(3-nitrophenyl)- 3-methyl5-[(3R)-1-(phenylmethyl)-3-piperidinyl] ester hydrochloride(1 1))
Benidipine influences processes connected with OS inseveral ways It prevents lysophosphatidylcholine- (lysoPC)-induced injury and ROS production in human aorticendothelial cells (HAECs) (Matsubara and Hasegawa [214])Matsubara et al [215] explained this effect based on stimula-tion of nitric oxide release
LysoPC is a component of oxidized low-density lipopro-teins (oxLDLs) which plays an important role in the patho-genesis of atherosclerosis Pretreatmentwith benidipine (03ndash3 120583molL) for 24 h protected against lysoPC-induced cyto-toxicity in the HAECs through inhibition of both lysoPC-stimulated ROS production and caspase-37-like activationwith a similar potency Since caspase-37 is involved inexecuting the apoptotic process the reduction of the activityof this enzyme by benidipine may explain the antiapoptoticeffect of the drug However benidipine did not suppresslysoPC-induced phosphorylation of mitogen-activated pro-tein kinases and Ca2+ influx in HAECs These results suggestthat the antioxidant properties of benidipine may be respon-sible for its ability to inhibit ROS production a possiblereason for reduced activation of caspase-37 In conclusionbenidipine suppresses lysoPC-induced endothelial dysfunc-tion through inhibition of ROS production which is due atleast in part to its antioxidant effect and not through theinhibition of L-type voltage-dependent calcium channels
Matsubara and Hasegawa [216] examined the effectsof benidipine on cytokine-induced expression of adhesionmolecules and chemokines (chemoattractants) which areimportant for the adhesion of monocytes to endotheliumPretreatment of HAECs with benidipine (03ndash10 120583molL)for 24 h significantly suppressed cytokine-induced vascularcell adhesion molecule-1 (VCAM-1) and intracellular celladhesion molecule-1 (ICAM-1) mRNA and protein expres-sion resulting in reduced adhesion of THP-1 monocytesBenidipine also suppressed induction of monocyte chemoat-tractant protein-1 (MCP-1) and interleukin-8 Benidipinealso inhibited redox-sensitive transcriptional nuclear factor-120581B (NF-120581B) pathway as determined by Western blotting ofinhibitory 120581B (I120581B) phosphorylation and luciferase reporterassay Results of analysis using optical isomers of benidip-ine and antioxidants suggest that these inhibitory effectswere dependent on pharmacological effects other than Ca2+antagonism Benidipine may thus have anti-inflammatoryproperties and benefits for the treatment of atherosclerosis
Oxidative Medicine and Cellular Longevity 21
Benidipine was also shown to inhibit ROS production inpolymorphonuclear leukocytes and oxidative stress in salt-loaded stroke-prone spontaneously hypertensive rats (Mat-subara et al [217])
It should be mentioned that other DHPs also haveendothelial AO actions [218]
357 Azelnidipine (AZL) Azelnidipine 3-[1-[di(phen-yl)methyl]azetidin-3-yl] 5-propan-2-yl 2-amino-6-methyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate(AZL) CAS number 123524-52-7 is commercially available4-nitroaryl-DHP type calcium antagonist with long-actingantihypertensive action (long-acting CA (CCB)) and a lowreported incidence of tachycardia It additionally possessesbeneficial effects in OS and diabetic conditions
Azelnidipine prevents cardiac dysfunction in strepto-zotocin-diabetic rats by reducing intracellular calcium accu-mulation (altering intracellular Ca2+ handling proteins) OSand apoptosis (Kain et al [219]) AZL can reduce the superox-ide production It exerts its protective effects by targeting theNADPH oxidase and mitochondrial redox enzymes AZL-treated diabetic rats express enhanced level of bcl-2 in thelysates of heart muscle indicating that AZL plays protectiverole in cardiac apoptosis
It has been previously observed that azelnidipine inhibitstumor necrosis factor-alpha-induced endothelial cell (EC)oxidative stress through its AO properties (Nakamura etal [220]) Azelnidipine but not nitrendipine completelyinhibits the Ang II-induced ROS generation in ECs (Matsuiet al [221])
Furthermore azelnidipine but not nitrendipine wasfound to partially restore decreased pigment epithelium-derived factor (PEDF) mRNA levels in Ang II-exposed ECsThis study suggests that AZL influence depends on its antiox-idative properties Authors concluded that upregulation ofPEDF by azelnidipine may become a therapeutic targetfor the treatment of diabetic retinopathy associated withhypertension
Antihypertensive agents with AO effects are potentiallyuseful for diabetic patients with hypertension While DHPtypeCAare among themost frequently used antihypertensivedrugs azelnidipine has been reported to have a unique AOeffect in vitro and in vivo in experimental animals (Ohmuraet al [222]) In hypertensive diabetic patients azelnidipinetreatment for 12 weeks induced a more significant decreasein erythrocyte LOOH level than amlodipine although thevalues related to blood pressure during each treatmentremained comparable These data confirm the usefulness ofLOOH level in erythrocyte membrane as a marker of OS invivo and indicate that azelnidipine has a unique antioxidativeproperty in humans
Daikuhara et al [223] reported the results of the OLCAstudy based on combination of (1) olmesartan and a calciumchannel blocker (azelnidipine) or (2) candesartan and a CCBamlodipine in two groups of diabetic hypertensive patientsPatients treated with the first combination presented highlypersistent early morning antihypertensive effect and strongerdecrease in heart rate fasting blood glucose andHbA1c levels
and microalbuminuria when compared to patients treatedwith the combination (2) Because diabetes is associated withsevere chronic OS the observed results might be at least in apart due to the AOA of azelnidipine
In favor of this are findings of Abe et al [224] who foundadditive antioxidative effects of azelnidipine on angiotensinreceptor blocker olmesartan treatment for type 2 diabeticpatients with albuminuria
Similarly the AOA of thiazolidinediones (insulin sensi-tizer) and their effect on cardiovascular function in type 2diabetic model rats and also those of some DHPs (nifedipineamlodipine or AZL commonly used antianginal and anti-hypertensive agents) in cultured human endothelial cells LPwere examined (Mizushige [225]) The AOA was evaluatedby measuring 8-iso-prostaglandine F
2120572concentration and
azelnidipine exhibited potent AOAInsulin (INS) resistance combined with hyperinsuline-
mia is involved in the generation of OS A relation-ship exists between increased production of ROS and thediverse pathogenic mechanisms involved in diabetic vascularcomplications including nephropathy Manabe et al [226]revealed that high doses of INS augmented mesangial cellproliferation through generation of intracellular ROS andactivation of redox signaling pathways Cell proliferation wasincreased in a dose-dependent manner by high doses of INS(01ndash10 120583M) but was inhibited by 01120583M AZL Namely theINS-increased phosphorylation of mitogen activated proteinkinaseextracellular signal-regulated kinase 12 (MAPKERK12) was inhibited by 01 120583MAZL The same AZL concen-tration blocked intracellular ROS production more effec-tively than 01 120583M nifedipine The NADPH oxidase inhibitorapocynin (001ndash01120583M) prevented INS-induced mesangialcell proliferation So azelnidipine inhibits insulin-inducedmesangial cell proliferation by inhibiting the productionof ROS Therefore azelnidipine may have the potential toprotect against the onset of diabetic nephropathy and slowits progression
Azelnidipine inhibited H2O2-induced cell death in
neonatal rat cardiomyocytes (Koyama et al [227]) Azelnidip-ine and nifedipine did not affect theH
2O2-induced activation
of extracellular signal-regulated protein kinases (ERK) andp38 MAPK (mitogen-activated protein kinase) In contrastazelnidipine but not nifedipine inhibited H
2O2-induced c-
Jun NH2-terminal kinases (JNK) activation Authors con-
cluded that azelnidipine has inhibited theH2O2-induced JNK
activation and cardiac cell death Therefore azelnidipine mayhave cardioprotective effects against OS
A specific atheroprotection activity of azelnidipine relatesto inhibition of TNF-120572-induced activator protein-1 activa-tion and interleukin-8 expression in human umbilical veinendothelial cells (HUVEC) through suppression of NADPHoxidase-mediated reactive oxygen species generation (Naka-mura et al [220]) TNF-120572 could play a central role in patho-genesis of insulin resistance and accelerated atherosclerosis inthe metabolic syndrome The concentration of AZL found tobe effective in these in vitro experiments is within therapeuticrange As EC do not possess voltage-operated L-type calciumchannels it is suggested that the beneficial effects of azelni-dipine are not likely due to CA property but to its unique AO
22 Oxidative Medicine and Cellular Longevity
ability Furthermore it has been recently found that serumlevels of monocyte chemoattractant protein-1 a biomarkerfor subclinical atherosclerosis were significantly decreased bythe AZL treatment in patients with essential hypertension Inthis paper [220] authors hypothesize that due to its uniqueTNF-120572 signalmodulatory activity and antioxidative propertyazelnidipine may be a promising DHP for targeting diabetesand cardiovascular diseases in hypertensive patients withmetabolic syndrome
Shinomiya et al [228] evaluated its AOA in culturedhuman arterial EC under OS Azelnidipine has shown apotent antioxidative effect that could be of significant clinicalbenefit when combined with its long-lasting antihypertensiveaction and low incidence of tachycardia
Azelnidipine inhibited TGF-1205731 and angiotensin II- (AngII-) activated 1205721(I) collagen mRNA expression in hepaticstellate cells (HSCs) (Ohyama et al [229]) FurthermoreTGF-1205731- and Ang II-induced OS and TGF-1205731-induced p38and JNK phosphorylation were reduced inHSCs treated withAZL Azelnidipine significantly decreased inflammatory cellinfiltration profibrotic genes expression HSC activation LPoxidative DNA damage and fibrosis in liver of CCl
4- or
TAA-treated mice Finally AZL prevented decrease of theexpression of some AO enzymes and accelerated regressionof liver fibrosis in CCl
4-treated mice Hence the antifibrotic
mechanism of AZL against CCl4-induced liver fibrosis in
mice may have been due to an increased level of AO defenseAs azelnidipine is widely used in clinical practice withoutserious adverse effects it may provide an effective newstrategy for antifibrotic therapy
358 Manidipine Manidipine (2-[4-(diphenylmethyl)pip-erazin-1-yl]ethyl methyl 26-dimethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate) is a DHP CCB withreported nephroprotective properties Calo et al [230] stud-ied effect of manidipine on gene expression and proteinlevel of OS related proteins p22(phox) (human neutrophilcytochrome b light chain (CYBA)) and heme oxygenase-1HO-1 Relevance for antihypertensive effects was revealedThe study assessed the effect of manidipine on normalsubjectsrsquo monocyte gene and protein expression of OS relatedproteins such as p22phox a NADPH oxidase system subunitcritical in generating O
2
∙minus and HO-1 induced by and pro-tective against OS Manidipine was compared with the ACEinhibitor captopril and the CCB nifedipine in the presenceand in the absence of sodiumarsenite (NaAsO
2) as an inducer
of OS Monocyte p22phox (CYBA) mRNA production wasreduced by both manidipine and captopril while no changeswere induced by nifedipine Manidipine increased monocyteHO-1 mRNA production while nifedipine and captoprilshowed no effect The effects of manidipine on p22phoxand HO-1 gene expression in the presence of OS were alsoconfirmed at the protein level Thus manidipine seems tosuppress p22phox and to increase the HO-1 mRNA produc-tion and protein level The manidipine-induced increase ofHO-1 gene and protein expression seems to be a peculiareffect of this drug since it is not observed with captopriland nifedipine This effect together with the reduction of
p22phoxmRNAproduction could play a role in its protectivemechanism against OS
359 Mebudipine The protective effect of mebudipine (14-dihydro-26-dimethyl-4-(3-nitrophenyl)-35-pyridinedicar-boxylic acid 3-methyl-5-tert-butyl ester BAY-n-6391) wasrevealed on OS and LP (MDA decrease SOD GPX andcatalase increase) in myocardial ischemic-reperfusion injuryin male rats (Ghyasi et al [231])
There are articles about other commercial and experi-mental DHPs on OS but we have reviewed only the mostcommonly studied compounds Effects of other commercialCA DHPs on OS are also mentioned in several parts of thisreview
36 14-DHPs Ca Agonists andTheir AOA and ARA For themost popular calcium agonist DHP Bay K 8644 no reactionwith peroxyl radicals was registered (Toniolo et al [114])However interactionwith other compounds possessing AOAand ARA (quercetin) was found
Opposite to that AON-acetylcysteine (NAC) diminishedincrease in Ca2+ transient amplitude and cell shorteninginduced by ISO and forskolin whereas NAC had no effecton the (S)-(minus)-methyl-14-dihydro-26-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylatemdash(minus)-BayK 8644-induced increases (Andersson et al [232])
Increased vasoconstriction responses to Bay K 8644 (3 times10minus7ndash3times 10minus5M)were significantly decreased by pyridoindoleantioxidant stobadine treatment in diabetes (Ceylan-Isik etal [233])
The functional interaction between two L-type Ca2+channel activators quercetin and Bay K 8644 has beeninvestigated in vascular smooth muscle cells Biological ARAcompound quercetin at nutritionally meaningful concen-trations limited the responsiveness of vascular L-type Ca2+channels to the pharmacological stimulation operated by BayK 8644 These data contribute to a better understanding ofquercetin effects on experimental in vivo cardioprotection(Saponara et al [234]) Thus these findings indicated thatalthough Bay K 8644 does not exert potent and direct AOAyet acting as calcium agonist it may affect efficiency of AOsubstances and vice versa
Interaction of grapefruit juice (containing quercetin andits analogues) with DHPs CA diminished effectiveness of CAaction of DHPs (Sica [235])
37 Interpretations of the Mechanism(s) of RadicalScavenging and AOA by DHPs
371 Molecular Mechanism(s) of Radical Scavenging andAOA of DHPs in the Model Systems 35-Dicarbonyl-14-di-hydropyridine derivatives possess powerful bis-120573-carbony-lvinyl-amino conjugation and for that reason cannot be con-sidered as ordinary amino antioxidants The electron andorH donation from DHPs ensures their reductant role andresults in AOA and ARA Oxidation reaction from DHPsresults in production of corresponding heteroaromatic pyri-dine derivatives
Oxidative Medicine and Cellular Longevity 23
Detailed studies were made about substituent in DHPring positions 14- namely 4-unsubstituted- 4-substituted4-alkyl- 4-aryl- 4-alkylaryl- ao 26- 35- (diacetyl ordialkoxycarbonyl chain ao) electronic and steric effects onAOA and ARA of DHPs [44 45 51] see Sections 331and 35 The bell-shaped dependence of DHPs AOA onthe 35-dialkoxycarbonyl- chain length was observed [4445 107 109 112] with the maximum activity at C
2H5ndash
C4H9 Decrease of AOA and incorporation into liposomes for
DHPs with alkyl chains longer than R gt C4H9further were
clarified as probable tendency to self-aggregation of thesecompounds ([51] and citation number 245 therein) Electronacceptorelectron donor properties are relevant for expres-sion of AOA or ARA of 35-disubstituted DHPs 35-Diacyl-substituted and 35-dicarbanilido- and 35-dipyridylamido-substituted DHPs are more active as AOs as their 35-dicyano-substituted analogues which have electron acceptorproperties [186]
Dubur et al [89] observed overwhelming steric influenceof substituents in position 4 of the DHP ring Gaviraghiet al [163 164] proposed that AO activity of DHPs ispartly dependent on capacity of the 14-DHP ring to donateelectrons to the propagating radical (ROO∙ or RO∙) and toreduce it to a less reactive form The abstraction (donation)of electron andor H in the oxidation and LP reactionstakes place from all 35-dicarbonyl-14-DHP systems andresults in the formation of corresponding pyridine derivatives(Augustyniak et al [51]) The physicochemical mechanism ofARA and AOA of 14-DHP has been extensively studied anddiscussed (Mulder et al [236]) but precise mechanisms oftheir activity need further clarification
The reactivity of C-4 substituted 14-DHPs possessingeither secondary or tertiary nitrogen atom in the DHP ringtoward alkyl alkylperoxyl radicals and ABTS radical cationwas determined in aqueous media at pH 74 [103] Thesecompounds reacted faster toward alkylperoxyl radicals andABTS radical cation than alkyl ones N-Ethyl-substitutedDHPs showed the lowest reactivity
The 4-methyl substituted DHP was the most reac-tive compound in previously mentioned reactions (Lopez-Alarcon et al [103]) However it was less active (068versus 10) than Trolox-C DHPs having electron-donatingsubstituents (4-Me-DHP and p-MeO-Phe-DHP) showed thehighest kinetic rate constants toward ABTS radical cation p-nitro-Phe-DHP a compound with an electron-withdrawingsubstituent showed a lower kinetic rate constant and N-alkyl-DHP compounds show kinetic rate constants lowerthan the -NH-DHP
Hydrogen at the 1-position of the DHP ring was revealedaccording to the deuteriumkinetic isotope effect studies to beinvolved in the proposedARAmechanismThis fact ismostlynoticeable in the case of alkyl radicals N-Ethyl-substitutedDHPs show the lowest reactivity when compared to Troloxor nisoldipine In all cases the respective pyridine derivativewas detected as the main product of the reaction (Lopez-Alarcon et al [103]) Authors indicate that the kinetic rateconstants toward alkyl alkylperoxyl andABTS radical cationdepend on the nature of the substituents in the C-4 positionof DHP and the presence of the secondary amine group in the
dihydropyridine ring that is the presence of the hydrogen in1-position
Yanez et al [197] have studied the reactivity of 11derivatives of 14-DHPs (including commercial CA) withalkylperoxyl radicals and ABTS radical cation The tested14-DHPs were 83-fold more reactive towards alkylperoxylradicals than to the ABTS cation radical All commercial14-DHP type CCBs were weaker than Trolox-C The par-ticipation of the hydrogen atom in the 1-position appearsto be very relevant for exhibited reactivity Hantzsch ester(diludine)was again found to be themost active compound inthe reaction with alkylperoxyl radicals 23-fold more activethan Trolox The photodegradation product of nifedipine(nitrosophenyl derivative of pyridine) also showed a highactivity Kinetic rate constants for the reaction between 14-DHP compounds and alkylperoxyl radicals exhibited a fairlygood linear correlation with the oxidation peak potentialof DHP derivatives However the activity of tested 14-DHPs towards ABTS radical cation showed an independencebetween kinetic rate constants and oxidation peak potentials
Kirule et al [195] andTirzit et al [196] studiedmechanismof AOA of 4-nitrophenyl-14-DHPs nifedipine and its ana-logues involving formation of 4-(21015840-nitrosophenyl)-pyridinederivative (as active principle) as a result of intramolecularredox reaction using chemical electrochemical and bio-chemical approaches (see Sections 331 and 351)
Nunez-Vergara et al [237] reported the electrochemicaloxidation of C4-hydroxyphenyl-substituted 14-DHP deriva-tives The oxidation proceeds via formation of the unstabledihydropyridyl radical as confirmed by controlled-potentialelectrolysis (CPE) and ESR experiments This type of 14-DHPs has significant activity towards the radicals even whencompared with commercial 14-DHP drugs with well-knownantioxidant ability
It was observed that nicardipine preferentially targets RO∙radicals and is inactive against ROO∙ Lacidipine on theother hand is equally active towards both types of radicals(Gaviraghi et al [164]) The cytoprotective effect againstexposure to H
2O2was more significant for lacidipine (ID
50=
14 nM its log119875 = 54 membrane partition = 136000 assumesposition located 7 A near to the membrane center otherless lipophilic DHPs located 12ndash16 A far from the center)as compared to amlodipine nifedipine and nicardipine insmooth muscle cell culture (Gaviraghi et al [164]) Oxidativeeffect of H
2O2shifts the Ca channel toward an open state
Thus the redox property of CCBs DHPs may augment theirCCB properties
Oxidation of pharmacologically active Hantzsch 14-dihydropyridines was found by electrogenerated superoxideusing a voltammetric approach in DMSO solutions (Ortiz etal [238] and Ortiz et al [239]) Raghuvanshi and Singh [240]have also reported oxidative aromatization of these DHPsinduced by superoxide
Chemiluminescence (CL) was used in the studies ana-lyzing the antioxidant activity of 12 various 4-flavonil-14-dihydropyridine derivatives (Kruk et al [241]) on a chemicalsystem involving a superoxide radical anion These deriva-tives showed structural similarity to flavonoids with respectto the presence of rings A B and C The results obtained in
24 Oxidative Medicine and Cellular Longevity
this study indicate that the tested derivatives may catalyzeconversion of superoxide radicals through mimicking theactivity of superoxide dismutase by delivering H+ for reac-tion
O2
minus∙+O2
minus∙+ 2H+ 997888rarr H
2O2+1O2
(3)
The enhanced emission of the light in the presence oftested compounds was significant and related to stimulatedproduction ofH
2O2and 1O
2fromO
2
∙The latter specieswereremoved from the reactionmixture by the following sequenceof reactions
H+
O2
minus∙997888rarr HO
2
∙
HO2
∙+O2
∙minus997888rarr HO
2
minus+1O2
2HO2
∙997888rarr H
2O2+1O2
2 (1O2) 997888rarr (O
2)2+ h]lowast
(4)
or to take part in spontaneous dismutation of H2O2
2H2O2997888rarr 2H
2O + 1O
2(5)
The authors have offered an original concept of action for 4-flavonil-14-dihydropyridine derivatives unrelated to that ofO2
∙ radical-trapping chain-breaking antioxidants Insteadthey showed that these compounds act similar to superoxidedismutases converting O
2
∙ to H2O2 Hydrogen peroxide
is less toxic for cells than O2
∙ because it is predominantlyremoved by peroxidases and catalases Finally AO effect ofthese DHPs differed from those mediated by flavonoids witha catechol structure of ring B which are well-known 1O
2
quenchersMulder and collaborators came to similar conclusions
especially related to molecular mechanisms of antioxidativeactivity of DHPs [236]TheAOproperties of Hantzsch 14-di-hydropyridine esters and two dibenzo-14-dihydropyridines910-dihydroacridine (DHAC) and N-methyl-910-dihydro-acridine (N-Me-DHAC) have been explored by determin-ing the autoxidation of styrene or cumene at 30∘C Theseexperiments showed that Hantzsch esters are virtually inac-tive as chain-breaking antioxidants (CB-AOs) contrary tothe findings observed by Lopez-Alarcon et al [103] whoused CB-AOA in aqueous media at pH 74 Their reactivitytoward peroxyl radicals was shown to be some 5 orders ofmagnitude lower than that of the excellent CB-AO 22578-pentamethyl-6-hydroxy-chroman (PMHC)
DHAC was found to be sim10 times less reactive thanPMHC kinetic measurements using DHAC N-deuterio-DHAC and N-Me-DHAC pointing out the abstraction ofN-H hydrogen in DHAC by peroxyl radicals despite the factthat the calculated C-H bond dissociation enthalpy (BDE) inDHAC is about 11 kcalmol lower than the N-H BDE Therates of hydrogen atom abstraction by the 22-diphenyl-1-picrylhydrazyl radical (DPPH∙) have also been determined
for the same series of compounds The trends in the peroxyl∙and DPPH∙ rate constants were found to be similar [236]
Tirzit et al [242] have observed quenching of singletoxygen by DHPs This observation paved the ground forfurther research related to reactions of DHPs with hydroxylradicals (Tirzit et al [243]) singlet oxygen (Kazush etal [94]) and mechanisms of action A series of 14-DHPderivatives in NAD-H-Cu2+-H
2O2system inhibited forming
of the hydroxyl radical (HO∙) while 14-DHP derivativeswith electron donor substituents in the molecule were shownto be capable themselves of generating HO∙ in the presenceof Cu2+ and H
2O2 Rubene et al [186] also described
interaction of 14-DHP derivatives with Fentonrsquos reagentwhich produces hydroxyl radical (HO∙) Rate constants ofthe DHPs reaction (1st order) with HO∙ radical were highin the range 109 L times mol times secminus1 close to that of NADHcysteine and thiourea 35-Diacetyl- derivatives reacted fastercompared to 35-dialkoxycarbonyl- ones The reaction ratedecrease was observed in the case of substitution at position4 as compared to 4-unsubstituted DHPs Some DHPs havingelectron donor -COOminus groups in the 35- or 26- positionsof DHP ring reacted immediately (having rate constantshigher as 109 L times mol times secminus1) Rate constants with HO
2
∙
and O2
∙minus radicals were of lower degree Thus DHPs actingas oxygen radical scavengers could effectively inhibit ROSrelated reactions of LP initiation stage
Nifedipine and nitrendipine reactivity toward singletoxygen was also studied [244] Nifedipine was shown tobe a good scavenger of excited oxygen mainly via physicaldeactivation with values of the total rate constant rangingfrom 208 times 105Mminus1 sminus1 (in dioxane) to 930 times 105Mminus1 sminus1(in propylene carbonate)The less reactive pathway generateda photooxidation product For that reason a mechanisminvolving a perepoxide-like encounter complex in the firststep of the reaction path was proposed (see [244] Figures8 and 9 therein) The dependence was observed on solventmicroscopic parameters of the total rate constant for the reac-tion between singlet oxygen and 14-DHPs These findingsshow that nifedipine possesses stronger protective activity inbiological systems than nitrendipine
Density-functional-theory (DFT) calculations made byWang et al [245] confirmed the former experimental obser-vations that Hantzsch ester diludine is potent antioxi-dant with high H atom-donating ability and relatively lowprooxidant activity Possible reaction pathways for radicalsderived from 14-dihydropyridine and the resonance modesfor radical species were given [245]
Moreover two ethoxycarbonyl (EtOCO) substituentsat C(2) and C(6) should further enhance Hantzsch esterdiludine H-atom-donating ability due to resonance effectsHowever DHPs should be used in nonpolar rather than inpolar solvents since in the latter not H-atom but electrontransfer is preferred in the radical scavenging process [245]
Mulder et al [246] proposed that quantum-thermochem-ical calculations must be used with caution to indicate ldquoapromising lead antioxidantrdquo as they criticized the density-functional-theory (DFT) calculations made by Wang et al[245]
Oxidative Medicine and Cellular Longevity 25
372 Possible Mechanisms of DHPs ARA and AOA in the Bio-logical Systems Interaction with Other OSModifiers Some ofthese mechanisms were already described (Sections 331 (2)-(b) 331 (2)-(c) 331 (3)-(b) 35)
Enzymatic sources of ROSwith confirmed functional rolein hypertension are NADPH oxidase NO synthase (NOS)xanthine oxidase and cyclooxygenase Godfraind [3] hasreviewed AO effects and protective action of calcium channelblockers (CCBs) Yao et al [247] observed antioxidant effects(as inhibition of LP) for cardio- and neuroprotective CCBs(3ndash300 120583molL) including 7 DHPs in homogenates of ratbrain IC
50values (120583M) were as follows nifedipine (515) gt
barnidipine (586) gt benidipine (712) gt nicardipine (1293)gt amlodipine (1355) gt nilvadipine (1673) gt nitrendipine(2521) gt diltiazem (gt300) = verapamil (gt300) There arealso research articles describing the AO properties of CCBsthrough direct scavenging effect or through preservationof the endogenous SOD activity These findings indicatethat CCBs may also act by reducing the production ofvasoconstrictors angiotensin and endothelin
When present in concentrations that can be achievedin plasma CCBs may inhibit LP formation [3] This AOactivity seems to be typical for high lipophilic CCBs becausetheir chemical structure facilitates proton-donating andresonance-stabilization mechanisms that quench the freeradical reaction Their insertion in the membrane nearpolyunsaturated fatty acids at relatively high concentrationspotentiates proton donation (or atomary H) to lipid peroxidemolecules thereby blocking the peroxidation process Theremaining unpaired free electron associated with the CCBmolecule can be stabilized in well-defined resonance struc-tures associated with the DHP ring (Mason et al [48])
The radical reaction (according to Godfraind [3]) thatdescribes the AO effects of a DHP CCBs is LOOlowast + DHPrarr LOOH + DHPlowast (where LOOlowast is lipid peroxide radical)which in general is reaction (7) of the LP reaction cascadeconsisting of sim10 reactions (Scheme 2) [89]
As the rate constants of in vitro interaction of 4-substituted DHPs with peroxyl radicals are three ordersof magnitude lower than that of the vitamin E derivativethese DHPs must be considered as weak AO (Ursini [204])However due to partition coefficient of DHPs in membranesand in case of specific binding high local concentration ofDHPs may be obtained
DHPs without CCB properties for instance Bay w 9798although structurally related to nifedipine inhibit TNF-120572-induced vascular cell adhesion molecule-1 expression inendothelial cells by suppressing reactive oxygen speciesgeneration [248]
Mitrega et al [249] have discovered that antiarrhythmicand hemodynamic effects of oxidized heteroaromatic DHPsoxy nifedipine oxy nimodipine oxy nitrendipine and oxynisoldipine suggest that CCB DHPs and their metabolitescould act at least in two ways targeting OS related eventsas reductants (see Section 351 (1)) andor bypassing OSrelatedmetabolic routes Authors postulated that contrary tocurrent belief NIF metabolites are pharmacologically activeATP sensitive potassium channels were mentioned as a tar-get
38 DHPs Anti- or Prooxidants Several substances (ascorbicacid being the most commonly studied) can serve either asantioxidants or as prooxidants depending on given condi-tions (Herbert [250]) Therefore Halliwell [251] has reporteddilemma related to polyphenols as possible antioxidantsand prooxidants causing experimental artifacts (about 25)by oxidation of antioxidant compounds in the cell culturemedia Nevertheless it is generally accepted opinion thatpolyphenols act as antioxidants in vivo Studies on DHPs alsoface such a dilemmaThe exact roles (anti- or prooxidative) ofany specific DHP depend on its structure appliedachievedconcentration and specificity of the targetexperimentaltesting system
This situation resembles the case of antioxidative effectsof tocopherol which depends on the fate of the secondaryradical as proposed by Winterbourn [252] The question wasldquoVitamin E - Pro- or Antioxidantrdquo
997888rarr chain termination of lipid peroxidation
(6)
Prooxidant
Toc∙ + Lipid-H 997888rarr Lipid∙ (in LDL particles) (7)
This example shows that generally speaking any AO mustfulfil several criteria to be considered as an effective com-pound physiologically
(i) It must be able to functionally interact with endoge-nous scavengers even at low concentrations
(ii) It must affect endogenous pathways of OS(iii) It should not have undesirable adverse effect(iv) It should manifest the antioxidant efficacy dependent
on the oxidant(v) It must discriminate among different strategies
needed for 1-electron and 2-electron processes(vi) Radical scavengers can be prooxidant unless linked to
a radical sink (Winterbourn [252])
According to these statements DHPs could be effective asAO under physiological conditions in vivo (Godfraind [3]and others [30 31 38]) and in vitro in various experimentalsystems (cell and tissue) (see Sections 33 34 35)
Hence calcium antagonists appeared to disrupt thefine balance between the production and scavenging ofROS Nifedipine verapamil and diltiazem were shown toinduce significant oxidative stress in the epididymal sperm(increased MDA and decreased catalase and superoxidedismutase activity) This may be the reason for the inductionof male infertility [253]
The dualism of 14-DHP effects has been recorded asinhibition or promotion of LP as quenching or initiating
26 Oxidative Medicine and Cellular Longevity
oxygen and nitrogen free radical chain reactions radiopro-tecting or radiosensitizing antagonizing or synergizing Ca2+in electromechanical coupling as well as in the membranestabilization or labilization
39 Could DHPs Be Involved in Antioxidative Stress Beforebeing applied in vivo the optimal dose and optimal timeintervals forDHPs applicationmust be knownNamely whileROS have been traditionally considered as toxic byproductsof aerobic metabolism we know nowadays that ROS may actas essential signaling molecules needed for the control ofmany different physiological processes Whether the role ofROS will be damaging protective or signaling depends onthe delicate equilibrium between time- and location-specificROS production and scavenging Accordingly the imbalanceof the increased AO potential so-called antioxidative stresscould be dangerous similar to chronic OS in particular incase of extended exposure Inappropriate interventions inthe oxidative homeostasis by excessive antioxidants especiallyin case of chronic exposure to antioxidants might havevery negative effects as was published in the ATBC studyshowing an increased cancer incidence in smokers treatedby excessive beta-carotene [254] Therefore overconsump-tion of any natural or synthetic AO including DHPs asdietary supplements or drugs must be avoided in order tosuppress oxidative damage and must not disrupt the well-integrated antioxidant defense network (Poljsak [255] andPoljsak and Milisav [256]) This is especially important whenadministrating lipid-soluble antioxidants that can be storedin biomembranes thus not only attenuating or preventing LPbut also affecting physiological effects of the natural antiox-idants in particular tocopherol The interrelationship withthe status of endogenous antioxidantsprooxidants should befollowed
DHPs primarily suppress the initiation stages of LPprocessThey do not entirely stop the LP propagation Actingsynergistically with tocopherol diludine may prevent patho-logical excess of ROS production within the lipid moiety ofthe cellular membranes and LDL However due to its lowsolubility and fast metabolism its concentration in the cellsis low For that reason it cannot cause antioxidative stresseven if used for an extended period of time Thus diludine(diethone) could be only a mild antioxidant it has potentialfor restoring the pool of natural antioxidants (as synergist of120572-tocopherol and polyphenols) in the cells
Moreover DHPs CA used for cardioprotection andvasodilatation as commercial drugs in low concentrationsare fast metabolized via CYP3A4 and for that reason theirapplication does not induce cellular AO stress [53 160]However Godfraind and Salomone [257] have postulated noevidence that allows recommending dietary supplementationwith antioxidants for the primary or secondary prevention ofcardiovascular disease
So far there are no reports on antioxidative stress causedby some DHPs diludine and its analogues Diludine andits analogues therefore could act as adaptogens supportinghormetic effects of mild oxidative stress These compoundsmay act as potential multisided modulators of Yin-Yang
cycles of redox and cell functions (the electroplasmic cycle)(Wagner et al [258])
4 Conclusions
14-Dihydropyridines (14-DHPs) have broad spectrum ofOS modulating activities DHPs have reducing and lipidperoxidation inhibitor properties act as reductants in simplechemical systems and stabilize various biological systems(LDL mitochondria microsomes cells and tissues) againstOS Examples and peculiarities and mechanisms of antiox-idant activity (AOA) and antiradical activity (ARA) as wellas stress-protective effect of DHPs including commercialcalcium antagonists (CA) were highlighted These activitiesdepend on various structural parameters related to DHPs(presence and character of substituents) lipophilicity anddepth of the incorporation in the biologicalmembranesTheyalso depend on the experimental model system for exploringthe lipid peroxidation or oxidative stress Stress-protectiveeffect of some metabolites of CA (nifedipine) is reviewedAlthough some DHPs including CA have prooxidant prop-erties (on epididymal sperm cells) they can generally beconsidered as potent antioxidants Therefore comparisonof the AOA and ARA of different DHPs (mutually andwith other AOs) was described in detail According to thedata presented the DHPs might be considered as bellwetheramong synthetic compounds targeting OS and as a kind ofpharmacological measure for respective field of organic andmedicinal chemistry
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
Authors from Latvian IOS acknowledge ESF 201300021DP1112013APIAVIAA011 and National Research Pro-gramme PUBLIC HEALTHBiomedicine of the Republicof Latvia for financial support administration of the Insti-tute for technical support and Rufus Smits PhD for con-sultations in English The support of Cooperation in Euro-pean System of Science and Technology (COST) Domain ofChemistry Molecular Sciences and Technologies (CMST)was of highest importance for preparation of this paper
[2] D J Triggle ldquo14-Dihydropyridines as calcium channel ligandsand privileged structuresrdquoCellular andMolecular Neurobiologyvol 23 no 3 pp 293ndash303 2003
[3] T Godfraind ldquoAntioxidant effects and the therapeutic modeof action of calcium channel blockers in hypertension andatherosclerosisrdquo Philosophical Transactions of the Royal SocietyB Biological Sciences vol 360 no 1464 pp 2259ndash2272 2005
[4] E Cadenas ldquoMitochondrial free radical production and cellsignalingrdquoMolecular Aspects of Medicine vol 25 no 1-2 pp 17ndash26 2004
[5] E Cadenas ldquoFree radicals oxidative stress and diseasesrdquo inLecture PSC 616 p 38 Missouri University of Science andTechnology Rolla Mo USA httpwwwcarnicominstituteorgarticlesenrique cadenaspdf
[6] K Rahman ldquoStudies on free radicals antioxidants and co-fac-torsrdquo Clinical Interventions in Aging vol 2 no 2 pp 219ndash2362007
[7] V Bocci and G Valacchi ldquoFree radicals and antioxidants howto reestablish redox homeostasis in chronic diseasesrdquo CurrentMedicinal Chemistry vol 20 no 27 pp 3397ndash3415 2013
[8] M Valko C J Rhodes J Moncol M Izakovic and M MazurldquoFree radicals metals and antioxidants in oxidative stress-induced cancerrdquo Chemico-Biological Interactions vol 160 no 1pp 1ndash40 2006
[9] G Bartosz ldquoReactive oxygen species destroyers or messen-gersrdquo Biochemical Pharmacology vol 77 no 8 pp 1303ndash13152009
[10] R Visconti and D Grieco ldquoNew insights on oxidative stress incancerrdquo Current Opinion in Drug Discovery and Developmentvol 12 no 2 pp 240ndash245 2009
[11] R N Kujundzic N Zarkovic and K G Troselj ldquoPyridinenucleotides in regulation of cell death and survival by redoxand non-redox reactionsrdquo Critical Reviews in Eukaryotic GeneExpression vol 24 no 4 pp 287ndash309 2014
[12] B Halliwell and J M C Gutteridge ldquoThe definition and mea-surement of antioxidants in biological systemsrdquo Free RadicalBiology and Medicine vol 18 no 1 pp 125ndash126 1995
[13] V D Kancheva and O T Kasaikina ldquoBio-antioxidantsmdashachemical base of their antioxidant activity and beneficial effect
on human healthrdquo Current Medicinal Chemistry vol 20 no 37pp 4784ndash4805 2013
[14] H V Panglossi Ed Frontiers in Antioxidants Research NovaScience Publishers New York NY USA 2006
[15] E B Burlakova E M Molochkina and G A NikiforovldquoHybrid antioxidantsrdquo Oxidation Communications vol 31 no4 pp 739ndash757 2008 httpmembraneustceducnpaperpdfHybrid20Antioxidantspdf
[16] A Bast and G R M M Haenen ldquoTen misconceptions aboutantioxidantsrdquo Trends in Pharmacological Sciences vol 34 no 8pp 430ndash436 2013
[17] E B Burlakova A V 0lesenko E M Molochkina N PPalmina and N G Khrapova Bioantioxidants for RadiationDamage and Malignant Growth Nauka Moscow Russia 1975(Russian)
[18] J Fang T Seki and H Maeda ldquoTherapeutic strategies by mod-ulating oxygen stress in cancer and inflammationrdquo AdvancedDrug Delivery Reviews vol 61 no 4 pp 290ndash302 2009
[19] M Valko D Leibfritz J Moncol M T D Cronin M Mazurand J Telser ldquoFree radicals and antioxidants in normal physi-ological functions and human diseaserdquo International Journal ofBiochemistry and Cell Biology vol 39 no 1 pp 44ndash84 2007
[20] M Jimenez-Del-Rio and C Velez-Pardo ldquoThe bad the goodand the ugly about oxidative stressrdquo Oxidative Medicine andCellular Longevity vol 2012 Article ID 163913 13 pages 2012
[21] C D Kamat S Gadal M Mhatre K S Williamson Q N Pyeand K Hensley ldquoAntioxidants in central nervous system dis-eases preclinical promise and translational challengesrdquo Journalof Alzheimerrsquos Disease vol 15 no 3 pp 473ndash493 2008
[22] A Pompella H Sies R Wacker et al ldquoThe use of totalantioxidant capacity as surrogate marker for food quality andits effect on health is to be discouragedrdquo Nutrition vol 30 no7-8 pp 791ndash793 2014
[23] Z Ye and H Song ldquoAntioxidant vitamins intake and the risk ofcoronary heart disease meta-analysis of cohort studiesrdquo Euro-pean Journal of Cardiovascular Prevention and Rehabilitationvol 15 no 1 pp 26ndash34 2008
[24] P Knekt J Ritz M A Pereira et al ldquoAntioxidant vitamins andcoronary heart disease risk a pooled analysis of 9 cohortsrdquoTheAmerican Journal of Clinical Nutrition vol 80 no 6 pp 1508ndash1520 2004
[25] A C Carr and M C M Vissers ldquoSynthetic or food-derivedvitamin Cmdashare they equally bioavailablerdquo Nutrients vol 5 no11 pp 4284ndash4304 2013
[26] R Tabrizchi ldquoEdaravoneMitsubishi-TokyordquoCurrentOpinion inInvestigational Drugs vol 1 no 3 pp 347ndash354 2000
[27] K Kikuchi S Tancharoen N Takeshige et al ldquoThe efficacy ofedaravone (radicut) a free radical scavenger for cardiovasculardiseaserdquo International Journal of Molecular Sciences vol 14 no7 pp 13909ndash13930 2013
[28] D Mauzerall and F H Westheimer ldquo1-Benzyldihydronicoti-namidemdasha model for reduced DPNrdquo Journal of the AmericanChemical Society vol 77 no 8 pp 2261ndash2264 1955 ChemicalAbstracts vol 50 Article ID 2588i 1956
[29] F Bossert and W Vater ldquo14-Dihydropyridinesmdasha basis fordeveloping new drugsrdquo Medicinal Research Reviews vol 9 no3 pp 291ndash324 1989
[30] G Swarnalatha G Prasanthi N Sirisha and CMadhusudhanaChetty ldquo14-Dihydropyridines a multtifunctional moleculemdash areviewrdquo International Journal of ChemTech Research vol 3 no1 pp 75ndash89 2011
28 Oxidative Medicine and Cellular Longevity
[31] M Cataldi and F Bruno ldquo14-Dihydropyridines the multiplepersonalities of a blockbuster drug familyrdquo Translational Medi-cine UniSa vol 4 no 2 pp 12ndash26 2012 httpwwwncbinlmnihgovpmcarticlesPMC3728803
[32] R Vitolina A Krauze G Duburs and A Velena ldquoAspects ofthe amlodipine pleiotropy in biochemistry pharmacology andclinicsrdquo International Journal of Pharmaceutical Sciences andResearch vol 3 no 5 pp 1215ndash1232 2012
[33] D Grover S N Mokale and M T Shete ldquoDihydropyridinea novel pharmacophorerdquo International Journal of Pharmaceu-tical Erudition vol 1 no 2 pp 16ndash29 2011 httppharmaeru-ditionorgContentPaper20111-RV-320Final2016-29pdf
[34] A M Vijesh A M Isloor S K Peethambar K N ShivanandaT Arulmoli and N A Isloor ldquoHantzsch reaction synthesis andcharacterization of somenew 14-dihydropyridine derivatives aspotent antimicrobial and antioxidant agentsrdquo European Journalof Medicinal Chemistry vol 46 no 11 pp 5591ndash5597 2011
[35] P Mehta and P Verma ldquoAntimicrobial activity of some deriva-tives of 14-dihydropyridinesrdquo Journal of Chemistry vol 2013Article ID 865128 4 pages 2013
[36] P Olejnıkova L Svorc D Olsovska et al ldquoAntimicrobialactivity of novel C2-substituted 14-dihydropyridine analoguesrdquoScientia Pharmaceutica vol 82 no 2 pp 221ndash232 2014
[37] S Sepehri H Perez Sanchez and A Fassihi ldquoHantzsch-typedihydropyridines and biginelli-type tetra-hydropyrimidinesa review of their chemotherapeutic activitiesrdquo Journal of Phar-macy amp Pharmaceutical Sciences vol 18 no 1 pp 1ndash52 2015httpsejournalslibraryualbertacaindexphpJPPSarticleview2383617863
[38] S A Khedkar and P B Auti ldquo14-Dihydropyridines a classof pharmacologically important moleculesrdquo Mini-Reviews inMedicinal Chemistry vol 14 no 3 pp 282ndash290 2014
[39] G D Tirzit and G Ya Duburs ldquo14-dihydropyridines as inhi-bitors of free-radical reactionsrdquo Chemistry of Heterocyclic Com-pounds vol 8 no 1 pp 126ndash127 1972 Translated from KhimiyaGeterotsiklicheskikh Soedinenii no1 pp 133ndash134 1972 (Rus-sian)
[40] I Bogeski R Kappl C Kummerow R Gulaboski M Hothand B A Niemeyer ldquoRedox regulation of calcium ion channelschemical and physiological aspectsrdquoCell Calcium vol 50 no 5pp 407ndash423 2011
[41] S A Giller G Y Dubur Y R Uldrikis et al ldquoDiludine [Themethod to obtain 35-dicarbonylderivatives of 26-dimethyl-14-dihydropyridines]rdquo Authors certificate of USSR no 3004651971 [Byull Izobret no13 p 95 1971] and following patentsPatent of England no 1294650 1973 Patent of France no2055458 1971 Patent of Japan no 702883 1973 Patent ofHolland no 149787 1976 Patent of Italy no 969022 1974 Patentof FRG no 2036403 1978 US Patent no 3883673 1975 USPatent no 3948924 1976
[42] S A Giller G Y Dubur Y R Uldrikis et al ldquoImprovementsin or relating to the stabilization of carotenerdquo GB Patent no1294650 1972
[43] S A Giller G Y Dubur Y R Uldrikis et al ldquoStabilization ofcarotenerdquo US Patent no 3883673 1975 Chemical Abstracts vol83 Article ID 95193 1975
[44] Yu A Zilber G Ya Dubur K K Kumsar and A Kh VelenaldquoThe effect of antioxidants on the peroxidation of bimole-cular phospholipid membranesrdquo Latvijas PSR ZA Vestis Izves-tia Akademii Nauk Latviyskoy SSR vol 6 pp 80ndash82 1971(Russian) translated from the original Russian Doc Accesion
No AD0771751 distributed by NTIS US Department of Com-merce httpwwwdticmildtictrfulltextu2771751pdf
[45] G Ya Dubur Yu A Zilbers A Kh Velena A O Kumerovaand G D Tirzitis ldquoMultistage study of regulation of peroxida-tion processes in biological membranes by antioxidants of 14-dihydropyridine grouprdquo Izvestiya Akademii Nauk LatviyskoySSR vol 336 no 7 pp 65ndash68 1975 (Russian)
[46] R P Mason and M W Trumbore ldquoDifferential membraneinteractions of calcium channel blockers Implications forantioxidant activityrdquo Biochemical Pharmacology vol 51 no 5pp 653ndash660 1996
[47] R P Mason M F Walter M W Trumbore E G Olmstead Jrand P E Mason ldquoMembrane antioxidant effects of the chargeddihydropyridine calcium antagonist amlodipinerdquo Journal ofMolecular and Cellular Cardiology vol 31 no 1 pp 275ndash2811999
[48] R PMason I T MakMW Trumbore and P EMason ldquoAnti-oxidant properties of calcium antagonists related to membranebiophysical interactionsrdquo American Journal of Cardiology vol84 no 4 pp 16ndash22 1999
[49] R PMasonMW Trumbore and P EMason ldquoMembrane bio-physical interaction of amlodipine and antioxidant propertiesrdquoDrugs vol 59 no 2 pp 9ndash16 2000 (French)
[50] R P Mason P Marche and T H Hintze ldquoNovel vascularbiology of third-generation L-type calcium channel antagonistsAncillary actions of amlodipinerdquo Arteriosclerosis Thrombosisand Vascular Biology vol 23 no 12 pp 2155ndash2163 2003
[51] A Augustyniak G Bartosz A Cipak et al ldquoNatural andsynthetic antioxidants an updated overviewrdquo Free RadicalResearch vol 44 no 10 pp 1216ndash1262 2010
[52] T Grune N Zarkovic and K Kostelidou ldquoLipid peroxidationresearch in Europe and the COST B35 action lsquoLipid Peroxida-tion Associated Disordersrsquordquo Free Radical Research vol 44 no10 pp 1095ndash1097 2010
[53] E Carosati P Ioan M Micucci et al ldquo14-Dihydropyridinescaffold in medicinal chemistry the story so far and perspec-tives (part 2) action in other targets and antitargetsrdquo CurrentMedicinal Chemistry vol 19 no 25 pp 4306ndash4323 2012
[54] U Eisner and J Kuthan ldquoThe chemistry of dihydropyridinesrdquoChemical Reviews vol 72 no 1 pp 1ndash42 1972 httpwwwsci-encemadnessorgtalkfilesphppid=138742ampaid=6475
[55] J Kuthan and A Kurfurst ldquoDevelopment in dihydropyri-dine chemistryrdquo Industrial amp Engineering Chemistry ProductResearch and Development vol 21 no 2 pp 191ndash261 1982
[56] A Sausins and G Duburs ldquoSynthesis of 14-dihydropyridinesby cyclocondensation reactionsrdquo Heterocycles vol 27 no 1 pp269ndash289 1988
[57] A E Sausins and G Y Duburs ldquoSynthesis of 14-dihydro-pyridines in cyclocondensation reactions (review)rdquo Chemistryof Heterocyclic Compounds vol 28 no 4 pp 363ndash391 1992Translated from Khimiya Geterotsiklicheskikh Soedinenii no 4pp 435ndash467 1992 (Russian)
[58] S Kazda ldquoTwenty years of dihydropyridinesrdquo in Dihydropy-ridines Progress in Pharmacology and Therapy W-D Busse BGarthoff and F Seuter Eds pp 1ndash12 Springer Verlag BerlinGermany 1993
[59] J-P Wan and Y Liu ldquoRecent advances in new multicomponentsynthesis of structurally diversified 14-dihydropyridinesrdquo RSCAdvances vol 2 no 26 pp 9763ndash9777 2012
[61] Reaxys Database[62] J Tuttle ldquoStructure mechanism and reactivity of hantzsch
estersrdquo in MacMillan Lab Group Meeting (082504) p 332004 httpwwwprincetoneduchemistrymacmillangroup-meetingsJBT20Hantzschpdf
[63] A Saini S Kumar and J S Sandhu ldquoHantzsch reaction recentadvances in Hantzsch 14-dihydropyridinesrdquo Journal of Sci-entific amp Industrial Research vol 67 pp 95ndash111 2008
[64] L LW Cheung S A Styler and A P Dicks ldquoRapid and conve-nient synthesis of the 14-dihydropyridine privileged structurerdquoJournal of Chemical Education vol 87 no 6 pp 628ndash630 2010
[65] A Kumar R A Maurya S Sharma M Kumar and G BhatialdquoSynthesis and biological evaluation of N-aryl-14-dihydro-pyridines as novel antidyslipidemic and antioxidant agentsrdquoEuropean Journal of Medicinal Chemistry vol 45 no 2 pp 501ndash509 2010
[66] R S Kumar A Idhayadhulla A J Abdul Nasser and J SelvinldquoSynthesis and anticoagulant activity of a new series of 14-dihydropyridine derivativesrdquo European Journal of MedicinalChemistry vol 46 no 2 pp 804ndash810 2011
[67] H A Stefani C B Oliveira R B Almeida et al ldquoDihydro-pyrimidin-(2H)-ones obtained by ultrasound irradiation anew class of potential antioxidant agentsrdquo European Journal ofMedicinal Chemistry vol 41 no 4 pp 513ndash518 2006
[68] H Sun C Shang L Jin and J Zhang ldquoSynthesis and antiox-idant activity of a series of novel 3-chalcone-substituted 14-dihydropyridine derivativesrdquoHeterocyclic Communications vol18 no 5-6 pp 239ndash243 2012
[69] D B Tikhonov and B S Zhorov ldquoStructural model for dihy-dropyridine binding to L-type calcium channelsrdquo The Journalof Biological Chemistry vol 284 no 28 pp 19006ndash19017 2009
[70] G Y Dubur and Y R Uldrikis ldquoThe oxidation of 14-dihydro-pyridinesrdquo Chemistry of Heterocyclic Compounds vol 6 no 1pp 80ndash84 1970 Translated from Khimiya GeterotsiklicheskikhSoedinenii no 1 pp 83ndash88 1970 (Russian)
[71] G Ya Duburs A O Kumerova and Ya R Uldrikis ldquoEnzymicoxidation of hydrogenated pyridines with peroxidase-hydrogenperoxide systemrdquoLatvijas PSRZAVestis vol 73 no 7 pp 73ndash771970 (Russian) Chemical Abstracts vol 73 Article ID 94913g1970
[72] K Xie Y-C Liu Y Cui J-GWang Y Fu andT CWMak ldquoN-methyl-(R)-3-(tert-butyl)-sulfinyl-14-dihydropyridine a novelNADHmodel compoundrdquoMolecules vol 12 no 3 pp 415ndash4222007
[73] S Tamagaki T Mimura and W Tagaki ldquoMetal-ion-facilitatedoxidations of dihydropyridines with molecular oxygen andhydrogen peroxiderdquo Journal of the Chemical Society PerkinTransactions 2 no 10 pp 1645ndash1650 1990
[74] D Tirzite G Tirzitis andD Antipova ldquoReductive ability of 14-dihydropyridine derivatives in relation to ions of trivalent ironrdquoChemistry of Heterocyclic Compounds vol 35 no 5 pp 592ndash594 1999
[76] J Ogle J Stradins and L Baumane ldquoFormation and decay offree cation-radicals in the course of electro-oxidation of 12- and14-dihydropyridines (Hantzsch esters)rdquo Electrochimica Actavol 39 no 1 pp 73ndash79 1994
[77] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for the
synthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts C Wittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Berlin Germany 2010
[78] WDu and Zh Yu ldquoBiomimetic in situ regeneration of cofactorsNAD(P)+ and NAD(P)H models hantzsch esters and dihy-drophenanthridinerdquo Synlett vol 23 no 9 pp 1300ndash1304 2012
[79] H K Chenault and G M Whitesides ldquoRegeneration ofnicotinamide cofactors for use in organic synthesisrdquo AppliedBiochemistry and Biotechnology vol 14 no 2 pp 147ndash197 1987
[80] Y R Uldrikis A A Zidermane E A Biseniex I E Preisa GY Dubur and G D Tirzit ldquoEsters of 26-dimethyl-14-dihydro-pyridine-35-dicarboxylic acid and method of obtainingthereofrdquo WO 8000345 A1 1978 httpworldwideespacenetcompublicationDetailsbiblioDB=EPODOCampII=1ampND=3ampadjacent=trueamplocale=en EPampFT=Dampdate=19800306ampCC=WOampNR=8000345A1ampKC=A1
[81] Y Sambongi H Nitta K Ichihashi M Futai and I Ueda ldquoAnovel water-soluble Hantzsch 14-dihydropyridine compoundthat functions in biological processes through NADH regener-ationrdquo Journal of Organic Chemistry vol 67 no 10 pp 3499ndash3501 2002
[82] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for thesynthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts ChWittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Verlag Berlin Germany 2010
[83] T Okamura T Kikuchi A Nagamine et al ldquoAn approach formeasuring in vivo cerebral redox states using the oxidative con-version of dihydropyridine to pyridinium ion and themetabolictrapping principlerdquo Free Radical Biology and Medicine vol 38no 9 pp 1197ndash1205 2005
[84] K A Schellenberg and F H Westheimer ldquoA free-radicaloxidation of a dihydropyridine1ardquo The Journal of OrganicChemistry vol 30 no 6 pp 1859ndash1862 1965
[85] K A Schellenberg ldquoReaction of hydroxyl radical with thymi-dine Scavenging by a dihydropyridinerdquo Federation Proceedingsvol 38 no 3 I p 1433 1979
[86] E S Huyser J A K Harmony and F L McMillian ldquoPeroxideoxidations of dihydropyridine derivativesrdquo Journal of the Amer-ican Chemical Society vol 94 no 9 pp 3176ndash3180 1972
[87] A Sakamoto S T Ohnishi and R Ogawa ldquoInhibition of lipidperoxidation by some dihydropyridine derivativesrdquo Journal ofAnesthesia vol 7 no 2 pp 193ndash197 1993
[88] R Hardeland ldquoReview Neuroprotection by radical avoidancesearch for suitable agentsrdquo Molecules vol 14 no 12 pp 5054ndash5102 2009
[89] G Ya Dubur A Kh Velena V M Gukasov and Yu AVladimirov ldquoRegulation of peroxidation of mitochondrialmembrane lipids initiated by Fe2+ ions by antoxidants of the14-dihydropyridine series in experiments in vitrordquo Biomed-itsinskaya Khimiya vol 22 no 5 pp 665ndash673 1976 (Russian)Chemical Abstracts vol 88 Article ID 2640 1977
[90] G RMMHaenenM J T J Arts A Bast andMD ColemanldquoStructure and activity in assessing antioxidant activity in vitroand in vivo a critical appraisal illustrated with the flavonoidsrdquoEnvironmental Toxicology and Pharmacology vol 21 no 2 pp191ndash198 2006
[91] G Tirzitis and G Bartosz ldquoDetermination of antiradical andantioxidant activity basic principles and new insightsrdquo ActaBiochimica Polonica vol 57 no 2 pp 139ndash142 2010
30 Oxidative Medicine and Cellular Longevity
[92] G R Buettner and R P Mason ldquoSpin-trapping methods fordetecting superoxide and hydroxyl free radicals in vitro and invivordquo inCritical Reviews of Oxidative Stress and Aging Advancesin Basic Science Diagnostics and Intervention R G Cutler andH Rodriguez Eds vol 1 chapter 2 pp 27ndash38World ScientificLondon UK 2003
[93] M M Tarpey and I Fridovich ldquoMethods of detection ofvascular reactive species Nitric oxide superoxide hydrogenperoxide and peroxynitriterdquo Circulation Research vol 89 no3 pp 224ndash236 2001
[94] E Y Kazush E I Sagun G D Tirzit and G Y DaburldquoQuenching of singlet oxygen by electron donating derivativesof 14-dihydropyridinerdquo Chemistry of Heterocyclic Compoundsvol 30 no 5 pp 562ndash563 1994
[95] G Tirzitis E Kazush and G Duburs ldquoReaction of 14-dihydropyridine derivatives with peroxynitrite anionrdquo Chem-istry of Heterocyclic Compounds vol 34 no 3 pp 321ndash3231998 (Russian) Translated from Khimiya GeterotsiklicheskikhSoedinenii no 3 pp 355ndash357 1998
[96] L J Nunez-Vergara C Lopez-Alarcon P A Navarrete-EncinaA M Atria C Camargo and J A Squella ldquoElectrochemicaland EPR characterization of 14-dihydropyridines Reactivitytowards alkyl radicalsrdquo Free Radical Research vol 37 no 1 pp109ndash120 2003
[97] D Tirzite A Krauze A Zubareva G Tirzitis and G DubursldquoSynthesis and antiradical activity of 5-acetyl-2-alkylthio-4-aryl-6-methyl-14-dihydropyridine-3-carboxylic acid nitrilesrdquoChemistry of Heterocyclic Compounds vol 38 no 7 pp 795ndash800 2002
[98] H Ohkawa N Ohishi and K Yagi ldquoAssay for lipid peroxidesin animal tissues by thiobarbituric acid reactionrdquo AnalyticalBiochemistry vol 95 no 2 pp 351ndash358 1979
[99] N Zarkovic ldquo4-Hydroxynonenal as a bioactive marker ofpathophysiological processesrdquo Molecular Aspects of Medicinevol 24 no 4-5 pp 281ndash291 2003
[100] M Parola G Bellomo G Robino G Barrera and M UDianzani ldquo4-Hydroxynonenal as a biological signal molecularbasis and pathophysiological implicationsrdquo Antioxidants andRedox Signaling vol 1 no 3 pp 255ndash284 1999
[101] T Lovakovic M Poljak-Blazi G Duburs et al ldquoGrowthmodulation of human cells in vitro by mild oxidative stressand 14-dihydropyridine derivative antioxidantsrdquo CollegiumAntropologicum vol 35 no 1 pp 137ndash141 2011
[102] R van den Berg G R M M Haenen H van den Bergand A Bast ldquoApplicability of an improved Trolox equivalentantioxidant capacity (TEAC) assay for evaluation of antioxidantcapacity measurements of mixturesrdquo Food Chemistry vol 66no 4 pp 511ndash517 1999
[103] C Lopez-Alarcon P Navarrete C Camargo J A Squella andL J Nunez-Vergara ldquoReactivity of 14-dihydropyridines towardalkyl alkylperoxyl radicals and ABTS radical cationrdquo ChemicalResearch in Toxicology vol 16 no 2 pp 208ndash215 2003
[104] V Valenzuela P Santander C Camargo J A Squella C Lopez-Alarcon and L J Nunez-Vergara ldquo14-Dihydropyridines reac-tivity of nitrosoaryl and nitroaryl derivatives with alkylperoxylradicals andABTS radical cationrdquo Free Radical Research vol 38no 7 pp 715ndash727 2004
[105] L G Tsetlin N A Chebotareva B I Kurganov A K VelenaG Y Dubur and V Z Lankin ldquoStudy of 14-dihydropyridinesas lipoxygenase inhibitors with the use of hydrated reversedmicellesrdquo Pharmaceutical Chemistry Journal vol 22 no 6 pp425ndash428 1988 (Russian)
[106] J Panek Z Reblova L Kocirkova et al ldquoAntioxidant activityof dihydropyridine derivativesrdquo Czech Journal of Food Sciencesvol 18 pp 144ndash145 2000
[107] G Tirzitis I Kirule and G Duburs ldquoAntioxidationsaktivitatder 35-dicarbonylderivate des 26-demethyl-14-dihydropyri-dinsrdquo Fett Wissenschaft TechnologieFat Science Technology vol90 no 10 pp 411ndash413 1988
[108] M Plotniece G Tirzitis Y Uldrikis et al ldquoSynthesis of 14-dihydropyridine derivatives having an oxy- alkoxy- or dimeth-ylaminophenyl substituent in the 4 position their antioxidantactivity and their binding to phospholipid membranesrdquo Chem-istry of Heterocyclic Compounds vol 32 no 10 pp 1166ndash11721996 Translated from Khimiya Geterotsiklicheskikh Soedineniino 10(352) pp 1358ndash1365 1996 (Russian)
[109] D Y Rubene V S Sharov V I Olenev G D Tirzit G Y Duburand Y A Vladimirov ldquoUse of chemiluminescent method forthe evaluation of antioxidant activity of some derivatives of 14-dihydropyridinerdquo Russian Journal of Physical Chemistry A vol55 no 2 pp 511ndash512 1981 (Russian)
[110] M C R Symons and JM C Gutteridge Free Radicals and IronChemistry Biology and Medicine Oxford Science PublicationsOxford University Press Oxford UK 1998
[111] M Repetto J Semprine and A Boveris ldquoLipid peroxidationchemical mechanism biological implications and analyticaldeterminationrdquo in Lipid Peroxidation A Catala Ed Section ILipid Peroxidation Chemical Mechanisms Antioxidants Bio-logical Implications of Biochemistry Genetics and MolecularBiology chapter 1 pp 3ndash30 InTech Rijeka Croatia 2012
[112] A Velena J Zilbers and G Duburs ldquoDerivatives of 14-dihydropyridines asmodulators of ascorbate-induced lipid per-oxidation and high-amplitude swelling ofmitochondria causedby ascorbate sodium linoleate and sodiumpyrophosphaterdquoCellBiochemistry and Function vol 17 no 4 pp 237ndash252 1999
[113] M V Bilenko L N Shelenkova G Y Dubur and A K VelenaldquoUse of antioxidants to prevent renal damage during acuteischemia and reperfusionrdquo Bulletin of Experimental Biology andMedicine vol 96 no 3 pp 1195ndash1198 1983 Translated fromByulletenrsquo Eksperimentalrsquonoi Biologii i Meditsiny vol 96 no 9pp 8ndash11 1983 (Russian)
[114] R Toniolo F Tubaro F Ursini and G Bontempelli ldquoAn elec-troanalytical investigation on the redox properties of calciumantagonist dihydropyridinesrdquo Electroanalysis vol 15 no 10 pp855ndash861 2003
[115] L Kourimska J Pokorny and G Tirzitis ldquoThe antioxidant aci-tivity of 26-dimethyl-35-diethoxycarbonyl-14-dihydropyri-dine in edible oilsrdquo Nahrung vol 37 no 1 pp 91ndash93 1993
[116] C Lopez-Alarcon H Speisky J A Squella C Olea-Azar CCamargo and L J Nunez-Vergara ldquoReactivity of 14-dihydro-pyridines toward SIN-1-derived peroxynitriterdquo PharmaceuticalResearch vol 21 no 10 pp 1750ndash1757 2004
[117] R A Olek W Ziolkowski J J Kaczor L Greci J Popinigisand J Antosiewicz ldquoAntioxidant activity of NADH and its ana-loguemdashan in vitro studyrdquo Journal of Biochemistry andMolecularBiology vol 37 no 4 pp 416ndash421 2004
[118] E Niki N Noguchi and N Gotoh ldquoInhibition of oxidativemodification of low density lipoprotein by antioxidantsrdquo Jour-nal of Nutritional Science andVitaminology vol 39 supplementpp S1ndashS8 1993
[119] N Rojstaczer and D J Triggle ldquoStructure-function relation-ships of calcium antagonists effect on oxidative modificationof low density lipoproteinrdquo Biochemical Pharmacology vol 51no 2 pp 141ndash150 1996
Oxidative Medicine and Cellular Longevity 31
[120] A Sevanian L Shen and FUrsini ldquoInhibition of LDLoxidationand oxidized LDL-induced cytotoxicity by dihydropyridinecalcium antagonistsrdquo Pharmaceutical Research vol 17 no 8 pp999ndash1006 2000
[121] A Negre-Salvayre and R Salvayre ldquoProtection by Ca2+ channelblockers (nifedipine diltiazem and verapamil) against the tox-icity of oxidized low density lipoprotein to cultured lymphoidcellsrdquo British Journal of Pharmacology vol 107 no 3 pp 738ndash744 1992
[122] A Negre-Salvayre G FitoussiM Troly and R Salvayre ldquoCom-parative cytoprotective effect of dihydropyridine calcium chan-nel blockers against the toxicity of oxidized low density lipopro-tein for cultured lymphoid cellsrdquo Biochemical Pharmacologyvol 44 no 12 pp 2379ndash2386 1992
[123] L Cominacini A F Pasini U Garbin et al ldquoAntioxidant activ-ity of different dihydropyridinesrdquo Biochemical and BiophysicalResearch Communications vol 302 no 4 pp 679ndash684 2003
[124] L Cominacini U Garbin A Fratta Pasini et al ldquoOxidized low-density lipoprotein increases the production of intracellularreactive oxygen species in endothelial cells inhibitory effect oflacidipinerdquo Journal of Hypertension vol 16 no 12 part 2 pp1913ndash1919 1998
[125] H M Lander ldquoAn essential role for free radicals and derivedspecies in signal transductionrdquo The FASEB Journal vol 11 no2 pp 118ndash124 1997
[126] M L L Martinez E Rizzi M M Castro et al ldquoLercanidipinedecreases vascular matrix metalloproteinase-2 activity andprotects against vascular dysfunction in diabetic ratsrdquo EuropeanJournal of Pharmacology vol 599 no 1ndash3 pp 110ndash116 2008
[127] P Lesnik C Dachet L Petit et al ldquoImpact of a combinationof a calcium antagonist and a 120573-blocker on cell- and copper-mediated oxidation of LDL and on the accumulation and effluxof cholesterol in human macrophages and murine J774 cellsrdquoArteriosclerosis Thrombosis and Vascular Biology vol 17 no 5pp 979ndash988 1997
[128] G Sobal E J Menzel and H Sinzinger ldquoCalcium antagonistsas inhibitors of in vitro low density lipoprotein oxidation andglycationrdquoBiochemical Pharmacology vol 61 no 3 pp 373ndash3792001
[129] E Lupo R Locher B Weisser and W Vetter ldquoIn vitro antiox-idant activity of calcium antagonists against LDL oxidationcompared with 120572-tocopherolrdquo Biochemical and BiophysicalResearch Communications vol 203 no 3 pp 1803ndash1808 1994
[130] J Zou Y Li H-Q Fan and J-G Wang ldquoEffects of dihydropy-ridine calcium channel blockers on oxidized low-density lipo-protein induced proliferation and oxidative stress of vascularsmooth muscle cellsrdquo BMC Research Notes vol 5 article 1682012
[131] C Napoli S Salomone T Godfraind et al ldquo14-Dihydro-pyridine calcium channel blockers inhibit plasma and LDL oxi-dation and formation of oxidation-specific epitopes in the arte-rial wall and prolong survival in stroke-prone spontaneouslyhypertensive ratsrdquo Stroke vol 30 no 9 pp 1907ndash1915 1999
[132] G Zernig I Graziadei T Moshammer C Zech N Reider andH Glossmann ldquoMitochondrial Ca2+ antagonist binding sitesare associated with an inner mitochondrial membrane anionchannelrdquo Molecular Pharmacology vol 38 no 3 pp 362ndash3691990
[133] F E Hunter Jr A Scott P E Hochstein et al ldquoStudies of themechanism of ascorbate-induced swelling and lysis of isolatedliver mitochondriardquo The Journal of Biological Chemistry vol239 pp 604ndash613 1964
[134] D R Janero B Burghardt and R Lopez ldquoProtection of cardiacmembrane phospholipid against oxidative injury by calciumantagonistsrdquoBiochemical Pharmacology vol 37 no 21 pp 4197ndash4203 1988
[135] A Karadag B Ozcelik and S S Saner ldquoReview of methods todetermine antioxidant capacitiesrdquo FoodAnalyticalMethods vol2 no 1 pp 41ndash60 2009
[136] Y I Gubskiı N V Litvinova and E V Shnurko-TabakovaldquoAntioxidant and antiradical activity of various classes of antiox-idantsrdquo Ukrainskiı Biokhimicheskiı Zhurnal vol 66 no 4 pp114ndash116 1994 (Russian)
[137] M Takei M Hiramatsu and A Mori ldquoInhibitory effects ofcalcium antagonists onmitochondrial swelling induced by lipidperoxidation or arachidonic acid in the rat brain in vitrordquoNeurochemical Research vol 19 no 9 pp 1199ndash1206 1994
[138] M Takei M Hiramatsu R Edamatsu and A Mori ldquoFreeradical scavenging by calcium antagonistsrdquo Neurosciences vol20 no 2 pp 75ndash82 1994
[139] Ya P Stradin G Ya Dubur Yu A Beilis Ya R Uldrikis andA F Korotkova ldquoVoltammetry of 14-dihydropyridine deriva-tives I Potentials of electrochemical oxidation of 35-diacyl-and 35-di(alkoxycarbonyl)-14-dihydropyridines in acetoni-trilerdquo Chemistry of Heterocyclic Compounds no 1 pp 84ndash871972 (Russian)
[140] E V Ivanov T V Ponomarjova G N Merkusev et al ldquoEinneuer Haut-Radioprotektor Diethon (experimentelle Unter-suchung)rdquo Radiobiologia Radiotherapia vol 31 no 1 pp 69ndash78 1990
[141] E V Ivanov T V Ponomareva G N Merkushev et al ldquoRadia-tion modulating properties of derivates of 14-dihydropyridineand 12345678910-decahydroacridine-18 dionerdquo Radiat-sionnaia Biologiia Radioecologiia vol 44 no 5 pp 550ndash5592004 (Russian)
[142] R O Vitolinia D A Berzinia A K Velena I A Vutsina A AKimenis and G Y Duburs ldquoThe protective effects of the cal-cium antagonist foridon in acute myocardial ischaemiardquo Kardi-ologiya vol 27 no 3 pp 90ndash93 1987 (Russian)
[143] A H Velena G Ya Duburs R O Vitolina et al ldquoEffect ofryodipine on electromechanical parameters of heart and vesselscAMP phosphodiesterase activity and swelling-contractioncycle of mitochondriardquo Arzneimittelforschung vol 35 no 6 pp907ndash914 1985
[144] L I Utno Z E Lipsberga A A Silova M I Girgensone EA Bisenieks and G I Ia ldquoCardioprotective properties of a 14-dihydropyridine derivative glutapyrone in deep hypothermiardquoBiulletenrsquo Eksperimentalrsquonoı Biologii i Meditsiny vol 108 no 11pp 558ndash561 1989 (Russian)
[145] M A S FernandesM S Santos J A F Vicente et al ldquoEffects of14-dihydropyridine derivatives (cerebrocrast gammapyroneglutapyrone and diethone) onmitochondrial bioenergetics andoxidative stress a comparative studyrdquoMitochondrion vol 3 no1 pp 47ndash59 2003
[146] M A S Fernandes M S Santos A J M Moreno et al ldquoEffectsof 5-acetyl(carbamoyl)-6-methylsulfanyl-14-dihydropyridine-5-carbonitriles on rat liver mitochondrial functionrdquo Toxicologyin Vitro vol 23 no 7 pp 1333ndash1341 2009
[147] L Klimaviciusa A Kalda A Kaasik et al ldquoNeuroprotectiveactivity of 14-dihydropyridine derivatives structure determi-nantsrdquo Proceedings of the Latvian Academy of Sciences BNatural Exact and Applied Sciences vol 61 no 1-2 pp 33ndash372007
32 Oxidative Medicine and Cellular Longevity
[148] L Klimaviciusa M A S Fernandes N Lencberga et alldquoTargeting the mitochondria by novel adamantane-containing14-dihydropyridine compoundsrdquo in Bioenergetics K B ClarkEd pp 257ndash272 InTech 2012
[149] V Klusa L Klimaviciusa G Duburs J Poikans and AZharkovsky ldquoAnti-neurotoxic effects of tauropyrone a taurineanaloguerdquo Advances in Experimental Medicine and Biology vol583 pp 499ndash508 2006
[150] N Sampson P Berger and Ch Zenzmaier ldquoRedox signalingas a therapeutic target to inhibit myofibroblast activation indegenerative fibrotic diseaserdquo BioMed Research Internationalvol 2014 Article ID 131737 14 pages 2014
[151] T L Leto and M Geiszt ldquoRole of Nox family NADPH oxidasesin host defenserdquoAntioxidantsampRedox Signaling vol 8 no 9-10pp 1549ndash1561 2006
[152] K K Griendling D Sorescu and M Ushio-Fukai ldquoNAD(P)Hoxidase role in cardiovascular biology and diseaserdquo CirculationResearch vol 86 no 5 pp 494ndash501 2000
[153] H Chen Y S Song and P H Chan ldquoInhibition of NADPHoxi-dase is neuroprotective after ischemia-reperfusionrdquo Journal ofCerebral Blood Flow and Metabolism vol 29 no 7 pp 1262ndash1272 2009
[154] P Hochstein and L Ernster ldquoADP-activated lipid peroxidationcoupled to the TPNH oxidase system of microsomesrdquo Biochem-ical and Biophysical Research Communications vol 12 no 5 pp388ndash394 1963
[155] I I Gubskiı AGGoriushkoNV Litvinova et al ldquoAntioxidantproperties and membranotropic effect of certain derivatives of14-dihydropyridinerdquo Ukrainskiı Biokhimicheskiı Zhurnal vol71 no 4 pp 35ndash39 1999 (Russian)
[156] F Engineer and R Sridhar ldquoInhibition of rat heart andliver microsomal lipid peroxidation by nifedipinerdquo BiochemicalPharmacology vol 38 no 8 pp 1279ndash1285 1989
[157] T Goncalves A P Carvalho and C R Oliveira ldquoAntioxidanteffect of calcium antagonists on microsomai membranes iso-lated from different brain areasrdquo European Journal of Pharma-cology vol 204 no 3 pp 315ndash322 1991
[158] M E Letelier P Izquierdo L Godoy A M Lepe and MFaundez ldquoLiver microsomal biotransformation of nitro-aryldrugs mechanism for potential oxidative stress inductionrdquoJournal of Applied Toxicology vol 24 no 6 pp 519ndash525 2004
[159] M E Letelier P Entrala C Lopez-Alarcon et al ldquoNitroaryl-14-dihydropyridines as antioxidants against rat liver microsomesoxidation induced by ironascorbate Nitrofurantoin and naph-thalenerdquo Toxicology in Vitro vol 21 no 8 pp 1610ndash1618 2007
[160] F P Guengerich W R Brian M Iwasaki M-A Sari CBaarnhielm and P Berntsson ldquoOxidation of dihydropyridinecalcium channel blockers and analogues by human liver cyto-chrome P-450 IIIA4rdquo Journal of Medicinal Chemistry vol 34no 6 pp 1838ndash1844 1991
[161] S H Park S-W RhaW-Y Shin et al ldquoAS-160 Calcium channelblockers of dihydropyridine class reduce the antiplatelet effectof Clopidogrel what is clinical impactrdquo The American Journalof Cardiology vol 107 no 8 supplement p 47A 2011
[162] C Asma and D M Reda ldquoEvaluation of dihydropyridinecalcium antagonist effects on the stress bioindicator orga-nism Saccharomyces cerevisiaerdquo Annals of Biological Researchvol 4 no 10 pp 40ndash46 2013 httpscholarsresearchlibrarycomABR-vol4-iss10ABR-2013-4-10-40-46pdf
[163] G Gaviraghi A M Pastorino E Ratti and D G TristldquoCalcium channel blockers with antioxidant activityrdquo in Free
Radicals Lipoprotein Oxidation andAtherosclerosis G BellomoG Finardi E Maggi and E Rice-Evans Eds pp 431ndash456Richelieu Press London UK 1995
[164] G Gaviraghi AM Pastorino E Ratti and D G Trist ldquoAntiox-idant dihydropyridines a new and comprehensive therapy forfree radical-induced cardiovascular diseasesrdquo in Free Radicalsin Biology and Environment F Minisci Ed vol 27 of NATOASI Series pp 193ndash221 Springer Dordrecht The Netherlands1997
[165] P D Henry ldquoAntiperoxidative actions of calcium antagonistsand atherogenesisrdquo Journal of Cardiovascular Pharmacologyvol 18 supplement 1 pp S6ndashS10 1991
[166] F Kouoh B Gressier T Dine et al ldquoAntioxidant effects andanti-elastase activity of the calcium antagonist nicardipine onactivated human and rabbit neutrophilsmdasha potential antiath-erosclerotic property of calcium antagonistsrdquo CardiovascularDrugs andTherapy vol 16 no 6 pp 515ndash520 2002
[167] S Parthasarathy D Litvinov K Selvarajan and M GarelnabildquoLipid peroxidation and decompositionmdashconflicting roles inplaque vulnerability and stabilityrdquo Biochimica et BiophysicaActa vol 1781 no 5 pp 221ndash231 2008
[168] D-Q Liu Z-Q Pang D-H Zhao and B-H Sheng ldquoEffects offuryl-dihydropyridines I on lipid peroxides of ischemic myo-cardium and ATPases activity of erythrocyte membranes inratsrdquo Acta Pharmacologica Sinica vol 12 no 3 pp 253ndash2561991
[169] V Lukic-Panin T Kamiya H Zhang et al ldquoPrevention of neu-ronal damage by calcium channel blockers with antioxidativeeffects after transient focal ischemia in ratsrdquo Brain Research vol1176 no 1 pp 143ndash150 2007
[170] Y Allanore D Borderie H Lemarechal O G Ekindjian andA Kahan ldquoAcute and sustained effects of dihydropyridine-typecalcium channel antagonists on oxidative stress in systemicsclerosisrdquo American Journal of Medicine vol 116 no 9 pp 595ndash600 2004
[171] I Casetta V Govoni and E Granieri ldquoOxidative stress antioxi-dants and neurodegenerative diseasesrdquo Current PharmaceuticalDesign vol 11 no 16 pp 2033ndash2052 2005
[172] M J T J Arts Assessing antioxidant activity [PhD the-sis] Maastricht University Maastricht The Netherlands 2007httparnounimaasnlshowcgifid=8676
[173] G Dıaz-Araya L Godoy L Naranjo A Squella M E Letelierand L J Nunez-Vergara ldquoAntioxidant effects of 14-dihydro-pyridine and nitroso aryl derivatives on the Fe+3ascorbate-stimulated lipid peroxidation in rat brain slicesrdquo General Phar-macology The Vascular System vol 31 no 3 pp 385ndash391 1998
[174] Y Fukuhara K Tsuchiya Y Horinouchi et al ldquoProtectiveeffect of photodegradation product of nifedipine against tumornecrosis factor 120572-induced oxidative stress in human glomerularendothelial cellsrdquo Journal of Medical Investigation vol 58 no1-2 pp 118ndash126 2011
[175] W Stengel M Jainz and K Andreas ldquoDifferent potencies ofdihydropyridine derivatives in blocking T-type but not L-typeCa2+ channels in neuroblastoma-glioma hybrid cellsrdquo EuropeanJournal of Pharmacology vol 342 no 2-3 pp 339ndash345 1998
[176] O M Panasenko D J Tirzite G D Tirzitis and G J DubursldquoEffect of some 14-dihydropyridine derivatives on structuralorganization of erythrocyte membranesrdquo Biologicheskie Mem-brany (Biochemistry (Moscow) Series A Membrane and CellBiology) vol 1 pp 919ndash925 1984 (Russian)
[177] L G Herbette Y M H Vant Erve and D G Rhodes ldquoInter-action of 14 dihydropyridine calcium channel antagonists with
Oxidative Medicine and Cellular Longevity 33
biological membranes lipid bilayer partitioning could occurbefore drug binding to receptorsrdquo Journal of Molecular andCellular Cardiology vol 21 no 2 pp 187ndash201 1989
[178] L G Herbette P E Mason G Gaviraghi T N Tulenko andR P Mason ldquoThe molecular basis for lacidipinersquos unique phar-macokinetics optimal hydrophobicity results in membraneinteractions that may facilitate the treatment of atherosclerosisrdquoJournal of Cardiovascular Pharmacology vol 23 supplement 5pp S16ndashS25 1994
[179] G V Belevitch G Y Dubur G E Dobretsov N K Kurek andM M Spirin ldquoCalcium antagonists riodipine nifedipine andverapamil binding to model and biological membranes fluore-scence analysisrdquo Biologicheskie Membrany (Biochemistry(Moscow) Series A Membrane and Cell Biology) vol 5 pp768ndash776 1988 (Russian)
[180] R P Mason G E Gonye D W Chester and L G HerbetteldquoPartitioning and location of Bay K 8644 14-dihydropyridinecalcium channel agonist in model and biological membranesrdquoBiophysical Journal vol 55 no 4 pp 769ndash778 1989
[181] M Cindric A Cipak J Serly et al ldquoReversal of multidrugresistance inmurine lymphoma cells by amphiphilic dihydropy-ridine antioxidant derivativerdquo Anticancer Research vol 30 no10 pp 4063ndash4070 2010
[182] F Shekari H Sadeghpour K Javidnia et al ldquoCytotoxic andmultidrug resistance reversal activities of novel 14-dihydro-pyridines against human cancer cellsrdquo European Journal ofPharmacology vol 746 no 1 pp 233ndash244 2015
[183] X-F Zhou Q Shao R A Coburn and M E Morris ldquoQuanti-tative structure-activity relationship and quantitative structure-pharmacokinetics relationship of 14-dihydropyridines andpyridines as multidrug resistance modulatorsrdquo PharmaceuticalResearch vol 22 no 12 pp 1989ndash1996 2005
[184] R Berkels T Breitenbach H Bartels et al ldquoDifferent antioxida-tive potencies of dihydropyridine calcium channel modulatorsin various modelsrdquo Vascular Pharmacology vol 42 no 4 pp145ndash152 2005
[185] S Borovic G Tirzitis D Tirzite et al ldquoBioactive 14-dihydro-isonicotinic acid derivatives prevent oxidative damage of livercellsrdquo European Journal of Pharmacology vol 537 no 1ndash3 pp12ndash19 2006
[186] D Ya Rubene G D Tirzitis and G Ya Duburs ldquoInteractionof some 14-dihydropyridine derivatives with Fentonrsquos reagentrdquoLatvijas PSRZinatnuAkademijas Vestis Kimijas Serija Proceed-ings of the Latvian SSR Academy of Sciences Chemistry Seriespp 212ndash216 1982 (Russian)
[187] K Ondrias V Misık D Gergel and A Stasko ldquoLipid per-oxidation of phosphatidylcholine liposomes depressed by thecalcium channel blockers nifedipine and verapamil and bythe antiarrhythmic-antihypoxic drug stobadinerdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1003 no 3pp 238ndash245 1989
[188] I T Mak and W B Weglicki ldquoComparative antioxidant acti-vities of propranolol nifedipine verapamil and diltiazemagainst sarcolemmal membrane lipid peroxidationrdquoCirculationResearch vol 66 no 5 pp 1449ndash1452 1990
[189] I T Mak P Boehme and W B Weglicki ldquoProtective effects ofcalcium channel blockers against free radical-impaired endo-thelial cell proliferationrdquo Biochemical Pharmacology vol 50 no9 pp 1531ndash1534 1995
[190] S Ray S Mondal and N Dana ldquoEvaluation of protective roleof nifedipine on lipid peroxidation using reduced glutathione as
model markerrdquo Oxidants and Antioxidants in Medical Sciencevol 1 no 2 pp 97ndash100 2012
[191] M Yamato T Shiba T Ide Y Honda K-I Yamada andH Tsutsui ldquoNifedipine treatment reduces brain damage aftertransient focal ischemia possibly through its antioxidativeeffectsrdquoHypertension Research vol 34 no 7 pp 840ndash845 2011
[192] V Chander and K Chopra ldquoNifedipine attenuates changes innitric oxide levels renal oxidative stress and nephrotoxicityinduced by cyclosporinerdquo Renal Failure vol 27 no 4 pp 441ndash450 2005
[193] K M Gaafa M M Badawy and A A Hamza ldquoThe protectiveeffects of ascorbic acid cimetidine and nifedipine on diethyl-dithiocarbamate-induced hepatic toxicity in albino ratsrdquo Drugand Chemical Toxicology vol 34 no 4 pp 405ndash419 2011
[194] H Sugawara K Tobise and S Onodera ldquoAbsence of antiox-idant effects of nifedipine and diltiazem on myocardial mem-brane lipid peroxidation in contrast with those of nisoldipineand propranololrdquo Biochemical Pharmacology vol 47 no 5 pp887ndash892 1994
[195] I E Kirule D Y Rubene E A Bisenieks G D Tirzit and GY Dubur ldquo4-Nitrophenyl-14-dihydropyridinesmdasha new groupof inhibitors of peroxide oxidationrdquo Chemistry of HeterocyclicCompounds vol 18 no 3 p 316 1982
[196] G D Tirzit I E Kirule L K Baumane R A Gavar Y PStradynrsquo andG YDubur ldquoMechanism of the antioxidant actionof 26-dimethyl-35-dimethoxy-carbonyl-4-(2-nitrophenyl)14-dihydropyridinerdquoChemistry ofHeterocyclic Compounds vol 20no 8 pp 915ndash918 1984
[197] C Yanez C Lopez-Alarcon C Camargo V Valenzuela J ASquella and L J Nunez-Vergara ldquoStructural effects on thereactivity 14-dihydropyridines with alkylperoxyl radicals andABTS radical cationrdquo Bioorganic and Medicinal Chemistry vol12 no 9 pp 2459ndash2468 2004
[198] VMisik A J Stasko D Gergel and K Ondrias ldquoSpin-trappingand antioxidant properties of illuminated and nonilluminatednifedipine and nimodipine in heart homogenate and modelsystemrdquo Molecular Pharmacology vol 40 no 3 pp 435ndash4391991
[199] K Ondrias V Misık A Stasko D Gergelrsquo and M HromadovaldquoComparison of antioxidant properties of nifedipine and illu-minated nifedipine with nitroso spin traps in low densitylipoproteins and phosphatidylcholine liposomesrdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1211 no 1pp 114ndash119 1994
[200] A Stasko V Brezova S Biskupic K Ondrias and V MisıkldquoReactive radical intermediates formed from illuminated nife-dipinerdquoFree Radical Biology andMedicine vol 17 no 6 pp 545ndash556 1994
[201] K Ishizawa Y Izawa-Ishizawa N Yamano et al ldquoNitrosoni-fedipine ameliorates the progression of type 2 diabetic nephro-pathy by exerting antioxidative effectsrdquo PLoS ONE vol 9 no 1Article ID e86335 2014
[202] H Fujii and L J Berliner ldquoIn vivo EPR evidence for free radicaladducts of nifedipinerdquoMagnetic Resonance in Medicine vol 42no 4 pp 691ndash694 1999
[203] S Bollo S Finger J C Sturm L J Nunez-Vergara and JA Squella ldquoCyclic voltammetry and scanning electrochemicalmicroscopy studies of the heterogeneous electron transferreaction of some nitrosoaromatic compoundsrdquo ElectrochimicaActa vol 52 no 15 pp 4892ndash4898 2007
34 Oxidative Medicine and Cellular Longevity
[204] F Ursini ldquoTissue protection by lacidipine insight from redoxbehaviorrdquo Journal of Cardiovascular Pharmacology vol 30supplement 2 pp S28ndashS30 1997
[205] P G Cristofori F A Crivellente I Faustinelli et al ldquoInvolve-ment of the nitric oxide system in the anti-atheroscleroticpotential of lacidipine in the apoE-deficient mouse a mor-phological functional and electrochemical studyrdquo ToxicologicPathology vol 32 no 4 pp 493ndash499 2004
[206] X-P Zhang E L Kit S Mital S Chahwala and T HHintze ldquoParadoxical release of nitric oxide by an L-type calciumchannel antagonist the R+ enantiomer of amlodipinerdquo Journalof Cardiovascular Pharmacology vol 39 no 2 pp 208ndash2142002
[207] F Franzoni G Santoro F Regoli et al ldquoAn in vitro study of theperoxyl and hydroxyl radical scavenging capacity of the calciumantagonist amlodipinerdquo Biomedicine and Pharmacotherapy vol58 no 8 pp 423ndash426 2004
[208] S V Gatsura ldquoOxygen-dependent mechanisms underlying theantiischemic effect of verapamil and amlodipinerdquo Bulletin ofExperimental Biology and Medicine vol 137 no 1 pp 40ndash422004
[209] Y Hirooka Y Kimura M Nozoe Y Sagara K Ito and KSunagawa ldquoAmlodipine-induced reduction of oxidative stressin the brain is associated with sympatho-inhibitory effects instroke-prone spontaneously hypertensive ratsrdquo HypertensionResearch vol 29 no 1 pp 49ndash56 2006
[210] B Tomlinson and I F F Benzie ldquoAntioxidant effect of lercani-dipine (note)rdquo Hypertension vol 42 no 4 pp e10ndashe11 2003
[211] A A Faraqui ldquoNeurochemical aspects of 4-hydroxynonenalrdquoin Lipid Mediators and Their Metabolism in the Brain A AFaraqui Ed chapter 6 pp 159ndash191 Springer New York NYUSA 2011
[212] V S NascimentoM S DrsquoAlva A AOliveira et al ldquoAntioxidanteffect of nimodipine in young rats after pilocarpine-inducedseizuresrdquo Pharmacology Biochemistry and Behavior vol 82 no1 pp 11ndash16 2005
[213] O Ismailoglu P Atilla S Palaoglu et al ldquoThe therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjuryrdquo Turkish Neurosurgery vol 22 no 6 pp 740ndash746 2012
[214] M Matsubara and K Hasegawa ldquoBenidipine a dihydropy-ridine-calcium channel blocker prevents lysophosphatidyl-choline-induced injury and reactive oxygen species productionin human aortic endothelial cellsrdquo Atherosclerosis vol 178 no1 pp 57ndash66 2005
[215] M Matsubara K Yao and K Hasegawa ldquoBenidipine adihydropyridine-calcium channel blocker inhibits lysophos-phatidylcholine-induced endothelial injury via stimulation ofnitric oxide releaserdquo Pharmacological Research vol 53 no 1 pp35ndash43 2006
[216] MMatsubara and K Hasegawa ldquoEffects of benidipine a dihyd-ropyridine-Ca2+ channel blocker on expression of cytokine-induced adhesion molecules and chemoattractants in humanaortic endothelial cellsrdquo European Journal of Pharmacology vol498 no 1ndash3 pp 303ndash314 2004
[217] M Matsubara O Akizuki J-I Ikeda K Saeki K Yao and KSasaki ldquoBenidipine an anti-hypertensive drug inhibits reactiveoxygen species production in polymorphonuclear leukocytesand oxidative stress in salt-loaded stroke-prone spontaneouslyhypertensive ratsrdquo European Journal of Pharmacology vol 580no 1-2 pp 201ndash213 2008
[218] A C Rosenkranz H Lob T Breitenbach R Berkels and RRoesen ldquoEndothelial antioxidant actions of dihydropyridines
and angiotensin converting enzyme inhibitorsrdquo European Jour-nal of Pharmacology vol 529 no 1ndash3 pp 55ndash62 2006
[219] V Kain S Kumar and S L Sitasawad ldquoAzelnidipine preventscardiac dysfunction in streptozotocin-diabetic rats by reducingintracellular calcium accumulation oxidative stress and apop-tosisrdquo Cardiovascular Diabetology vol 10 article 97 2011
[220] K Nakamura S Yamagishi and H Inoue ldquoUnique atheropro-tective property of azelnidipine a dihydropyridine-based cal-cium antagonistrdquoMedical Hypotheses vol 65 no 1 pp 155ndash1572005
[221] TMatsui S Yamagishi K Nakamura S Kikuchi andH InoueldquoAzelnidipine a dihydropyridine-based calcium antagonistinhibits angiotensin II-induced oxidative stress generation anddownregulation of pigment epithelium-derived factor mRNAlevels in microvascular endothelial cellsrdquo Drugs under Experi-mental and Clinical Research vol 31 no 5-6 pp 215ndash219 2005
[222] C Ohmura H Watada T Shimizu et al ldquoCalcium channelblocker azelnidipine reduces lipid hydroperoxides in patientswith type 2 diabetes independent of blood pressurerdquo EndocrineJournal vol 54 no 5 pp 805ndash811 2007
[223] H Daikuhara F Kikuchi and T Ishida ldquoThe combination ofOLmesartan and a CAlcium channel blocker (azelnidipine) orcandesartan and a calcium channel blocker (amlodipine) intype 2 diabetic hypertensive patients theOLCA studyrdquoDiabetesand Vascular Disease Research vol 9 no 4 pp 280ndash286 2012
[224] MAbe NMaruyama KOkada SMatsumoto KMatsumotoand M Soma ldquoAdditive antioxidative effects of azelnidipine onangiotensin receptor blocker olmesartan treatment for type 2diabetic patients with albuminuriardquoHypertension Research vol34 no 8 pp 935ndash941 2011
[225] K Mizushige ldquoAntioxidative activities of thiazolidinedionesand dihydropyridine-type calcium antagonistsrdquo IRYOmdashJapa-nese Journal of National Medical Services vol 59 no 11 pp 581ndash592 2005
[226] S Manabe T Okura T Fukuoka and J Higaki ldquoAntioxidativeeffects of azelnidipine on mesangial cell proliferation inducedby highly concentrated insulinrdquo European Journal of Pharma-cology vol 567 no 3 pp 252ndash257 2007
[227] Y Koyama Y Takeishi H Takahashi et al ldquoAzelnidipine inhi-bits H
2O2-induced cell death in neonatal rat cardiomyocytesrdquo
CardiovascularDrugs andTherapy vol 21 no 1 pp 69ndash72 2007[228] K Shinomiya K Mizushige M Fukunaga et al ldquoAntioxidant
effect of a new calcium antagonist azelnipidine in culturedhuman arterial endothelial cellsrdquo Journal of International Med-ical Research vol 32 no 2 pp 170ndash175 2004
[229] T Ohyama K Sato K Kishimoto et al ldquoAzelnidipine is acalcium blocker that attenuates liver fibrosis and may increaseantioxidant defencerdquo British Journal of Pharmacology vol 165no 4 pp 1173ndash1187 2012
[230] L A Calo F Zaghetto E Pagnin P A Davis A Sempliciniand A C Pessina ldquoEffect of manidipine on gene expressionand protein level of oxidative stress-related proteins p22phoxand HO-1 Relevance for antihypertensive and anti-remodelingeffectsrdquo Journal of Cardiovascular Pharmacology vol 43 no 4pp 531ndash538 2004
[231] R Ghyasi G Sepehri M Mohammadi R Badalzadeh and AGhyasi ldquoEffect of mebudipine on oxidative stress and lipid per-oxidation in myocardial ischemic-reperfusion injury in maleratrdquo Journal of Research in Medical Sciences vol 17 no 12 pp1150ndash1155 2012
Oxidative Medicine and Cellular Longevity 35
[232] DCAndersson J Fauconnier T Yamada et al ldquoMitochondrialproduction of reactive oxygen species contributes to the 120573-adrenergic stimulation of mouse cardiomycytesrdquoThe Journal ofPhysiology vol 589 no 7 pp 1791ndash1801 2011
[233] A F Ceylan-Isik N Ari M Stefek et al ldquoEffects of a long-term treatment with an antioxidant pyridoindole on vascularresponsiveness in diabetes-induced aging ratsrdquo Current AgingScience vol 4 no 2 pp 150ndash157 2011
[234] S Saponara G Sgaragli and F Fusi ldquoQuercetin antagonismof Bay K 8644 effects on rat tail artery L-type Ca2+ channelsrdquoEuropean Journal of Pharmacology vol 598 no 1ndash3 pp 75ndash802008
[235] D A Sica ldquoInteraction of grapefruit juice and calcium channelblockersrdquo American Journal of Hypertension vol 19 no 7 pp768ndash773 2006
[236] P Mulder G Litwinienko S Lin P D MacLean L R CBarclay and K U Ingold ldquoThe L-type calcium channel block-ers Hantzsch 14-dihydropyridines are not peroxyl radical-trapping chain-breaking antioxidantsrdquo Chemical Research inToxicology vol 19 no 1 pp 79ndash85 2006
[237] L J Nunez-Vergara R Salazar C Camargo et al ldquoOxidation ofC4-hydroxyphenyl 14-dihydropyridines in dimethylsulfoxideand its reactivity towards alkylperoxyl radicals in aqueousmediumrdquo Bioorganic and Medicinal Chemistry vol 15 no 12pp 4318ndash4326 2007
[238] M E Ortiz L J Nunez-Vergara and J A Squella ldquoRelativereactivity of dihydropyridine derivatives to electrogeneratedsuperoxide ion in DMSO solutions a voltammetric approachrdquoPharmaceutical Research vol 20 no 2 pp 292ndash296 2003
[239] M E Ortiz L J Nunez-Vergara C Camargo and J A SquellaldquoOxidation of Hantzsch 14-dihydropyridines of pharmacolog-ical significance by electrogenerated superoxiderdquo Pharmaceuti-cal Research vol 21 no 3 pp 428ndash435 2004
[240] R S Raghuvanshi and K N Singh ldquoSuperoxide induced oxida-tive aromatization of Hantzsch 14-dihydropyridinesrdquo IndianJournal of Chemistry Section B Organic and Medicinal Chem-istry vol 47 no 11 pp 1735ndash1738 2008
[241] I Kruk A Kladna K Lichszteld et al ldquoAntioxidant activityof 4-flavonil-14-dihydropyridine derivativesrdquo Biopolymers vol62 no 3 pp 163ndash167 2001
[242] G D Tirzit I M Byteva K I Salokhiddinov G P Gurinovichand G Y Dubur ldquo14-Dihydropyridine derivatives as deactiva-tors of singlet oxygenrdquo Chemistry of Heterocyclic Compoundsvol 17 no 7 pp 682ndash684 1981
[243] G D Tirzit E Y Kazush and G Y Dubur ldquoInfluence of14-dihydropyridine derivatives on the generation of hydroxylradicalsrdquo Chemistry of Heterocyclic Compounds vol 28 no 4pp 435ndash437 1992
[244] N A Pizarro-Urzua and L J Nunez-Vergara ldquoNifedipine andnitrendipine reactivity toward singlet oxygenrdquo Journal of Photo-chemistry and Photobiology A Chemistry vol 175 no 2-3 pp129ndash137 2005
[245] L-F Wang H-Y Zhang L Konga Z-W Chena and J-G ShildquoDFT calculations indicate that 14-dihydropyridine is a promis-ing lead antioxidantrdquo Helvetica Chimica Acta vol 87 no 6 pp1515ndash1521 2004
[246] P Mulder H-G Korth and K U Ingold ldquoWhy quantum-thermochemical calculations must be used with caution toindicate lsquoa promising lead antioxidantrsquordquoHelvetica Chimica Actavol 88 no 2 pp 370ndash374 2005
[247] K Yao Y Ina K Nagashima K Ohmori and T Ohno ldquoAntiox-idant effects of calcium antagonists in rat brain homogenatesrdquo
Biological and Pharmaceutical Bulletin vol 23 no 6 pp 766ndash769 2000
[248] T Matsui S-I Yamagishi K Nakamura and H Inoue ldquoBayw 9798 a dihydropyridine structurally related to nifedipinewith no calcium channel-blocking properties inhibits tumournecrosis factor-120572-induced vascular cell adhesion molecule-1expression in endothelial cells by suppressing reactive oxygenspecies generationrdquo Journal of International Medical Researchvol 35 no 6 pp 886ndash891 2007
[249] K AMitrega B VargheseM Porc and T F Krzeminski ldquoAnti-arrhythmic and hemodynamic effects of oxy nifedipine oxynimodipine oxy nitrendipine and oxy nisoldipinerdquo Pharmaco-logical Research vol 66 no 4 pp 300ndash308 2012
[250] V Herbert ldquoSymposium prooxidant effects of antioxidantvitamins Introductionrdquo The Journal of Nutrition vol 126 no4 supplement pp 1197Sndash1200S 1996 httpjnnutritionorgcontent1264 Suppl1197Sfullpdf
[251] B Halliwell ldquoAre polyphenols antioxidants or pro-oxidantsWhat do we learn from cell culture and in vivo studiesrdquoArchives of Biochemistry and Biophysics vol 476 no 2 pp 107ndash112 2008
[252] C Winterbourn Pro-Oxidants or Antioxidants ChristchurchSchool of Medicine Depatment of Pathology Free RadicalSchool SFRBMUniversity of Otago San Francisco Calif USA2009 httpwwwsfrbmorgfrsWinterbournpdf
[253] A Morakinyo B Iranloye and O Adegoke ldquoCalcium antag-onists modulate oxidative stress and acrosomal reaction in ratspermatozoardquo Archives of Medical Science vol 7 no 4 pp 613ndash618 2011
[254] The Alpha-Tocopherol Beta Carotene Cancer Prevention StudyGroup ldquoThe effect of vitamin E and beta carotene on theincidence of lung cancer and other cancers in male smokersrdquoTheNew England Journal of Medicine vol 330 no 15 pp 1029ndash1035 1994
[255] B Poljsak ldquoStrategies for reducing or preventing the generationof oxidative stressrdquo Oxidative Medicine and Cellular Longevityvol 2011 Article ID 194586 15 pages 2011
[256] B Poljsak and I Milisav ldquoThe neglected significance of lsquoanti-oxidative stressrsquordquoOxidativeMedicine and Cellular Longevity vol2012 Article ID 480895 12 pages 2012
[257] T Godfraind and S Salomone ldquoAmbiguities in dietary antiox-idant supplementation compared to calcium channel blockerstherapyrdquo Frontiers in Pharmacology vol 6 article 10 2015
[258] H Wagner H Norr and H Winterhoff ldquoDrugs with adap-togenic effects for strengthening the powers of resistancerdquoZeitschrift fur Phytotherapie vol 13 no 2 pp 42ndash54 1992
Oxidative Medicine and Cellular Longevity 19
As a result nitrosonifedipine was already a long time agoclaimed as a candidate for a new class of antioxidative drugs(Kirule et al [195]) cellular protectors against oxidative stressin glomerular endothelial cells [174]
Moreover Misik et al [198] Ondrias et al [199] andStasko et al [200] studied AOA of nifedipine and its oxidizednitroso analogue NO-NIF prevents the progression of type2 diabetic nephropathy associated with endothelial dysfunc-tion through selective AO effects (Ishizawa et al [201]) NO-NIF administration reduces albuminuria and proteinuriaas well as glomerular expansion without affecting glucosemetabolism or systolic blood pressure NO-NIF also sup-presses renal and systemic OS and decreases the expressionof intercellular adhesion molecule-1 (ICAM-1) a marker ofendothelial cell injury in the glomeruli of the KKAy miceSimilar effects were achieved in endothelial nitric oxide syn-thase (eNOS) knockout mice Moreover NO-NIF suppressesurinary angiotensinogen (AGT) excretion and intrarenalAGT protein expression in proximal tubular cells in theKKAy mice On the other hand hyperglycemia-inducedmitochondrial superoxide production was not attenuated byNO-NIF in cultured endothelial cells
Fujii and Berliner found EPR evidence for free radicaladducts of nifedipine in vivo [202] The nature of these rad-icals was surmised by comparing the reaction of illuminatednitrosonifedipine with polyunsaturated fatty acids Surpris-ingly identical radical spectra were detected from excisedliver doped with nonilluminated nifedipine suggesting thatthis drug can be enzymatically converted in vivo to its nitrosoanalogue without the requirement for illumination This isone of the first reports of in vivo EPR evidence for a class ofunsaturated fatty acid radical conjugates resulting from thenormal metabolism of a common drug
Dıaz-Araya et al [173] studied some 4-nitrophenyl-DHPson Fe3+ initiated LP in rat brain slices LP as measuredby MDA formation was inhibited by all the tested nitro-aryl derivatives of 14-DHP over a wide range of concen-trations On the basis of both time course and IC
50experi-
ments the tentative order of AOA on rat brain slices wasnicardipine gt nisoldipine gt (RSSR)-furnidipine gt (RRSS)-furnidipine gt nitrendipine gt nimodipine gt nifedipine14-DHP derivatives that lack a nitro group in the mole-cule (isradipine and amlodipine) also inhibited LP in ratbrain slices but at higher concentrations than that of nitro-substituted derivatives All tested compounds reduced andoxidized nitrosoaryl derivatives (26-dimethyl-4-(2-nitro-sophenyl)-35-pyridinedicarboxylic acid dimethyl ester (pho-tooxidation product of nifedipine ndash NTP) ao) and weremore potent inhibitors of LP than their parent molecules(Valenzuela et al [104])
The electrooxidation process of 4-nitrosoaromatic DHPsis a strongly pH-dependent (two-electron two-proton mech-anism) ECEC type of mechanism that is the sequenceeminusH+eminusH+ at pH gt 85 ECCE mechanism (eminusH+H+eminus)at pH lt 85 dominates Reduction reaction of nitroso groupis as follows R-NO + 2eminus + 2H+ rarr RNHOH (Bollo et al[203])
352 Lacidipine It is a generic DHP type antihypertensiveCA 35-diethyl 4-2-[(1E)-3-(tert-butoxy)-3-oxoprop-1-en-1-yl]phenyl-26-dimethyl-14-dihydropyridine-35-dicarboxy-late
Ursini [204] described redox behaviour of lacidipine andshowed its tissue protective features Cristofori et al studiedantiatherosclerotic activity in addition to lacidipinersquos CAand AO properties [205] Lacidipine reduced the extent ofatherosclerotic area in hypercholesterolemic apoE-deficientmice (these mice show widespread vascular lesions whichclosely resemble the inflammatory fibrous plaques seen inhumans in atherosclerosis) The reduction may be associatedwith the capacity of the drug to maintain endothelial NOlevels at concentrations useful to protect against vasculardamage This work suggested that DHPs modulate vascularrelaxation via increased release of NO
Herbette et al [178] remarked optimal hydrophobicity oflacidipine due to cinnamic acid substituent so membraneinteractions and facilitation of the treatment of atherosclero-sis could proceed (see also Section 331 (2)-(a))
353 Amlodipine Amlodipine (Norvasc) (RS)-3-ethyl5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-14-dihydropyridine-35-dicarboxylate (AML) hasan antioxidant effect on vessels in vitro and is a 3rd genera-tion of charged dihydropyridine CCB that is widely used forthe treatment of hypertensive patients
Amlodipine was shown to have the highest affinity(amlodipine gt verapamil ≫ diltiazem) for the membranebilayer (119870
119901= 104) It produced the significant changes in
membrane thermodynamic properties including a reductionin the thermal phase transition temperature (minus11) enthalpy(minus14) and cooperative unit size (minus59) relative to thecontrol phosphatidylcholine liposomes (Mason et al [49])
Amlodipine AOA is related to its reductant nature orhydrogen donor properties respectively Its ability for donat-ing protons and electrons to the lipid peroxide moleculesblocks the LP process
Amlodipine and even its enantiomers (Zhang et al [206])act as ROS andNOS effectors in several model systems of OSAntioxidant properties of amlodipine were recently reviewedby Vitolina et al [32] Both in vitro and in vivo studiesof amlodipine AO properties revealed inhibition of lipidsoxidative damage primarily those associated with cellularmembranes and lipoprotein particles (LDL) (Mason et al[50])
Under controlled experimental conditions in vitro amlo-dipine showed AOA and ARA by inhibition of lipid peroxideformation and trapping ROS Its scavenging activity forhydroxyl and peroxyl radicals at concentrations as low as100 nmolL (which is remarkably less compared to the classi-cal antioxidants GSH uric acid and Trolox) was shown to beindependent of the calcium channel modulation (Franzoni etal [207])
AML showed efficiency as scavenger of peroxyl radicals(TOSC assay 5945 plusmn 544 unitsmg) significantly stronger(gt50 119875 lt 0001) than GSH (2733plusmn 636 unitsmg) and 70weaker (119875 lt 00001) than uric acid (18144 plusmn 696 unitsmg)and Trolox (17522 plusmn 734 unitsmg)
20 Oxidative Medicine and Cellular Longevity
Of interest the scavenging capacity of AML towardshydroxyl radicals (1455 plusmn 154 unitsmg) was 320 higher(119875 lt 000001) than that of GSH (358 plusmn 112 unitsmg) 20higher than that of uric acid (1198plusmn121 unitsmg) and 100higher than that of Trolox (759 plusmn 143 unitsmg)
Amlodipine was shown to increase enzyme activity ofparaoxonase (PON) and glutathione peroxidase (GSH-Px)However it also decreases glutathione reductase (GSSG-R)activity and diminishes the concentration of the endogenousantioxidant 120572-tocopherol (vitamin E) Moreover AML in aconcentration of 2 ngmL decreased the content of malonicdialdehyde and activity of superoxide dismutase in the blood(Gatsura [208])
Verapamil and amlodipine produced a potent anti-ischemic effect and reduced area of myocardial infarction inrats The observed changes were accompanied by inhibitionof LP In contrast to verapamil in vitro application of AML ina dose of 50 ngmL decreased hemoglobin affinity for oxygenWhen present in a concentration of 2 ngmLAMDdecreasedthe content of MDA and activity of SOD in the blood
On the other hand amlodipine shows no activity relatedto inhibition of macrophage superoxide release and cellmigration which occurs as a consequence of decreasedTNF120572induced O
2
∙ releaseAmlodipine-induced reduction of OS in the brain is
associated with sympathoinhibitory effects in stroke-pronespontaneously hypertensive rats (SHRSP) (Hirooka et al[209]) Antihypertensive treatment with amlodipine reducedOS in all examined areas of the brain and decreased bloodpressure without a reflex increase in sympathetic nerveactivity Nicardipine another CA DHP surprisingly wassignificantly less active than amlodipine
354 Lercanidipine Tomlinson and Benzie reported AOeffect of lercanidipine [210] which is well known as anti-hypertensive drug Zanidip 2[(33-diphenylpropyl)(methyl)-amino]-11-dimethylethyl methyl 26-dimethyl-4-(3-nitro-phenyl)-14-dihydropyridine-35-dicarboxylate Compara-tive data about this drug AOA were presented in parts of thispaper about other individual CA DHPs and in the part aboutthe ex vivo DHPs effects on LDL
355 Nimodipine Nimodipine (ND) commercially knownas Nimotop is 3-(2-methoxyethyl) 5-propan-2-yl 26-dim-ethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxy-late It is centrally active CA
Treatment with glutathione blocked andwith nimodipineattenuated neuronal cell death caused by prolonged exposureof cell culture to 4-HNE (Faraqui [211])
Nascimento et al [212] found AO effect of nimodipine inyoung rats after pilocarpine- (PIL-) induced (in 400mgkg)seizures The PIL administration increased the striatal cata-lase (CAT) activity The administration of ND 30mgkg30min before PIL preserved normal value of CAT activityOn the other hand no difference was detected in the animalstreated with lower dose 10mgkg These results confirmthe neuroprotectiveantiepileptic effect of ND in young ratssuggesting that this drug acts positively on lipid peroxidation
(in both doses) Nimodipine cannot induce these effects viablockade of Ca2+ channel
Ismailoglu et al [213] studied the therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjury These beneficial effects in rats after cerebral corticalinjury seemed to be related to AOA of nimodipine
356 Benidipine Licensed in Japan and South Asia as CA(CCB) benidipine possesses AO properties Chemically it is5-methyl 3-[(3R)-1-(phenylmethyl)piperidin-3-yl] 26-dim-ethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxy-late (or its hydrochloride (4R)-rel-35-pyridinedicarboxylicacid 14-dihydro-26-dimethyl-4-(3-nitrophenyl)- 3-methyl5-[(3R)-1-(phenylmethyl)-3-piperidinyl] ester hydrochloride(1 1))
Benidipine influences processes connected with OS inseveral ways It prevents lysophosphatidylcholine- (lysoPC)-induced injury and ROS production in human aorticendothelial cells (HAECs) (Matsubara and Hasegawa [214])Matsubara et al [215] explained this effect based on stimula-tion of nitric oxide release
LysoPC is a component of oxidized low-density lipopro-teins (oxLDLs) which plays an important role in the patho-genesis of atherosclerosis Pretreatmentwith benidipine (03ndash3 120583molL) for 24 h protected against lysoPC-induced cyto-toxicity in the HAECs through inhibition of both lysoPC-stimulated ROS production and caspase-37-like activationwith a similar potency Since caspase-37 is involved inexecuting the apoptotic process the reduction of the activityof this enzyme by benidipine may explain the antiapoptoticeffect of the drug However benidipine did not suppresslysoPC-induced phosphorylation of mitogen-activated pro-tein kinases and Ca2+ influx in HAECs These results suggestthat the antioxidant properties of benidipine may be respon-sible for its ability to inhibit ROS production a possiblereason for reduced activation of caspase-37 In conclusionbenidipine suppresses lysoPC-induced endothelial dysfunc-tion through inhibition of ROS production which is due atleast in part to its antioxidant effect and not through theinhibition of L-type voltage-dependent calcium channels
Matsubara and Hasegawa [216] examined the effectsof benidipine on cytokine-induced expression of adhesionmolecules and chemokines (chemoattractants) which areimportant for the adhesion of monocytes to endotheliumPretreatment of HAECs with benidipine (03ndash10 120583molL)for 24 h significantly suppressed cytokine-induced vascularcell adhesion molecule-1 (VCAM-1) and intracellular celladhesion molecule-1 (ICAM-1) mRNA and protein expres-sion resulting in reduced adhesion of THP-1 monocytesBenidipine also suppressed induction of monocyte chemoat-tractant protein-1 (MCP-1) and interleukin-8 Benidipinealso inhibited redox-sensitive transcriptional nuclear factor-120581B (NF-120581B) pathway as determined by Western blotting ofinhibitory 120581B (I120581B) phosphorylation and luciferase reporterassay Results of analysis using optical isomers of benidip-ine and antioxidants suggest that these inhibitory effectswere dependent on pharmacological effects other than Ca2+antagonism Benidipine may thus have anti-inflammatoryproperties and benefits for the treatment of atherosclerosis
Oxidative Medicine and Cellular Longevity 21
Benidipine was also shown to inhibit ROS production inpolymorphonuclear leukocytes and oxidative stress in salt-loaded stroke-prone spontaneously hypertensive rats (Mat-subara et al [217])
It should be mentioned that other DHPs also haveendothelial AO actions [218]
357 Azelnidipine (AZL) Azelnidipine 3-[1-[di(phen-yl)methyl]azetidin-3-yl] 5-propan-2-yl 2-amino-6-methyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate(AZL) CAS number 123524-52-7 is commercially available4-nitroaryl-DHP type calcium antagonist with long-actingantihypertensive action (long-acting CA (CCB)) and a lowreported incidence of tachycardia It additionally possessesbeneficial effects in OS and diabetic conditions
Azelnidipine prevents cardiac dysfunction in strepto-zotocin-diabetic rats by reducing intracellular calcium accu-mulation (altering intracellular Ca2+ handling proteins) OSand apoptosis (Kain et al [219]) AZL can reduce the superox-ide production It exerts its protective effects by targeting theNADPH oxidase and mitochondrial redox enzymes AZL-treated diabetic rats express enhanced level of bcl-2 in thelysates of heart muscle indicating that AZL plays protectiverole in cardiac apoptosis
It has been previously observed that azelnidipine inhibitstumor necrosis factor-alpha-induced endothelial cell (EC)oxidative stress through its AO properties (Nakamura etal [220]) Azelnidipine but not nitrendipine completelyinhibits the Ang II-induced ROS generation in ECs (Matsuiet al [221])
Furthermore azelnidipine but not nitrendipine wasfound to partially restore decreased pigment epithelium-derived factor (PEDF) mRNA levels in Ang II-exposed ECsThis study suggests that AZL influence depends on its antiox-idative properties Authors concluded that upregulation ofPEDF by azelnidipine may become a therapeutic targetfor the treatment of diabetic retinopathy associated withhypertension
Antihypertensive agents with AO effects are potentiallyuseful for diabetic patients with hypertension While DHPtypeCAare among themost frequently used antihypertensivedrugs azelnidipine has been reported to have a unique AOeffect in vitro and in vivo in experimental animals (Ohmuraet al [222]) In hypertensive diabetic patients azelnidipinetreatment for 12 weeks induced a more significant decreasein erythrocyte LOOH level than amlodipine although thevalues related to blood pressure during each treatmentremained comparable These data confirm the usefulness ofLOOH level in erythrocyte membrane as a marker of OS invivo and indicate that azelnidipine has a unique antioxidativeproperty in humans
Daikuhara et al [223] reported the results of the OLCAstudy based on combination of (1) olmesartan and a calciumchannel blocker (azelnidipine) or (2) candesartan and a CCBamlodipine in two groups of diabetic hypertensive patientsPatients treated with the first combination presented highlypersistent early morning antihypertensive effect and strongerdecrease in heart rate fasting blood glucose andHbA1c levels
and microalbuminuria when compared to patients treatedwith the combination (2) Because diabetes is associated withsevere chronic OS the observed results might be at least in apart due to the AOA of azelnidipine
In favor of this are findings of Abe et al [224] who foundadditive antioxidative effects of azelnidipine on angiotensinreceptor blocker olmesartan treatment for type 2 diabeticpatients with albuminuria
Similarly the AOA of thiazolidinediones (insulin sensi-tizer) and their effect on cardiovascular function in type 2diabetic model rats and also those of some DHPs (nifedipineamlodipine or AZL commonly used antianginal and anti-hypertensive agents) in cultured human endothelial cells LPwere examined (Mizushige [225]) The AOA was evaluatedby measuring 8-iso-prostaglandine F
2120572concentration and
azelnidipine exhibited potent AOAInsulin (INS) resistance combined with hyperinsuline-
mia is involved in the generation of OS A relation-ship exists between increased production of ROS and thediverse pathogenic mechanisms involved in diabetic vascularcomplications including nephropathy Manabe et al [226]revealed that high doses of INS augmented mesangial cellproliferation through generation of intracellular ROS andactivation of redox signaling pathways Cell proliferation wasincreased in a dose-dependent manner by high doses of INS(01ndash10 120583M) but was inhibited by 01120583M AZL Namely theINS-increased phosphorylation of mitogen activated proteinkinaseextracellular signal-regulated kinase 12 (MAPKERK12) was inhibited by 01 120583MAZL The same AZL concen-tration blocked intracellular ROS production more effec-tively than 01 120583M nifedipine The NADPH oxidase inhibitorapocynin (001ndash01120583M) prevented INS-induced mesangialcell proliferation So azelnidipine inhibits insulin-inducedmesangial cell proliferation by inhibiting the productionof ROS Therefore azelnidipine may have the potential toprotect against the onset of diabetic nephropathy and slowits progression
Azelnidipine inhibited H2O2-induced cell death in
neonatal rat cardiomyocytes (Koyama et al [227]) Azelnidip-ine and nifedipine did not affect theH
2O2-induced activation
of extracellular signal-regulated protein kinases (ERK) andp38 MAPK (mitogen-activated protein kinase) In contrastazelnidipine but not nifedipine inhibited H
2O2-induced c-
Jun NH2-terminal kinases (JNK) activation Authors con-
cluded that azelnidipine has inhibited theH2O2-induced JNK
activation and cardiac cell death Therefore azelnidipine mayhave cardioprotective effects against OS
A specific atheroprotection activity of azelnidipine relatesto inhibition of TNF-120572-induced activator protein-1 activa-tion and interleukin-8 expression in human umbilical veinendothelial cells (HUVEC) through suppression of NADPHoxidase-mediated reactive oxygen species generation (Naka-mura et al [220]) TNF-120572 could play a central role in patho-genesis of insulin resistance and accelerated atherosclerosis inthe metabolic syndrome The concentration of AZL found tobe effective in these in vitro experiments is within therapeuticrange As EC do not possess voltage-operated L-type calciumchannels it is suggested that the beneficial effects of azelni-dipine are not likely due to CA property but to its unique AO
22 Oxidative Medicine and Cellular Longevity
ability Furthermore it has been recently found that serumlevels of monocyte chemoattractant protein-1 a biomarkerfor subclinical atherosclerosis were significantly decreased bythe AZL treatment in patients with essential hypertension Inthis paper [220] authors hypothesize that due to its uniqueTNF-120572 signalmodulatory activity and antioxidative propertyazelnidipine may be a promising DHP for targeting diabetesand cardiovascular diseases in hypertensive patients withmetabolic syndrome
Shinomiya et al [228] evaluated its AOA in culturedhuman arterial EC under OS Azelnidipine has shown apotent antioxidative effect that could be of significant clinicalbenefit when combined with its long-lasting antihypertensiveaction and low incidence of tachycardia
Azelnidipine inhibited TGF-1205731 and angiotensin II- (AngII-) activated 1205721(I) collagen mRNA expression in hepaticstellate cells (HSCs) (Ohyama et al [229]) FurthermoreTGF-1205731- and Ang II-induced OS and TGF-1205731-induced p38and JNK phosphorylation were reduced inHSCs treated withAZL Azelnidipine significantly decreased inflammatory cellinfiltration profibrotic genes expression HSC activation LPoxidative DNA damage and fibrosis in liver of CCl
4- or
TAA-treated mice Finally AZL prevented decrease of theexpression of some AO enzymes and accelerated regressionof liver fibrosis in CCl
4-treated mice Hence the antifibrotic
mechanism of AZL against CCl4-induced liver fibrosis in
mice may have been due to an increased level of AO defenseAs azelnidipine is widely used in clinical practice withoutserious adverse effects it may provide an effective newstrategy for antifibrotic therapy
358 Manidipine Manidipine (2-[4-(diphenylmethyl)pip-erazin-1-yl]ethyl methyl 26-dimethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate) is a DHP CCB withreported nephroprotective properties Calo et al [230] stud-ied effect of manidipine on gene expression and proteinlevel of OS related proteins p22(phox) (human neutrophilcytochrome b light chain (CYBA)) and heme oxygenase-1HO-1 Relevance for antihypertensive effects was revealedThe study assessed the effect of manidipine on normalsubjectsrsquo monocyte gene and protein expression of OS relatedproteins such as p22phox a NADPH oxidase system subunitcritical in generating O
2
∙minus and HO-1 induced by and pro-tective against OS Manidipine was compared with the ACEinhibitor captopril and the CCB nifedipine in the presenceand in the absence of sodiumarsenite (NaAsO
2) as an inducer
of OS Monocyte p22phox (CYBA) mRNA production wasreduced by both manidipine and captopril while no changeswere induced by nifedipine Manidipine increased monocyteHO-1 mRNA production while nifedipine and captoprilshowed no effect The effects of manidipine on p22phoxand HO-1 gene expression in the presence of OS were alsoconfirmed at the protein level Thus manidipine seems tosuppress p22phox and to increase the HO-1 mRNA produc-tion and protein level The manidipine-induced increase ofHO-1 gene and protein expression seems to be a peculiareffect of this drug since it is not observed with captopriland nifedipine This effect together with the reduction of
p22phoxmRNAproduction could play a role in its protectivemechanism against OS
359 Mebudipine The protective effect of mebudipine (14-dihydro-26-dimethyl-4-(3-nitrophenyl)-35-pyridinedicar-boxylic acid 3-methyl-5-tert-butyl ester BAY-n-6391) wasrevealed on OS and LP (MDA decrease SOD GPX andcatalase increase) in myocardial ischemic-reperfusion injuryin male rats (Ghyasi et al [231])
There are articles about other commercial and experi-mental DHPs on OS but we have reviewed only the mostcommonly studied compounds Effects of other commercialCA DHPs on OS are also mentioned in several parts of thisreview
36 14-DHPs Ca Agonists andTheir AOA and ARA For themost popular calcium agonist DHP Bay K 8644 no reactionwith peroxyl radicals was registered (Toniolo et al [114])However interactionwith other compounds possessing AOAand ARA (quercetin) was found
Opposite to that AON-acetylcysteine (NAC) diminishedincrease in Ca2+ transient amplitude and cell shorteninginduced by ISO and forskolin whereas NAC had no effecton the (S)-(minus)-methyl-14-dihydro-26-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylatemdash(minus)-BayK 8644-induced increases (Andersson et al [232])
Increased vasoconstriction responses to Bay K 8644 (3 times10minus7ndash3times 10minus5M)were significantly decreased by pyridoindoleantioxidant stobadine treatment in diabetes (Ceylan-Isik etal [233])
The functional interaction between two L-type Ca2+channel activators quercetin and Bay K 8644 has beeninvestigated in vascular smooth muscle cells Biological ARAcompound quercetin at nutritionally meaningful concen-trations limited the responsiveness of vascular L-type Ca2+channels to the pharmacological stimulation operated by BayK 8644 These data contribute to a better understanding ofquercetin effects on experimental in vivo cardioprotection(Saponara et al [234]) Thus these findings indicated thatalthough Bay K 8644 does not exert potent and direct AOAyet acting as calcium agonist it may affect efficiency of AOsubstances and vice versa
Interaction of grapefruit juice (containing quercetin andits analogues) with DHPs CA diminished effectiveness of CAaction of DHPs (Sica [235])
37 Interpretations of the Mechanism(s) of RadicalScavenging and AOA by DHPs
371 Molecular Mechanism(s) of Radical Scavenging andAOA of DHPs in the Model Systems 35-Dicarbonyl-14-di-hydropyridine derivatives possess powerful bis-120573-carbony-lvinyl-amino conjugation and for that reason cannot be con-sidered as ordinary amino antioxidants The electron andorH donation from DHPs ensures their reductant role andresults in AOA and ARA Oxidation reaction from DHPsresults in production of corresponding heteroaromatic pyri-dine derivatives
Oxidative Medicine and Cellular Longevity 23
Detailed studies were made about substituent in DHPring positions 14- namely 4-unsubstituted- 4-substituted4-alkyl- 4-aryl- 4-alkylaryl- ao 26- 35- (diacetyl ordialkoxycarbonyl chain ao) electronic and steric effects onAOA and ARA of DHPs [44 45 51] see Sections 331and 35 The bell-shaped dependence of DHPs AOA onthe 35-dialkoxycarbonyl- chain length was observed [4445 107 109 112] with the maximum activity at C
2H5ndash
C4H9 Decrease of AOA and incorporation into liposomes for
DHPs with alkyl chains longer than R gt C4H9further were
clarified as probable tendency to self-aggregation of thesecompounds ([51] and citation number 245 therein) Electronacceptorelectron donor properties are relevant for expres-sion of AOA or ARA of 35-disubstituted DHPs 35-Diacyl-substituted and 35-dicarbanilido- and 35-dipyridylamido-substituted DHPs are more active as AOs as their 35-dicyano-substituted analogues which have electron acceptorproperties [186]
Dubur et al [89] observed overwhelming steric influenceof substituents in position 4 of the DHP ring Gaviraghiet al [163 164] proposed that AO activity of DHPs ispartly dependent on capacity of the 14-DHP ring to donateelectrons to the propagating radical (ROO∙ or RO∙) and toreduce it to a less reactive form The abstraction (donation)of electron andor H in the oxidation and LP reactionstakes place from all 35-dicarbonyl-14-DHP systems andresults in the formation of corresponding pyridine derivatives(Augustyniak et al [51]) The physicochemical mechanism ofARA and AOA of 14-DHP has been extensively studied anddiscussed (Mulder et al [236]) but precise mechanisms oftheir activity need further clarification
The reactivity of C-4 substituted 14-DHPs possessingeither secondary or tertiary nitrogen atom in the DHP ringtoward alkyl alkylperoxyl radicals and ABTS radical cationwas determined in aqueous media at pH 74 [103] Thesecompounds reacted faster toward alkylperoxyl radicals andABTS radical cation than alkyl ones N-Ethyl-substitutedDHPs showed the lowest reactivity
The 4-methyl substituted DHP was the most reac-tive compound in previously mentioned reactions (Lopez-Alarcon et al [103]) However it was less active (068versus 10) than Trolox-C DHPs having electron-donatingsubstituents (4-Me-DHP and p-MeO-Phe-DHP) showed thehighest kinetic rate constants toward ABTS radical cation p-nitro-Phe-DHP a compound with an electron-withdrawingsubstituent showed a lower kinetic rate constant and N-alkyl-DHP compounds show kinetic rate constants lowerthan the -NH-DHP
Hydrogen at the 1-position of the DHP ring was revealedaccording to the deuteriumkinetic isotope effect studies to beinvolved in the proposedARAmechanismThis fact ismostlynoticeable in the case of alkyl radicals N-Ethyl-substitutedDHPs show the lowest reactivity when compared to Troloxor nisoldipine In all cases the respective pyridine derivativewas detected as the main product of the reaction (Lopez-Alarcon et al [103]) Authors indicate that the kinetic rateconstants toward alkyl alkylperoxyl andABTS radical cationdepend on the nature of the substituents in the C-4 positionof DHP and the presence of the secondary amine group in the
dihydropyridine ring that is the presence of the hydrogen in1-position
Yanez et al [197] have studied the reactivity of 11derivatives of 14-DHPs (including commercial CA) withalkylperoxyl radicals and ABTS radical cation The tested14-DHPs were 83-fold more reactive towards alkylperoxylradicals than to the ABTS cation radical All commercial14-DHP type CCBs were weaker than Trolox-C The par-ticipation of the hydrogen atom in the 1-position appearsto be very relevant for exhibited reactivity Hantzsch ester(diludine)was again found to be themost active compound inthe reaction with alkylperoxyl radicals 23-fold more activethan Trolox The photodegradation product of nifedipine(nitrosophenyl derivative of pyridine) also showed a highactivity Kinetic rate constants for the reaction between 14-DHP compounds and alkylperoxyl radicals exhibited a fairlygood linear correlation with the oxidation peak potentialof DHP derivatives However the activity of tested 14-DHPs towards ABTS radical cation showed an independencebetween kinetic rate constants and oxidation peak potentials
Kirule et al [195] andTirzit et al [196] studiedmechanismof AOA of 4-nitrophenyl-14-DHPs nifedipine and its ana-logues involving formation of 4-(21015840-nitrosophenyl)-pyridinederivative (as active principle) as a result of intramolecularredox reaction using chemical electrochemical and bio-chemical approaches (see Sections 331 and 351)
Nunez-Vergara et al [237] reported the electrochemicaloxidation of C4-hydroxyphenyl-substituted 14-DHP deriva-tives The oxidation proceeds via formation of the unstabledihydropyridyl radical as confirmed by controlled-potentialelectrolysis (CPE) and ESR experiments This type of 14-DHPs has significant activity towards the radicals even whencompared with commercial 14-DHP drugs with well-knownantioxidant ability
It was observed that nicardipine preferentially targets RO∙radicals and is inactive against ROO∙ Lacidipine on theother hand is equally active towards both types of radicals(Gaviraghi et al [164]) The cytoprotective effect againstexposure to H
2O2was more significant for lacidipine (ID
50=
14 nM its log119875 = 54 membrane partition = 136000 assumesposition located 7 A near to the membrane center otherless lipophilic DHPs located 12ndash16 A far from the center)as compared to amlodipine nifedipine and nicardipine insmooth muscle cell culture (Gaviraghi et al [164]) Oxidativeeffect of H
2O2shifts the Ca channel toward an open state
Thus the redox property of CCBs DHPs may augment theirCCB properties
Oxidation of pharmacologically active Hantzsch 14-dihydropyridines was found by electrogenerated superoxideusing a voltammetric approach in DMSO solutions (Ortiz etal [238] and Ortiz et al [239]) Raghuvanshi and Singh [240]have also reported oxidative aromatization of these DHPsinduced by superoxide
Chemiluminescence (CL) was used in the studies ana-lyzing the antioxidant activity of 12 various 4-flavonil-14-dihydropyridine derivatives (Kruk et al [241]) on a chemicalsystem involving a superoxide radical anion These deriva-tives showed structural similarity to flavonoids with respectto the presence of rings A B and C The results obtained in
24 Oxidative Medicine and Cellular Longevity
this study indicate that the tested derivatives may catalyzeconversion of superoxide radicals through mimicking theactivity of superoxide dismutase by delivering H+ for reac-tion
O2
minus∙+O2
minus∙+ 2H+ 997888rarr H
2O2+1O2
(3)
The enhanced emission of the light in the presence oftested compounds was significant and related to stimulatedproduction ofH
2O2and 1O
2fromO
2
∙The latter specieswereremoved from the reactionmixture by the following sequenceof reactions
H+
O2
minus∙997888rarr HO
2
∙
HO2
∙+O2
∙minus997888rarr HO
2
minus+1O2
2HO2
∙997888rarr H
2O2+1O2
2 (1O2) 997888rarr (O
2)2+ h]lowast
(4)
or to take part in spontaneous dismutation of H2O2
2H2O2997888rarr 2H
2O + 1O
2(5)
The authors have offered an original concept of action for 4-flavonil-14-dihydropyridine derivatives unrelated to that ofO2
∙ radical-trapping chain-breaking antioxidants Insteadthey showed that these compounds act similar to superoxidedismutases converting O
2
∙ to H2O2 Hydrogen peroxide
is less toxic for cells than O2
∙ because it is predominantlyremoved by peroxidases and catalases Finally AO effect ofthese DHPs differed from those mediated by flavonoids witha catechol structure of ring B which are well-known 1O
2
quenchersMulder and collaborators came to similar conclusions
especially related to molecular mechanisms of antioxidativeactivity of DHPs [236]TheAOproperties of Hantzsch 14-di-hydropyridine esters and two dibenzo-14-dihydropyridines910-dihydroacridine (DHAC) and N-methyl-910-dihydro-acridine (N-Me-DHAC) have been explored by determin-ing the autoxidation of styrene or cumene at 30∘C Theseexperiments showed that Hantzsch esters are virtually inac-tive as chain-breaking antioxidants (CB-AOs) contrary tothe findings observed by Lopez-Alarcon et al [103] whoused CB-AOA in aqueous media at pH 74 Their reactivitytoward peroxyl radicals was shown to be some 5 orders ofmagnitude lower than that of the excellent CB-AO 22578-pentamethyl-6-hydroxy-chroman (PMHC)
DHAC was found to be sim10 times less reactive thanPMHC kinetic measurements using DHAC N-deuterio-DHAC and N-Me-DHAC pointing out the abstraction ofN-H hydrogen in DHAC by peroxyl radicals despite the factthat the calculated C-H bond dissociation enthalpy (BDE) inDHAC is about 11 kcalmol lower than the N-H BDE Therates of hydrogen atom abstraction by the 22-diphenyl-1-picrylhydrazyl radical (DPPH∙) have also been determined
for the same series of compounds The trends in the peroxyl∙and DPPH∙ rate constants were found to be similar [236]
Tirzit et al [242] have observed quenching of singletoxygen by DHPs This observation paved the ground forfurther research related to reactions of DHPs with hydroxylradicals (Tirzit et al [243]) singlet oxygen (Kazush etal [94]) and mechanisms of action A series of 14-DHPderivatives in NAD-H-Cu2+-H
2O2system inhibited forming
of the hydroxyl radical (HO∙) while 14-DHP derivativeswith electron donor substituents in the molecule were shownto be capable themselves of generating HO∙ in the presenceof Cu2+ and H
2O2 Rubene et al [186] also described
interaction of 14-DHP derivatives with Fentonrsquos reagentwhich produces hydroxyl radical (HO∙) Rate constants ofthe DHPs reaction (1st order) with HO∙ radical were highin the range 109 L times mol times secminus1 close to that of NADHcysteine and thiourea 35-Diacetyl- derivatives reacted fastercompared to 35-dialkoxycarbonyl- ones The reaction ratedecrease was observed in the case of substitution at position4 as compared to 4-unsubstituted DHPs Some DHPs havingelectron donor -COOminus groups in the 35- or 26- positionsof DHP ring reacted immediately (having rate constantshigher as 109 L times mol times secminus1) Rate constants with HO
2
∙
and O2
∙minus radicals were of lower degree Thus DHPs actingas oxygen radical scavengers could effectively inhibit ROSrelated reactions of LP initiation stage
Nifedipine and nitrendipine reactivity toward singletoxygen was also studied [244] Nifedipine was shown tobe a good scavenger of excited oxygen mainly via physicaldeactivation with values of the total rate constant rangingfrom 208 times 105Mminus1 sminus1 (in dioxane) to 930 times 105Mminus1 sminus1(in propylene carbonate)The less reactive pathway generateda photooxidation product For that reason a mechanisminvolving a perepoxide-like encounter complex in the firststep of the reaction path was proposed (see [244] Figures8 and 9 therein) The dependence was observed on solventmicroscopic parameters of the total rate constant for the reac-tion between singlet oxygen and 14-DHPs These findingsshow that nifedipine possesses stronger protective activity inbiological systems than nitrendipine
Density-functional-theory (DFT) calculations made byWang et al [245] confirmed the former experimental obser-vations that Hantzsch ester diludine is potent antioxi-dant with high H atom-donating ability and relatively lowprooxidant activity Possible reaction pathways for radicalsderived from 14-dihydropyridine and the resonance modesfor radical species were given [245]
Moreover two ethoxycarbonyl (EtOCO) substituentsat C(2) and C(6) should further enhance Hantzsch esterdiludine H-atom-donating ability due to resonance effectsHowever DHPs should be used in nonpolar rather than inpolar solvents since in the latter not H-atom but electrontransfer is preferred in the radical scavenging process [245]
Mulder et al [246] proposed that quantum-thermochem-ical calculations must be used with caution to indicate ldquoapromising lead antioxidantrdquo as they criticized the density-functional-theory (DFT) calculations made by Wang et al[245]
Oxidative Medicine and Cellular Longevity 25
372 Possible Mechanisms of DHPs ARA and AOA in the Bio-logical Systems Interaction with Other OSModifiers Some ofthese mechanisms were already described (Sections 331 (2)-(b) 331 (2)-(c) 331 (3)-(b) 35)
Enzymatic sources of ROSwith confirmed functional rolein hypertension are NADPH oxidase NO synthase (NOS)xanthine oxidase and cyclooxygenase Godfraind [3] hasreviewed AO effects and protective action of calcium channelblockers (CCBs) Yao et al [247] observed antioxidant effects(as inhibition of LP) for cardio- and neuroprotective CCBs(3ndash300 120583molL) including 7 DHPs in homogenates of ratbrain IC
50values (120583M) were as follows nifedipine (515) gt
barnidipine (586) gt benidipine (712) gt nicardipine (1293)gt amlodipine (1355) gt nilvadipine (1673) gt nitrendipine(2521) gt diltiazem (gt300) = verapamil (gt300) There arealso research articles describing the AO properties of CCBsthrough direct scavenging effect or through preservationof the endogenous SOD activity These findings indicatethat CCBs may also act by reducing the production ofvasoconstrictors angiotensin and endothelin
When present in concentrations that can be achievedin plasma CCBs may inhibit LP formation [3] This AOactivity seems to be typical for high lipophilic CCBs becausetheir chemical structure facilitates proton-donating andresonance-stabilization mechanisms that quench the freeradical reaction Their insertion in the membrane nearpolyunsaturated fatty acids at relatively high concentrationspotentiates proton donation (or atomary H) to lipid peroxidemolecules thereby blocking the peroxidation process Theremaining unpaired free electron associated with the CCBmolecule can be stabilized in well-defined resonance struc-tures associated with the DHP ring (Mason et al [48])
The radical reaction (according to Godfraind [3]) thatdescribes the AO effects of a DHP CCBs is LOOlowast + DHPrarr LOOH + DHPlowast (where LOOlowast is lipid peroxide radical)which in general is reaction (7) of the LP reaction cascadeconsisting of sim10 reactions (Scheme 2) [89]
As the rate constants of in vitro interaction of 4-substituted DHPs with peroxyl radicals are three ordersof magnitude lower than that of the vitamin E derivativethese DHPs must be considered as weak AO (Ursini [204])However due to partition coefficient of DHPs in membranesand in case of specific binding high local concentration ofDHPs may be obtained
DHPs without CCB properties for instance Bay w 9798although structurally related to nifedipine inhibit TNF-120572-induced vascular cell adhesion molecule-1 expression inendothelial cells by suppressing reactive oxygen speciesgeneration [248]
Mitrega et al [249] have discovered that antiarrhythmicand hemodynamic effects of oxidized heteroaromatic DHPsoxy nifedipine oxy nimodipine oxy nitrendipine and oxynisoldipine suggest that CCB DHPs and their metabolitescould act at least in two ways targeting OS related eventsas reductants (see Section 351 (1)) andor bypassing OSrelatedmetabolic routes Authors postulated that contrary tocurrent belief NIF metabolites are pharmacologically activeATP sensitive potassium channels were mentioned as a tar-get
38 DHPs Anti- or Prooxidants Several substances (ascorbicacid being the most commonly studied) can serve either asantioxidants or as prooxidants depending on given condi-tions (Herbert [250]) Therefore Halliwell [251] has reporteddilemma related to polyphenols as possible antioxidantsand prooxidants causing experimental artifacts (about 25)by oxidation of antioxidant compounds in the cell culturemedia Nevertheless it is generally accepted opinion thatpolyphenols act as antioxidants in vivo Studies on DHPs alsoface such a dilemmaThe exact roles (anti- or prooxidative) ofany specific DHP depend on its structure appliedachievedconcentration and specificity of the targetexperimentaltesting system
This situation resembles the case of antioxidative effectsof tocopherol which depends on the fate of the secondaryradical as proposed by Winterbourn [252] The question wasldquoVitamin E - Pro- or Antioxidantrdquo
997888rarr chain termination of lipid peroxidation
(6)
Prooxidant
Toc∙ + Lipid-H 997888rarr Lipid∙ (in LDL particles) (7)
This example shows that generally speaking any AO mustfulfil several criteria to be considered as an effective com-pound physiologically
(i) It must be able to functionally interact with endoge-nous scavengers even at low concentrations
(ii) It must affect endogenous pathways of OS(iii) It should not have undesirable adverse effect(iv) It should manifest the antioxidant efficacy dependent
on the oxidant(v) It must discriminate among different strategies
needed for 1-electron and 2-electron processes(vi) Radical scavengers can be prooxidant unless linked to
a radical sink (Winterbourn [252])
According to these statements DHPs could be effective asAO under physiological conditions in vivo (Godfraind [3]and others [30 31 38]) and in vitro in various experimentalsystems (cell and tissue) (see Sections 33 34 35)
Hence calcium antagonists appeared to disrupt thefine balance between the production and scavenging ofROS Nifedipine verapamil and diltiazem were shown toinduce significant oxidative stress in the epididymal sperm(increased MDA and decreased catalase and superoxidedismutase activity) This may be the reason for the inductionof male infertility [253]
The dualism of 14-DHP effects has been recorded asinhibition or promotion of LP as quenching or initiating
26 Oxidative Medicine and Cellular Longevity
oxygen and nitrogen free radical chain reactions radiopro-tecting or radiosensitizing antagonizing or synergizing Ca2+in electromechanical coupling as well as in the membranestabilization or labilization
39 Could DHPs Be Involved in Antioxidative Stress Beforebeing applied in vivo the optimal dose and optimal timeintervals forDHPs applicationmust be knownNamely whileROS have been traditionally considered as toxic byproductsof aerobic metabolism we know nowadays that ROS may actas essential signaling molecules needed for the control ofmany different physiological processes Whether the role ofROS will be damaging protective or signaling depends onthe delicate equilibrium between time- and location-specificROS production and scavenging Accordingly the imbalanceof the increased AO potential so-called antioxidative stresscould be dangerous similar to chronic OS in particular incase of extended exposure Inappropriate interventions inthe oxidative homeostasis by excessive antioxidants especiallyin case of chronic exposure to antioxidants might havevery negative effects as was published in the ATBC studyshowing an increased cancer incidence in smokers treatedby excessive beta-carotene [254] Therefore overconsump-tion of any natural or synthetic AO including DHPs asdietary supplements or drugs must be avoided in order tosuppress oxidative damage and must not disrupt the well-integrated antioxidant defense network (Poljsak [255] andPoljsak and Milisav [256]) This is especially important whenadministrating lipid-soluble antioxidants that can be storedin biomembranes thus not only attenuating or preventing LPbut also affecting physiological effects of the natural antiox-idants in particular tocopherol The interrelationship withthe status of endogenous antioxidantsprooxidants should befollowed
DHPs primarily suppress the initiation stages of LPprocessThey do not entirely stop the LP propagation Actingsynergistically with tocopherol diludine may prevent patho-logical excess of ROS production within the lipid moiety ofthe cellular membranes and LDL However due to its lowsolubility and fast metabolism its concentration in the cellsis low For that reason it cannot cause antioxidative stresseven if used for an extended period of time Thus diludine(diethone) could be only a mild antioxidant it has potentialfor restoring the pool of natural antioxidants (as synergist of120572-tocopherol and polyphenols) in the cells
Moreover DHPs CA used for cardioprotection andvasodilatation as commercial drugs in low concentrationsare fast metabolized via CYP3A4 and for that reason theirapplication does not induce cellular AO stress [53 160]However Godfraind and Salomone [257] have postulated noevidence that allows recommending dietary supplementationwith antioxidants for the primary or secondary prevention ofcardiovascular disease
So far there are no reports on antioxidative stress causedby some DHPs diludine and its analogues Diludine andits analogues therefore could act as adaptogens supportinghormetic effects of mild oxidative stress These compoundsmay act as potential multisided modulators of Yin-Yang
cycles of redox and cell functions (the electroplasmic cycle)(Wagner et al [258])
4 Conclusions
14-Dihydropyridines (14-DHPs) have broad spectrum ofOS modulating activities DHPs have reducing and lipidperoxidation inhibitor properties act as reductants in simplechemical systems and stabilize various biological systems(LDL mitochondria microsomes cells and tissues) againstOS Examples and peculiarities and mechanisms of antiox-idant activity (AOA) and antiradical activity (ARA) as wellas stress-protective effect of DHPs including commercialcalcium antagonists (CA) were highlighted These activitiesdepend on various structural parameters related to DHPs(presence and character of substituents) lipophilicity anddepth of the incorporation in the biologicalmembranesTheyalso depend on the experimental model system for exploringthe lipid peroxidation or oxidative stress Stress-protectiveeffect of some metabolites of CA (nifedipine) is reviewedAlthough some DHPs including CA have prooxidant prop-erties (on epididymal sperm cells) they can generally beconsidered as potent antioxidants Therefore comparisonof the AOA and ARA of different DHPs (mutually andwith other AOs) was described in detail According to thedata presented the DHPs might be considered as bellwetheramong synthetic compounds targeting OS and as a kind ofpharmacological measure for respective field of organic andmedicinal chemistry
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
Authors from Latvian IOS acknowledge ESF 201300021DP1112013APIAVIAA011 and National Research Pro-gramme PUBLIC HEALTHBiomedicine of the Republicof Latvia for financial support administration of the Insti-tute for technical support and Rufus Smits PhD for con-sultations in English The support of Cooperation in Euro-pean System of Science and Technology (COST) Domain ofChemistry Molecular Sciences and Technologies (CMST)was of highest importance for preparation of this paper
[2] D J Triggle ldquo14-Dihydropyridines as calcium channel ligandsand privileged structuresrdquoCellular andMolecular Neurobiologyvol 23 no 3 pp 293ndash303 2003
[3] T Godfraind ldquoAntioxidant effects and the therapeutic modeof action of calcium channel blockers in hypertension andatherosclerosisrdquo Philosophical Transactions of the Royal SocietyB Biological Sciences vol 360 no 1464 pp 2259ndash2272 2005
[4] E Cadenas ldquoMitochondrial free radical production and cellsignalingrdquoMolecular Aspects of Medicine vol 25 no 1-2 pp 17ndash26 2004
[5] E Cadenas ldquoFree radicals oxidative stress and diseasesrdquo inLecture PSC 616 p 38 Missouri University of Science andTechnology Rolla Mo USA httpwwwcarnicominstituteorgarticlesenrique cadenaspdf
[6] K Rahman ldquoStudies on free radicals antioxidants and co-fac-torsrdquo Clinical Interventions in Aging vol 2 no 2 pp 219ndash2362007
[7] V Bocci and G Valacchi ldquoFree radicals and antioxidants howto reestablish redox homeostasis in chronic diseasesrdquo CurrentMedicinal Chemistry vol 20 no 27 pp 3397ndash3415 2013
[8] M Valko C J Rhodes J Moncol M Izakovic and M MazurldquoFree radicals metals and antioxidants in oxidative stress-induced cancerrdquo Chemico-Biological Interactions vol 160 no 1pp 1ndash40 2006
[9] G Bartosz ldquoReactive oxygen species destroyers or messen-gersrdquo Biochemical Pharmacology vol 77 no 8 pp 1303ndash13152009
[10] R Visconti and D Grieco ldquoNew insights on oxidative stress incancerrdquo Current Opinion in Drug Discovery and Developmentvol 12 no 2 pp 240ndash245 2009
[11] R N Kujundzic N Zarkovic and K G Troselj ldquoPyridinenucleotides in regulation of cell death and survival by redoxand non-redox reactionsrdquo Critical Reviews in Eukaryotic GeneExpression vol 24 no 4 pp 287ndash309 2014
[12] B Halliwell and J M C Gutteridge ldquoThe definition and mea-surement of antioxidants in biological systemsrdquo Free RadicalBiology and Medicine vol 18 no 1 pp 125ndash126 1995
[13] V D Kancheva and O T Kasaikina ldquoBio-antioxidantsmdashachemical base of their antioxidant activity and beneficial effect
on human healthrdquo Current Medicinal Chemistry vol 20 no 37pp 4784ndash4805 2013
[14] H V Panglossi Ed Frontiers in Antioxidants Research NovaScience Publishers New York NY USA 2006
[15] E B Burlakova E M Molochkina and G A NikiforovldquoHybrid antioxidantsrdquo Oxidation Communications vol 31 no4 pp 739ndash757 2008 httpmembraneustceducnpaperpdfHybrid20Antioxidantspdf
[16] A Bast and G R M M Haenen ldquoTen misconceptions aboutantioxidantsrdquo Trends in Pharmacological Sciences vol 34 no 8pp 430ndash436 2013
[17] E B Burlakova A V 0lesenko E M Molochkina N PPalmina and N G Khrapova Bioantioxidants for RadiationDamage and Malignant Growth Nauka Moscow Russia 1975(Russian)
[18] J Fang T Seki and H Maeda ldquoTherapeutic strategies by mod-ulating oxygen stress in cancer and inflammationrdquo AdvancedDrug Delivery Reviews vol 61 no 4 pp 290ndash302 2009
[19] M Valko D Leibfritz J Moncol M T D Cronin M Mazurand J Telser ldquoFree radicals and antioxidants in normal physi-ological functions and human diseaserdquo International Journal ofBiochemistry and Cell Biology vol 39 no 1 pp 44ndash84 2007
[20] M Jimenez-Del-Rio and C Velez-Pardo ldquoThe bad the goodand the ugly about oxidative stressrdquo Oxidative Medicine andCellular Longevity vol 2012 Article ID 163913 13 pages 2012
[21] C D Kamat S Gadal M Mhatre K S Williamson Q N Pyeand K Hensley ldquoAntioxidants in central nervous system dis-eases preclinical promise and translational challengesrdquo Journalof Alzheimerrsquos Disease vol 15 no 3 pp 473ndash493 2008
[22] A Pompella H Sies R Wacker et al ldquoThe use of totalantioxidant capacity as surrogate marker for food quality andits effect on health is to be discouragedrdquo Nutrition vol 30 no7-8 pp 791ndash793 2014
[23] Z Ye and H Song ldquoAntioxidant vitamins intake and the risk ofcoronary heart disease meta-analysis of cohort studiesrdquo Euro-pean Journal of Cardiovascular Prevention and Rehabilitationvol 15 no 1 pp 26ndash34 2008
[24] P Knekt J Ritz M A Pereira et al ldquoAntioxidant vitamins andcoronary heart disease risk a pooled analysis of 9 cohortsrdquoTheAmerican Journal of Clinical Nutrition vol 80 no 6 pp 1508ndash1520 2004
[25] A C Carr and M C M Vissers ldquoSynthetic or food-derivedvitamin Cmdashare they equally bioavailablerdquo Nutrients vol 5 no11 pp 4284ndash4304 2013
[26] R Tabrizchi ldquoEdaravoneMitsubishi-TokyordquoCurrentOpinion inInvestigational Drugs vol 1 no 3 pp 347ndash354 2000
[27] K Kikuchi S Tancharoen N Takeshige et al ldquoThe efficacy ofedaravone (radicut) a free radical scavenger for cardiovasculardiseaserdquo International Journal of Molecular Sciences vol 14 no7 pp 13909ndash13930 2013
[28] D Mauzerall and F H Westheimer ldquo1-Benzyldihydronicoti-namidemdasha model for reduced DPNrdquo Journal of the AmericanChemical Society vol 77 no 8 pp 2261ndash2264 1955 ChemicalAbstracts vol 50 Article ID 2588i 1956
[29] F Bossert and W Vater ldquo14-Dihydropyridinesmdasha basis fordeveloping new drugsrdquo Medicinal Research Reviews vol 9 no3 pp 291ndash324 1989
[30] G Swarnalatha G Prasanthi N Sirisha and CMadhusudhanaChetty ldquo14-Dihydropyridines a multtifunctional moleculemdash areviewrdquo International Journal of ChemTech Research vol 3 no1 pp 75ndash89 2011
28 Oxidative Medicine and Cellular Longevity
[31] M Cataldi and F Bruno ldquo14-Dihydropyridines the multiplepersonalities of a blockbuster drug familyrdquo Translational Medi-cine UniSa vol 4 no 2 pp 12ndash26 2012 httpwwwncbinlmnihgovpmcarticlesPMC3728803
[32] R Vitolina A Krauze G Duburs and A Velena ldquoAspects ofthe amlodipine pleiotropy in biochemistry pharmacology andclinicsrdquo International Journal of Pharmaceutical Sciences andResearch vol 3 no 5 pp 1215ndash1232 2012
[33] D Grover S N Mokale and M T Shete ldquoDihydropyridinea novel pharmacophorerdquo International Journal of Pharmaceu-tical Erudition vol 1 no 2 pp 16ndash29 2011 httppharmaeru-ditionorgContentPaper20111-RV-320Final2016-29pdf
[34] A M Vijesh A M Isloor S K Peethambar K N ShivanandaT Arulmoli and N A Isloor ldquoHantzsch reaction synthesis andcharacterization of somenew 14-dihydropyridine derivatives aspotent antimicrobial and antioxidant agentsrdquo European Journalof Medicinal Chemistry vol 46 no 11 pp 5591ndash5597 2011
[35] P Mehta and P Verma ldquoAntimicrobial activity of some deriva-tives of 14-dihydropyridinesrdquo Journal of Chemistry vol 2013Article ID 865128 4 pages 2013
[36] P Olejnıkova L Svorc D Olsovska et al ldquoAntimicrobialactivity of novel C2-substituted 14-dihydropyridine analoguesrdquoScientia Pharmaceutica vol 82 no 2 pp 221ndash232 2014
[37] S Sepehri H Perez Sanchez and A Fassihi ldquoHantzsch-typedihydropyridines and biginelli-type tetra-hydropyrimidinesa review of their chemotherapeutic activitiesrdquo Journal of Phar-macy amp Pharmaceutical Sciences vol 18 no 1 pp 1ndash52 2015httpsejournalslibraryualbertacaindexphpJPPSarticleview2383617863
[38] S A Khedkar and P B Auti ldquo14-Dihydropyridines a classof pharmacologically important moleculesrdquo Mini-Reviews inMedicinal Chemistry vol 14 no 3 pp 282ndash290 2014
[39] G D Tirzit and G Ya Duburs ldquo14-dihydropyridines as inhi-bitors of free-radical reactionsrdquo Chemistry of Heterocyclic Com-pounds vol 8 no 1 pp 126ndash127 1972 Translated from KhimiyaGeterotsiklicheskikh Soedinenii no1 pp 133ndash134 1972 (Rus-sian)
[40] I Bogeski R Kappl C Kummerow R Gulaboski M Hothand B A Niemeyer ldquoRedox regulation of calcium ion channelschemical and physiological aspectsrdquoCell Calcium vol 50 no 5pp 407ndash423 2011
[41] S A Giller G Y Dubur Y R Uldrikis et al ldquoDiludine [Themethod to obtain 35-dicarbonylderivatives of 26-dimethyl-14-dihydropyridines]rdquo Authors certificate of USSR no 3004651971 [Byull Izobret no13 p 95 1971] and following patentsPatent of England no 1294650 1973 Patent of France no2055458 1971 Patent of Japan no 702883 1973 Patent ofHolland no 149787 1976 Patent of Italy no 969022 1974 Patentof FRG no 2036403 1978 US Patent no 3883673 1975 USPatent no 3948924 1976
[42] S A Giller G Y Dubur Y R Uldrikis et al ldquoImprovementsin or relating to the stabilization of carotenerdquo GB Patent no1294650 1972
[43] S A Giller G Y Dubur Y R Uldrikis et al ldquoStabilization ofcarotenerdquo US Patent no 3883673 1975 Chemical Abstracts vol83 Article ID 95193 1975
[44] Yu A Zilber G Ya Dubur K K Kumsar and A Kh VelenaldquoThe effect of antioxidants on the peroxidation of bimole-cular phospholipid membranesrdquo Latvijas PSR ZA Vestis Izves-tia Akademii Nauk Latviyskoy SSR vol 6 pp 80ndash82 1971(Russian) translated from the original Russian Doc Accesion
No AD0771751 distributed by NTIS US Department of Com-merce httpwwwdticmildtictrfulltextu2771751pdf
[45] G Ya Dubur Yu A Zilbers A Kh Velena A O Kumerovaand G D Tirzitis ldquoMultistage study of regulation of peroxida-tion processes in biological membranes by antioxidants of 14-dihydropyridine grouprdquo Izvestiya Akademii Nauk LatviyskoySSR vol 336 no 7 pp 65ndash68 1975 (Russian)
[46] R P Mason and M W Trumbore ldquoDifferential membraneinteractions of calcium channel blockers Implications forantioxidant activityrdquo Biochemical Pharmacology vol 51 no 5pp 653ndash660 1996
[47] R P Mason M F Walter M W Trumbore E G Olmstead Jrand P E Mason ldquoMembrane antioxidant effects of the chargeddihydropyridine calcium antagonist amlodipinerdquo Journal ofMolecular and Cellular Cardiology vol 31 no 1 pp 275ndash2811999
[48] R PMason I T MakMW Trumbore and P EMason ldquoAnti-oxidant properties of calcium antagonists related to membranebiophysical interactionsrdquo American Journal of Cardiology vol84 no 4 pp 16ndash22 1999
[49] R PMasonMW Trumbore and P EMason ldquoMembrane bio-physical interaction of amlodipine and antioxidant propertiesrdquoDrugs vol 59 no 2 pp 9ndash16 2000 (French)
[50] R P Mason P Marche and T H Hintze ldquoNovel vascularbiology of third-generation L-type calcium channel antagonistsAncillary actions of amlodipinerdquo Arteriosclerosis Thrombosisand Vascular Biology vol 23 no 12 pp 2155ndash2163 2003
[51] A Augustyniak G Bartosz A Cipak et al ldquoNatural andsynthetic antioxidants an updated overviewrdquo Free RadicalResearch vol 44 no 10 pp 1216ndash1262 2010
[52] T Grune N Zarkovic and K Kostelidou ldquoLipid peroxidationresearch in Europe and the COST B35 action lsquoLipid Peroxida-tion Associated Disordersrsquordquo Free Radical Research vol 44 no10 pp 1095ndash1097 2010
[53] E Carosati P Ioan M Micucci et al ldquo14-Dihydropyridinescaffold in medicinal chemistry the story so far and perspec-tives (part 2) action in other targets and antitargetsrdquo CurrentMedicinal Chemistry vol 19 no 25 pp 4306ndash4323 2012
[54] U Eisner and J Kuthan ldquoThe chemistry of dihydropyridinesrdquoChemical Reviews vol 72 no 1 pp 1ndash42 1972 httpwwwsci-encemadnessorgtalkfilesphppid=138742ampaid=6475
[55] J Kuthan and A Kurfurst ldquoDevelopment in dihydropyri-dine chemistryrdquo Industrial amp Engineering Chemistry ProductResearch and Development vol 21 no 2 pp 191ndash261 1982
[56] A Sausins and G Duburs ldquoSynthesis of 14-dihydropyridinesby cyclocondensation reactionsrdquo Heterocycles vol 27 no 1 pp269ndash289 1988
[57] A E Sausins and G Y Duburs ldquoSynthesis of 14-dihydro-pyridines in cyclocondensation reactions (review)rdquo Chemistryof Heterocyclic Compounds vol 28 no 4 pp 363ndash391 1992Translated from Khimiya Geterotsiklicheskikh Soedinenii no 4pp 435ndash467 1992 (Russian)
[58] S Kazda ldquoTwenty years of dihydropyridinesrdquo in Dihydropy-ridines Progress in Pharmacology and Therapy W-D Busse BGarthoff and F Seuter Eds pp 1ndash12 Springer Verlag BerlinGermany 1993
[59] J-P Wan and Y Liu ldquoRecent advances in new multicomponentsynthesis of structurally diversified 14-dihydropyridinesrdquo RSCAdvances vol 2 no 26 pp 9763ndash9777 2012
[61] Reaxys Database[62] J Tuttle ldquoStructure mechanism and reactivity of hantzsch
estersrdquo in MacMillan Lab Group Meeting (082504) p 332004 httpwwwprincetoneduchemistrymacmillangroup-meetingsJBT20Hantzschpdf
[63] A Saini S Kumar and J S Sandhu ldquoHantzsch reaction recentadvances in Hantzsch 14-dihydropyridinesrdquo Journal of Sci-entific amp Industrial Research vol 67 pp 95ndash111 2008
[64] L LW Cheung S A Styler and A P Dicks ldquoRapid and conve-nient synthesis of the 14-dihydropyridine privileged structurerdquoJournal of Chemical Education vol 87 no 6 pp 628ndash630 2010
[65] A Kumar R A Maurya S Sharma M Kumar and G BhatialdquoSynthesis and biological evaluation of N-aryl-14-dihydro-pyridines as novel antidyslipidemic and antioxidant agentsrdquoEuropean Journal of Medicinal Chemistry vol 45 no 2 pp 501ndash509 2010
[66] R S Kumar A Idhayadhulla A J Abdul Nasser and J SelvinldquoSynthesis and anticoagulant activity of a new series of 14-dihydropyridine derivativesrdquo European Journal of MedicinalChemistry vol 46 no 2 pp 804ndash810 2011
[67] H A Stefani C B Oliveira R B Almeida et al ldquoDihydro-pyrimidin-(2H)-ones obtained by ultrasound irradiation anew class of potential antioxidant agentsrdquo European Journal ofMedicinal Chemistry vol 41 no 4 pp 513ndash518 2006
[68] H Sun C Shang L Jin and J Zhang ldquoSynthesis and antiox-idant activity of a series of novel 3-chalcone-substituted 14-dihydropyridine derivativesrdquoHeterocyclic Communications vol18 no 5-6 pp 239ndash243 2012
[69] D B Tikhonov and B S Zhorov ldquoStructural model for dihy-dropyridine binding to L-type calcium channelsrdquo The Journalof Biological Chemistry vol 284 no 28 pp 19006ndash19017 2009
[70] G Y Dubur and Y R Uldrikis ldquoThe oxidation of 14-dihydro-pyridinesrdquo Chemistry of Heterocyclic Compounds vol 6 no 1pp 80ndash84 1970 Translated from Khimiya GeterotsiklicheskikhSoedinenii no 1 pp 83ndash88 1970 (Russian)
[71] G Ya Duburs A O Kumerova and Ya R Uldrikis ldquoEnzymicoxidation of hydrogenated pyridines with peroxidase-hydrogenperoxide systemrdquoLatvijas PSRZAVestis vol 73 no 7 pp 73ndash771970 (Russian) Chemical Abstracts vol 73 Article ID 94913g1970
[72] K Xie Y-C Liu Y Cui J-GWang Y Fu andT CWMak ldquoN-methyl-(R)-3-(tert-butyl)-sulfinyl-14-dihydropyridine a novelNADHmodel compoundrdquoMolecules vol 12 no 3 pp 415ndash4222007
[73] S Tamagaki T Mimura and W Tagaki ldquoMetal-ion-facilitatedoxidations of dihydropyridines with molecular oxygen andhydrogen peroxiderdquo Journal of the Chemical Society PerkinTransactions 2 no 10 pp 1645ndash1650 1990
[74] D Tirzite G Tirzitis andD Antipova ldquoReductive ability of 14-dihydropyridine derivatives in relation to ions of trivalent ironrdquoChemistry of Heterocyclic Compounds vol 35 no 5 pp 592ndash594 1999
[76] J Ogle J Stradins and L Baumane ldquoFormation and decay offree cation-radicals in the course of electro-oxidation of 12- and14-dihydropyridines (Hantzsch esters)rdquo Electrochimica Actavol 39 no 1 pp 73ndash79 1994
[77] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for the
synthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts C Wittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Berlin Germany 2010
[78] WDu and Zh Yu ldquoBiomimetic in situ regeneration of cofactorsNAD(P)+ and NAD(P)H models hantzsch esters and dihy-drophenanthridinerdquo Synlett vol 23 no 9 pp 1300ndash1304 2012
[79] H K Chenault and G M Whitesides ldquoRegeneration ofnicotinamide cofactors for use in organic synthesisrdquo AppliedBiochemistry and Biotechnology vol 14 no 2 pp 147ndash197 1987
[80] Y R Uldrikis A A Zidermane E A Biseniex I E Preisa GY Dubur and G D Tirzit ldquoEsters of 26-dimethyl-14-dihydro-pyridine-35-dicarboxylic acid and method of obtainingthereofrdquo WO 8000345 A1 1978 httpworldwideespacenetcompublicationDetailsbiblioDB=EPODOCampII=1ampND=3ampadjacent=trueamplocale=en EPampFT=Dampdate=19800306ampCC=WOampNR=8000345A1ampKC=A1
[81] Y Sambongi H Nitta K Ichihashi M Futai and I Ueda ldquoAnovel water-soluble Hantzsch 14-dihydropyridine compoundthat functions in biological processes through NADH regener-ationrdquo Journal of Organic Chemistry vol 67 no 10 pp 3499ndash3501 2002
[82] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for thesynthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts ChWittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Verlag Berlin Germany 2010
[83] T Okamura T Kikuchi A Nagamine et al ldquoAn approach formeasuring in vivo cerebral redox states using the oxidative con-version of dihydropyridine to pyridinium ion and themetabolictrapping principlerdquo Free Radical Biology and Medicine vol 38no 9 pp 1197ndash1205 2005
[84] K A Schellenberg and F H Westheimer ldquoA free-radicaloxidation of a dihydropyridine1ardquo The Journal of OrganicChemistry vol 30 no 6 pp 1859ndash1862 1965
[85] K A Schellenberg ldquoReaction of hydroxyl radical with thymi-dine Scavenging by a dihydropyridinerdquo Federation Proceedingsvol 38 no 3 I p 1433 1979
[86] E S Huyser J A K Harmony and F L McMillian ldquoPeroxideoxidations of dihydropyridine derivativesrdquo Journal of the Amer-ican Chemical Society vol 94 no 9 pp 3176ndash3180 1972
[87] A Sakamoto S T Ohnishi and R Ogawa ldquoInhibition of lipidperoxidation by some dihydropyridine derivativesrdquo Journal ofAnesthesia vol 7 no 2 pp 193ndash197 1993
[88] R Hardeland ldquoReview Neuroprotection by radical avoidancesearch for suitable agentsrdquo Molecules vol 14 no 12 pp 5054ndash5102 2009
[89] G Ya Dubur A Kh Velena V M Gukasov and Yu AVladimirov ldquoRegulation of peroxidation of mitochondrialmembrane lipids initiated by Fe2+ ions by antoxidants of the14-dihydropyridine series in experiments in vitrordquo Biomed-itsinskaya Khimiya vol 22 no 5 pp 665ndash673 1976 (Russian)Chemical Abstracts vol 88 Article ID 2640 1977
[90] G RMMHaenenM J T J Arts A Bast andMD ColemanldquoStructure and activity in assessing antioxidant activity in vitroand in vivo a critical appraisal illustrated with the flavonoidsrdquoEnvironmental Toxicology and Pharmacology vol 21 no 2 pp191ndash198 2006
[91] G Tirzitis and G Bartosz ldquoDetermination of antiradical andantioxidant activity basic principles and new insightsrdquo ActaBiochimica Polonica vol 57 no 2 pp 139ndash142 2010
30 Oxidative Medicine and Cellular Longevity
[92] G R Buettner and R P Mason ldquoSpin-trapping methods fordetecting superoxide and hydroxyl free radicals in vitro and invivordquo inCritical Reviews of Oxidative Stress and Aging Advancesin Basic Science Diagnostics and Intervention R G Cutler andH Rodriguez Eds vol 1 chapter 2 pp 27ndash38World ScientificLondon UK 2003
[93] M M Tarpey and I Fridovich ldquoMethods of detection ofvascular reactive species Nitric oxide superoxide hydrogenperoxide and peroxynitriterdquo Circulation Research vol 89 no3 pp 224ndash236 2001
[94] E Y Kazush E I Sagun G D Tirzit and G Y DaburldquoQuenching of singlet oxygen by electron donating derivativesof 14-dihydropyridinerdquo Chemistry of Heterocyclic Compoundsvol 30 no 5 pp 562ndash563 1994
[95] G Tirzitis E Kazush and G Duburs ldquoReaction of 14-dihydropyridine derivatives with peroxynitrite anionrdquo Chem-istry of Heterocyclic Compounds vol 34 no 3 pp 321ndash3231998 (Russian) Translated from Khimiya GeterotsiklicheskikhSoedinenii no 3 pp 355ndash357 1998
[96] L J Nunez-Vergara C Lopez-Alarcon P A Navarrete-EncinaA M Atria C Camargo and J A Squella ldquoElectrochemicaland EPR characterization of 14-dihydropyridines Reactivitytowards alkyl radicalsrdquo Free Radical Research vol 37 no 1 pp109ndash120 2003
[97] D Tirzite A Krauze A Zubareva G Tirzitis and G DubursldquoSynthesis and antiradical activity of 5-acetyl-2-alkylthio-4-aryl-6-methyl-14-dihydropyridine-3-carboxylic acid nitrilesrdquoChemistry of Heterocyclic Compounds vol 38 no 7 pp 795ndash800 2002
[98] H Ohkawa N Ohishi and K Yagi ldquoAssay for lipid peroxidesin animal tissues by thiobarbituric acid reactionrdquo AnalyticalBiochemistry vol 95 no 2 pp 351ndash358 1979
[99] N Zarkovic ldquo4-Hydroxynonenal as a bioactive marker ofpathophysiological processesrdquo Molecular Aspects of Medicinevol 24 no 4-5 pp 281ndash291 2003
[100] M Parola G Bellomo G Robino G Barrera and M UDianzani ldquo4-Hydroxynonenal as a biological signal molecularbasis and pathophysiological implicationsrdquo Antioxidants andRedox Signaling vol 1 no 3 pp 255ndash284 1999
[101] T Lovakovic M Poljak-Blazi G Duburs et al ldquoGrowthmodulation of human cells in vitro by mild oxidative stressand 14-dihydropyridine derivative antioxidantsrdquo CollegiumAntropologicum vol 35 no 1 pp 137ndash141 2011
[102] R van den Berg G R M M Haenen H van den Bergand A Bast ldquoApplicability of an improved Trolox equivalentantioxidant capacity (TEAC) assay for evaluation of antioxidantcapacity measurements of mixturesrdquo Food Chemistry vol 66no 4 pp 511ndash517 1999
[103] C Lopez-Alarcon P Navarrete C Camargo J A Squella andL J Nunez-Vergara ldquoReactivity of 14-dihydropyridines towardalkyl alkylperoxyl radicals and ABTS radical cationrdquo ChemicalResearch in Toxicology vol 16 no 2 pp 208ndash215 2003
[104] V Valenzuela P Santander C Camargo J A Squella C Lopez-Alarcon and L J Nunez-Vergara ldquo14-Dihydropyridines reac-tivity of nitrosoaryl and nitroaryl derivatives with alkylperoxylradicals andABTS radical cationrdquo Free Radical Research vol 38no 7 pp 715ndash727 2004
[105] L G Tsetlin N A Chebotareva B I Kurganov A K VelenaG Y Dubur and V Z Lankin ldquoStudy of 14-dihydropyridinesas lipoxygenase inhibitors with the use of hydrated reversedmicellesrdquo Pharmaceutical Chemistry Journal vol 22 no 6 pp425ndash428 1988 (Russian)
[106] J Panek Z Reblova L Kocirkova et al ldquoAntioxidant activityof dihydropyridine derivativesrdquo Czech Journal of Food Sciencesvol 18 pp 144ndash145 2000
[107] G Tirzitis I Kirule and G Duburs ldquoAntioxidationsaktivitatder 35-dicarbonylderivate des 26-demethyl-14-dihydropyri-dinsrdquo Fett Wissenschaft TechnologieFat Science Technology vol90 no 10 pp 411ndash413 1988
[108] M Plotniece G Tirzitis Y Uldrikis et al ldquoSynthesis of 14-dihydropyridine derivatives having an oxy- alkoxy- or dimeth-ylaminophenyl substituent in the 4 position their antioxidantactivity and their binding to phospholipid membranesrdquo Chem-istry of Heterocyclic Compounds vol 32 no 10 pp 1166ndash11721996 Translated from Khimiya Geterotsiklicheskikh Soedineniino 10(352) pp 1358ndash1365 1996 (Russian)
[109] D Y Rubene V S Sharov V I Olenev G D Tirzit G Y Duburand Y A Vladimirov ldquoUse of chemiluminescent method forthe evaluation of antioxidant activity of some derivatives of 14-dihydropyridinerdquo Russian Journal of Physical Chemistry A vol55 no 2 pp 511ndash512 1981 (Russian)
[110] M C R Symons and JM C Gutteridge Free Radicals and IronChemistry Biology and Medicine Oxford Science PublicationsOxford University Press Oxford UK 1998
[111] M Repetto J Semprine and A Boveris ldquoLipid peroxidationchemical mechanism biological implications and analyticaldeterminationrdquo in Lipid Peroxidation A Catala Ed Section ILipid Peroxidation Chemical Mechanisms Antioxidants Bio-logical Implications of Biochemistry Genetics and MolecularBiology chapter 1 pp 3ndash30 InTech Rijeka Croatia 2012
[112] A Velena J Zilbers and G Duburs ldquoDerivatives of 14-dihydropyridines asmodulators of ascorbate-induced lipid per-oxidation and high-amplitude swelling ofmitochondria causedby ascorbate sodium linoleate and sodiumpyrophosphaterdquoCellBiochemistry and Function vol 17 no 4 pp 237ndash252 1999
[113] M V Bilenko L N Shelenkova G Y Dubur and A K VelenaldquoUse of antioxidants to prevent renal damage during acuteischemia and reperfusionrdquo Bulletin of Experimental Biology andMedicine vol 96 no 3 pp 1195ndash1198 1983 Translated fromByulletenrsquo Eksperimentalrsquonoi Biologii i Meditsiny vol 96 no 9pp 8ndash11 1983 (Russian)
[114] R Toniolo F Tubaro F Ursini and G Bontempelli ldquoAn elec-troanalytical investigation on the redox properties of calciumantagonist dihydropyridinesrdquo Electroanalysis vol 15 no 10 pp855ndash861 2003
[115] L Kourimska J Pokorny and G Tirzitis ldquoThe antioxidant aci-tivity of 26-dimethyl-35-diethoxycarbonyl-14-dihydropyri-dine in edible oilsrdquo Nahrung vol 37 no 1 pp 91ndash93 1993
[116] C Lopez-Alarcon H Speisky J A Squella C Olea-Azar CCamargo and L J Nunez-Vergara ldquoReactivity of 14-dihydro-pyridines toward SIN-1-derived peroxynitriterdquo PharmaceuticalResearch vol 21 no 10 pp 1750ndash1757 2004
[117] R A Olek W Ziolkowski J J Kaczor L Greci J Popinigisand J Antosiewicz ldquoAntioxidant activity of NADH and its ana-loguemdashan in vitro studyrdquo Journal of Biochemistry andMolecularBiology vol 37 no 4 pp 416ndash421 2004
[118] E Niki N Noguchi and N Gotoh ldquoInhibition of oxidativemodification of low density lipoprotein by antioxidantsrdquo Jour-nal of Nutritional Science andVitaminology vol 39 supplementpp S1ndashS8 1993
[119] N Rojstaczer and D J Triggle ldquoStructure-function relation-ships of calcium antagonists effect on oxidative modificationof low density lipoproteinrdquo Biochemical Pharmacology vol 51no 2 pp 141ndash150 1996
Oxidative Medicine and Cellular Longevity 31
[120] A Sevanian L Shen and FUrsini ldquoInhibition of LDLoxidationand oxidized LDL-induced cytotoxicity by dihydropyridinecalcium antagonistsrdquo Pharmaceutical Research vol 17 no 8 pp999ndash1006 2000
[121] A Negre-Salvayre and R Salvayre ldquoProtection by Ca2+ channelblockers (nifedipine diltiazem and verapamil) against the tox-icity of oxidized low density lipoprotein to cultured lymphoidcellsrdquo British Journal of Pharmacology vol 107 no 3 pp 738ndash744 1992
[122] A Negre-Salvayre G FitoussiM Troly and R Salvayre ldquoCom-parative cytoprotective effect of dihydropyridine calcium chan-nel blockers against the toxicity of oxidized low density lipopro-tein for cultured lymphoid cellsrdquo Biochemical Pharmacologyvol 44 no 12 pp 2379ndash2386 1992
[123] L Cominacini A F Pasini U Garbin et al ldquoAntioxidant activ-ity of different dihydropyridinesrdquo Biochemical and BiophysicalResearch Communications vol 302 no 4 pp 679ndash684 2003
[124] L Cominacini U Garbin A Fratta Pasini et al ldquoOxidized low-density lipoprotein increases the production of intracellularreactive oxygen species in endothelial cells inhibitory effect oflacidipinerdquo Journal of Hypertension vol 16 no 12 part 2 pp1913ndash1919 1998
[125] H M Lander ldquoAn essential role for free radicals and derivedspecies in signal transductionrdquo The FASEB Journal vol 11 no2 pp 118ndash124 1997
[126] M L L Martinez E Rizzi M M Castro et al ldquoLercanidipinedecreases vascular matrix metalloproteinase-2 activity andprotects against vascular dysfunction in diabetic ratsrdquo EuropeanJournal of Pharmacology vol 599 no 1ndash3 pp 110ndash116 2008
[127] P Lesnik C Dachet L Petit et al ldquoImpact of a combinationof a calcium antagonist and a 120573-blocker on cell- and copper-mediated oxidation of LDL and on the accumulation and effluxof cholesterol in human macrophages and murine J774 cellsrdquoArteriosclerosis Thrombosis and Vascular Biology vol 17 no 5pp 979ndash988 1997
[128] G Sobal E J Menzel and H Sinzinger ldquoCalcium antagonistsas inhibitors of in vitro low density lipoprotein oxidation andglycationrdquoBiochemical Pharmacology vol 61 no 3 pp 373ndash3792001
[129] E Lupo R Locher B Weisser and W Vetter ldquoIn vitro antiox-idant activity of calcium antagonists against LDL oxidationcompared with 120572-tocopherolrdquo Biochemical and BiophysicalResearch Communications vol 203 no 3 pp 1803ndash1808 1994
[130] J Zou Y Li H-Q Fan and J-G Wang ldquoEffects of dihydropy-ridine calcium channel blockers on oxidized low-density lipo-protein induced proliferation and oxidative stress of vascularsmooth muscle cellsrdquo BMC Research Notes vol 5 article 1682012
[131] C Napoli S Salomone T Godfraind et al ldquo14-Dihydro-pyridine calcium channel blockers inhibit plasma and LDL oxi-dation and formation of oxidation-specific epitopes in the arte-rial wall and prolong survival in stroke-prone spontaneouslyhypertensive ratsrdquo Stroke vol 30 no 9 pp 1907ndash1915 1999
[132] G Zernig I Graziadei T Moshammer C Zech N Reider andH Glossmann ldquoMitochondrial Ca2+ antagonist binding sitesare associated with an inner mitochondrial membrane anionchannelrdquo Molecular Pharmacology vol 38 no 3 pp 362ndash3691990
[133] F E Hunter Jr A Scott P E Hochstein et al ldquoStudies of themechanism of ascorbate-induced swelling and lysis of isolatedliver mitochondriardquo The Journal of Biological Chemistry vol239 pp 604ndash613 1964
[134] D R Janero B Burghardt and R Lopez ldquoProtection of cardiacmembrane phospholipid against oxidative injury by calciumantagonistsrdquoBiochemical Pharmacology vol 37 no 21 pp 4197ndash4203 1988
[135] A Karadag B Ozcelik and S S Saner ldquoReview of methods todetermine antioxidant capacitiesrdquo FoodAnalyticalMethods vol2 no 1 pp 41ndash60 2009
[136] Y I Gubskiı N V Litvinova and E V Shnurko-TabakovaldquoAntioxidant and antiradical activity of various classes of antiox-idantsrdquo Ukrainskiı Biokhimicheskiı Zhurnal vol 66 no 4 pp114ndash116 1994 (Russian)
[137] M Takei M Hiramatsu and A Mori ldquoInhibitory effects ofcalcium antagonists onmitochondrial swelling induced by lipidperoxidation or arachidonic acid in the rat brain in vitrordquoNeurochemical Research vol 19 no 9 pp 1199ndash1206 1994
[138] M Takei M Hiramatsu R Edamatsu and A Mori ldquoFreeradical scavenging by calcium antagonistsrdquo Neurosciences vol20 no 2 pp 75ndash82 1994
[139] Ya P Stradin G Ya Dubur Yu A Beilis Ya R Uldrikis andA F Korotkova ldquoVoltammetry of 14-dihydropyridine deriva-tives I Potentials of electrochemical oxidation of 35-diacyl-and 35-di(alkoxycarbonyl)-14-dihydropyridines in acetoni-trilerdquo Chemistry of Heterocyclic Compounds no 1 pp 84ndash871972 (Russian)
[140] E V Ivanov T V Ponomarjova G N Merkusev et al ldquoEinneuer Haut-Radioprotektor Diethon (experimentelle Unter-suchung)rdquo Radiobiologia Radiotherapia vol 31 no 1 pp 69ndash78 1990
[141] E V Ivanov T V Ponomareva G N Merkushev et al ldquoRadia-tion modulating properties of derivates of 14-dihydropyridineand 12345678910-decahydroacridine-18 dionerdquo Radiat-sionnaia Biologiia Radioecologiia vol 44 no 5 pp 550ndash5592004 (Russian)
[142] R O Vitolinia D A Berzinia A K Velena I A Vutsina A AKimenis and G Y Duburs ldquoThe protective effects of the cal-cium antagonist foridon in acute myocardial ischaemiardquo Kardi-ologiya vol 27 no 3 pp 90ndash93 1987 (Russian)
[143] A H Velena G Ya Duburs R O Vitolina et al ldquoEffect ofryodipine on electromechanical parameters of heart and vesselscAMP phosphodiesterase activity and swelling-contractioncycle of mitochondriardquo Arzneimittelforschung vol 35 no 6 pp907ndash914 1985
[144] L I Utno Z E Lipsberga A A Silova M I Girgensone EA Bisenieks and G I Ia ldquoCardioprotective properties of a 14-dihydropyridine derivative glutapyrone in deep hypothermiardquoBiulletenrsquo Eksperimentalrsquonoı Biologii i Meditsiny vol 108 no 11pp 558ndash561 1989 (Russian)
[145] M A S FernandesM S Santos J A F Vicente et al ldquoEffects of14-dihydropyridine derivatives (cerebrocrast gammapyroneglutapyrone and diethone) onmitochondrial bioenergetics andoxidative stress a comparative studyrdquoMitochondrion vol 3 no1 pp 47ndash59 2003
[146] M A S Fernandes M S Santos A J M Moreno et al ldquoEffectsof 5-acetyl(carbamoyl)-6-methylsulfanyl-14-dihydropyridine-5-carbonitriles on rat liver mitochondrial functionrdquo Toxicologyin Vitro vol 23 no 7 pp 1333ndash1341 2009
[147] L Klimaviciusa A Kalda A Kaasik et al ldquoNeuroprotectiveactivity of 14-dihydropyridine derivatives structure determi-nantsrdquo Proceedings of the Latvian Academy of Sciences BNatural Exact and Applied Sciences vol 61 no 1-2 pp 33ndash372007
32 Oxidative Medicine and Cellular Longevity
[148] L Klimaviciusa M A S Fernandes N Lencberga et alldquoTargeting the mitochondria by novel adamantane-containing14-dihydropyridine compoundsrdquo in Bioenergetics K B ClarkEd pp 257ndash272 InTech 2012
[149] V Klusa L Klimaviciusa G Duburs J Poikans and AZharkovsky ldquoAnti-neurotoxic effects of tauropyrone a taurineanaloguerdquo Advances in Experimental Medicine and Biology vol583 pp 499ndash508 2006
[150] N Sampson P Berger and Ch Zenzmaier ldquoRedox signalingas a therapeutic target to inhibit myofibroblast activation indegenerative fibrotic diseaserdquo BioMed Research Internationalvol 2014 Article ID 131737 14 pages 2014
[151] T L Leto and M Geiszt ldquoRole of Nox family NADPH oxidasesin host defenserdquoAntioxidantsampRedox Signaling vol 8 no 9-10pp 1549ndash1561 2006
[152] K K Griendling D Sorescu and M Ushio-Fukai ldquoNAD(P)Hoxidase role in cardiovascular biology and diseaserdquo CirculationResearch vol 86 no 5 pp 494ndash501 2000
[153] H Chen Y S Song and P H Chan ldquoInhibition of NADPHoxi-dase is neuroprotective after ischemia-reperfusionrdquo Journal ofCerebral Blood Flow and Metabolism vol 29 no 7 pp 1262ndash1272 2009
[154] P Hochstein and L Ernster ldquoADP-activated lipid peroxidationcoupled to the TPNH oxidase system of microsomesrdquo Biochem-ical and Biophysical Research Communications vol 12 no 5 pp388ndash394 1963
[155] I I Gubskiı AGGoriushkoNV Litvinova et al ldquoAntioxidantproperties and membranotropic effect of certain derivatives of14-dihydropyridinerdquo Ukrainskiı Biokhimicheskiı Zhurnal vol71 no 4 pp 35ndash39 1999 (Russian)
[156] F Engineer and R Sridhar ldquoInhibition of rat heart andliver microsomal lipid peroxidation by nifedipinerdquo BiochemicalPharmacology vol 38 no 8 pp 1279ndash1285 1989
[157] T Goncalves A P Carvalho and C R Oliveira ldquoAntioxidanteffect of calcium antagonists on microsomai membranes iso-lated from different brain areasrdquo European Journal of Pharma-cology vol 204 no 3 pp 315ndash322 1991
[158] M E Letelier P Izquierdo L Godoy A M Lepe and MFaundez ldquoLiver microsomal biotransformation of nitro-aryldrugs mechanism for potential oxidative stress inductionrdquoJournal of Applied Toxicology vol 24 no 6 pp 519ndash525 2004
[159] M E Letelier P Entrala C Lopez-Alarcon et al ldquoNitroaryl-14-dihydropyridines as antioxidants against rat liver microsomesoxidation induced by ironascorbate Nitrofurantoin and naph-thalenerdquo Toxicology in Vitro vol 21 no 8 pp 1610ndash1618 2007
[160] F P Guengerich W R Brian M Iwasaki M-A Sari CBaarnhielm and P Berntsson ldquoOxidation of dihydropyridinecalcium channel blockers and analogues by human liver cyto-chrome P-450 IIIA4rdquo Journal of Medicinal Chemistry vol 34no 6 pp 1838ndash1844 1991
[161] S H Park S-W RhaW-Y Shin et al ldquoAS-160 Calcium channelblockers of dihydropyridine class reduce the antiplatelet effectof Clopidogrel what is clinical impactrdquo The American Journalof Cardiology vol 107 no 8 supplement p 47A 2011
[162] C Asma and D M Reda ldquoEvaluation of dihydropyridinecalcium antagonist effects on the stress bioindicator orga-nism Saccharomyces cerevisiaerdquo Annals of Biological Researchvol 4 no 10 pp 40ndash46 2013 httpscholarsresearchlibrarycomABR-vol4-iss10ABR-2013-4-10-40-46pdf
[163] G Gaviraghi A M Pastorino E Ratti and D G TristldquoCalcium channel blockers with antioxidant activityrdquo in Free
Radicals Lipoprotein Oxidation andAtherosclerosis G BellomoG Finardi E Maggi and E Rice-Evans Eds pp 431ndash456Richelieu Press London UK 1995
[164] G Gaviraghi AM Pastorino E Ratti and D G Trist ldquoAntiox-idant dihydropyridines a new and comprehensive therapy forfree radical-induced cardiovascular diseasesrdquo in Free Radicalsin Biology and Environment F Minisci Ed vol 27 of NATOASI Series pp 193ndash221 Springer Dordrecht The Netherlands1997
[165] P D Henry ldquoAntiperoxidative actions of calcium antagonistsand atherogenesisrdquo Journal of Cardiovascular Pharmacologyvol 18 supplement 1 pp S6ndashS10 1991
[166] F Kouoh B Gressier T Dine et al ldquoAntioxidant effects andanti-elastase activity of the calcium antagonist nicardipine onactivated human and rabbit neutrophilsmdasha potential antiath-erosclerotic property of calcium antagonistsrdquo CardiovascularDrugs andTherapy vol 16 no 6 pp 515ndash520 2002
[167] S Parthasarathy D Litvinov K Selvarajan and M GarelnabildquoLipid peroxidation and decompositionmdashconflicting roles inplaque vulnerability and stabilityrdquo Biochimica et BiophysicaActa vol 1781 no 5 pp 221ndash231 2008
[168] D-Q Liu Z-Q Pang D-H Zhao and B-H Sheng ldquoEffects offuryl-dihydropyridines I on lipid peroxides of ischemic myo-cardium and ATPases activity of erythrocyte membranes inratsrdquo Acta Pharmacologica Sinica vol 12 no 3 pp 253ndash2561991
[169] V Lukic-Panin T Kamiya H Zhang et al ldquoPrevention of neu-ronal damage by calcium channel blockers with antioxidativeeffects after transient focal ischemia in ratsrdquo Brain Research vol1176 no 1 pp 143ndash150 2007
[170] Y Allanore D Borderie H Lemarechal O G Ekindjian andA Kahan ldquoAcute and sustained effects of dihydropyridine-typecalcium channel antagonists on oxidative stress in systemicsclerosisrdquo American Journal of Medicine vol 116 no 9 pp 595ndash600 2004
[171] I Casetta V Govoni and E Granieri ldquoOxidative stress antioxi-dants and neurodegenerative diseasesrdquo Current PharmaceuticalDesign vol 11 no 16 pp 2033ndash2052 2005
[172] M J T J Arts Assessing antioxidant activity [PhD the-sis] Maastricht University Maastricht The Netherlands 2007httparnounimaasnlshowcgifid=8676
[173] G Dıaz-Araya L Godoy L Naranjo A Squella M E Letelierand L J Nunez-Vergara ldquoAntioxidant effects of 14-dihydro-pyridine and nitroso aryl derivatives on the Fe+3ascorbate-stimulated lipid peroxidation in rat brain slicesrdquo General Phar-macology The Vascular System vol 31 no 3 pp 385ndash391 1998
[174] Y Fukuhara K Tsuchiya Y Horinouchi et al ldquoProtectiveeffect of photodegradation product of nifedipine against tumornecrosis factor 120572-induced oxidative stress in human glomerularendothelial cellsrdquo Journal of Medical Investigation vol 58 no1-2 pp 118ndash126 2011
[175] W Stengel M Jainz and K Andreas ldquoDifferent potencies ofdihydropyridine derivatives in blocking T-type but not L-typeCa2+ channels in neuroblastoma-glioma hybrid cellsrdquo EuropeanJournal of Pharmacology vol 342 no 2-3 pp 339ndash345 1998
[176] O M Panasenko D J Tirzite G D Tirzitis and G J DubursldquoEffect of some 14-dihydropyridine derivatives on structuralorganization of erythrocyte membranesrdquo Biologicheskie Mem-brany (Biochemistry (Moscow) Series A Membrane and CellBiology) vol 1 pp 919ndash925 1984 (Russian)
[177] L G Herbette Y M H Vant Erve and D G Rhodes ldquoInter-action of 14 dihydropyridine calcium channel antagonists with
Oxidative Medicine and Cellular Longevity 33
biological membranes lipid bilayer partitioning could occurbefore drug binding to receptorsrdquo Journal of Molecular andCellular Cardiology vol 21 no 2 pp 187ndash201 1989
[178] L G Herbette P E Mason G Gaviraghi T N Tulenko andR P Mason ldquoThe molecular basis for lacidipinersquos unique phar-macokinetics optimal hydrophobicity results in membraneinteractions that may facilitate the treatment of atherosclerosisrdquoJournal of Cardiovascular Pharmacology vol 23 supplement 5pp S16ndashS25 1994
[179] G V Belevitch G Y Dubur G E Dobretsov N K Kurek andM M Spirin ldquoCalcium antagonists riodipine nifedipine andverapamil binding to model and biological membranes fluore-scence analysisrdquo Biologicheskie Membrany (Biochemistry(Moscow) Series A Membrane and Cell Biology) vol 5 pp768ndash776 1988 (Russian)
[180] R P Mason G E Gonye D W Chester and L G HerbetteldquoPartitioning and location of Bay K 8644 14-dihydropyridinecalcium channel agonist in model and biological membranesrdquoBiophysical Journal vol 55 no 4 pp 769ndash778 1989
[181] M Cindric A Cipak J Serly et al ldquoReversal of multidrugresistance inmurine lymphoma cells by amphiphilic dihydropy-ridine antioxidant derivativerdquo Anticancer Research vol 30 no10 pp 4063ndash4070 2010
[182] F Shekari H Sadeghpour K Javidnia et al ldquoCytotoxic andmultidrug resistance reversal activities of novel 14-dihydro-pyridines against human cancer cellsrdquo European Journal ofPharmacology vol 746 no 1 pp 233ndash244 2015
[183] X-F Zhou Q Shao R A Coburn and M E Morris ldquoQuanti-tative structure-activity relationship and quantitative structure-pharmacokinetics relationship of 14-dihydropyridines andpyridines as multidrug resistance modulatorsrdquo PharmaceuticalResearch vol 22 no 12 pp 1989ndash1996 2005
[184] R Berkels T Breitenbach H Bartels et al ldquoDifferent antioxida-tive potencies of dihydropyridine calcium channel modulatorsin various modelsrdquo Vascular Pharmacology vol 42 no 4 pp145ndash152 2005
[185] S Borovic G Tirzitis D Tirzite et al ldquoBioactive 14-dihydro-isonicotinic acid derivatives prevent oxidative damage of livercellsrdquo European Journal of Pharmacology vol 537 no 1ndash3 pp12ndash19 2006
[186] D Ya Rubene G D Tirzitis and G Ya Duburs ldquoInteractionof some 14-dihydropyridine derivatives with Fentonrsquos reagentrdquoLatvijas PSRZinatnuAkademijas Vestis Kimijas Serija Proceed-ings of the Latvian SSR Academy of Sciences Chemistry Seriespp 212ndash216 1982 (Russian)
[187] K Ondrias V Misık D Gergel and A Stasko ldquoLipid per-oxidation of phosphatidylcholine liposomes depressed by thecalcium channel blockers nifedipine and verapamil and bythe antiarrhythmic-antihypoxic drug stobadinerdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1003 no 3pp 238ndash245 1989
[188] I T Mak and W B Weglicki ldquoComparative antioxidant acti-vities of propranolol nifedipine verapamil and diltiazemagainst sarcolemmal membrane lipid peroxidationrdquoCirculationResearch vol 66 no 5 pp 1449ndash1452 1990
[189] I T Mak P Boehme and W B Weglicki ldquoProtective effects ofcalcium channel blockers against free radical-impaired endo-thelial cell proliferationrdquo Biochemical Pharmacology vol 50 no9 pp 1531ndash1534 1995
[190] S Ray S Mondal and N Dana ldquoEvaluation of protective roleof nifedipine on lipid peroxidation using reduced glutathione as
model markerrdquo Oxidants and Antioxidants in Medical Sciencevol 1 no 2 pp 97ndash100 2012
[191] M Yamato T Shiba T Ide Y Honda K-I Yamada andH Tsutsui ldquoNifedipine treatment reduces brain damage aftertransient focal ischemia possibly through its antioxidativeeffectsrdquoHypertension Research vol 34 no 7 pp 840ndash845 2011
[192] V Chander and K Chopra ldquoNifedipine attenuates changes innitric oxide levels renal oxidative stress and nephrotoxicityinduced by cyclosporinerdquo Renal Failure vol 27 no 4 pp 441ndash450 2005
[193] K M Gaafa M M Badawy and A A Hamza ldquoThe protectiveeffects of ascorbic acid cimetidine and nifedipine on diethyl-dithiocarbamate-induced hepatic toxicity in albino ratsrdquo Drugand Chemical Toxicology vol 34 no 4 pp 405ndash419 2011
[194] H Sugawara K Tobise and S Onodera ldquoAbsence of antiox-idant effects of nifedipine and diltiazem on myocardial mem-brane lipid peroxidation in contrast with those of nisoldipineand propranololrdquo Biochemical Pharmacology vol 47 no 5 pp887ndash892 1994
[195] I E Kirule D Y Rubene E A Bisenieks G D Tirzit and GY Dubur ldquo4-Nitrophenyl-14-dihydropyridinesmdasha new groupof inhibitors of peroxide oxidationrdquo Chemistry of HeterocyclicCompounds vol 18 no 3 p 316 1982
[196] G D Tirzit I E Kirule L K Baumane R A Gavar Y PStradynrsquo andG YDubur ldquoMechanism of the antioxidant actionof 26-dimethyl-35-dimethoxy-carbonyl-4-(2-nitrophenyl)14-dihydropyridinerdquoChemistry ofHeterocyclic Compounds vol 20no 8 pp 915ndash918 1984
[197] C Yanez C Lopez-Alarcon C Camargo V Valenzuela J ASquella and L J Nunez-Vergara ldquoStructural effects on thereactivity 14-dihydropyridines with alkylperoxyl radicals andABTS radical cationrdquo Bioorganic and Medicinal Chemistry vol12 no 9 pp 2459ndash2468 2004
[198] VMisik A J Stasko D Gergel and K Ondrias ldquoSpin-trappingand antioxidant properties of illuminated and nonilluminatednifedipine and nimodipine in heart homogenate and modelsystemrdquo Molecular Pharmacology vol 40 no 3 pp 435ndash4391991
[199] K Ondrias V Misık A Stasko D Gergelrsquo and M HromadovaldquoComparison of antioxidant properties of nifedipine and illu-minated nifedipine with nitroso spin traps in low densitylipoproteins and phosphatidylcholine liposomesrdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1211 no 1pp 114ndash119 1994
[200] A Stasko V Brezova S Biskupic K Ondrias and V MisıkldquoReactive radical intermediates formed from illuminated nife-dipinerdquoFree Radical Biology andMedicine vol 17 no 6 pp 545ndash556 1994
[201] K Ishizawa Y Izawa-Ishizawa N Yamano et al ldquoNitrosoni-fedipine ameliorates the progression of type 2 diabetic nephro-pathy by exerting antioxidative effectsrdquo PLoS ONE vol 9 no 1Article ID e86335 2014
[202] H Fujii and L J Berliner ldquoIn vivo EPR evidence for free radicaladducts of nifedipinerdquoMagnetic Resonance in Medicine vol 42no 4 pp 691ndash694 1999
[203] S Bollo S Finger J C Sturm L J Nunez-Vergara and JA Squella ldquoCyclic voltammetry and scanning electrochemicalmicroscopy studies of the heterogeneous electron transferreaction of some nitrosoaromatic compoundsrdquo ElectrochimicaActa vol 52 no 15 pp 4892ndash4898 2007
34 Oxidative Medicine and Cellular Longevity
[204] F Ursini ldquoTissue protection by lacidipine insight from redoxbehaviorrdquo Journal of Cardiovascular Pharmacology vol 30supplement 2 pp S28ndashS30 1997
[205] P G Cristofori F A Crivellente I Faustinelli et al ldquoInvolve-ment of the nitric oxide system in the anti-atheroscleroticpotential of lacidipine in the apoE-deficient mouse a mor-phological functional and electrochemical studyrdquo ToxicologicPathology vol 32 no 4 pp 493ndash499 2004
[206] X-P Zhang E L Kit S Mital S Chahwala and T HHintze ldquoParadoxical release of nitric oxide by an L-type calciumchannel antagonist the R+ enantiomer of amlodipinerdquo Journalof Cardiovascular Pharmacology vol 39 no 2 pp 208ndash2142002
[207] F Franzoni G Santoro F Regoli et al ldquoAn in vitro study of theperoxyl and hydroxyl radical scavenging capacity of the calciumantagonist amlodipinerdquo Biomedicine and Pharmacotherapy vol58 no 8 pp 423ndash426 2004
[208] S V Gatsura ldquoOxygen-dependent mechanisms underlying theantiischemic effect of verapamil and amlodipinerdquo Bulletin ofExperimental Biology and Medicine vol 137 no 1 pp 40ndash422004
[209] Y Hirooka Y Kimura M Nozoe Y Sagara K Ito and KSunagawa ldquoAmlodipine-induced reduction of oxidative stressin the brain is associated with sympatho-inhibitory effects instroke-prone spontaneously hypertensive ratsrdquo HypertensionResearch vol 29 no 1 pp 49ndash56 2006
[210] B Tomlinson and I F F Benzie ldquoAntioxidant effect of lercani-dipine (note)rdquo Hypertension vol 42 no 4 pp e10ndashe11 2003
[211] A A Faraqui ldquoNeurochemical aspects of 4-hydroxynonenalrdquoin Lipid Mediators and Their Metabolism in the Brain A AFaraqui Ed chapter 6 pp 159ndash191 Springer New York NYUSA 2011
[212] V S NascimentoM S DrsquoAlva A AOliveira et al ldquoAntioxidanteffect of nimodipine in young rats after pilocarpine-inducedseizuresrdquo Pharmacology Biochemistry and Behavior vol 82 no1 pp 11ndash16 2005
[213] O Ismailoglu P Atilla S Palaoglu et al ldquoThe therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjuryrdquo Turkish Neurosurgery vol 22 no 6 pp 740ndash746 2012
[214] M Matsubara and K Hasegawa ldquoBenidipine a dihydropy-ridine-calcium channel blocker prevents lysophosphatidyl-choline-induced injury and reactive oxygen species productionin human aortic endothelial cellsrdquo Atherosclerosis vol 178 no1 pp 57ndash66 2005
[215] M Matsubara K Yao and K Hasegawa ldquoBenidipine adihydropyridine-calcium channel blocker inhibits lysophos-phatidylcholine-induced endothelial injury via stimulation ofnitric oxide releaserdquo Pharmacological Research vol 53 no 1 pp35ndash43 2006
[216] MMatsubara and K Hasegawa ldquoEffects of benidipine a dihyd-ropyridine-Ca2+ channel blocker on expression of cytokine-induced adhesion molecules and chemoattractants in humanaortic endothelial cellsrdquo European Journal of Pharmacology vol498 no 1ndash3 pp 303ndash314 2004
[217] M Matsubara O Akizuki J-I Ikeda K Saeki K Yao and KSasaki ldquoBenidipine an anti-hypertensive drug inhibits reactiveoxygen species production in polymorphonuclear leukocytesand oxidative stress in salt-loaded stroke-prone spontaneouslyhypertensive ratsrdquo European Journal of Pharmacology vol 580no 1-2 pp 201ndash213 2008
[218] A C Rosenkranz H Lob T Breitenbach R Berkels and RRoesen ldquoEndothelial antioxidant actions of dihydropyridines
and angiotensin converting enzyme inhibitorsrdquo European Jour-nal of Pharmacology vol 529 no 1ndash3 pp 55ndash62 2006
[219] V Kain S Kumar and S L Sitasawad ldquoAzelnidipine preventscardiac dysfunction in streptozotocin-diabetic rats by reducingintracellular calcium accumulation oxidative stress and apop-tosisrdquo Cardiovascular Diabetology vol 10 article 97 2011
[220] K Nakamura S Yamagishi and H Inoue ldquoUnique atheropro-tective property of azelnidipine a dihydropyridine-based cal-cium antagonistrdquoMedical Hypotheses vol 65 no 1 pp 155ndash1572005
[221] TMatsui S Yamagishi K Nakamura S Kikuchi andH InoueldquoAzelnidipine a dihydropyridine-based calcium antagonistinhibits angiotensin II-induced oxidative stress generation anddownregulation of pigment epithelium-derived factor mRNAlevels in microvascular endothelial cellsrdquo Drugs under Experi-mental and Clinical Research vol 31 no 5-6 pp 215ndash219 2005
[222] C Ohmura H Watada T Shimizu et al ldquoCalcium channelblocker azelnidipine reduces lipid hydroperoxides in patientswith type 2 diabetes independent of blood pressurerdquo EndocrineJournal vol 54 no 5 pp 805ndash811 2007
[223] H Daikuhara F Kikuchi and T Ishida ldquoThe combination ofOLmesartan and a CAlcium channel blocker (azelnidipine) orcandesartan and a calcium channel blocker (amlodipine) intype 2 diabetic hypertensive patients theOLCA studyrdquoDiabetesand Vascular Disease Research vol 9 no 4 pp 280ndash286 2012
[224] MAbe NMaruyama KOkada SMatsumoto KMatsumotoand M Soma ldquoAdditive antioxidative effects of azelnidipine onangiotensin receptor blocker olmesartan treatment for type 2diabetic patients with albuminuriardquoHypertension Research vol34 no 8 pp 935ndash941 2011
[225] K Mizushige ldquoAntioxidative activities of thiazolidinedionesand dihydropyridine-type calcium antagonistsrdquo IRYOmdashJapa-nese Journal of National Medical Services vol 59 no 11 pp 581ndash592 2005
[226] S Manabe T Okura T Fukuoka and J Higaki ldquoAntioxidativeeffects of azelnidipine on mesangial cell proliferation inducedby highly concentrated insulinrdquo European Journal of Pharma-cology vol 567 no 3 pp 252ndash257 2007
[227] Y Koyama Y Takeishi H Takahashi et al ldquoAzelnidipine inhi-bits H
2O2-induced cell death in neonatal rat cardiomyocytesrdquo
CardiovascularDrugs andTherapy vol 21 no 1 pp 69ndash72 2007[228] K Shinomiya K Mizushige M Fukunaga et al ldquoAntioxidant
effect of a new calcium antagonist azelnipidine in culturedhuman arterial endothelial cellsrdquo Journal of International Med-ical Research vol 32 no 2 pp 170ndash175 2004
[229] T Ohyama K Sato K Kishimoto et al ldquoAzelnidipine is acalcium blocker that attenuates liver fibrosis and may increaseantioxidant defencerdquo British Journal of Pharmacology vol 165no 4 pp 1173ndash1187 2012
[230] L A Calo F Zaghetto E Pagnin P A Davis A Sempliciniand A C Pessina ldquoEffect of manidipine on gene expressionand protein level of oxidative stress-related proteins p22phoxand HO-1 Relevance for antihypertensive and anti-remodelingeffectsrdquo Journal of Cardiovascular Pharmacology vol 43 no 4pp 531ndash538 2004
[231] R Ghyasi G Sepehri M Mohammadi R Badalzadeh and AGhyasi ldquoEffect of mebudipine on oxidative stress and lipid per-oxidation in myocardial ischemic-reperfusion injury in maleratrdquo Journal of Research in Medical Sciences vol 17 no 12 pp1150ndash1155 2012
Oxidative Medicine and Cellular Longevity 35
[232] DCAndersson J Fauconnier T Yamada et al ldquoMitochondrialproduction of reactive oxygen species contributes to the 120573-adrenergic stimulation of mouse cardiomycytesrdquoThe Journal ofPhysiology vol 589 no 7 pp 1791ndash1801 2011
[233] A F Ceylan-Isik N Ari M Stefek et al ldquoEffects of a long-term treatment with an antioxidant pyridoindole on vascularresponsiveness in diabetes-induced aging ratsrdquo Current AgingScience vol 4 no 2 pp 150ndash157 2011
[234] S Saponara G Sgaragli and F Fusi ldquoQuercetin antagonismof Bay K 8644 effects on rat tail artery L-type Ca2+ channelsrdquoEuropean Journal of Pharmacology vol 598 no 1ndash3 pp 75ndash802008
[235] D A Sica ldquoInteraction of grapefruit juice and calcium channelblockersrdquo American Journal of Hypertension vol 19 no 7 pp768ndash773 2006
[236] P Mulder G Litwinienko S Lin P D MacLean L R CBarclay and K U Ingold ldquoThe L-type calcium channel block-ers Hantzsch 14-dihydropyridines are not peroxyl radical-trapping chain-breaking antioxidantsrdquo Chemical Research inToxicology vol 19 no 1 pp 79ndash85 2006
[237] L J Nunez-Vergara R Salazar C Camargo et al ldquoOxidation ofC4-hydroxyphenyl 14-dihydropyridines in dimethylsulfoxideand its reactivity towards alkylperoxyl radicals in aqueousmediumrdquo Bioorganic and Medicinal Chemistry vol 15 no 12pp 4318ndash4326 2007
[238] M E Ortiz L J Nunez-Vergara and J A Squella ldquoRelativereactivity of dihydropyridine derivatives to electrogeneratedsuperoxide ion in DMSO solutions a voltammetric approachrdquoPharmaceutical Research vol 20 no 2 pp 292ndash296 2003
[239] M E Ortiz L J Nunez-Vergara C Camargo and J A SquellaldquoOxidation of Hantzsch 14-dihydropyridines of pharmacolog-ical significance by electrogenerated superoxiderdquo Pharmaceuti-cal Research vol 21 no 3 pp 428ndash435 2004
[240] R S Raghuvanshi and K N Singh ldquoSuperoxide induced oxida-tive aromatization of Hantzsch 14-dihydropyridinesrdquo IndianJournal of Chemistry Section B Organic and Medicinal Chem-istry vol 47 no 11 pp 1735ndash1738 2008
[241] I Kruk A Kladna K Lichszteld et al ldquoAntioxidant activityof 4-flavonil-14-dihydropyridine derivativesrdquo Biopolymers vol62 no 3 pp 163ndash167 2001
[242] G D Tirzit I M Byteva K I Salokhiddinov G P Gurinovichand G Y Dubur ldquo14-Dihydropyridine derivatives as deactiva-tors of singlet oxygenrdquo Chemistry of Heterocyclic Compoundsvol 17 no 7 pp 682ndash684 1981
[243] G D Tirzit E Y Kazush and G Y Dubur ldquoInfluence of14-dihydropyridine derivatives on the generation of hydroxylradicalsrdquo Chemistry of Heterocyclic Compounds vol 28 no 4pp 435ndash437 1992
[244] N A Pizarro-Urzua and L J Nunez-Vergara ldquoNifedipine andnitrendipine reactivity toward singlet oxygenrdquo Journal of Photo-chemistry and Photobiology A Chemistry vol 175 no 2-3 pp129ndash137 2005
[245] L-F Wang H-Y Zhang L Konga Z-W Chena and J-G ShildquoDFT calculations indicate that 14-dihydropyridine is a promis-ing lead antioxidantrdquo Helvetica Chimica Acta vol 87 no 6 pp1515ndash1521 2004
[246] P Mulder H-G Korth and K U Ingold ldquoWhy quantum-thermochemical calculations must be used with caution toindicate lsquoa promising lead antioxidantrsquordquoHelvetica Chimica Actavol 88 no 2 pp 370ndash374 2005
[247] K Yao Y Ina K Nagashima K Ohmori and T Ohno ldquoAntiox-idant effects of calcium antagonists in rat brain homogenatesrdquo
Biological and Pharmaceutical Bulletin vol 23 no 6 pp 766ndash769 2000
[248] T Matsui S-I Yamagishi K Nakamura and H Inoue ldquoBayw 9798 a dihydropyridine structurally related to nifedipinewith no calcium channel-blocking properties inhibits tumournecrosis factor-120572-induced vascular cell adhesion molecule-1expression in endothelial cells by suppressing reactive oxygenspecies generationrdquo Journal of International Medical Researchvol 35 no 6 pp 886ndash891 2007
[249] K AMitrega B VargheseM Porc and T F Krzeminski ldquoAnti-arrhythmic and hemodynamic effects of oxy nifedipine oxynimodipine oxy nitrendipine and oxy nisoldipinerdquo Pharmaco-logical Research vol 66 no 4 pp 300ndash308 2012
[250] V Herbert ldquoSymposium prooxidant effects of antioxidantvitamins Introductionrdquo The Journal of Nutrition vol 126 no4 supplement pp 1197Sndash1200S 1996 httpjnnutritionorgcontent1264 Suppl1197Sfullpdf
[251] B Halliwell ldquoAre polyphenols antioxidants or pro-oxidantsWhat do we learn from cell culture and in vivo studiesrdquoArchives of Biochemistry and Biophysics vol 476 no 2 pp 107ndash112 2008
[252] C Winterbourn Pro-Oxidants or Antioxidants ChristchurchSchool of Medicine Depatment of Pathology Free RadicalSchool SFRBMUniversity of Otago San Francisco Calif USA2009 httpwwwsfrbmorgfrsWinterbournpdf
[253] A Morakinyo B Iranloye and O Adegoke ldquoCalcium antag-onists modulate oxidative stress and acrosomal reaction in ratspermatozoardquo Archives of Medical Science vol 7 no 4 pp 613ndash618 2011
[254] The Alpha-Tocopherol Beta Carotene Cancer Prevention StudyGroup ldquoThe effect of vitamin E and beta carotene on theincidence of lung cancer and other cancers in male smokersrdquoTheNew England Journal of Medicine vol 330 no 15 pp 1029ndash1035 1994
[255] B Poljsak ldquoStrategies for reducing or preventing the generationof oxidative stressrdquo Oxidative Medicine and Cellular Longevityvol 2011 Article ID 194586 15 pages 2011
[256] B Poljsak and I Milisav ldquoThe neglected significance of lsquoanti-oxidative stressrsquordquoOxidativeMedicine and Cellular Longevity vol2012 Article ID 480895 12 pages 2012
[257] T Godfraind and S Salomone ldquoAmbiguities in dietary antiox-idant supplementation compared to calcium channel blockerstherapyrdquo Frontiers in Pharmacology vol 6 article 10 2015
[258] H Wagner H Norr and H Winterhoff ldquoDrugs with adap-togenic effects for strengthening the powers of resistancerdquoZeitschrift fur Phytotherapie vol 13 no 2 pp 42ndash54 1992
20 Oxidative Medicine and Cellular Longevity
Of interest the scavenging capacity of AML towardshydroxyl radicals (1455 plusmn 154 unitsmg) was 320 higher(119875 lt 000001) than that of GSH (358 plusmn 112 unitsmg) 20higher than that of uric acid (1198plusmn121 unitsmg) and 100higher than that of Trolox (759 plusmn 143 unitsmg)
Amlodipine was shown to increase enzyme activity ofparaoxonase (PON) and glutathione peroxidase (GSH-Px)However it also decreases glutathione reductase (GSSG-R)activity and diminishes the concentration of the endogenousantioxidant 120572-tocopherol (vitamin E) Moreover AML in aconcentration of 2 ngmL decreased the content of malonicdialdehyde and activity of superoxide dismutase in the blood(Gatsura [208])
Verapamil and amlodipine produced a potent anti-ischemic effect and reduced area of myocardial infarction inrats The observed changes were accompanied by inhibitionof LP In contrast to verapamil in vitro application of AML ina dose of 50 ngmL decreased hemoglobin affinity for oxygenWhen present in a concentration of 2 ngmLAMDdecreasedthe content of MDA and activity of SOD in the blood
On the other hand amlodipine shows no activity relatedto inhibition of macrophage superoxide release and cellmigration which occurs as a consequence of decreasedTNF120572induced O
2
∙ releaseAmlodipine-induced reduction of OS in the brain is
associated with sympathoinhibitory effects in stroke-pronespontaneously hypertensive rats (SHRSP) (Hirooka et al[209]) Antihypertensive treatment with amlodipine reducedOS in all examined areas of the brain and decreased bloodpressure without a reflex increase in sympathetic nerveactivity Nicardipine another CA DHP surprisingly wassignificantly less active than amlodipine
354 Lercanidipine Tomlinson and Benzie reported AOeffect of lercanidipine [210] which is well known as anti-hypertensive drug Zanidip 2[(33-diphenylpropyl)(methyl)-amino]-11-dimethylethyl methyl 26-dimethyl-4-(3-nitro-phenyl)-14-dihydropyridine-35-dicarboxylate Compara-tive data about this drug AOA were presented in parts of thispaper about other individual CA DHPs and in the part aboutthe ex vivo DHPs effects on LDL
355 Nimodipine Nimodipine (ND) commercially knownas Nimotop is 3-(2-methoxyethyl) 5-propan-2-yl 26-dim-ethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxy-late It is centrally active CA
Treatment with glutathione blocked andwith nimodipineattenuated neuronal cell death caused by prolonged exposureof cell culture to 4-HNE (Faraqui [211])
Nascimento et al [212] found AO effect of nimodipine inyoung rats after pilocarpine- (PIL-) induced (in 400mgkg)seizures The PIL administration increased the striatal cata-lase (CAT) activity The administration of ND 30mgkg30min before PIL preserved normal value of CAT activityOn the other hand no difference was detected in the animalstreated with lower dose 10mgkg These results confirmthe neuroprotectiveantiepileptic effect of ND in young ratssuggesting that this drug acts positively on lipid peroxidation
(in both doses) Nimodipine cannot induce these effects viablockade of Ca2+ channel
Ismailoglu et al [213] studied the therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjury These beneficial effects in rats after cerebral corticalinjury seemed to be related to AOA of nimodipine
356 Benidipine Licensed in Japan and South Asia as CA(CCB) benidipine possesses AO properties Chemically it is5-methyl 3-[(3R)-1-(phenylmethyl)piperidin-3-yl] 26-dim-ethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxy-late (or its hydrochloride (4R)-rel-35-pyridinedicarboxylicacid 14-dihydro-26-dimethyl-4-(3-nitrophenyl)- 3-methyl5-[(3R)-1-(phenylmethyl)-3-piperidinyl] ester hydrochloride(1 1))
Benidipine influences processes connected with OS inseveral ways It prevents lysophosphatidylcholine- (lysoPC)-induced injury and ROS production in human aorticendothelial cells (HAECs) (Matsubara and Hasegawa [214])Matsubara et al [215] explained this effect based on stimula-tion of nitric oxide release
LysoPC is a component of oxidized low-density lipopro-teins (oxLDLs) which plays an important role in the patho-genesis of atherosclerosis Pretreatmentwith benidipine (03ndash3 120583molL) for 24 h protected against lysoPC-induced cyto-toxicity in the HAECs through inhibition of both lysoPC-stimulated ROS production and caspase-37-like activationwith a similar potency Since caspase-37 is involved inexecuting the apoptotic process the reduction of the activityof this enzyme by benidipine may explain the antiapoptoticeffect of the drug However benidipine did not suppresslysoPC-induced phosphorylation of mitogen-activated pro-tein kinases and Ca2+ influx in HAECs These results suggestthat the antioxidant properties of benidipine may be respon-sible for its ability to inhibit ROS production a possiblereason for reduced activation of caspase-37 In conclusionbenidipine suppresses lysoPC-induced endothelial dysfunc-tion through inhibition of ROS production which is due atleast in part to its antioxidant effect and not through theinhibition of L-type voltage-dependent calcium channels
Matsubara and Hasegawa [216] examined the effectsof benidipine on cytokine-induced expression of adhesionmolecules and chemokines (chemoattractants) which areimportant for the adhesion of monocytes to endotheliumPretreatment of HAECs with benidipine (03ndash10 120583molL)for 24 h significantly suppressed cytokine-induced vascularcell adhesion molecule-1 (VCAM-1) and intracellular celladhesion molecule-1 (ICAM-1) mRNA and protein expres-sion resulting in reduced adhesion of THP-1 monocytesBenidipine also suppressed induction of monocyte chemoat-tractant protein-1 (MCP-1) and interleukin-8 Benidipinealso inhibited redox-sensitive transcriptional nuclear factor-120581B (NF-120581B) pathway as determined by Western blotting ofinhibitory 120581B (I120581B) phosphorylation and luciferase reporterassay Results of analysis using optical isomers of benidip-ine and antioxidants suggest that these inhibitory effectswere dependent on pharmacological effects other than Ca2+antagonism Benidipine may thus have anti-inflammatoryproperties and benefits for the treatment of atherosclerosis
Oxidative Medicine and Cellular Longevity 21
Benidipine was also shown to inhibit ROS production inpolymorphonuclear leukocytes and oxidative stress in salt-loaded stroke-prone spontaneously hypertensive rats (Mat-subara et al [217])
It should be mentioned that other DHPs also haveendothelial AO actions [218]
357 Azelnidipine (AZL) Azelnidipine 3-[1-[di(phen-yl)methyl]azetidin-3-yl] 5-propan-2-yl 2-amino-6-methyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate(AZL) CAS number 123524-52-7 is commercially available4-nitroaryl-DHP type calcium antagonist with long-actingantihypertensive action (long-acting CA (CCB)) and a lowreported incidence of tachycardia It additionally possessesbeneficial effects in OS and diabetic conditions
Azelnidipine prevents cardiac dysfunction in strepto-zotocin-diabetic rats by reducing intracellular calcium accu-mulation (altering intracellular Ca2+ handling proteins) OSand apoptosis (Kain et al [219]) AZL can reduce the superox-ide production It exerts its protective effects by targeting theNADPH oxidase and mitochondrial redox enzymes AZL-treated diabetic rats express enhanced level of bcl-2 in thelysates of heart muscle indicating that AZL plays protectiverole in cardiac apoptosis
It has been previously observed that azelnidipine inhibitstumor necrosis factor-alpha-induced endothelial cell (EC)oxidative stress through its AO properties (Nakamura etal [220]) Azelnidipine but not nitrendipine completelyinhibits the Ang II-induced ROS generation in ECs (Matsuiet al [221])
Furthermore azelnidipine but not nitrendipine wasfound to partially restore decreased pigment epithelium-derived factor (PEDF) mRNA levels in Ang II-exposed ECsThis study suggests that AZL influence depends on its antiox-idative properties Authors concluded that upregulation ofPEDF by azelnidipine may become a therapeutic targetfor the treatment of diabetic retinopathy associated withhypertension
Antihypertensive agents with AO effects are potentiallyuseful for diabetic patients with hypertension While DHPtypeCAare among themost frequently used antihypertensivedrugs azelnidipine has been reported to have a unique AOeffect in vitro and in vivo in experimental animals (Ohmuraet al [222]) In hypertensive diabetic patients azelnidipinetreatment for 12 weeks induced a more significant decreasein erythrocyte LOOH level than amlodipine although thevalues related to blood pressure during each treatmentremained comparable These data confirm the usefulness ofLOOH level in erythrocyte membrane as a marker of OS invivo and indicate that azelnidipine has a unique antioxidativeproperty in humans
Daikuhara et al [223] reported the results of the OLCAstudy based on combination of (1) olmesartan and a calciumchannel blocker (azelnidipine) or (2) candesartan and a CCBamlodipine in two groups of diabetic hypertensive patientsPatients treated with the first combination presented highlypersistent early morning antihypertensive effect and strongerdecrease in heart rate fasting blood glucose andHbA1c levels
and microalbuminuria when compared to patients treatedwith the combination (2) Because diabetes is associated withsevere chronic OS the observed results might be at least in apart due to the AOA of azelnidipine
In favor of this are findings of Abe et al [224] who foundadditive antioxidative effects of azelnidipine on angiotensinreceptor blocker olmesartan treatment for type 2 diabeticpatients with albuminuria
Similarly the AOA of thiazolidinediones (insulin sensi-tizer) and their effect on cardiovascular function in type 2diabetic model rats and also those of some DHPs (nifedipineamlodipine or AZL commonly used antianginal and anti-hypertensive agents) in cultured human endothelial cells LPwere examined (Mizushige [225]) The AOA was evaluatedby measuring 8-iso-prostaglandine F
2120572concentration and
azelnidipine exhibited potent AOAInsulin (INS) resistance combined with hyperinsuline-
mia is involved in the generation of OS A relation-ship exists between increased production of ROS and thediverse pathogenic mechanisms involved in diabetic vascularcomplications including nephropathy Manabe et al [226]revealed that high doses of INS augmented mesangial cellproliferation through generation of intracellular ROS andactivation of redox signaling pathways Cell proliferation wasincreased in a dose-dependent manner by high doses of INS(01ndash10 120583M) but was inhibited by 01120583M AZL Namely theINS-increased phosphorylation of mitogen activated proteinkinaseextracellular signal-regulated kinase 12 (MAPKERK12) was inhibited by 01 120583MAZL The same AZL concen-tration blocked intracellular ROS production more effec-tively than 01 120583M nifedipine The NADPH oxidase inhibitorapocynin (001ndash01120583M) prevented INS-induced mesangialcell proliferation So azelnidipine inhibits insulin-inducedmesangial cell proliferation by inhibiting the productionof ROS Therefore azelnidipine may have the potential toprotect against the onset of diabetic nephropathy and slowits progression
Azelnidipine inhibited H2O2-induced cell death in
neonatal rat cardiomyocytes (Koyama et al [227]) Azelnidip-ine and nifedipine did not affect theH
2O2-induced activation
of extracellular signal-regulated protein kinases (ERK) andp38 MAPK (mitogen-activated protein kinase) In contrastazelnidipine but not nifedipine inhibited H
2O2-induced c-
Jun NH2-terminal kinases (JNK) activation Authors con-
cluded that azelnidipine has inhibited theH2O2-induced JNK
activation and cardiac cell death Therefore azelnidipine mayhave cardioprotective effects against OS
A specific atheroprotection activity of azelnidipine relatesto inhibition of TNF-120572-induced activator protein-1 activa-tion and interleukin-8 expression in human umbilical veinendothelial cells (HUVEC) through suppression of NADPHoxidase-mediated reactive oxygen species generation (Naka-mura et al [220]) TNF-120572 could play a central role in patho-genesis of insulin resistance and accelerated atherosclerosis inthe metabolic syndrome The concentration of AZL found tobe effective in these in vitro experiments is within therapeuticrange As EC do not possess voltage-operated L-type calciumchannels it is suggested that the beneficial effects of azelni-dipine are not likely due to CA property but to its unique AO
22 Oxidative Medicine and Cellular Longevity
ability Furthermore it has been recently found that serumlevels of monocyte chemoattractant protein-1 a biomarkerfor subclinical atherosclerosis were significantly decreased bythe AZL treatment in patients with essential hypertension Inthis paper [220] authors hypothesize that due to its uniqueTNF-120572 signalmodulatory activity and antioxidative propertyazelnidipine may be a promising DHP for targeting diabetesand cardiovascular diseases in hypertensive patients withmetabolic syndrome
Shinomiya et al [228] evaluated its AOA in culturedhuman arterial EC under OS Azelnidipine has shown apotent antioxidative effect that could be of significant clinicalbenefit when combined with its long-lasting antihypertensiveaction and low incidence of tachycardia
Azelnidipine inhibited TGF-1205731 and angiotensin II- (AngII-) activated 1205721(I) collagen mRNA expression in hepaticstellate cells (HSCs) (Ohyama et al [229]) FurthermoreTGF-1205731- and Ang II-induced OS and TGF-1205731-induced p38and JNK phosphorylation were reduced inHSCs treated withAZL Azelnidipine significantly decreased inflammatory cellinfiltration profibrotic genes expression HSC activation LPoxidative DNA damage and fibrosis in liver of CCl
4- or
TAA-treated mice Finally AZL prevented decrease of theexpression of some AO enzymes and accelerated regressionof liver fibrosis in CCl
4-treated mice Hence the antifibrotic
mechanism of AZL against CCl4-induced liver fibrosis in
mice may have been due to an increased level of AO defenseAs azelnidipine is widely used in clinical practice withoutserious adverse effects it may provide an effective newstrategy for antifibrotic therapy
358 Manidipine Manidipine (2-[4-(diphenylmethyl)pip-erazin-1-yl]ethyl methyl 26-dimethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate) is a DHP CCB withreported nephroprotective properties Calo et al [230] stud-ied effect of manidipine on gene expression and proteinlevel of OS related proteins p22(phox) (human neutrophilcytochrome b light chain (CYBA)) and heme oxygenase-1HO-1 Relevance for antihypertensive effects was revealedThe study assessed the effect of manidipine on normalsubjectsrsquo monocyte gene and protein expression of OS relatedproteins such as p22phox a NADPH oxidase system subunitcritical in generating O
2
∙minus and HO-1 induced by and pro-tective against OS Manidipine was compared with the ACEinhibitor captopril and the CCB nifedipine in the presenceand in the absence of sodiumarsenite (NaAsO
2) as an inducer
of OS Monocyte p22phox (CYBA) mRNA production wasreduced by both manidipine and captopril while no changeswere induced by nifedipine Manidipine increased monocyteHO-1 mRNA production while nifedipine and captoprilshowed no effect The effects of manidipine on p22phoxand HO-1 gene expression in the presence of OS were alsoconfirmed at the protein level Thus manidipine seems tosuppress p22phox and to increase the HO-1 mRNA produc-tion and protein level The manidipine-induced increase ofHO-1 gene and protein expression seems to be a peculiareffect of this drug since it is not observed with captopriland nifedipine This effect together with the reduction of
p22phoxmRNAproduction could play a role in its protectivemechanism against OS
359 Mebudipine The protective effect of mebudipine (14-dihydro-26-dimethyl-4-(3-nitrophenyl)-35-pyridinedicar-boxylic acid 3-methyl-5-tert-butyl ester BAY-n-6391) wasrevealed on OS and LP (MDA decrease SOD GPX andcatalase increase) in myocardial ischemic-reperfusion injuryin male rats (Ghyasi et al [231])
There are articles about other commercial and experi-mental DHPs on OS but we have reviewed only the mostcommonly studied compounds Effects of other commercialCA DHPs on OS are also mentioned in several parts of thisreview
36 14-DHPs Ca Agonists andTheir AOA and ARA For themost popular calcium agonist DHP Bay K 8644 no reactionwith peroxyl radicals was registered (Toniolo et al [114])However interactionwith other compounds possessing AOAand ARA (quercetin) was found
Opposite to that AON-acetylcysteine (NAC) diminishedincrease in Ca2+ transient amplitude and cell shorteninginduced by ISO and forskolin whereas NAC had no effecton the (S)-(minus)-methyl-14-dihydro-26-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylatemdash(minus)-BayK 8644-induced increases (Andersson et al [232])
Increased vasoconstriction responses to Bay K 8644 (3 times10minus7ndash3times 10minus5M)were significantly decreased by pyridoindoleantioxidant stobadine treatment in diabetes (Ceylan-Isik etal [233])
The functional interaction between two L-type Ca2+channel activators quercetin and Bay K 8644 has beeninvestigated in vascular smooth muscle cells Biological ARAcompound quercetin at nutritionally meaningful concen-trations limited the responsiveness of vascular L-type Ca2+channels to the pharmacological stimulation operated by BayK 8644 These data contribute to a better understanding ofquercetin effects on experimental in vivo cardioprotection(Saponara et al [234]) Thus these findings indicated thatalthough Bay K 8644 does not exert potent and direct AOAyet acting as calcium agonist it may affect efficiency of AOsubstances and vice versa
Interaction of grapefruit juice (containing quercetin andits analogues) with DHPs CA diminished effectiveness of CAaction of DHPs (Sica [235])
37 Interpretations of the Mechanism(s) of RadicalScavenging and AOA by DHPs
371 Molecular Mechanism(s) of Radical Scavenging andAOA of DHPs in the Model Systems 35-Dicarbonyl-14-di-hydropyridine derivatives possess powerful bis-120573-carbony-lvinyl-amino conjugation and for that reason cannot be con-sidered as ordinary amino antioxidants The electron andorH donation from DHPs ensures their reductant role andresults in AOA and ARA Oxidation reaction from DHPsresults in production of corresponding heteroaromatic pyri-dine derivatives
Oxidative Medicine and Cellular Longevity 23
Detailed studies were made about substituent in DHPring positions 14- namely 4-unsubstituted- 4-substituted4-alkyl- 4-aryl- 4-alkylaryl- ao 26- 35- (diacetyl ordialkoxycarbonyl chain ao) electronic and steric effects onAOA and ARA of DHPs [44 45 51] see Sections 331and 35 The bell-shaped dependence of DHPs AOA onthe 35-dialkoxycarbonyl- chain length was observed [4445 107 109 112] with the maximum activity at C
2H5ndash
C4H9 Decrease of AOA and incorporation into liposomes for
DHPs with alkyl chains longer than R gt C4H9further were
clarified as probable tendency to self-aggregation of thesecompounds ([51] and citation number 245 therein) Electronacceptorelectron donor properties are relevant for expres-sion of AOA or ARA of 35-disubstituted DHPs 35-Diacyl-substituted and 35-dicarbanilido- and 35-dipyridylamido-substituted DHPs are more active as AOs as their 35-dicyano-substituted analogues which have electron acceptorproperties [186]
Dubur et al [89] observed overwhelming steric influenceof substituents in position 4 of the DHP ring Gaviraghiet al [163 164] proposed that AO activity of DHPs ispartly dependent on capacity of the 14-DHP ring to donateelectrons to the propagating radical (ROO∙ or RO∙) and toreduce it to a less reactive form The abstraction (donation)of electron andor H in the oxidation and LP reactionstakes place from all 35-dicarbonyl-14-DHP systems andresults in the formation of corresponding pyridine derivatives(Augustyniak et al [51]) The physicochemical mechanism ofARA and AOA of 14-DHP has been extensively studied anddiscussed (Mulder et al [236]) but precise mechanisms oftheir activity need further clarification
The reactivity of C-4 substituted 14-DHPs possessingeither secondary or tertiary nitrogen atom in the DHP ringtoward alkyl alkylperoxyl radicals and ABTS radical cationwas determined in aqueous media at pH 74 [103] Thesecompounds reacted faster toward alkylperoxyl radicals andABTS radical cation than alkyl ones N-Ethyl-substitutedDHPs showed the lowest reactivity
The 4-methyl substituted DHP was the most reac-tive compound in previously mentioned reactions (Lopez-Alarcon et al [103]) However it was less active (068versus 10) than Trolox-C DHPs having electron-donatingsubstituents (4-Me-DHP and p-MeO-Phe-DHP) showed thehighest kinetic rate constants toward ABTS radical cation p-nitro-Phe-DHP a compound with an electron-withdrawingsubstituent showed a lower kinetic rate constant and N-alkyl-DHP compounds show kinetic rate constants lowerthan the -NH-DHP
Hydrogen at the 1-position of the DHP ring was revealedaccording to the deuteriumkinetic isotope effect studies to beinvolved in the proposedARAmechanismThis fact ismostlynoticeable in the case of alkyl radicals N-Ethyl-substitutedDHPs show the lowest reactivity when compared to Troloxor nisoldipine In all cases the respective pyridine derivativewas detected as the main product of the reaction (Lopez-Alarcon et al [103]) Authors indicate that the kinetic rateconstants toward alkyl alkylperoxyl andABTS radical cationdepend on the nature of the substituents in the C-4 positionof DHP and the presence of the secondary amine group in the
dihydropyridine ring that is the presence of the hydrogen in1-position
Yanez et al [197] have studied the reactivity of 11derivatives of 14-DHPs (including commercial CA) withalkylperoxyl radicals and ABTS radical cation The tested14-DHPs were 83-fold more reactive towards alkylperoxylradicals than to the ABTS cation radical All commercial14-DHP type CCBs were weaker than Trolox-C The par-ticipation of the hydrogen atom in the 1-position appearsto be very relevant for exhibited reactivity Hantzsch ester(diludine)was again found to be themost active compound inthe reaction with alkylperoxyl radicals 23-fold more activethan Trolox The photodegradation product of nifedipine(nitrosophenyl derivative of pyridine) also showed a highactivity Kinetic rate constants for the reaction between 14-DHP compounds and alkylperoxyl radicals exhibited a fairlygood linear correlation with the oxidation peak potentialof DHP derivatives However the activity of tested 14-DHPs towards ABTS radical cation showed an independencebetween kinetic rate constants and oxidation peak potentials
Kirule et al [195] andTirzit et al [196] studiedmechanismof AOA of 4-nitrophenyl-14-DHPs nifedipine and its ana-logues involving formation of 4-(21015840-nitrosophenyl)-pyridinederivative (as active principle) as a result of intramolecularredox reaction using chemical electrochemical and bio-chemical approaches (see Sections 331 and 351)
Nunez-Vergara et al [237] reported the electrochemicaloxidation of C4-hydroxyphenyl-substituted 14-DHP deriva-tives The oxidation proceeds via formation of the unstabledihydropyridyl radical as confirmed by controlled-potentialelectrolysis (CPE) and ESR experiments This type of 14-DHPs has significant activity towards the radicals even whencompared with commercial 14-DHP drugs with well-knownantioxidant ability
It was observed that nicardipine preferentially targets RO∙radicals and is inactive against ROO∙ Lacidipine on theother hand is equally active towards both types of radicals(Gaviraghi et al [164]) The cytoprotective effect againstexposure to H
2O2was more significant for lacidipine (ID
50=
14 nM its log119875 = 54 membrane partition = 136000 assumesposition located 7 A near to the membrane center otherless lipophilic DHPs located 12ndash16 A far from the center)as compared to amlodipine nifedipine and nicardipine insmooth muscle cell culture (Gaviraghi et al [164]) Oxidativeeffect of H
2O2shifts the Ca channel toward an open state
Thus the redox property of CCBs DHPs may augment theirCCB properties
Oxidation of pharmacologically active Hantzsch 14-dihydropyridines was found by electrogenerated superoxideusing a voltammetric approach in DMSO solutions (Ortiz etal [238] and Ortiz et al [239]) Raghuvanshi and Singh [240]have also reported oxidative aromatization of these DHPsinduced by superoxide
Chemiluminescence (CL) was used in the studies ana-lyzing the antioxidant activity of 12 various 4-flavonil-14-dihydropyridine derivatives (Kruk et al [241]) on a chemicalsystem involving a superoxide radical anion These deriva-tives showed structural similarity to flavonoids with respectto the presence of rings A B and C The results obtained in
24 Oxidative Medicine and Cellular Longevity
this study indicate that the tested derivatives may catalyzeconversion of superoxide radicals through mimicking theactivity of superoxide dismutase by delivering H+ for reac-tion
O2
minus∙+O2
minus∙+ 2H+ 997888rarr H
2O2+1O2
(3)
The enhanced emission of the light in the presence oftested compounds was significant and related to stimulatedproduction ofH
2O2and 1O
2fromO
2
∙The latter specieswereremoved from the reactionmixture by the following sequenceof reactions
H+
O2
minus∙997888rarr HO
2
∙
HO2
∙+O2
∙minus997888rarr HO
2
minus+1O2
2HO2
∙997888rarr H
2O2+1O2
2 (1O2) 997888rarr (O
2)2+ h]lowast
(4)
or to take part in spontaneous dismutation of H2O2
2H2O2997888rarr 2H
2O + 1O
2(5)
The authors have offered an original concept of action for 4-flavonil-14-dihydropyridine derivatives unrelated to that ofO2
∙ radical-trapping chain-breaking antioxidants Insteadthey showed that these compounds act similar to superoxidedismutases converting O
2
∙ to H2O2 Hydrogen peroxide
is less toxic for cells than O2
∙ because it is predominantlyremoved by peroxidases and catalases Finally AO effect ofthese DHPs differed from those mediated by flavonoids witha catechol structure of ring B which are well-known 1O
2
quenchersMulder and collaborators came to similar conclusions
especially related to molecular mechanisms of antioxidativeactivity of DHPs [236]TheAOproperties of Hantzsch 14-di-hydropyridine esters and two dibenzo-14-dihydropyridines910-dihydroacridine (DHAC) and N-methyl-910-dihydro-acridine (N-Me-DHAC) have been explored by determin-ing the autoxidation of styrene or cumene at 30∘C Theseexperiments showed that Hantzsch esters are virtually inac-tive as chain-breaking antioxidants (CB-AOs) contrary tothe findings observed by Lopez-Alarcon et al [103] whoused CB-AOA in aqueous media at pH 74 Their reactivitytoward peroxyl radicals was shown to be some 5 orders ofmagnitude lower than that of the excellent CB-AO 22578-pentamethyl-6-hydroxy-chroman (PMHC)
DHAC was found to be sim10 times less reactive thanPMHC kinetic measurements using DHAC N-deuterio-DHAC and N-Me-DHAC pointing out the abstraction ofN-H hydrogen in DHAC by peroxyl radicals despite the factthat the calculated C-H bond dissociation enthalpy (BDE) inDHAC is about 11 kcalmol lower than the N-H BDE Therates of hydrogen atom abstraction by the 22-diphenyl-1-picrylhydrazyl radical (DPPH∙) have also been determined
for the same series of compounds The trends in the peroxyl∙and DPPH∙ rate constants were found to be similar [236]
Tirzit et al [242] have observed quenching of singletoxygen by DHPs This observation paved the ground forfurther research related to reactions of DHPs with hydroxylradicals (Tirzit et al [243]) singlet oxygen (Kazush etal [94]) and mechanisms of action A series of 14-DHPderivatives in NAD-H-Cu2+-H
2O2system inhibited forming
of the hydroxyl radical (HO∙) while 14-DHP derivativeswith electron donor substituents in the molecule were shownto be capable themselves of generating HO∙ in the presenceof Cu2+ and H
2O2 Rubene et al [186] also described
interaction of 14-DHP derivatives with Fentonrsquos reagentwhich produces hydroxyl radical (HO∙) Rate constants ofthe DHPs reaction (1st order) with HO∙ radical were highin the range 109 L times mol times secminus1 close to that of NADHcysteine and thiourea 35-Diacetyl- derivatives reacted fastercompared to 35-dialkoxycarbonyl- ones The reaction ratedecrease was observed in the case of substitution at position4 as compared to 4-unsubstituted DHPs Some DHPs havingelectron donor -COOminus groups in the 35- or 26- positionsof DHP ring reacted immediately (having rate constantshigher as 109 L times mol times secminus1) Rate constants with HO
2
∙
and O2
∙minus radicals were of lower degree Thus DHPs actingas oxygen radical scavengers could effectively inhibit ROSrelated reactions of LP initiation stage
Nifedipine and nitrendipine reactivity toward singletoxygen was also studied [244] Nifedipine was shown tobe a good scavenger of excited oxygen mainly via physicaldeactivation with values of the total rate constant rangingfrom 208 times 105Mminus1 sminus1 (in dioxane) to 930 times 105Mminus1 sminus1(in propylene carbonate)The less reactive pathway generateda photooxidation product For that reason a mechanisminvolving a perepoxide-like encounter complex in the firststep of the reaction path was proposed (see [244] Figures8 and 9 therein) The dependence was observed on solventmicroscopic parameters of the total rate constant for the reac-tion between singlet oxygen and 14-DHPs These findingsshow that nifedipine possesses stronger protective activity inbiological systems than nitrendipine
Density-functional-theory (DFT) calculations made byWang et al [245] confirmed the former experimental obser-vations that Hantzsch ester diludine is potent antioxi-dant with high H atom-donating ability and relatively lowprooxidant activity Possible reaction pathways for radicalsderived from 14-dihydropyridine and the resonance modesfor radical species were given [245]
Moreover two ethoxycarbonyl (EtOCO) substituentsat C(2) and C(6) should further enhance Hantzsch esterdiludine H-atom-donating ability due to resonance effectsHowever DHPs should be used in nonpolar rather than inpolar solvents since in the latter not H-atom but electrontransfer is preferred in the radical scavenging process [245]
Mulder et al [246] proposed that quantum-thermochem-ical calculations must be used with caution to indicate ldquoapromising lead antioxidantrdquo as they criticized the density-functional-theory (DFT) calculations made by Wang et al[245]
Oxidative Medicine and Cellular Longevity 25
372 Possible Mechanisms of DHPs ARA and AOA in the Bio-logical Systems Interaction with Other OSModifiers Some ofthese mechanisms were already described (Sections 331 (2)-(b) 331 (2)-(c) 331 (3)-(b) 35)
Enzymatic sources of ROSwith confirmed functional rolein hypertension are NADPH oxidase NO synthase (NOS)xanthine oxidase and cyclooxygenase Godfraind [3] hasreviewed AO effects and protective action of calcium channelblockers (CCBs) Yao et al [247] observed antioxidant effects(as inhibition of LP) for cardio- and neuroprotective CCBs(3ndash300 120583molL) including 7 DHPs in homogenates of ratbrain IC
50values (120583M) were as follows nifedipine (515) gt
barnidipine (586) gt benidipine (712) gt nicardipine (1293)gt amlodipine (1355) gt nilvadipine (1673) gt nitrendipine(2521) gt diltiazem (gt300) = verapamil (gt300) There arealso research articles describing the AO properties of CCBsthrough direct scavenging effect or through preservationof the endogenous SOD activity These findings indicatethat CCBs may also act by reducing the production ofvasoconstrictors angiotensin and endothelin
When present in concentrations that can be achievedin plasma CCBs may inhibit LP formation [3] This AOactivity seems to be typical for high lipophilic CCBs becausetheir chemical structure facilitates proton-donating andresonance-stabilization mechanisms that quench the freeradical reaction Their insertion in the membrane nearpolyunsaturated fatty acids at relatively high concentrationspotentiates proton donation (or atomary H) to lipid peroxidemolecules thereby blocking the peroxidation process Theremaining unpaired free electron associated with the CCBmolecule can be stabilized in well-defined resonance struc-tures associated with the DHP ring (Mason et al [48])
The radical reaction (according to Godfraind [3]) thatdescribes the AO effects of a DHP CCBs is LOOlowast + DHPrarr LOOH + DHPlowast (where LOOlowast is lipid peroxide radical)which in general is reaction (7) of the LP reaction cascadeconsisting of sim10 reactions (Scheme 2) [89]
As the rate constants of in vitro interaction of 4-substituted DHPs with peroxyl radicals are three ordersof magnitude lower than that of the vitamin E derivativethese DHPs must be considered as weak AO (Ursini [204])However due to partition coefficient of DHPs in membranesand in case of specific binding high local concentration ofDHPs may be obtained
DHPs without CCB properties for instance Bay w 9798although structurally related to nifedipine inhibit TNF-120572-induced vascular cell adhesion molecule-1 expression inendothelial cells by suppressing reactive oxygen speciesgeneration [248]
Mitrega et al [249] have discovered that antiarrhythmicand hemodynamic effects of oxidized heteroaromatic DHPsoxy nifedipine oxy nimodipine oxy nitrendipine and oxynisoldipine suggest that CCB DHPs and their metabolitescould act at least in two ways targeting OS related eventsas reductants (see Section 351 (1)) andor bypassing OSrelatedmetabolic routes Authors postulated that contrary tocurrent belief NIF metabolites are pharmacologically activeATP sensitive potassium channels were mentioned as a tar-get
38 DHPs Anti- or Prooxidants Several substances (ascorbicacid being the most commonly studied) can serve either asantioxidants or as prooxidants depending on given condi-tions (Herbert [250]) Therefore Halliwell [251] has reporteddilemma related to polyphenols as possible antioxidantsand prooxidants causing experimental artifacts (about 25)by oxidation of antioxidant compounds in the cell culturemedia Nevertheless it is generally accepted opinion thatpolyphenols act as antioxidants in vivo Studies on DHPs alsoface such a dilemmaThe exact roles (anti- or prooxidative) ofany specific DHP depend on its structure appliedachievedconcentration and specificity of the targetexperimentaltesting system
This situation resembles the case of antioxidative effectsof tocopherol which depends on the fate of the secondaryradical as proposed by Winterbourn [252] The question wasldquoVitamin E - Pro- or Antioxidantrdquo
997888rarr chain termination of lipid peroxidation
(6)
Prooxidant
Toc∙ + Lipid-H 997888rarr Lipid∙ (in LDL particles) (7)
This example shows that generally speaking any AO mustfulfil several criteria to be considered as an effective com-pound physiologically
(i) It must be able to functionally interact with endoge-nous scavengers even at low concentrations
(ii) It must affect endogenous pathways of OS(iii) It should not have undesirable adverse effect(iv) It should manifest the antioxidant efficacy dependent
on the oxidant(v) It must discriminate among different strategies
needed for 1-electron and 2-electron processes(vi) Radical scavengers can be prooxidant unless linked to
a radical sink (Winterbourn [252])
According to these statements DHPs could be effective asAO under physiological conditions in vivo (Godfraind [3]and others [30 31 38]) and in vitro in various experimentalsystems (cell and tissue) (see Sections 33 34 35)
Hence calcium antagonists appeared to disrupt thefine balance between the production and scavenging ofROS Nifedipine verapamil and diltiazem were shown toinduce significant oxidative stress in the epididymal sperm(increased MDA and decreased catalase and superoxidedismutase activity) This may be the reason for the inductionof male infertility [253]
The dualism of 14-DHP effects has been recorded asinhibition or promotion of LP as quenching or initiating
26 Oxidative Medicine and Cellular Longevity
oxygen and nitrogen free radical chain reactions radiopro-tecting or radiosensitizing antagonizing or synergizing Ca2+in electromechanical coupling as well as in the membranestabilization or labilization
39 Could DHPs Be Involved in Antioxidative Stress Beforebeing applied in vivo the optimal dose and optimal timeintervals forDHPs applicationmust be knownNamely whileROS have been traditionally considered as toxic byproductsof aerobic metabolism we know nowadays that ROS may actas essential signaling molecules needed for the control ofmany different physiological processes Whether the role ofROS will be damaging protective or signaling depends onthe delicate equilibrium between time- and location-specificROS production and scavenging Accordingly the imbalanceof the increased AO potential so-called antioxidative stresscould be dangerous similar to chronic OS in particular incase of extended exposure Inappropriate interventions inthe oxidative homeostasis by excessive antioxidants especiallyin case of chronic exposure to antioxidants might havevery negative effects as was published in the ATBC studyshowing an increased cancer incidence in smokers treatedby excessive beta-carotene [254] Therefore overconsump-tion of any natural or synthetic AO including DHPs asdietary supplements or drugs must be avoided in order tosuppress oxidative damage and must not disrupt the well-integrated antioxidant defense network (Poljsak [255] andPoljsak and Milisav [256]) This is especially important whenadministrating lipid-soluble antioxidants that can be storedin biomembranes thus not only attenuating or preventing LPbut also affecting physiological effects of the natural antiox-idants in particular tocopherol The interrelationship withthe status of endogenous antioxidantsprooxidants should befollowed
DHPs primarily suppress the initiation stages of LPprocessThey do not entirely stop the LP propagation Actingsynergistically with tocopherol diludine may prevent patho-logical excess of ROS production within the lipid moiety ofthe cellular membranes and LDL However due to its lowsolubility and fast metabolism its concentration in the cellsis low For that reason it cannot cause antioxidative stresseven if used for an extended period of time Thus diludine(diethone) could be only a mild antioxidant it has potentialfor restoring the pool of natural antioxidants (as synergist of120572-tocopherol and polyphenols) in the cells
Moreover DHPs CA used for cardioprotection andvasodilatation as commercial drugs in low concentrationsare fast metabolized via CYP3A4 and for that reason theirapplication does not induce cellular AO stress [53 160]However Godfraind and Salomone [257] have postulated noevidence that allows recommending dietary supplementationwith antioxidants for the primary or secondary prevention ofcardiovascular disease
So far there are no reports on antioxidative stress causedby some DHPs diludine and its analogues Diludine andits analogues therefore could act as adaptogens supportinghormetic effects of mild oxidative stress These compoundsmay act as potential multisided modulators of Yin-Yang
cycles of redox and cell functions (the electroplasmic cycle)(Wagner et al [258])
4 Conclusions
14-Dihydropyridines (14-DHPs) have broad spectrum ofOS modulating activities DHPs have reducing and lipidperoxidation inhibitor properties act as reductants in simplechemical systems and stabilize various biological systems(LDL mitochondria microsomes cells and tissues) againstOS Examples and peculiarities and mechanisms of antiox-idant activity (AOA) and antiradical activity (ARA) as wellas stress-protective effect of DHPs including commercialcalcium antagonists (CA) were highlighted These activitiesdepend on various structural parameters related to DHPs(presence and character of substituents) lipophilicity anddepth of the incorporation in the biologicalmembranesTheyalso depend on the experimental model system for exploringthe lipid peroxidation or oxidative stress Stress-protectiveeffect of some metabolites of CA (nifedipine) is reviewedAlthough some DHPs including CA have prooxidant prop-erties (on epididymal sperm cells) they can generally beconsidered as potent antioxidants Therefore comparisonof the AOA and ARA of different DHPs (mutually andwith other AOs) was described in detail According to thedata presented the DHPs might be considered as bellwetheramong synthetic compounds targeting OS and as a kind ofpharmacological measure for respective field of organic andmedicinal chemistry
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
Authors from Latvian IOS acknowledge ESF 201300021DP1112013APIAVIAA011 and National Research Pro-gramme PUBLIC HEALTHBiomedicine of the Republicof Latvia for financial support administration of the Insti-tute for technical support and Rufus Smits PhD for con-sultations in English The support of Cooperation in Euro-pean System of Science and Technology (COST) Domain ofChemistry Molecular Sciences and Technologies (CMST)was of highest importance for preparation of this paper
[2] D J Triggle ldquo14-Dihydropyridines as calcium channel ligandsand privileged structuresrdquoCellular andMolecular Neurobiologyvol 23 no 3 pp 293ndash303 2003
[3] T Godfraind ldquoAntioxidant effects and the therapeutic modeof action of calcium channel blockers in hypertension andatherosclerosisrdquo Philosophical Transactions of the Royal SocietyB Biological Sciences vol 360 no 1464 pp 2259ndash2272 2005
[4] E Cadenas ldquoMitochondrial free radical production and cellsignalingrdquoMolecular Aspects of Medicine vol 25 no 1-2 pp 17ndash26 2004
[5] E Cadenas ldquoFree radicals oxidative stress and diseasesrdquo inLecture PSC 616 p 38 Missouri University of Science andTechnology Rolla Mo USA httpwwwcarnicominstituteorgarticlesenrique cadenaspdf
[6] K Rahman ldquoStudies on free radicals antioxidants and co-fac-torsrdquo Clinical Interventions in Aging vol 2 no 2 pp 219ndash2362007
[7] V Bocci and G Valacchi ldquoFree radicals and antioxidants howto reestablish redox homeostasis in chronic diseasesrdquo CurrentMedicinal Chemistry vol 20 no 27 pp 3397ndash3415 2013
[8] M Valko C J Rhodes J Moncol M Izakovic and M MazurldquoFree radicals metals and antioxidants in oxidative stress-induced cancerrdquo Chemico-Biological Interactions vol 160 no 1pp 1ndash40 2006
[9] G Bartosz ldquoReactive oxygen species destroyers or messen-gersrdquo Biochemical Pharmacology vol 77 no 8 pp 1303ndash13152009
[10] R Visconti and D Grieco ldquoNew insights on oxidative stress incancerrdquo Current Opinion in Drug Discovery and Developmentvol 12 no 2 pp 240ndash245 2009
[11] R N Kujundzic N Zarkovic and K G Troselj ldquoPyridinenucleotides in regulation of cell death and survival by redoxand non-redox reactionsrdquo Critical Reviews in Eukaryotic GeneExpression vol 24 no 4 pp 287ndash309 2014
[12] B Halliwell and J M C Gutteridge ldquoThe definition and mea-surement of antioxidants in biological systemsrdquo Free RadicalBiology and Medicine vol 18 no 1 pp 125ndash126 1995
[13] V D Kancheva and O T Kasaikina ldquoBio-antioxidantsmdashachemical base of their antioxidant activity and beneficial effect
on human healthrdquo Current Medicinal Chemistry vol 20 no 37pp 4784ndash4805 2013
[14] H V Panglossi Ed Frontiers in Antioxidants Research NovaScience Publishers New York NY USA 2006
[15] E B Burlakova E M Molochkina and G A NikiforovldquoHybrid antioxidantsrdquo Oxidation Communications vol 31 no4 pp 739ndash757 2008 httpmembraneustceducnpaperpdfHybrid20Antioxidantspdf
[16] A Bast and G R M M Haenen ldquoTen misconceptions aboutantioxidantsrdquo Trends in Pharmacological Sciences vol 34 no 8pp 430ndash436 2013
[17] E B Burlakova A V 0lesenko E M Molochkina N PPalmina and N G Khrapova Bioantioxidants for RadiationDamage and Malignant Growth Nauka Moscow Russia 1975(Russian)
[18] J Fang T Seki and H Maeda ldquoTherapeutic strategies by mod-ulating oxygen stress in cancer and inflammationrdquo AdvancedDrug Delivery Reviews vol 61 no 4 pp 290ndash302 2009
[19] M Valko D Leibfritz J Moncol M T D Cronin M Mazurand J Telser ldquoFree radicals and antioxidants in normal physi-ological functions and human diseaserdquo International Journal ofBiochemistry and Cell Biology vol 39 no 1 pp 44ndash84 2007
[20] M Jimenez-Del-Rio and C Velez-Pardo ldquoThe bad the goodand the ugly about oxidative stressrdquo Oxidative Medicine andCellular Longevity vol 2012 Article ID 163913 13 pages 2012
[21] C D Kamat S Gadal M Mhatre K S Williamson Q N Pyeand K Hensley ldquoAntioxidants in central nervous system dis-eases preclinical promise and translational challengesrdquo Journalof Alzheimerrsquos Disease vol 15 no 3 pp 473ndash493 2008
[22] A Pompella H Sies R Wacker et al ldquoThe use of totalantioxidant capacity as surrogate marker for food quality andits effect on health is to be discouragedrdquo Nutrition vol 30 no7-8 pp 791ndash793 2014
[23] Z Ye and H Song ldquoAntioxidant vitamins intake and the risk ofcoronary heart disease meta-analysis of cohort studiesrdquo Euro-pean Journal of Cardiovascular Prevention and Rehabilitationvol 15 no 1 pp 26ndash34 2008
[24] P Knekt J Ritz M A Pereira et al ldquoAntioxidant vitamins andcoronary heart disease risk a pooled analysis of 9 cohortsrdquoTheAmerican Journal of Clinical Nutrition vol 80 no 6 pp 1508ndash1520 2004
[25] A C Carr and M C M Vissers ldquoSynthetic or food-derivedvitamin Cmdashare they equally bioavailablerdquo Nutrients vol 5 no11 pp 4284ndash4304 2013
[26] R Tabrizchi ldquoEdaravoneMitsubishi-TokyordquoCurrentOpinion inInvestigational Drugs vol 1 no 3 pp 347ndash354 2000
[27] K Kikuchi S Tancharoen N Takeshige et al ldquoThe efficacy ofedaravone (radicut) a free radical scavenger for cardiovasculardiseaserdquo International Journal of Molecular Sciences vol 14 no7 pp 13909ndash13930 2013
[28] D Mauzerall and F H Westheimer ldquo1-Benzyldihydronicoti-namidemdasha model for reduced DPNrdquo Journal of the AmericanChemical Society vol 77 no 8 pp 2261ndash2264 1955 ChemicalAbstracts vol 50 Article ID 2588i 1956
[29] F Bossert and W Vater ldquo14-Dihydropyridinesmdasha basis fordeveloping new drugsrdquo Medicinal Research Reviews vol 9 no3 pp 291ndash324 1989
[30] G Swarnalatha G Prasanthi N Sirisha and CMadhusudhanaChetty ldquo14-Dihydropyridines a multtifunctional moleculemdash areviewrdquo International Journal of ChemTech Research vol 3 no1 pp 75ndash89 2011
28 Oxidative Medicine and Cellular Longevity
[31] M Cataldi and F Bruno ldquo14-Dihydropyridines the multiplepersonalities of a blockbuster drug familyrdquo Translational Medi-cine UniSa vol 4 no 2 pp 12ndash26 2012 httpwwwncbinlmnihgovpmcarticlesPMC3728803
[32] R Vitolina A Krauze G Duburs and A Velena ldquoAspects ofthe amlodipine pleiotropy in biochemistry pharmacology andclinicsrdquo International Journal of Pharmaceutical Sciences andResearch vol 3 no 5 pp 1215ndash1232 2012
[33] D Grover S N Mokale and M T Shete ldquoDihydropyridinea novel pharmacophorerdquo International Journal of Pharmaceu-tical Erudition vol 1 no 2 pp 16ndash29 2011 httppharmaeru-ditionorgContentPaper20111-RV-320Final2016-29pdf
[34] A M Vijesh A M Isloor S K Peethambar K N ShivanandaT Arulmoli and N A Isloor ldquoHantzsch reaction synthesis andcharacterization of somenew 14-dihydropyridine derivatives aspotent antimicrobial and antioxidant agentsrdquo European Journalof Medicinal Chemistry vol 46 no 11 pp 5591ndash5597 2011
[35] P Mehta and P Verma ldquoAntimicrobial activity of some deriva-tives of 14-dihydropyridinesrdquo Journal of Chemistry vol 2013Article ID 865128 4 pages 2013
[36] P Olejnıkova L Svorc D Olsovska et al ldquoAntimicrobialactivity of novel C2-substituted 14-dihydropyridine analoguesrdquoScientia Pharmaceutica vol 82 no 2 pp 221ndash232 2014
[37] S Sepehri H Perez Sanchez and A Fassihi ldquoHantzsch-typedihydropyridines and biginelli-type tetra-hydropyrimidinesa review of their chemotherapeutic activitiesrdquo Journal of Phar-macy amp Pharmaceutical Sciences vol 18 no 1 pp 1ndash52 2015httpsejournalslibraryualbertacaindexphpJPPSarticleview2383617863
[38] S A Khedkar and P B Auti ldquo14-Dihydropyridines a classof pharmacologically important moleculesrdquo Mini-Reviews inMedicinal Chemistry vol 14 no 3 pp 282ndash290 2014
[39] G D Tirzit and G Ya Duburs ldquo14-dihydropyridines as inhi-bitors of free-radical reactionsrdquo Chemistry of Heterocyclic Com-pounds vol 8 no 1 pp 126ndash127 1972 Translated from KhimiyaGeterotsiklicheskikh Soedinenii no1 pp 133ndash134 1972 (Rus-sian)
[40] I Bogeski R Kappl C Kummerow R Gulaboski M Hothand B A Niemeyer ldquoRedox regulation of calcium ion channelschemical and physiological aspectsrdquoCell Calcium vol 50 no 5pp 407ndash423 2011
[41] S A Giller G Y Dubur Y R Uldrikis et al ldquoDiludine [Themethod to obtain 35-dicarbonylderivatives of 26-dimethyl-14-dihydropyridines]rdquo Authors certificate of USSR no 3004651971 [Byull Izobret no13 p 95 1971] and following patentsPatent of England no 1294650 1973 Patent of France no2055458 1971 Patent of Japan no 702883 1973 Patent ofHolland no 149787 1976 Patent of Italy no 969022 1974 Patentof FRG no 2036403 1978 US Patent no 3883673 1975 USPatent no 3948924 1976
[42] S A Giller G Y Dubur Y R Uldrikis et al ldquoImprovementsin or relating to the stabilization of carotenerdquo GB Patent no1294650 1972
[43] S A Giller G Y Dubur Y R Uldrikis et al ldquoStabilization ofcarotenerdquo US Patent no 3883673 1975 Chemical Abstracts vol83 Article ID 95193 1975
[44] Yu A Zilber G Ya Dubur K K Kumsar and A Kh VelenaldquoThe effect of antioxidants on the peroxidation of bimole-cular phospholipid membranesrdquo Latvijas PSR ZA Vestis Izves-tia Akademii Nauk Latviyskoy SSR vol 6 pp 80ndash82 1971(Russian) translated from the original Russian Doc Accesion
No AD0771751 distributed by NTIS US Department of Com-merce httpwwwdticmildtictrfulltextu2771751pdf
[45] G Ya Dubur Yu A Zilbers A Kh Velena A O Kumerovaand G D Tirzitis ldquoMultistage study of regulation of peroxida-tion processes in biological membranes by antioxidants of 14-dihydropyridine grouprdquo Izvestiya Akademii Nauk LatviyskoySSR vol 336 no 7 pp 65ndash68 1975 (Russian)
[46] R P Mason and M W Trumbore ldquoDifferential membraneinteractions of calcium channel blockers Implications forantioxidant activityrdquo Biochemical Pharmacology vol 51 no 5pp 653ndash660 1996
[47] R P Mason M F Walter M W Trumbore E G Olmstead Jrand P E Mason ldquoMembrane antioxidant effects of the chargeddihydropyridine calcium antagonist amlodipinerdquo Journal ofMolecular and Cellular Cardiology vol 31 no 1 pp 275ndash2811999
[48] R PMason I T MakMW Trumbore and P EMason ldquoAnti-oxidant properties of calcium antagonists related to membranebiophysical interactionsrdquo American Journal of Cardiology vol84 no 4 pp 16ndash22 1999
[49] R PMasonMW Trumbore and P EMason ldquoMembrane bio-physical interaction of amlodipine and antioxidant propertiesrdquoDrugs vol 59 no 2 pp 9ndash16 2000 (French)
[50] R P Mason P Marche and T H Hintze ldquoNovel vascularbiology of third-generation L-type calcium channel antagonistsAncillary actions of amlodipinerdquo Arteriosclerosis Thrombosisand Vascular Biology vol 23 no 12 pp 2155ndash2163 2003
[51] A Augustyniak G Bartosz A Cipak et al ldquoNatural andsynthetic antioxidants an updated overviewrdquo Free RadicalResearch vol 44 no 10 pp 1216ndash1262 2010
[52] T Grune N Zarkovic and K Kostelidou ldquoLipid peroxidationresearch in Europe and the COST B35 action lsquoLipid Peroxida-tion Associated Disordersrsquordquo Free Radical Research vol 44 no10 pp 1095ndash1097 2010
[53] E Carosati P Ioan M Micucci et al ldquo14-Dihydropyridinescaffold in medicinal chemistry the story so far and perspec-tives (part 2) action in other targets and antitargetsrdquo CurrentMedicinal Chemistry vol 19 no 25 pp 4306ndash4323 2012
[54] U Eisner and J Kuthan ldquoThe chemistry of dihydropyridinesrdquoChemical Reviews vol 72 no 1 pp 1ndash42 1972 httpwwwsci-encemadnessorgtalkfilesphppid=138742ampaid=6475
[55] J Kuthan and A Kurfurst ldquoDevelopment in dihydropyri-dine chemistryrdquo Industrial amp Engineering Chemistry ProductResearch and Development vol 21 no 2 pp 191ndash261 1982
[56] A Sausins and G Duburs ldquoSynthesis of 14-dihydropyridinesby cyclocondensation reactionsrdquo Heterocycles vol 27 no 1 pp269ndash289 1988
[57] A E Sausins and G Y Duburs ldquoSynthesis of 14-dihydro-pyridines in cyclocondensation reactions (review)rdquo Chemistryof Heterocyclic Compounds vol 28 no 4 pp 363ndash391 1992Translated from Khimiya Geterotsiklicheskikh Soedinenii no 4pp 435ndash467 1992 (Russian)
[58] S Kazda ldquoTwenty years of dihydropyridinesrdquo in Dihydropy-ridines Progress in Pharmacology and Therapy W-D Busse BGarthoff and F Seuter Eds pp 1ndash12 Springer Verlag BerlinGermany 1993
[59] J-P Wan and Y Liu ldquoRecent advances in new multicomponentsynthesis of structurally diversified 14-dihydropyridinesrdquo RSCAdvances vol 2 no 26 pp 9763ndash9777 2012
[61] Reaxys Database[62] J Tuttle ldquoStructure mechanism and reactivity of hantzsch
estersrdquo in MacMillan Lab Group Meeting (082504) p 332004 httpwwwprincetoneduchemistrymacmillangroup-meetingsJBT20Hantzschpdf
[63] A Saini S Kumar and J S Sandhu ldquoHantzsch reaction recentadvances in Hantzsch 14-dihydropyridinesrdquo Journal of Sci-entific amp Industrial Research vol 67 pp 95ndash111 2008
[64] L LW Cheung S A Styler and A P Dicks ldquoRapid and conve-nient synthesis of the 14-dihydropyridine privileged structurerdquoJournal of Chemical Education vol 87 no 6 pp 628ndash630 2010
[65] A Kumar R A Maurya S Sharma M Kumar and G BhatialdquoSynthesis and biological evaluation of N-aryl-14-dihydro-pyridines as novel antidyslipidemic and antioxidant agentsrdquoEuropean Journal of Medicinal Chemistry vol 45 no 2 pp 501ndash509 2010
[66] R S Kumar A Idhayadhulla A J Abdul Nasser and J SelvinldquoSynthesis and anticoagulant activity of a new series of 14-dihydropyridine derivativesrdquo European Journal of MedicinalChemistry vol 46 no 2 pp 804ndash810 2011
[67] H A Stefani C B Oliveira R B Almeida et al ldquoDihydro-pyrimidin-(2H)-ones obtained by ultrasound irradiation anew class of potential antioxidant agentsrdquo European Journal ofMedicinal Chemistry vol 41 no 4 pp 513ndash518 2006
[68] H Sun C Shang L Jin and J Zhang ldquoSynthesis and antiox-idant activity of a series of novel 3-chalcone-substituted 14-dihydropyridine derivativesrdquoHeterocyclic Communications vol18 no 5-6 pp 239ndash243 2012
[69] D B Tikhonov and B S Zhorov ldquoStructural model for dihy-dropyridine binding to L-type calcium channelsrdquo The Journalof Biological Chemistry vol 284 no 28 pp 19006ndash19017 2009
[70] G Y Dubur and Y R Uldrikis ldquoThe oxidation of 14-dihydro-pyridinesrdquo Chemistry of Heterocyclic Compounds vol 6 no 1pp 80ndash84 1970 Translated from Khimiya GeterotsiklicheskikhSoedinenii no 1 pp 83ndash88 1970 (Russian)
[71] G Ya Duburs A O Kumerova and Ya R Uldrikis ldquoEnzymicoxidation of hydrogenated pyridines with peroxidase-hydrogenperoxide systemrdquoLatvijas PSRZAVestis vol 73 no 7 pp 73ndash771970 (Russian) Chemical Abstracts vol 73 Article ID 94913g1970
[72] K Xie Y-C Liu Y Cui J-GWang Y Fu andT CWMak ldquoN-methyl-(R)-3-(tert-butyl)-sulfinyl-14-dihydropyridine a novelNADHmodel compoundrdquoMolecules vol 12 no 3 pp 415ndash4222007
[73] S Tamagaki T Mimura and W Tagaki ldquoMetal-ion-facilitatedoxidations of dihydropyridines with molecular oxygen andhydrogen peroxiderdquo Journal of the Chemical Society PerkinTransactions 2 no 10 pp 1645ndash1650 1990
[74] D Tirzite G Tirzitis andD Antipova ldquoReductive ability of 14-dihydropyridine derivatives in relation to ions of trivalent ironrdquoChemistry of Heterocyclic Compounds vol 35 no 5 pp 592ndash594 1999
[76] J Ogle J Stradins and L Baumane ldquoFormation and decay offree cation-radicals in the course of electro-oxidation of 12- and14-dihydropyridines (Hantzsch esters)rdquo Electrochimica Actavol 39 no 1 pp 73ndash79 1994
[77] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for the
synthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts C Wittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Berlin Germany 2010
[78] WDu and Zh Yu ldquoBiomimetic in situ regeneration of cofactorsNAD(P)+ and NAD(P)H models hantzsch esters and dihy-drophenanthridinerdquo Synlett vol 23 no 9 pp 1300ndash1304 2012
[79] H K Chenault and G M Whitesides ldquoRegeneration ofnicotinamide cofactors for use in organic synthesisrdquo AppliedBiochemistry and Biotechnology vol 14 no 2 pp 147ndash197 1987
[80] Y R Uldrikis A A Zidermane E A Biseniex I E Preisa GY Dubur and G D Tirzit ldquoEsters of 26-dimethyl-14-dihydro-pyridine-35-dicarboxylic acid and method of obtainingthereofrdquo WO 8000345 A1 1978 httpworldwideespacenetcompublicationDetailsbiblioDB=EPODOCampII=1ampND=3ampadjacent=trueamplocale=en EPampFT=Dampdate=19800306ampCC=WOampNR=8000345A1ampKC=A1
[81] Y Sambongi H Nitta K Ichihashi M Futai and I Ueda ldquoAnovel water-soluble Hantzsch 14-dihydropyridine compoundthat functions in biological processes through NADH regener-ationrdquo Journal of Organic Chemistry vol 67 no 10 pp 3499ndash3501 2002
[82] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for thesynthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts ChWittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Verlag Berlin Germany 2010
[83] T Okamura T Kikuchi A Nagamine et al ldquoAn approach formeasuring in vivo cerebral redox states using the oxidative con-version of dihydropyridine to pyridinium ion and themetabolictrapping principlerdquo Free Radical Biology and Medicine vol 38no 9 pp 1197ndash1205 2005
[84] K A Schellenberg and F H Westheimer ldquoA free-radicaloxidation of a dihydropyridine1ardquo The Journal of OrganicChemistry vol 30 no 6 pp 1859ndash1862 1965
[85] K A Schellenberg ldquoReaction of hydroxyl radical with thymi-dine Scavenging by a dihydropyridinerdquo Federation Proceedingsvol 38 no 3 I p 1433 1979
[86] E S Huyser J A K Harmony and F L McMillian ldquoPeroxideoxidations of dihydropyridine derivativesrdquo Journal of the Amer-ican Chemical Society vol 94 no 9 pp 3176ndash3180 1972
[87] A Sakamoto S T Ohnishi and R Ogawa ldquoInhibition of lipidperoxidation by some dihydropyridine derivativesrdquo Journal ofAnesthesia vol 7 no 2 pp 193ndash197 1993
[88] R Hardeland ldquoReview Neuroprotection by radical avoidancesearch for suitable agentsrdquo Molecules vol 14 no 12 pp 5054ndash5102 2009
[89] G Ya Dubur A Kh Velena V M Gukasov and Yu AVladimirov ldquoRegulation of peroxidation of mitochondrialmembrane lipids initiated by Fe2+ ions by antoxidants of the14-dihydropyridine series in experiments in vitrordquo Biomed-itsinskaya Khimiya vol 22 no 5 pp 665ndash673 1976 (Russian)Chemical Abstracts vol 88 Article ID 2640 1977
[90] G RMMHaenenM J T J Arts A Bast andMD ColemanldquoStructure and activity in assessing antioxidant activity in vitroand in vivo a critical appraisal illustrated with the flavonoidsrdquoEnvironmental Toxicology and Pharmacology vol 21 no 2 pp191ndash198 2006
[91] G Tirzitis and G Bartosz ldquoDetermination of antiradical andantioxidant activity basic principles and new insightsrdquo ActaBiochimica Polonica vol 57 no 2 pp 139ndash142 2010
30 Oxidative Medicine and Cellular Longevity
[92] G R Buettner and R P Mason ldquoSpin-trapping methods fordetecting superoxide and hydroxyl free radicals in vitro and invivordquo inCritical Reviews of Oxidative Stress and Aging Advancesin Basic Science Diagnostics and Intervention R G Cutler andH Rodriguez Eds vol 1 chapter 2 pp 27ndash38World ScientificLondon UK 2003
[93] M M Tarpey and I Fridovich ldquoMethods of detection ofvascular reactive species Nitric oxide superoxide hydrogenperoxide and peroxynitriterdquo Circulation Research vol 89 no3 pp 224ndash236 2001
[94] E Y Kazush E I Sagun G D Tirzit and G Y DaburldquoQuenching of singlet oxygen by electron donating derivativesof 14-dihydropyridinerdquo Chemistry of Heterocyclic Compoundsvol 30 no 5 pp 562ndash563 1994
[95] G Tirzitis E Kazush and G Duburs ldquoReaction of 14-dihydropyridine derivatives with peroxynitrite anionrdquo Chem-istry of Heterocyclic Compounds vol 34 no 3 pp 321ndash3231998 (Russian) Translated from Khimiya GeterotsiklicheskikhSoedinenii no 3 pp 355ndash357 1998
[96] L J Nunez-Vergara C Lopez-Alarcon P A Navarrete-EncinaA M Atria C Camargo and J A Squella ldquoElectrochemicaland EPR characterization of 14-dihydropyridines Reactivitytowards alkyl radicalsrdquo Free Radical Research vol 37 no 1 pp109ndash120 2003
[97] D Tirzite A Krauze A Zubareva G Tirzitis and G DubursldquoSynthesis and antiradical activity of 5-acetyl-2-alkylthio-4-aryl-6-methyl-14-dihydropyridine-3-carboxylic acid nitrilesrdquoChemistry of Heterocyclic Compounds vol 38 no 7 pp 795ndash800 2002
[98] H Ohkawa N Ohishi and K Yagi ldquoAssay for lipid peroxidesin animal tissues by thiobarbituric acid reactionrdquo AnalyticalBiochemistry vol 95 no 2 pp 351ndash358 1979
[99] N Zarkovic ldquo4-Hydroxynonenal as a bioactive marker ofpathophysiological processesrdquo Molecular Aspects of Medicinevol 24 no 4-5 pp 281ndash291 2003
[100] M Parola G Bellomo G Robino G Barrera and M UDianzani ldquo4-Hydroxynonenal as a biological signal molecularbasis and pathophysiological implicationsrdquo Antioxidants andRedox Signaling vol 1 no 3 pp 255ndash284 1999
[101] T Lovakovic M Poljak-Blazi G Duburs et al ldquoGrowthmodulation of human cells in vitro by mild oxidative stressand 14-dihydropyridine derivative antioxidantsrdquo CollegiumAntropologicum vol 35 no 1 pp 137ndash141 2011
[102] R van den Berg G R M M Haenen H van den Bergand A Bast ldquoApplicability of an improved Trolox equivalentantioxidant capacity (TEAC) assay for evaluation of antioxidantcapacity measurements of mixturesrdquo Food Chemistry vol 66no 4 pp 511ndash517 1999
[103] C Lopez-Alarcon P Navarrete C Camargo J A Squella andL J Nunez-Vergara ldquoReactivity of 14-dihydropyridines towardalkyl alkylperoxyl radicals and ABTS radical cationrdquo ChemicalResearch in Toxicology vol 16 no 2 pp 208ndash215 2003
[104] V Valenzuela P Santander C Camargo J A Squella C Lopez-Alarcon and L J Nunez-Vergara ldquo14-Dihydropyridines reac-tivity of nitrosoaryl and nitroaryl derivatives with alkylperoxylradicals andABTS radical cationrdquo Free Radical Research vol 38no 7 pp 715ndash727 2004
[105] L G Tsetlin N A Chebotareva B I Kurganov A K VelenaG Y Dubur and V Z Lankin ldquoStudy of 14-dihydropyridinesas lipoxygenase inhibitors with the use of hydrated reversedmicellesrdquo Pharmaceutical Chemistry Journal vol 22 no 6 pp425ndash428 1988 (Russian)
[106] J Panek Z Reblova L Kocirkova et al ldquoAntioxidant activityof dihydropyridine derivativesrdquo Czech Journal of Food Sciencesvol 18 pp 144ndash145 2000
[107] G Tirzitis I Kirule and G Duburs ldquoAntioxidationsaktivitatder 35-dicarbonylderivate des 26-demethyl-14-dihydropyri-dinsrdquo Fett Wissenschaft TechnologieFat Science Technology vol90 no 10 pp 411ndash413 1988
[108] M Plotniece G Tirzitis Y Uldrikis et al ldquoSynthesis of 14-dihydropyridine derivatives having an oxy- alkoxy- or dimeth-ylaminophenyl substituent in the 4 position their antioxidantactivity and their binding to phospholipid membranesrdquo Chem-istry of Heterocyclic Compounds vol 32 no 10 pp 1166ndash11721996 Translated from Khimiya Geterotsiklicheskikh Soedineniino 10(352) pp 1358ndash1365 1996 (Russian)
[109] D Y Rubene V S Sharov V I Olenev G D Tirzit G Y Duburand Y A Vladimirov ldquoUse of chemiluminescent method forthe evaluation of antioxidant activity of some derivatives of 14-dihydropyridinerdquo Russian Journal of Physical Chemistry A vol55 no 2 pp 511ndash512 1981 (Russian)
[110] M C R Symons and JM C Gutteridge Free Radicals and IronChemistry Biology and Medicine Oxford Science PublicationsOxford University Press Oxford UK 1998
[111] M Repetto J Semprine and A Boveris ldquoLipid peroxidationchemical mechanism biological implications and analyticaldeterminationrdquo in Lipid Peroxidation A Catala Ed Section ILipid Peroxidation Chemical Mechanisms Antioxidants Bio-logical Implications of Biochemistry Genetics and MolecularBiology chapter 1 pp 3ndash30 InTech Rijeka Croatia 2012
[112] A Velena J Zilbers and G Duburs ldquoDerivatives of 14-dihydropyridines asmodulators of ascorbate-induced lipid per-oxidation and high-amplitude swelling ofmitochondria causedby ascorbate sodium linoleate and sodiumpyrophosphaterdquoCellBiochemistry and Function vol 17 no 4 pp 237ndash252 1999
[113] M V Bilenko L N Shelenkova G Y Dubur and A K VelenaldquoUse of antioxidants to prevent renal damage during acuteischemia and reperfusionrdquo Bulletin of Experimental Biology andMedicine vol 96 no 3 pp 1195ndash1198 1983 Translated fromByulletenrsquo Eksperimentalrsquonoi Biologii i Meditsiny vol 96 no 9pp 8ndash11 1983 (Russian)
[114] R Toniolo F Tubaro F Ursini and G Bontempelli ldquoAn elec-troanalytical investigation on the redox properties of calciumantagonist dihydropyridinesrdquo Electroanalysis vol 15 no 10 pp855ndash861 2003
[115] L Kourimska J Pokorny and G Tirzitis ldquoThe antioxidant aci-tivity of 26-dimethyl-35-diethoxycarbonyl-14-dihydropyri-dine in edible oilsrdquo Nahrung vol 37 no 1 pp 91ndash93 1993
[116] C Lopez-Alarcon H Speisky J A Squella C Olea-Azar CCamargo and L J Nunez-Vergara ldquoReactivity of 14-dihydro-pyridines toward SIN-1-derived peroxynitriterdquo PharmaceuticalResearch vol 21 no 10 pp 1750ndash1757 2004
[117] R A Olek W Ziolkowski J J Kaczor L Greci J Popinigisand J Antosiewicz ldquoAntioxidant activity of NADH and its ana-loguemdashan in vitro studyrdquo Journal of Biochemistry andMolecularBiology vol 37 no 4 pp 416ndash421 2004
[118] E Niki N Noguchi and N Gotoh ldquoInhibition of oxidativemodification of low density lipoprotein by antioxidantsrdquo Jour-nal of Nutritional Science andVitaminology vol 39 supplementpp S1ndashS8 1993
[119] N Rojstaczer and D J Triggle ldquoStructure-function relation-ships of calcium antagonists effect on oxidative modificationof low density lipoproteinrdquo Biochemical Pharmacology vol 51no 2 pp 141ndash150 1996
Oxidative Medicine and Cellular Longevity 31
[120] A Sevanian L Shen and FUrsini ldquoInhibition of LDLoxidationand oxidized LDL-induced cytotoxicity by dihydropyridinecalcium antagonistsrdquo Pharmaceutical Research vol 17 no 8 pp999ndash1006 2000
[121] A Negre-Salvayre and R Salvayre ldquoProtection by Ca2+ channelblockers (nifedipine diltiazem and verapamil) against the tox-icity of oxidized low density lipoprotein to cultured lymphoidcellsrdquo British Journal of Pharmacology vol 107 no 3 pp 738ndash744 1992
[122] A Negre-Salvayre G FitoussiM Troly and R Salvayre ldquoCom-parative cytoprotective effect of dihydropyridine calcium chan-nel blockers against the toxicity of oxidized low density lipopro-tein for cultured lymphoid cellsrdquo Biochemical Pharmacologyvol 44 no 12 pp 2379ndash2386 1992
[123] L Cominacini A F Pasini U Garbin et al ldquoAntioxidant activ-ity of different dihydropyridinesrdquo Biochemical and BiophysicalResearch Communications vol 302 no 4 pp 679ndash684 2003
[124] L Cominacini U Garbin A Fratta Pasini et al ldquoOxidized low-density lipoprotein increases the production of intracellularreactive oxygen species in endothelial cells inhibitory effect oflacidipinerdquo Journal of Hypertension vol 16 no 12 part 2 pp1913ndash1919 1998
[125] H M Lander ldquoAn essential role for free radicals and derivedspecies in signal transductionrdquo The FASEB Journal vol 11 no2 pp 118ndash124 1997
[126] M L L Martinez E Rizzi M M Castro et al ldquoLercanidipinedecreases vascular matrix metalloproteinase-2 activity andprotects against vascular dysfunction in diabetic ratsrdquo EuropeanJournal of Pharmacology vol 599 no 1ndash3 pp 110ndash116 2008
[127] P Lesnik C Dachet L Petit et al ldquoImpact of a combinationof a calcium antagonist and a 120573-blocker on cell- and copper-mediated oxidation of LDL and on the accumulation and effluxof cholesterol in human macrophages and murine J774 cellsrdquoArteriosclerosis Thrombosis and Vascular Biology vol 17 no 5pp 979ndash988 1997
[128] G Sobal E J Menzel and H Sinzinger ldquoCalcium antagonistsas inhibitors of in vitro low density lipoprotein oxidation andglycationrdquoBiochemical Pharmacology vol 61 no 3 pp 373ndash3792001
[129] E Lupo R Locher B Weisser and W Vetter ldquoIn vitro antiox-idant activity of calcium antagonists against LDL oxidationcompared with 120572-tocopherolrdquo Biochemical and BiophysicalResearch Communications vol 203 no 3 pp 1803ndash1808 1994
[130] J Zou Y Li H-Q Fan and J-G Wang ldquoEffects of dihydropy-ridine calcium channel blockers on oxidized low-density lipo-protein induced proliferation and oxidative stress of vascularsmooth muscle cellsrdquo BMC Research Notes vol 5 article 1682012
[131] C Napoli S Salomone T Godfraind et al ldquo14-Dihydro-pyridine calcium channel blockers inhibit plasma and LDL oxi-dation and formation of oxidation-specific epitopes in the arte-rial wall and prolong survival in stroke-prone spontaneouslyhypertensive ratsrdquo Stroke vol 30 no 9 pp 1907ndash1915 1999
[132] G Zernig I Graziadei T Moshammer C Zech N Reider andH Glossmann ldquoMitochondrial Ca2+ antagonist binding sitesare associated with an inner mitochondrial membrane anionchannelrdquo Molecular Pharmacology vol 38 no 3 pp 362ndash3691990
[133] F E Hunter Jr A Scott P E Hochstein et al ldquoStudies of themechanism of ascorbate-induced swelling and lysis of isolatedliver mitochondriardquo The Journal of Biological Chemistry vol239 pp 604ndash613 1964
[134] D R Janero B Burghardt and R Lopez ldquoProtection of cardiacmembrane phospholipid against oxidative injury by calciumantagonistsrdquoBiochemical Pharmacology vol 37 no 21 pp 4197ndash4203 1988
[135] A Karadag B Ozcelik and S S Saner ldquoReview of methods todetermine antioxidant capacitiesrdquo FoodAnalyticalMethods vol2 no 1 pp 41ndash60 2009
[136] Y I Gubskiı N V Litvinova and E V Shnurko-TabakovaldquoAntioxidant and antiradical activity of various classes of antiox-idantsrdquo Ukrainskiı Biokhimicheskiı Zhurnal vol 66 no 4 pp114ndash116 1994 (Russian)
[137] M Takei M Hiramatsu and A Mori ldquoInhibitory effects ofcalcium antagonists onmitochondrial swelling induced by lipidperoxidation or arachidonic acid in the rat brain in vitrordquoNeurochemical Research vol 19 no 9 pp 1199ndash1206 1994
[138] M Takei M Hiramatsu R Edamatsu and A Mori ldquoFreeradical scavenging by calcium antagonistsrdquo Neurosciences vol20 no 2 pp 75ndash82 1994
[139] Ya P Stradin G Ya Dubur Yu A Beilis Ya R Uldrikis andA F Korotkova ldquoVoltammetry of 14-dihydropyridine deriva-tives I Potentials of electrochemical oxidation of 35-diacyl-and 35-di(alkoxycarbonyl)-14-dihydropyridines in acetoni-trilerdquo Chemistry of Heterocyclic Compounds no 1 pp 84ndash871972 (Russian)
[140] E V Ivanov T V Ponomarjova G N Merkusev et al ldquoEinneuer Haut-Radioprotektor Diethon (experimentelle Unter-suchung)rdquo Radiobiologia Radiotherapia vol 31 no 1 pp 69ndash78 1990
[141] E V Ivanov T V Ponomareva G N Merkushev et al ldquoRadia-tion modulating properties of derivates of 14-dihydropyridineand 12345678910-decahydroacridine-18 dionerdquo Radiat-sionnaia Biologiia Radioecologiia vol 44 no 5 pp 550ndash5592004 (Russian)
[142] R O Vitolinia D A Berzinia A K Velena I A Vutsina A AKimenis and G Y Duburs ldquoThe protective effects of the cal-cium antagonist foridon in acute myocardial ischaemiardquo Kardi-ologiya vol 27 no 3 pp 90ndash93 1987 (Russian)
[143] A H Velena G Ya Duburs R O Vitolina et al ldquoEffect ofryodipine on electromechanical parameters of heart and vesselscAMP phosphodiesterase activity and swelling-contractioncycle of mitochondriardquo Arzneimittelforschung vol 35 no 6 pp907ndash914 1985
[144] L I Utno Z E Lipsberga A A Silova M I Girgensone EA Bisenieks and G I Ia ldquoCardioprotective properties of a 14-dihydropyridine derivative glutapyrone in deep hypothermiardquoBiulletenrsquo Eksperimentalrsquonoı Biologii i Meditsiny vol 108 no 11pp 558ndash561 1989 (Russian)
[145] M A S FernandesM S Santos J A F Vicente et al ldquoEffects of14-dihydropyridine derivatives (cerebrocrast gammapyroneglutapyrone and diethone) onmitochondrial bioenergetics andoxidative stress a comparative studyrdquoMitochondrion vol 3 no1 pp 47ndash59 2003
[146] M A S Fernandes M S Santos A J M Moreno et al ldquoEffectsof 5-acetyl(carbamoyl)-6-methylsulfanyl-14-dihydropyridine-5-carbonitriles on rat liver mitochondrial functionrdquo Toxicologyin Vitro vol 23 no 7 pp 1333ndash1341 2009
[147] L Klimaviciusa A Kalda A Kaasik et al ldquoNeuroprotectiveactivity of 14-dihydropyridine derivatives structure determi-nantsrdquo Proceedings of the Latvian Academy of Sciences BNatural Exact and Applied Sciences vol 61 no 1-2 pp 33ndash372007
32 Oxidative Medicine and Cellular Longevity
[148] L Klimaviciusa M A S Fernandes N Lencberga et alldquoTargeting the mitochondria by novel adamantane-containing14-dihydropyridine compoundsrdquo in Bioenergetics K B ClarkEd pp 257ndash272 InTech 2012
[149] V Klusa L Klimaviciusa G Duburs J Poikans and AZharkovsky ldquoAnti-neurotoxic effects of tauropyrone a taurineanaloguerdquo Advances in Experimental Medicine and Biology vol583 pp 499ndash508 2006
[150] N Sampson P Berger and Ch Zenzmaier ldquoRedox signalingas a therapeutic target to inhibit myofibroblast activation indegenerative fibrotic diseaserdquo BioMed Research Internationalvol 2014 Article ID 131737 14 pages 2014
[151] T L Leto and M Geiszt ldquoRole of Nox family NADPH oxidasesin host defenserdquoAntioxidantsampRedox Signaling vol 8 no 9-10pp 1549ndash1561 2006
[152] K K Griendling D Sorescu and M Ushio-Fukai ldquoNAD(P)Hoxidase role in cardiovascular biology and diseaserdquo CirculationResearch vol 86 no 5 pp 494ndash501 2000
[153] H Chen Y S Song and P H Chan ldquoInhibition of NADPHoxi-dase is neuroprotective after ischemia-reperfusionrdquo Journal ofCerebral Blood Flow and Metabolism vol 29 no 7 pp 1262ndash1272 2009
[154] P Hochstein and L Ernster ldquoADP-activated lipid peroxidationcoupled to the TPNH oxidase system of microsomesrdquo Biochem-ical and Biophysical Research Communications vol 12 no 5 pp388ndash394 1963
[155] I I Gubskiı AGGoriushkoNV Litvinova et al ldquoAntioxidantproperties and membranotropic effect of certain derivatives of14-dihydropyridinerdquo Ukrainskiı Biokhimicheskiı Zhurnal vol71 no 4 pp 35ndash39 1999 (Russian)
[156] F Engineer and R Sridhar ldquoInhibition of rat heart andliver microsomal lipid peroxidation by nifedipinerdquo BiochemicalPharmacology vol 38 no 8 pp 1279ndash1285 1989
[157] T Goncalves A P Carvalho and C R Oliveira ldquoAntioxidanteffect of calcium antagonists on microsomai membranes iso-lated from different brain areasrdquo European Journal of Pharma-cology vol 204 no 3 pp 315ndash322 1991
[158] M E Letelier P Izquierdo L Godoy A M Lepe and MFaundez ldquoLiver microsomal biotransformation of nitro-aryldrugs mechanism for potential oxidative stress inductionrdquoJournal of Applied Toxicology vol 24 no 6 pp 519ndash525 2004
[159] M E Letelier P Entrala C Lopez-Alarcon et al ldquoNitroaryl-14-dihydropyridines as antioxidants against rat liver microsomesoxidation induced by ironascorbate Nitrofurantoin and naph-thalenerdquo Toxicology in Vitro vol 21 no 8 pp 1610ndash1618 2007
[160] F P Guengerich W R Brian M Iwasaki M-A Sari CBaarnhielm and P Berntsson ldquoOxidation of dihydropyridinecalcium channel blockers and analogues by human liver cyto-chrome P-450 IIIA4rdquo Journal of Medicinal Chemistry vol 34no 6 pp 1838ndash1844 1991
[161] S H Park S-W RhaW-Y Shin et al ldquoAS-160 Calcium channelblockers of dihydropyridine class reduce the antiplatelet effectof Clopidogrel what is clinical impactrdquo The American Journalof Cardiology vol 107 no 8 supplement p 47A 2011
[162] C Asma and D M Reda ldquoEvaluation of dihydropyridinecalcium antagonist effects on the stress bioindicator orga-nism Saccharomyces cerevisiaerdquo Annals of Biological Researchvol 4 no 10 pp 40ndash46 2013 httpscholarsresearchlibrarycomABR-vol4-iss10ABR-2013-4-10-40-46pdf
[163] G Gaviraghi A M Pastorino E Ratti and D G TristldquoCalcium channel blockers with antioxidant activityrdquo in Free
Radicals Lipoprotein Oxidation andAtherosclerosis G BellomoG Finardi E Maggi and E Rice-Evans Eds pp 431ndash456Richelieu Press London UK 1995
[164] G Gaviraghi AM Pastorino E Ratti and D G Trist ldquoAntiox-idant dihydropyridines a new and comprehensive therapy forfree radical-induced cardiovascular diseasesrdquo in Free Radicalsin Biology and Environment F Minisci Ed vol 27 of NATOASI Series pp 193ndash221 Springer Dordrecht The Netherlands1997
[165] P D Henry ldquoAntiperoxidative actions of calcium antagonistsand atherogenesisrdquo Journal of Cardiovascular Pharmacologyvol 18 supplement 1 pp S6ndashS10 1991
[166] F Kouoh B Gressier T Dine et al ldquoAntioxidant effects andanti-elastase activity of the calcium antagonist nicardipine onactivated human and rabbit neutrophilsmdasha potential antiath-erosclerotic property of calcium antagonistsrdquo CardiovascularDrugs andTherapy vol 16 no 6 pp 515ndash520 2002
[167] S Parthasarathy D Litvinov K Selvarajan and M GarelnabildquoLipid peroxidation and decompositionmdashconflicting roles inplaque vulnerability and stabilityrdquo Biochimica et BiophysicaActa vol 1781 no 5 pp 221ndash231 2008
[168] D-Q Liu Z-Q Pang D-H Zhao and B-H Sheng ldquoEffects offuryl-dihydropyridines I on lipid peroxides of ischemic myo-cardium and ATPases activity of erythrocyte membranes inratsrdquo Acta Pharmacologica Sinica vol 12 no 3 pp 253ndash2561991
[169] V Lukic-Panin T Kamiya H Zhang et al ldquoPrevention of neu-ronal damage by calcium channel blockers with antioxidativeeffects after transient focal ischemia in ratsrdquo Brain Research vol1176 no 1 pp 143ndash150 2007
[170] Y Allanore D Borderie H Lemarechal O G Ekindjian andA Kahan ldquoAcute and sustained effects of dihydropyridine-typecalcium channel antagonists on oxidative stress in systemicsclerosisrdquo American Journal of Medicine vol 116 no 9 pp 595ndash600 2004
[171] I Casetta V Govoni and E Granieri ldquoOxidative stress antioxi-dants and neurodegenerative diseasesrdquo Current PharmaceuticalDesign vol 11 no 16 pp 2033ndash2052 2005
[172] M J T J Arts Assessing antioxidant activity [PhD the-sis] Maastricht University Maastricht The Netherlands 2007httparnounimaasnlshowcgifid=8676
[173] G Dıaz-Araya L Godoy L Naranjo A Squella M E Letelierand L J Nunez-Vergara ldquoAntioxidant effects of 14-dihydro-pyridine and nitroso aryl derivatives on the Fe+3ascorbate-stimulated lipid peroxidation in rat brain slicesrdquo General Phar-macology The Vascular System vol 31 no 3 pp 385ndash391 1998
[174] Y Fukuhara K Tsuchiya Y Horinouchi et al ldquoProtectiveeffect of photodegradation product of nifedipine against tumornecrosis factor 120572-induced oxidative stress in human glomerularendothelial cellsrdquo Journal of Medical Investigation vol 58 no1-2 pp 118ndash126 2011
[175] W Stengel M Jainz and K Andreas ldquoDifferent potencies ofdihydropyridine derivatives in blocking T-type but not L-typeCa2+ channels in neuroblastoma-glioma hybrid cellsrdquo EuropeanJournal of Pharmacology vol 342 no 2-3 pp 339ndash345 1998
[176] O M Panasenko D J Tirzite G D Tirzitis and G J DubursldquoEffect of some 14-dihydropyridine derivatives on structuralorganization of erythrocyte membranesrdquo Biologicheskie Mem-brany (Biochemistry (Moscow) Series A Membrane and CellBiology) vol 1 pp 919ndash925 1984 (Russian)
[177] L G Herbette Y M H Vant Erve and D G Rhodes ldquoInter-action of 14 dihydropyridine calcium channel antagonists with
Oxidative Medicine and Cellular Longevity 33
biological membranes lipid bilayer partitioning could occurbefore drug binding to receptorsrdquo Journal of Molecular andCellular Cardiology vol 21 no 2 pp 187ndash201 1989
[178] L G Herbette P E Mason G Gaviraghi T N Tulenko andR P Mason ldquoThe molecular basis for lacidipinersquos unique phar-macokinetics optimal hydrophobicity results in membraneinteractions that may facilitate the treatment of atherosclerosisrdquoJournal of Cardiovascular Pharmacology vol 23 supplement 5pp S16ndashS25 1994
[179] G V Belevitch G Y Dubur G E Dobretsov N K Kurek andM M Spirin ldquoCalcium antagonists riodipine nifedipine andverapamil binding to model and biological membranes fluore-scence analysisrdquo Biologicheskie Membrany (Biochemistry(Moscow) Series A Membrane and Cell Biology) vol 5 pp768ndash776 1988 (Russian)
[180] R P Mason G E Gonye D W Chester and L G HerbetteldquoPartitioning and location of Bay K 8644 14-dihydropyridinecalcium channel agonist in model and biological membranesrdquoBiophysical Journal vol 55 no 4 pp 769ndash778 1989
[181] M Cindric A Cipak J Serly et al ldquoReversal of multidrugresistance inmurine lymphoma cells by amphiphilic dihydropy-ridine antioxidant derivativerdquo Anticancer Research vol 30 no10 pp 4063ndash4070 2010
[182] F Shekari H Sadeghpour K Javidnia et al ldquoCytotoxic andmultidrug resistance reversal activities of novel 14-dihydro-pyridines against human cancer cellsrdquo European Journal ofPharmacology vol 746 no 1 pp 233ndash244 2015
[183] X-F Zhou Q Shao R A Coburn and M E Morris ldquoQuanti-tative structure-activity relationship and quantitative structure-pharmacokinetics relationship of 14-dihydropyridines andpyridines as multidrug resistance modulatorsrdquo PharmaceuticalResearch vol 22 no 12 pp 1989ndash1996 2005
[184] R Berkels T Breitenbach H Bartels et al ldquoDifferent antioxida-tive potencies of dihydropyridine calcium channel modulatorsin various modelsrdquo Vascular Pharmacology vol 42 no 4 pp145ndash152 2005
[185] S Borovic G Tirzitis D Tirzite et al ldquoBioactive 14-dihydro-isonicotinic acid derivatives prevent oxidative damage of livercellsrdquo European Journal of Pharmacology vol 537 no 1ndash3 pp12ndash19 2006
[186] D Ya Rubene G D Tirzitis and G Ya Duburs ldquoInteractionof some 14-dihydropyridine derivatives with Fentonrsquos reagentrdquoLatvijas PSRZinatnuAkademijas Vestis Kimijas Serija Proceed-ings of the Latvian SSR Academy of Sciences Chemistry Seriespp 212ndash216 1982 (Russian)
[187] K Ondrias V Misık D Gergel and A Stasko ldquoLipid per-oxidation of phosphatidylcholine liposomes depressed by thecalcium channel blockers nifedipine and verapamil and bythe antiarrhythmic-antihypoxic drug stobadinerdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1003 no 3pp 238ndash245 1989
[188] I T Mak and W B Weglicki ldquoComparative antioxidant acti-vities of propranolol nifedipine verapamil and diltiazemagainst sarcolemmal membrane lipid peroxidationrdquoCirculationResearch vol 66 no 5 pp 1449ndash1452 1990
[189] I T Mak P Boehme and W B Weglicki ldquoProtective effects ofcalcium channel blockers against free radical-impaired endo-thelial cell proliferationrdquo Biochemical Pharmacology vol 50 no9 pp 1531ndash1534 1995
[190] S Ray S Mondal and N Dana ldquoEvaluation of protective roleof nifedipine on lipid peroxidation using reduced glutathione as
model markerrdquo Oxidants and Antioxidants in Medical Sciencevol 1 no 2 pp 97ndash100 2012
[191] M Yamato T Shiba T Ide Y Honda K-I Yamada andH Tsutsui ldquoNifedipine treatment reduces brain damage aftertransient focal ischemia possibly through its antioxidativeeffectsrdquoHypertension Research vol 34 no 7 pp 840ndash845 2011
[192] V Chander and K Chopra ldquoNifedipine attenuates changes innitric oxide levels renal oxidative stress and nephrotoxicityinduced by cyclosporinerdquo Renal Failure vol 27 no 4 pp 441ndash450 2005
[193] K M Gaafa M M Badawy and A A Hamza ldquoThe protectiveeffects of ascorbic acid cimetidine and nifedipine on diethyl-dithiocarbamate-induced hepatic toxicity in albino ratsrdquo Drugand Chemical Toxicology vol 34 no 4 pp 405ndash419 2011
[194] H Sugawara K Tobise and S Onodera ldquoAbsence of antiox-idant effects of nifedipine and diltiazem on myocardial mem-brane lipid peroxidation in contrast with those of nisoldipineand propranololrdquo Biochemical Pharmacology vol 47 no 5 pp887ndash892 1994
[195] I E Kirule D Y Rubene E A Bisenieks G D Tirzit and GY Dubur ldquo4-Nitrophenyl-14-dihydropyridinesmdasha new groupof inhibitors of peroxide oxidationrdquo Chemistry of HeterocyclicCompounds vol 18 no 3 p 316 1982
[196] G D Tirzit I E Kirule L K Baumane R A Gavar Y PStradynrsquo andG YDubur ldquoMechanism of the antioxidant actionof 26-dimethyl-35-dimethoxy-carbonyl-4-(2-nitrophenyl)14-dihydropyridinerdquoChemistry ofHeterocyclic Compounds vol 20no 8 pp 915ndash918 1984
[197] C Yanez C Lopez-Alarcon C Camargo V Valenzuela J ASquella and L J Nunez-Vergara ldquoStructural effects on thereactivity 14-dihydropyridines with alkylperoxyl radicals andABTS radical cationrdquo Bioorganic and Medicinal Chemistry vol12 no 9 pp 2459ndash2468 2004
[198] VMisik A J Stasko D Gergel and K Ondrias ldquoSpin-trappingand antioxidant properties of illuminated and nonilluminatednifedipine and nimodipine in heart homogenate and modelsystemrdquo Molecular Pharmacology vol 40 no 3 pp 435ndash4391991
[199] K Ondrias V Misık A Stasko D Gergelrsquo and M HromadovaldquoComparison of antioxidant properties of nifedipine and illu-minated nifedipine with nitroso spin traps in low densitylipoproteins and phosphatidylcholine liposomesrdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1211 no 1pp 114ndash119 1994
[200] A Stasko V Brezova S Biskupic K Ondrias and V MisıkldquoReactive radical intermediates formed from illuminated nife-dipinerdquoFree Radical Biology andMedicine vol 17 no 6 pp 545ndash556 1994
[201] K Ishizawa Y Izawa-Ishizawa N Yamano et al ldquoNitrosoni-fedipine ameliorates the progression of type 2 diabetic nephro-pathy by exerting antioxidative effectsrdquo PLoS ONE vol 9 no 1Article ID e86335 2014
[202] H Fujii and L J Berliner ldquoIn vivo EPR evidence for free radicaladducts of nifedipinerdquoMagnetic Resonance in Medicine vol 42no 4 pp 691ndash694 1999
[203] S Bollo S Finger J C Sturm L J Nunez-Vergara and JA Squella ldquoCyclic voltammetry and scanning electrochemicalmicroscopy studies of the heterogeneous electron transferreaction of some nitrosoaromatic compoundsrdquo ElectrochimicaActa vol 52 no 15 pp 4892ndash4898 2007
34 Oxidative Medicine and Cellular Longevity
[204] F Ursini ldquoTissue protection by lacidipine insight from redoxbehaviorrdquo Journal of Cardiovascular Pharmacology vol 30supplement 2 pp S28ndashS30 1997
[205] P G Cristofori F A Crivellente I Faustinelli et al ldquoInvolve-ment of the nitric oxide system in the anti-atheroscleroticpotential of lacidipine in the apoE-deficient mouse a mor-phological functional and electrochemical studyrdquo ToxicologicPathology vol 32 no 4 pp 493ndash499 2004
[206] X-P Zhang E L Kit S Mital S Chahwala and T HHintze ldquoParadoxical release of nitric oxide by an L-type calciumchannel antagonist the R+ enantiomer of amlodipinerdquo Journalof Cardiovascular Pharmacology vol 39 no 2 pp 208ndash2142002
[207] F Franzoni G Santoro F Regoli et al ldquoAn in vitro study of theperoxyl and hydroxyl radical scavenging capacity of the calciumantagonist amlodipinerdquo Biomedicine and Pharmacotherapy vol58 no 8 pp 423ndash426 2004
[208] S V Gatsura ldquoOxygen-dependent mechanisms underlying theantiischemic effect of verapamil and amlodipinerdquo Bulletin ofExperimental Biology and Medicine vol 137 no 1 pp 40ndash422004
[209] Y Hirooka Y Kimura M Nozoe Y Sagara K Ito and KSunagawa ldquoAmlodipine-induced reduction of oxidative stressin the brain is associated with sympatho-inhibitory effects instroke-prone spontaneously hypertensive ratsrdquo HypertensionResearch vol 29 no 1 pp 49ndash56 2006
[210] B Tomlinson and I F F Benzie ldquoAntioxidant effect of lercani-dipine (note)rdquo Hypertension vol 42 no 4 pp e10ndashe11 2003
[211] A A Faraqui ldquoNeurochemical aspects of 4-hydroxynonenalrdquoin Lipid Mediators and Their Metabolism in the Brain A AFaraqui Ed chapter 6 pp 159ndash191 Springer New York NYUSA 2011
[212] V S NascimentoM S DrsquoAlva A AOliveira et al ldquoAntioxidanteffect of nimodipine in young rats after pilocarpine-inducedseizuresrdquo Pharmacology Biochemistry and Behavior vol 82 no1 pp 11ndash16 2005
[213] O Ismailoglu P Atilla S Palaoglu et al ldquoThe therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjuryrdquo Turkish Neurosurgery vol 22 no 6 pp 740ndash746 2012
[214] M Matsubara and K Hasegawa ldquoBenidipine a dihydropy-ridine-calcium channel blocker prevents lysophosphatidyl-choline-induced injury and reactive oxygen species productionin human aortic endothelial cellsrdquo Atherosclerosis vol 178 no1 pp 57ndash66 2005
[215] M Matsubara K Yao and K Hasegawa ldquoBenidipine adihydropyridine-calcium channel blocker inhibits lysophos-phatidylcholine-induced endothelial injury via stimulation ofnitric oxide releaserdquo Pharmacological Research vol 53 no 1 pp35ndash43 2006
[216] MMatsubara and K Hasegawa ldquoEffects of benidipine a dihyd-ropyridine-Ca2+ channel blocker on expression of cytokine-induced adhesion molecules and chemoattractants in humanaortic endothelial cellsrdquo European Journal of Pharmacology vol498 no 1ndash3 pp 303ndash314 2004
[217] M Matsubara O Akizuki J-I Ikeda K Saeki K Yao and KSasaki ldquoBenidipine an anti-hypertensive drug inhibits reactiveoxygen species production in polymorphonuclear leukocytesand oxidative stress in salt-loaded stroke-prone spontaneouslyhypertensive ratsrdquo European Journal of Pharmacology vol 580no 1-2 pp 201ndash213 2008
[218] A C Rosenkranz H Lob T Breitenbach R Berkels and RRoesen ldquoEndothelial antioxidant actions of dihydropyridines
and angiotensin converting enzyme inhibitorsrdquo European Jour-nal of Pharmacology vol 529 no 1ndash3 pp 55ndash62 2006
[219] V Kain S Kumar and S L Sitasawad ldquoAzelnidipine preventscardiac dysfunction in streptozotocin-diabetic rats by reducingintracellular calcium accumulation oxidative stress and apop-tosisrdquo Cardiovascular Diabetology vol 10 article 97 2011
[220] K Nakamura S Yamagishi and H Inoue ldquoUnique atheropro-tective property of azelnidipine a dihydropyridine-based cal-cium antagonistrdquoMedical Hypotheses vol 65 no 1 pp 155ndash1572005
[221] TMatsui S Yamagishi K Nakamura S Kikuchi andH InoueldquoAzelnidipine a dihydropyridine-based calcium antagonistinhibits angiotensin II-induced oxidative stress generation anddownregulation of pigment epithelium-derived factor mRNAlevels in microvascular endothelial cellsrdquo Drugs under Experi-mental and Clinical Research vol 31 no 5-6 pp 215ndash219 2005
[222] C Ohmura H Watada T Shimizu et al ldquoCalcium channelblocker azelnidipine reduces lipid hydroperoxides in patientswith type 2 diabetes independent of blood pressurerdquo EndocrineJournal vol 54 no 5 pp 805ndash811 2007
[223] H Daikuhara F Kikuchi and T Ishida ldquoThe combination ofOLmesartan and a CAlcium channel blocker (azelnidipine) orcandesartan and a calcium channel blocker (amlodipine) intype 2 diabetic hypertensive patients theOLCA studyrdquoDiabetesand Vascular Disease Research vol 9 no 4 pp 280ndash286 2012
[224] MAbe NMaruyama KOkada SMatsumoto KMatsumotoand M Soma ldquoAdditive antioxidative effects of azelnidipine onangiotensin receptor blocker olmesartan treatment for type 2diabetic patients with albuminuriardquoHypertension Research vol34 no 8 pp 935ndash941 2011
[225] K Mizushige ldquoAntioxidative activities of thiazolidinedionesand dihydropyridine-type calcium antagonistsrdquo IRYOmdashJapa-nese Journal of National Medical Services vol 59 no 11 pp 581ndash592 2005
[226] S Manabe T Okura T Fukuoka and J Higaki ldquoAntioxidativeeffects of azelnidipine on mesangial cell proliferation inducedby highly concentrated insulinrdquo European Journal of Pharma-cology vol 567 no 3 pp 252ndash257 2007
[227] Y Koyama Y Takeishi H Takahashi et al ldquoAzelnidipine inhi-bits H
2O2-induced cell death in neonatal rat cardiomyocytesrdquo
CardiovascularDrugs andTherapy vol 21 no 1 pp 69ndash72 2007[228] K Shinomiya K Mizushige M Fukunaga et al ldquoAntioxidant
effect of a new calcium antagonist azelnipidine in culturedhuman arterial endothelial cellsrdquo Journal of International Med-ical Research vol 32 no 2 pp 170ndash175 2004
[229] T Ohyama K Sato K Kishimoto et al ldquoAzelnidipine is acalcium blocker that attenuates liver fibrosis and may increaseantioxidant defencerdquo British Journal of Pharmacology vol 165no 4 pp 1173ndash1187 2012
[230] L A Calo F Zaghetto E Pagnin P A Davis A Sempliciniand A C Pessina ldquoEffect of manidipine on gene expressionand protein level of oxidative stress-related proteins p22phoxand HO-1 Relevance for antihypertensive and anti-remodelingeffectsrdquo Journal of Cardiovascular Pharmacology vol 43 no 4pp 531ndash538 2004
[231] R Ghyasi G Sepehri M Mohammadi R Badalzadeh and AGhyasi ldquoEffect of mebudipine on oxidative stress and lipid per-oxidation in myocardial ischemic-reperfusion injury in maleratrdquo Journal of Research in Medical Sciences vol 17 no 12 pp1150ndash1155 2012
Oxidative Medicine and Cellular Longevity 35
[232] DCAndersson J Fauconnier T Yamada et al ldquoMitochondrialproduction of reactive oxygen species contributes to the 120573-adrenergic stimulation of mouse cardiomycytesrdquoThe Journal ofPhysiology vol 589 no 7 pp 1791ndash1801 2011
[233] A F Ceylan-Isik N Ari M Stefek et al ldquoEffects of a long-term treatment with an antioxidant pyridoindole on vascularresponsiveness in diabetes-induced aging ratsrdquo Current AgingScience vol 4 no 2 pp 150ndash157 2011
[234] S Saponara G Sgaragli and F Fusi ldquoQuercetin antagonismof Bay K 8644 effects on rat tail artery L-type Ca2+ channelsrdquoEuropean Journal of Pharmacology vol 598 no 1ndash3 pp 75ndash802008
[235] D A Sica ldquoInteraction of grapefruit juice and calcium channelblockersrdquo American Journal of Hypertension vol 19 no 7 pp768ndash773 2006
[236] P Mulder G Litwinienko S Lin P D MacLean L R CBarclay and K U Ingold ldquoThe L-type calcium channel block-ers Hantzsch 14-dihydropyridines are not peroxyl radical-trapping chain-breaking antioxidantsrdquo Chemical Research inToxicology vol 19 no 1 pp 79ndash85 2006
[237] L J Nunez-Vergara R Salazar C Camargo et al ldquoOxidation ofC4-hydroxyphenyl 14-dihydropyridines in dimethylsulfoxideand its reactivity towards alkylperoxyl radicals in aqueousmediumrdquo Bioorganic and Medicinal Chemistry vol 15 no 12pp 4318ndash4326 2007
[238] M E Ortiz L J Nunez-Vergara and J A Squella ldquoRelativereactivity of dihydropyridine derivatives to electrogeneratedsuperoxide ion in DMSO solutions a voltammetric approachrdquoPharmaceutical Research vol 20 no 2 pp 292ndash296 2003
[239] M E Ortiz L J Nunez-Vergara C Camargo and J A SquellaldquoOxidation of Hantzsch 14-dihydropyridines of pharmacolog-ical significance by electrogenerated superoxiderdquo Pharmaceuti-cal Research vol 21 no 3 pp 428ndash435 2004
[240] R S Raghuvanshi and K N Singh ldquoSuperoxide induced oxida-tive aromatization of Hantzsch 14-dihydropyridinesrdquo IndianJournal of Chemistry Section B Organic and Medicinal Chem-istry vol 47 no 11 pp 1735ndash1738 2008
[241] I Kruk A Kladna K Lichszteld et al ldquoAntioxidant activityof 4-flavonil-14-dihydropyridine derivativesrdquo Biopolymers vol62 no 3 pp 163ndash167 2001
[242] G D Tirzit I M Byteva K I Salokhiddinov G P Gurinovichand G Y Dubur ldquo14-Dihydropyridine derivatives as deactiva-tors of singlet oxygenrdquo Chemistry of Heterocyclic Compoundsvol 17 no 7 pp 682ndash684 1981
[243] G D Tirzit E Y Kazush and G Y Dubur ldquoInfluence of14-dihydropyridine derivatives on the generation of hydroxylradicalsrdquo Chemistry of Heterocyclic Compounds vol 28 no 4pp 435ndash437 1992
[244] N A Pizarro-Urzua and L J Nunez-Vergara ldquoNifedipine andnitrendipine reactivity toward singlet oxygenrdquo Journal of Photo-chemistry and Photobiology A Chemistry vol 175 no 2-3 pp129ndash137 2005
[245] L-F Wang H-Y Zhang L Konga Z-W Chena and J-G ShildquoDFT calculations indicate that 14-dihydropyridine is a promis-ing lead antioxidantrdquo Helvetica Chimica Acta vol 87 no 6 pp1515ndash1521 2004
[246] P Mulder H-G Korth and K U Ingold ldquoWhy quantum-thermochemical calculations must be used with caution toindicate lsquoa promising lead antioxidantrsquordquoHelvetica Chimica Actavol 88 no 2 pp 370ndash374 2005
[247] K Yao Y Ina K Nagashima K Ohmori and T Ohno ldquoAntiox-idant effects of calcium antagonists in rat brain homogenatesrdquo
Biological and Pharmaceutical Bulletin vol 23 no 6 pp 766ndash769 2000
[248] T Matsui S-I Yamagishi K Nakamura and H Inoue ldquoBayw 9798 a dihydropyridine structurally related to nifedipinewith no calcium channel-blocking properties inhibits tumournecrosis factor-120572-induced vascular cell adhesion molecule-1expression in endothelial cells by suppressing reactive oxygenspecies generationrdquo Journal of International Medical Researchvol 35 no 6 pp 886ndash891 2007
[249] K AMitrega B VargheseM Porc and T F Krzeminski ldquoAnti-arrhythmic and hemodynamic effects of oxy nifedipine oxynimodipine oxy nitrendipine and oxy nisoldipinerdquo Pharmaco-logical Research vol 66 no 4 pp 300ndash308 2012
[250] V Herbert ldquoSymposium prooxidant effects of antioxidantvitamins Introductionrdquo The Journal of Nutrition vol 126 no4 supplement pp 1197Sndash1200S 1996 httpjnnutritionorgcontent1264 Suppl1197Sfullpdf
[251] B Halliwell ldquoAre polyphenols antioxidants or pro-oxidantsWhat do we learn from cell culture and in vivo studiesrdquoArchives of Biochemistry and Biophysics vol 476 no 2 pp 107ndash112 2008
[252] C Winterbourn Pro-Oxidants or Antioxidants ChristchurchSchool of Medicine Depatment of Pathology Free RadicalSchool SFRBMUniversity of Otago San Francisco Calif USA2009 httpwwwsfrbmorgfrsWinterbournpdf
[253] A Morakinyo B Iranloye and O Adegoke ldquoCalcium antag-onists modulate oxidative stress and acrosomal reaction in ratspermatozoardquo Archives of Medical Science vol 7 no 4 pp 613ndash618 2011
[254] The Alpha-Tocopherol Beta Carotene Cancer Prevention StudyGroup ldquoThe effect of vitamin E and beta carotene on theincidence of lung cancer and other cancers in male smokersrdquoTheNew England Journal of Medicine vol 330 no 15 pp 1029ndash1035 1994
[255] B Poljsak ldquoStrategies for reducing or preventing the generationof oxidative stressrdquo Oxidative Medicine and Cellular Longevityvol 2011 Article ID 194586 15 pages 2011
[256] B Poljsak and I Milisav ldquoThe neglected significance of lsquoanti-oxidative stressrsquordquoOxidativeMedicine and Cellular Longevity vol2012 Article ID 480895 12 pages 2012
[257] T Godfraind and S Salomone ldquoAmbiguities in dietary antiox-idant supplementation compared to calcium channel blockerstherapyrdquo Frontiers in Pharmacology vol 6 article 10 2015
[258] H Wagner H Norr and H Winterhoff ldquoDrugs with adap-togenic effects for strengthening the powers of resistancerdquoZeitschrift fur Phytotherapie vol 13 no 2 pp 42ndash54 1992
Oxidative Medicine and Cellular Longevity 21
Benidipine was also shown to inhibit ROS production inpolymorphonuclear leukocytes and oxidative stress in salt-loaded stroke-prone spontaneously hypertensive rats (Mat-subara et al [217])
It should be mentioned that other DHPs also haveendothelial AO actions [218]
357 Azelnidipine (AZL) Azelnidipine 3-[1-[di(phen-yl)methyl]azetidin-3-yl] 5-propan-2-yl 2-amino-6-methyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate(AZL) CAS number 123524-52-7 is commercially available4-nitroaryl-DHP type calcium antagonist with long-actingantihypertensive action (long-acting CA (CCB)) and a lowreported incidence of tachycardia It additionally possessesbeneficial effects in OS and diabetic conditions
Azelnidipine prevents cardiac dysfunction in strepto-zotocin-diabetic rats by reducing intracellular calcium accu-mulation (altering intracellular Ca2+ handling proteins) OSand apoptosis (Kain et al [219]) AZL can reduce the superox-ide production It exerts its protective effects by targeting theNADPH oxidase and mitochondrial redox enzymes AZL-treated diabetic rats express enhanced level of bcl-2 in thelysates of heart muscle indicating that AZL plays protectiverole in cardiac apoptosis
It has been previously observed that azelnidipine inhibitstumor necrosis factor-alpha-induced endothelial cell (EC)oxidative stress through its AO properties (Nakamura etal [220]) Azelnidipine but not nitrendipine completelyinhibits the Ang II-induced ROS generation in ECs (Matsuiet al [221])
Furthermore azelnidipine but not nitrendipine wasfound to partially restore decreased pigment epithelium-derived factor (PEDF) mRNA levels in Ang II-exposed ECsThis study suggests that AZL influence depends on its antiox-idative properties Authors concluded that upregulation ofPEDF by azelnidipine may become a therapeutic targetfor the treatment of diabetic retinopathy associated withhypertension
Antihypertensive agents with AO effects are potentiallyuseful for diabetic patients with hypertension While DHPtypeCAare among themost frequently used antihypertensivedrugs azelnidipine has been reported to have a unique AOeffect in vitro and in vivo in experimental animals (Ohmuraet al [222]) In hypertensive diabetic patients azelnidipinetreatment for 12 weeks induced a more significant decreasein erythrocyte LOOH level than amlodipine although thevalues related to blood pressure during each treatmentremained comparable These data confirm the usefulness ofLOOH level in erythrocyte membrane as a marker of OS invivo and indicate that azelnidipine has a unique antioxidativeproperty in humans
Daikuhara et al [223] reported the results of the OLCAstudy based on combination of (1) olmesartan and a calciumchannel blocker (azelnidipine) or (2) candesartan and a CCBamlodipine in two groups of diabetic hypertensive patientsPatients treated with the first combination presented highlypersistent early morning antihypertensive effect and strongerdecrease in heart rate fasting blood glucose andHbA1c levels
and microalbuminuria when compared to patients treatedwith the combination (2) Because diabetes is associated withsevere chronic OS the observed results might be at least in apart due to the AOA of azelnidipine
In favor of this are findings of Abe et al [224] who foundadditive antioxidative effects of azelnidipine on angiotensinreceptor blocker olmesartan treatment for type 2 diabeticpatients with albuminuria
Similarly the AOA of thiazolidinediones (insulin sensi-tizer) and their effect on cardiovascular function in type 2diabetic model rats and also those of some DHPs (nifedipineamlodipine or AZL commonly used antianginal and anti-hypertensive agents) in cultured human endothelial cells LPwere examined (Mizushige [225]) The AOA was evaluatedby measuring 8-iso-prostaglandine F
2120572concentration and
azelnidipine exhibited potent AOAInsulin (INS) resistance combined with hyperinsuline-
mia is involved in the generation of OS A relation-ship exists between increased production of ROS and thediverse pathogenic mechanisms involved in diabetic vascularcomplications including nephropathy Manabe et al [226]revealed that high doses of INS augmented mesangial cellproliferation through generation of intracellular ROS andactivation of redox signaling pathways Cell proliferation wasincreased in a dose-dependent manner by high doses of INS(01ndash10 120583M) but was inhibited by 01120583M AZL Namely theINS-increased phosphorylation of mitogen activated proteinkinaseextracellular signal-regulated kinase 12 (MAPKERK12) was inhibited by 01 120583MAZL The same AZL concen-tration blocked intracellular ROS production more effec-tively than 01 120583M nifedipine The NADPH oxidase inhibitorapocynin (001ndash01120583M) prevented INS-induced mesangialcell proliferation So azelnidipine inhibits insulin-inducedmesangial cell proliferation by inhibiting the productionof ROS Therefore azelnidipine may have the potential toprotect against the onset of diabetic nephropathy and slowits progression
Azelnidipine inhibited H2O2-induced cell death in
neonatal rat cardiomyocytes (Koyama et al [227]) Azelnidip-ine and nifedipine did not affect theH
2O2-induced activation
of extracellular signal-regulated protein kinases (ERK) andp38 MAPK (mitogen-activated protein kinase) In contrastazelnidipine but not nifedipine inhibited H
2O2-induced c-
Jun NH2-terminal kinases (JNK) activation Authors con-
cluded that azelnidipine has inhibited theH2O2-induced JNK
activation and cardiac cell death Therefore azelnidipine mayhave cardioprotective effects against OS
A specific atheroprotection activity of azelnidipine relatesto inhibition of TNF-120572-induced activator protein-1 activa-tion and interleukin-8 expression in human umbilical veinendothelial cells (HUVEC) through suppression of NADPHoxidase-mediated reactive oxygen species generation (Naka-mura et al [220]) TNF-120572 could play a central role in patho-genesis of insulin resistance and accelerated atherosclerosis inthe metabolic syndrome The concentration of AZL found tobe effective in these in vitro experiments is within therapeuticrange As EC do not possess voltage-operated L-type calciumchannels it is suggested that the beneficial effects of azelni-dipine are not likely due to CA property but to its unique AO
22 Oxidative Medicine and Cellular Longevity
ability Furthermore it has been recently found that serumlevels of monocyte chemoattractant protein-1 a biomarkerfor subclinical atherosclerosis were significantly decreased bythe AZL treatment in patients with essential hypertension Inthis paper [220] authors hypothesize that due to its uniqueTNF-120572 signalmodulatory activity and antioxidative propertyazelnidipine may be a promising DHP for targeting diabetesand cardiovascular diseases in hypertensive patients withmetabolic syndrome
Shinomiya et al [228] evaluated its AOA in culturedhuman arterial EC under OS Azelnidipine has shown apotent antioxidative effect that could be of significant clinicalbenefit when combined with its long-lasting antihypertensiveaction and low incidence of tachycardia
Azelnidipine inhibited TGF-1205731 and angiotensin II- (AngII-) activated 1205721(I) collagen mRNA expression in hepaticstellate cells (HSCs) (Ohyama et al [229]) FurthermoreTGF-1205731- and Ang II-induced OS and TGF-1205731-induced p38and JNK phosphorylation were reduced inHSCs treated withAZL Azelnidipine significantly decreased inflammatory cellinfiltration profibrotic genes expression HSC activation LPoxidative DNA damage and fibrosis in liver of CCl
4- or
TAA-treated mice Finally AZL prevented decrease of theexpression of some AO enzymes and accelerated regressionof liver fibrosis in CCl
4-treated mice Hence the antifibrotic
mechanism of AZL against CCl4-induced liver fibrosis in
mice may have been due to an increased level of AO defenseAs azelnidipine is widely used in clinical practice withoutserious adverse effects it may provide an effective newstrategy for antifibrotic therapy
358 Manidipine Manidipine (2-[4-(diphenylmethyl)pip-erazin-1-yl]ethyl methyl 26-dimethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate) is a DHP CCB withreported nephroprotective properties Calo et al [230] stud-ied effect of manidipine on gene expression and proteinlevel of OS related proteins p22(phox) (human neutrophilcytochrome b light chain (CYBA)) and heme oxygenase-1HO-1 Relevance for antihypertensive effects was revealedThe study assessed the effect of manidipine on normalsubjectsrsquo monocyte gene and protein expression of OS relatedproteins such as p22phox a NADPH oxidase system subunitcritical in generating O
2
∙minus and HO-1 induced by and pro-tective against OS Manidipine was compared with the ACEinhibitor captopril and the CCB nifedipine in the presenceand in the absence of sodiumarsenite (NaAsO
2) as an inducer
of OS Monocyte p22phox (CYBA) mRNA production wasreduced by both manidipine and captopril while no changeswere induced by nifedipine Manidipine increased monocyteHO-1 mRNA production while nifedipine and captoprilshowed no effect The effects of manidipine on p22phoxand HO-1 gene expression in the presence of OS were alsoconfirmed at the protein level Thus manidipine seems tosuppress p22phox and to increase the HO-1 mRNA produc-tion and protein level The manidipine-induced increase ofHO-1 gene and protein expression seems to be a peculiareffect of this drug since it is not observed with captopriland nifedipine This effect together with the reduction of
p22phoxmRNAproduction could play a role in its protectivemechanism against OS
359 Mebudipine The protective effect of mebudipine (14-dihydro-26-dimethyl-4-(3-nitrophenyl)-35-pyridinedicar-boxylic acid 3-methyl-5-tert-butyl ester BAY-n-6391) wasrevealed on OS and LP (MDA decrease SOD GPX andcatalase increase) in myocardial ischemic-reperfusion injuryin male rats (Ghyasi et al [231])
There are articles about other commercial and experi-mental DHPs on OS but we have reviewed only the mostcommonly studied compounds Effects of other commercialCA DHPs on OS are also mentioned in several parts of thisreview
36 14-DHPs Ca Agonists andTheir AOA and ARA For themost popular calcium agonist DHP Bay K 8644 no reactionwith peroxyl radicals was registered (Toniolo et al [114])However interactionwith other compounds possessing AOAand ARA (quercetin) was found
Opposite to that AON-acetylcysteine (NAC) diminishedincrease in Ca2+ transient amplitude and cell shorteninginduced by ISO and forskolin whereas NAC had no effecton the (S)-(minus)-methyl-14-dihydro-26-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylatemdash(minus)-BayK 8644-induced increases (Andersson et al [232])
Increased vasoconstriction responses to Bay K 8644 (3 times10minus7ndash3times 10minus5M)were significantly decreased by pyridoindoleantioxidant stobadine treatment in diabetes (Ceylan-Isik etal [233])
The functional interaction between two L-type Ca2+channel activators quercetin and Bay K 8644 has beeninvestigated in vascular smooth muscle cells Biological ARAcompound quercetin at nutritionally meaningful concen-trations limited the responsiveness of vascular L-type Ca2+channels to the pharmacological stimulation operated by BayK 8644 These data contribute to a better understanding ofquercetin effects on experimental in vivo cardioprotection(Saponara et al [234]) Thus these findings indicated thatalthough Bay K 8644 does not exert potent and direct AOAyet acting as calcium agonist it may affect efficiency of AOsubstances and vice versa
Interaction of grapefruit juice (containing quercetin andits analogues) with DHPs CA diminished effectiveness of CAaction of DHPs (Sica [235])
37 Interpretations of the Mechanism(s) of RadicalScavenging and AOA by DHPs
371 Molecular Mechanism(s) of Radical Scavenging andAOA of DHPs in the Model Systems 35-Dicarbonyl-14-di-hydropyridine derivatives possess powerful bis-120573-carbony-lvinyl-amino conjugation and for that reason cannot be con-sidered as ordinary amino antioxidants The electron andorH donation from DHPs ensures their reductant role andresults in AOA and ARA Oxidation reaction from DHPsresults in production of corresponding heteroaromatic pyri-dine derivatives
Oxidative Medicine and Cellular Longevity 23
Detailed studies were made about substituent in DHPring positions 14- namely 4-unsubstituted- 4-substituted4-alkyl- 4-aryl- 4-alkylaryl- ao 26- 35- (diacetyl ordialkoxycarbonyl chain ao) electronic and steric effects onAOA and ARA of DHPs [44 45 51] see Sections 331and 35 The bell-shaped dependence of DHPs AOA onthe 35-dialkoxycarbonyl- chain length was observed [4445 107 109 112] with the maximum activity at C
2H5ndash
C4H9 Decrease of AOA and incorporation into liposomes for
DHPs with alkyl chains longer than R gt C4H9further were
clarified as probable tendency to self-aggregation of thesecompounds ([51] and citation number 245 therein) Electronacceptorelectron donor properties are relevant for expres-sion of AOA or ARA of 35-disubstituted DHPs 35-Diacyl-substituted and 35-dicarbanilido- and 35-dipyridylamido-substituted DHPs are more active as AOs as their 35-dicyano-substituted analogues which have electron acceptorproperties [186]
Dubur et al [89] observed overwhelming steric influenceof substituents in position 4 of the DHP ring Gaviraghiet al [163 164] proposed that AO activity of DHPs ispartly dependent on capacity of the 14-DHP ring to donateelectrons to the propagating radical (ROO∙ or RO∙) and toreduce it to a less reactive form The abstraction (donation)of electron andor H in the oxidation and LP reactionstakes place from all 35-dicarbonyl-14-DHP systems andresults in the formation of corresponding pyridine derivatives(Augustyniak et al [51]) The physicochemical mechanism ofARA and AOA of 14-DHP has been extensively studied anddiscussed (Mulder et al [236]) but precise mechanisms oftheir activity need further clarification
The reactivity of C-4 substituted 14-DHPs possessingeither secondary or tertiary nitrogen atom in the DHP ringtoward alkyl alkylperoxyl radicals and ABTS radical cationwas determined in aqueous media at pH 74 [103] Thesecompounds reacted faster toward alkylperoxyl radicals andABTS radical cation than alkyl ones N-Ethyl-substitutedDHPs showed the lowest reactivity
The 4-methyl substituted DHP was the most reac-tive compound in previously mentioned reactions (Lopez-Alarcon et al [103]) However it was less active (068versus 10) than Trolox-C DHPs having electron-donatingsubstituents (4-Me-DHP and p-MeO-Phe-DHP) showed thehighest kinetic rate constants toward ABTS radical cation p-nitro-Phe-DHP a compound with an electron-withdrawingsubstituent showed a lower kinetic rate constant and N-alkyl-DHP compounds show kinetic rate constants lowerthan the -NH-DHP
Hydrogen at the 1-position of the DHP ring was revealedaccording to the deuteriumkinetic isotope effect studies to beinvolved in the proposedARAmechanismThis fact ismostlynoticeable in the case of alkyl radicals N-Ethyl-substitutedDHPs show the lowest reactivity when compared to Troloxor nisoldipine In all cases the respective pyridine derivativewas detected as the main product of the reaction (Lopez-Alarcon et al [103]) Authors indicate that the kinetic rateconstants toward alkyl alkylperoxyl andABTS radical cationdepend on the nature of the substituents in the C-4 positionof DHP and the presence of the secondary amine group in the
dihydropyridine ring that is the presence of the hydrogen in1-position
Yanez et al [197] have studied the reactivity of 11derivatives of 14-DHPs (including commercial CA) withalkylperoxyl radicals and ABTS radical cation The tested14-DHPs were 83-fold more reactive towards alkylperoxylradicals than to the ABTS cation radical All commercial14-DHP type CCBs were weaker than Trolox-C The par-ticipation of the hydrogen atom in the 1-position appearsto be very relevant for exhibited reactivity Hantzsch ester(diludine)was again found to be themost active compound inthe reaction with alkylperoxyl radicals 23-fold more activethan Trolox The photodegradation product of nifedipine(nitrosophenyl derivative of pyridine) also showed a highactivity Kinetic rate constants for the reaction between 14-DHP compounds and alkylperoxyl radicals exhibited a fairlygood linear correlation with the oxidation peak potentialof DHP derivatives However the activity of tested 14-DHPs towards ABTS radical cation showed an independencebetween kinetic rate constants and oxidation peak potentials
Kirule et al [195] andTirzit et al [196] studiedmechanismof AOA of 4-nitrophenyl-14-DHPs nifedipine and its ana-logues involving formation of 4-(21015840-nitrosophenyl)-pyridinederivative (as active principle) as a result of intramolecularredox reaction using chemical electrochemical and bio-chemical approaches (see Sections 331 and 351)
Nunez-Vergara et al [237] reported the electrochemicaloxidation of C4-hydroxyphenyl-substituted 14-DHP deriva-tives The oxidation proceeds via formation of the unstabledihydropyridyl radical as confirmed by controlled-potentialelectrolysis (CPE) and ESR experiments This type of 14-DHPs has significant activity towards the radicals even whencompared with commercial 14-DHP drugs with well-knownantioxidant ability
It was observed that nicardipine preferentially targets RO∙radicals and is inactive against ROO∙ Lacidipine on theother hand is equally active towards both types of radicals(Gaviraghi et al [164]) The cytoprotective effect againstexposure to H
2O2was more significant for lacidipine (ID
50=
14 nM its log119875 = 54 membrane partition = 136000 assumesposition located 7 A near to the membrane center otherless lipophilic DHPs located 12ndash16 A far from the center)as compared to amlodipine nifedipine and nicardipine insmooth muscle cell culture (Gaviraghi et al [164]) Oxidativeeffect of H
2O2shifts the Ca channel toward an open state
Thus the redox property of CCBs DHPs may augment theirCCB properties
Oxidation of pharmacologically active Hantzsch 14-dihydropyridines was found by electrogenerated superoxideusing a voltammetric approach in DMSO solutions (Ortiz etal [238] and Ortiz et al [239]) Raghuvanshi and Singh [240]have also reported oxidative aromatization of these DHPsinduced by superoxide
Chemiluminescence (CL) was used in the studies ana-lyzing the antioxidant activity of 12 various 4-flavonil-14-dihydropyridine derivatives (Kruk et al [241]) on a chemicalsystem involving a superoxide radical anion These deriva-tives showed structural similarity to flavonoids with respectto the presence of rings A B and C The results obtained in
24 Oxidative Medicine and Cellular Longevity
this study indicate that the tested derivatives may catalyzeconversion of superoxide radicals through mimicking theactivity of superoxide dismutase by delivering H+ for reac-tion
O2
minus∙+O2
minus∙+ 2H+ 997888rarr H
2O2+1O2
(3)
The enhanced emission of the light in the presence oftested compounds was significant and related to stimulatedproduction ofH
2O2and 1O
2fromO
2
∙The latter specieswereremoved from the reactionmixture by the following sequenceof reactions
H+
O2
minus∙997888rarr HO
2
∙
HO2
∙+O2
∙minus997888rarr HO
2
minus+1O2
2HO2
∙997888rarr H
2O2+1O2
2 (1O2) 997888rarr (O
2)2+ h]lowast
(4)
or to take part in spontaneous dismutation of H2O2
2H2O2997888rarr 2H
2O + 1O
2(5)
The authors have offered an original concept of action for 4-flavonil-14-dihydropyridine derivatives unrelated to that ofO2
∙ radical-trapping chain-breaking antioxidants Insteadthey showed that these compounds act similar to superoxidedismutases converting O
2
∙ to H2O2 Hydrogen peroxide
is less toxic for cells than O2
∙ because it is predominantlyremoved by peroxidases and catalases Finally AO effect ofthese DHPs differed from those mediated by flavonoids witha catechol structure of ring B which are well-known 1O
2
quenchersMulder and collaborators came to similar conclusions
especially related to molecular mechanisms of antioxidativeactivity of DHPs [236]TheAOproperties of Hantzsch 14-di-hydropyridine esters and two dibenzo-14-dihydropyridines910-dihydroacridine (DHAC) and N-methyl-910-dihydro-acridine (N-Me-DHAC) have been explored by determin-ing the autoxidation of styrene or cumene at 30∘C Theseexperiments showed that Hantzsch esters are virtually inac-tive as chain-breaking antioxidants (CB-AOs) contrary tothe findings observed by Lopez-Alarcon et al [103] whoused CB-AOA in aqueous media at pH 74 Their reactivitytoward peroxyl radicals was shown to be some 5 orders ofmagnitude lower than that of the excellent CB-AO 22578-pentamethyl-6-hydroxy-chroman (PMHC)
DHAC was found to be sim10 times less reactive thanPMHC kinetic measurements using DHAC N-deuterio-DHAC and N-Me-DHAC pointing out the abstraction ofN-H hydrogen in DHAC by peroxyl radicals despite the factthat the calculated C-H bond dissociation enthalpy (BDE) inDHAC is about 11 kcalmol lower than the N-H BDE Therates of hydrogen atom abstraction by the 22-diphenyl-1-picrylhydrazyl radical (DPPH∙) have also been determined
for the same series of compounds The trends in the peroxyl∙and DPPH∙ rate constants were found to be similar [236]
Tirzit et al [242] have observed quenching of singletoxygen by DHPs This observation paved the ground forfurther research related to reactions of DHPs with hydroxylradicals (Tirzit et al [243]) singlet oxygen (Kazush etal [94]) and mechanisms of action A series of 14-DHPderivatives in NAD-H-Cu2+-H
2O2system inhibited forming
of the hydroxyl radical (HO∙) while 14-DHP derivativeswith electron donor substituents in the molecule were shownto be capable themselves of generating HO∙ in the presenceof Cu2+ and H
2O2 Rubene et al [186] also described
interaction of 14-DHP derivatives with Fentonrsquos reagentwhich produces hydroxyl radical (HO∙) Rate constants ofthe DHPs reaction (1st order) with HO∙ radical were highin the range 109 L times mol times secminus1 close to that of NADHcysteine and thiourea 35-Diacetyl- derivatives reacted fastercompared to 35-dialkoxycarbonyl- ones The reaction ratedecrease was observed in the case of substitution at position4 as compared to 4-unsubstituted DHPs Some DHPs havingelectron donor -COOminus groups in the 35- or 26- positionsof DHP ring reacted immediately (having rate constantshigher as 109 L times mol times secminus1) Rate constants with HO
2
∙
and O2
∙minus radicals were of lower degree Thus DHPs actingas oxygen radical scavengers could effectively inhibit ROSrelated reactions of LP initiation stage
Nifedipine and nitrendipine reactivity toward singletoxygen was also studied [244] Nifedipine was shown tobe a good scavenger of excited oxygen mainly via physicaldeactivation with values of the total rate constant rangingfrom 208 times 105Mminus1 sminus1 (in dioxane) to 930 times 105Mminus1 sminus1(in propylene carbonate)The less reactive pathway generateda photooxidation product For that reason a mechanisminvolving a perepoxide-like encounter complex in the firststep of the reaction path was proposed (see [244] Figures8 and 9 therein) The dependence was observed on solventmicroscopic parameters of the total rate constant for the reac-tion between singlet oxygen and 14-DHPs These findingsshow that nifedipine possesses stronger protective activity inbiological systems than nitrendipine
Density-functional-theory (DFT) calculations made byWang et al [245] confirmed the former experimental obser-vations that Hantzsch ester diludine is potent antioxi-dant with high H atom-donating ability and relatively lowprooxidant activity Possible reaction pathways for radicalsderived from 14-dihydropyridine and the resonance modesfor radical species were given [245]
Moreover two ethoxycarbonyl (EtOCO) substituentsat C(2) and C(6) should further enhance Hantzsch esterdiludine H-atom-donating ability due to resonance effectsHowever DHPs should be used in nonpolar rather than inpolar solvents since in the latter not H-atom but electrontransfer is preferred in the radical scavenging process [245]
Mulder et al [246] proposed that quantum-thermochem-ical calculations must be used with caution to indicate ldquoapromising lead antioxidantrdquo as they criticized the density-functional-theory (DFT) calculations made by Wang et al[245]
Oxidative Medicine and Cellular Longevity 25
372 Possible Mechanisms of DHPs ARA and AOA in the Bio-logical Systems Interaction with Other OSModifiers Some ofthese mechanisms were already described (Sections 331 (2)-(b) 331 (2)-(c) 331 (3)-(b) 35)
Enzymatic sources of ROSwith confirmed functional rolein hypertension are NADPH oxidase NO synthase (NOS)xanthine oxidase and cyclooxygenase Godfraind [3] hasreviewed AO effects and protective action of calcium channelblockers (CCBs) Yao et al [247] observed antioxidant effects(as inhibition of LP) for cardio- and neuroprotective CCBs(3ndash300 120583molL) including 7 DHPs in homogenates of ratbrain IC
50values (120583M) were as follows nifedipine (515) gt
barnidipine (586) gt benidipine (712) gt nicardipine (1293)gt amlodipine (1355) gt nilvadipine (1673) gt nitrendipine(2521) gt diltiazem (gt300) = verapamil (gt300) There arealso research articles describing the AO properties of CCBsthrough direct scavenging effect or through preservationof the endogenous SOD activity These findings indicatethat CCBs may also act by reducing the production ofvasoconstrictors angiotensin and endothelin
When present in concentrations that can be achievedin plasma CCBs may inhibit LP formation [3] This AOactivity seems to be typical for high lipophilic CCBs becausetheir chemical structure facilitates proton-donating andresonance-stabilization mechanisms that quench the freeradical reaction Their insertion in the membrane nearpolyunsaturated fatty acids at relatively high concentrationspotentiates proton donation (or atomary H) to lipid peroxidemolecules thereby blocking the peroxidation process Theremaining unpaired free electron associated with the CCBmolecule can be stabilized in well-defined resonance struc-tures associated with the DHP ring (Mason et al [48])
The radical reaction (according to Godfraind [3]) thatdescribes the AO effects of a DHP CCBs is LOOlowast + DHPrarr LOOH + DHPlowast (where LOOlowast is lipid peroxide radical)which in general is reaction (7) of the LP reaction cascadeconsisting of sim10 reactions (Scheme 2) [89]
As the rate constants of in vitro interaction of 4-substituted DHPs with peroxyl radicals are three ordersof magnitude lower than that of the vitamin E derivativethese DHPs must be considered as weak AO (Ursini [204])However due to partition coefficient of DHPs in membranesand in case of specific binding high local concentration ofDHPs may be obtained
DHPs without CCB properties for instance Bay w 9798although structurally related to nifedipine inhibit TNF-120572-induced vascular cell adhesion molecule-1 expression inendothelial cells by suppressing reactive oxygen speciesgeneration [248]
Mitrega et al [249] have discovered that antiarrhythmicand hemodynamic effects of oxidized heteroaromatic DHPsoxy nifedipine oxy nimodipine oxy nitrendipine and oxynisoldipine suggest that CCB DHPs and their metabolitescould act at least in two ways targeting OS related eventsas reductants (see Section 351 (1)) andor bypassing OSrelatedmetabolic routes Authors postulated that contrary tocurrent belief NIF metabolites are pharmacologically activeATP sensitive potassium channels were mentioned as a tar-get
38 DHPs Anti- or Prooxidants Several substances (ascorbicacid being the most commonly studied) can serve either asantioxidants or as prooxidants depending on given condi-tions (Herbert [250]) Therefore Halliwell [251] has reporteddilemma related to polyphenols as possible antioxidantsand prooxidants causing experimental artifacts (about 25)by oxidation of antioxidant compounds in the cell culturemedia Nevertheless it is generally accepted opinion thatpolyphenols act as antioxidants in vivo Studies on DHPs alsoface such a dilemmaThe exact roles (anti- or prooxidative) ofany specific DHP depend on its structure appliedachievedconcentration and specificity of the targetexperimentaltesting system
This situation resembles the case of antioxidative effectsof tocopherol which depends on the fate of the secondaryradical as proposed by Winterbourn [252] The question wasldquoVitamin E - Pro- or Antioxidantrdquo
997888rarr chain termination of lipid peroxidation
(6)
Prooxidant
Toc∙ + Lipid-H 997888rarr Lipid∙ (in LDL particles) (7)
This example shows that generally speaking any AO mustfulfil several criteria to be considered as an effective com-pound physiologically
(i) It must be able to functionally interact with endoge-nous scavengers even at low concentrations
(ii) It must affect endogenous pathways of OS(iii) It should not have undesirable adverse effect(iv) It should manifest the antioxidant efficacy dependent
on the oxidant(v) It must discriminate among different strategies
needed for 1-electron and 2-electron processes(vi) Radical scavengers can be prooxidant unless linked to
a radical sink (Winterbourn [252])
According to these statements DHPs could be effective asAO under physiological conditions in vivo (Godfraind [3]and others [30 31 38]) and in vitro in various experimentalsystems (cell and tissue) (see Sections 33 34 35)
Hence calcium antagonists appeared to disrupt thefine balance between the production and scavenging ofROS Nifedipine verapamil and diltiazem were shown toinduce significant oxidative stress in the epididymal sperm(increased MDA and decreased catalase and superoxidedismutase activity) This may be the reason for the inductionof male infertility [253]
The dualism of 14-DHP effects has been recorded asinhibition or promotion of LP as quenching or initiating
26 Oxidative Medicine and Cellular Longevity
oxygen and nitrogen free radical chain reactions radiopro-tecting or radiosensitizing antagonizing or synergizing Ca2+in electromechanical coupling as well as in the membranestabilization or labilization
39 Could DHPs Be Involved in Antioxidative Stress Beforebeing applied in vivo the optimal dose and optimal timeintervals forDHPs applicationmust be knownNamely whileROS have been traditionally considered as toxic byproductsof aerobic metabolism we know nowadays that ROS may actas essential signaling molecules needed for the control ofmany different physiological processes Whether the role ofROS will be damaging protective or signaling depends onthe delicate equilibrium between time- and location-specificROS production and scavenging Accordingly the imbalanceof the increased AO potential so-called antioxidative stresscould be dangerous similar to chronic OS in particular incase of extended exposure Inappropriate interventions inthe oxidative homeostasis by excessive antioxidants especiallyin case of chronic exposure to antioxidants might havevery negative effects as was published in the ATBC studyshowing an increased cancer incidence in smokers treatedby excessive beta-carotene [254] Therefore overconsump-tion of any natural or synthetic AO including DHPs asdietary supplements or drugs must be avoided in order tosuppress oxidative damage and must not disrupt the well-integrated antioxidant defense network (Poljsak [255] andPoljsak and Milisav [256]) This is especially important whenadministrating lipid-soluble antioxidants that can be storedin biomembranes thus not only attenuating or preventing LPbut also affecting physiological effects of the natural antiox-idants in particular tocopherol The interrelationship withthe status of endogenous antioxidantsprooxidants should befollowed
DHPs primarily suppress the initiation stages of LPprocessThey do not entirely stop the LP propagation Actingsynergistically with tocopherol diludine may prevent patho-logical excess of ROS production within the lipid moiety ofthe cellular membranes and LDL However due to its lowsolubility and fast metabolism its concentration in the cellsis low For that reason it cannot cause antioxidative stresseven if used for an extended period of time Thus diludine(diethone) could be only a mild antioxidant it has potentialfor restoring the pool of natural antioxidants (as synergist of120572-tocopherol and polyphenols) in the cells
Moreover DHPs CA used for cardioprotection andvasodilatation as commercial drugs in low concentrationsare fast metabolized via CYP3A4 and for that reason theirapplication does not induce cellular AO stress [53 160]However Godfraind and Salomone [257] have postulated noevidence that allows recommending dietary supplementationwith antioxidants for the primary or secondary prevention ofcardiovascular disease
So far there are no reports on antioxidative stress causedby some DHPs diludine and its analogues Diludine andits analogues therefore could act as adaptogens supportinghormetic effects of mild oxidative stress These compoundsmay act as potential multisided modulators of Yin-Yang
cycles of redox and cell functions (the electroplasmic cycle)(Wagner et al [258])
4 Conclusions
14-Dihydropyridines (14-DHPs) have broad spectrum ofOS modulating activities DHPs have reducing and lipidperoxidation inhibitor properties act as reductants in simplechemical systems and stabilize various biological systems(LDL mitochondria microsomes cells and tissues) againstOS Examples and peculiarities and mechanisms of antiox-idant activity (AOA) and antiradical activity (ARA) as wellas stress-protective effect of DHPs including commercialcalcium antagonists (CA) were highlighted These activitiesdepend on various structural parameters related to DHPs(presence and character of substituents) lipophilicity anddepth of the incorporation in the biologicalmembranesTheyalso depend on the experimental model system for exploringthe lipid peroxidation or oxidative stress Stress-protectiveeffect of some metabolites of CA (nifedipine) is reviewedAlthough some DHPs including CA have prooxidant prop-erties (on epididymal sperm cells) they can generally beconsidered as potent antioxidants Therefore comparisonof the AOA and ARA of different DHPs (mutually andwith other AOs) was described in detail According to thedata presented the DHPs might be considered as bellwetheramong synthetic compounds targeting OS and as a kind ofpharmacological measure for respective field of organic andmedicinal chemistry
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
Authors from Latvian IOS acknowledge ESF 201300021DP1112013APIAVIAA011 and National Research Pro-gramme PUBLIC HEALTHBiomedicine of the Republicof Latvia for financial support administration of the Insti-tute for technical support and Rufus Smits PhD for con-sultations in English The support of Cooperation in Euro-pean System of Science and Technology (COST) Domain ofChemistry Molecular Sciences and Technologies (CMST)was of highest importance for preparation of this paper
[2] D J Triggle ldquo14-Dihydropyridines as calcium channel ligandsand privileged structuresrdquoCellular andMolecular Neurobiologyvol 23 no 3 pp 293ndash303 2003
[3] T Godfraind ldquoAntioxidant effects and the therapeutic modeof action of calcium channel blockers in hypertension andatherosclerosisrdquo Philosophical Transactions of the Royal SocietyB Biological Sciences vol 360 no 1464 pp 2259ndash2272 2005
[4] E Cadenas ldquoMitochondrial free radical production and cellsignalingrdquoMolecular Aspects of Medicine vol 25 no 1-2 pp 17ndash26 2004
[5] E Cadenas ldquoFree radicals oxidative stress and diseasesrdquo inLecture PSC 616 p 38 Missouri University of Science andTechnology Rolla Mo USA httpwwwcarnicominstituteorgarticlesenrique cadenaspdf
[6] K Rahman ldquoStudies on free radicals antioxidants and co-fac-torsrdquo Clinical Interventions in Aging vol 2 no 2 pp 219ndash2362007
[7] V Bocci and G Valacchi ldquoFree radicals and antioxidants howto reestablish redox homeostasis in chronic diseasesrdquo CurrentMedicinal Chemistry vol 20 no 27 pp 3397ndash3415 2013
[8] M Valko C J Rhodes J Moncol M Izakovic and M MazurldquoFree radicals metals and antioxidants in oxidative stress-induced cancerrdquo Chemico-Biological Interactions vol 160 no 1pp 1ndash40 2006
[9] G Bartosz ldquoReactive oxygen species destroyers or messen-gersrdquo Biochemical Pharmacology vol 77 no 8 pp 1303ndash13152009
[10] R Visconti and D Grieco ldquoNew insights on oxidative stress incancerrdquo Current Opinion in Drug Discovery and Developmentvol 12 no 2 pp 240ndash245 2009
[11] R N Kujundzic N Zarkovic and K G Troselj ldquoPyridinenucleotides in regulation of cell death and survival by redoxand non-redox reactionsrdquo Critical Reviews in Eukaryotic GeneExpression vol 24 no 4 pp 287ndash309 2014
[12] B Halliwell and J M C Gutteridge ldquoThe definition and mea-surement of antioxidants in biological systemsrdquo Free RadicalBiology and Medicine vol 18 no 1 pp 125ndash126 1995
[13] V D Kancheva and O T Kasaikina ldquoBio-antioxidantsmdashachemical base of their antioxidant activity and beneficial effect
on human healthrdquo Current Medicinal Chemistry vol 20 no 37pp 4784ndash4805 2013
[14] H V Panglossi Ed Frontiers in Antioxidants Research NovaScience Publishers New York NY USA 2006
[15] E B Burlakova E M Molochkina and G A NikiforovldquoHybrid antioxidantsrdquo Oxidation Communications vol 31 no4 pp 739ndash757 2008 httpmembraneustceducnpaperpdfHybrid20Antioxidantspdf
[16] A Bast and G R M M Haenen ldquoTen misconceptions aboutantioxidantsrdquo Trends in Pharmacological Sciences vol 34 no 8pp 430ndash436 2013
[17] E B Burlakova A V 0lesenko E M Molochkina N PPalmina and N G Khrapova Bioantioxidants for RadiationDamage and Malignant Growth Nauka Moscow Russia 1975(Russian)
[18] J Fang T Seki and H Maeda ldquoTherapeutic strategies by mod-ulating oxygen stress in cancer and inflammationrdquo AdvancedDrug Delivery Reviews vol 61 no 4 pp 290ndash302 2009
[19] M Valko D Leibfritz J Moncol M T D Cronin M Mazurand J Telser ldquoFree radicals and antioxidants in normal physi-ological functions and human diseaserdquo International Journal ofBiochemistry and Cell Biology vol 39 no 1 pp 44ndash84 2007
[20] M Jimenez-Del-Rio and C Velez-Pardo ldquoThe bad the goodand the ugly about oxidative stressrdquo Oxidative Medicine andCellular Longevity vol 2012 Article ID 163913 13 pages 2012
[21] C D Kamat S Gadal M Mhatre K S Williamson Q N Pyeand K Hensley ldquoAntioxidants in central nervous system dis-eases preclinical promise and translational challengesrdquo Journalof Alzheimerrsquos Disease vol 15 no 3 pp 473ndash493 2008
[22] A Pompella H Sies R Wacker et al ldquoThe use of totalantioxidant capacity as surrogate marker for food quality andits effect on health is to be discouragedrdquo Nutrition vol 30 no7-8 pp 791ndash793 2014
[23] Z Ye and H Song ldquoAntioxidant vitamins intake and the risk ofcoronary heart disease meta-analysis of cohort studiesrdquo Euro-pean Journal of Cardiovascular Prevention and Rehabilitationvol 15 no 1 pp 26ndash34 2008
[24] P Knekt J Ritz M A Pereira et al ldquoAntioxidant vitamins andcoronary heart disease risk a pooled analysis of 9 cohortsrdquoTheAmerican Journal of Clinical Nutrition vol 80 no 6 pp 1508ndash1520 2004
[25] A C Carr and M C M Vissers ldquoSynthetic or food-derivedvitamin Cmdashare they equally bioavailablerdquo Nutrients vol 5 no11 pp 4284ndash4304 2013
[26] R Tabrizchi ldquoEdaravoneMitsubishi-TokyordquoCurrentOpinion inInvestigational Drugs vol 1 no 3 pp 347ndash354 2000
[27] K Kikuchi S Tancharoen N Takeshige et al ldquoThe efficacy ofedaravone (radicut) a free radical scavenger for cardiovasculardiseaserdquo International Journal of Molecular Sciences vol 14 no7 pp 13909ndash13930 2013
[28] D Mauzerall and F H Westheimer ldquo1-Benzyldihydronicoti-namidemdasha model for reduced DPNrdquo Journal of the AmericanChemical Society vol 77 no 8 pp 2261ndash2264 1955 ChemicalAbstracts vol 50 Article ID 2588i 1956
[29] F Bossert and W Vater ldquo14-Dihydropyridinesmdasha basis fordeveloping new drugsrdquo Medicinal Research Reviews vol 9 no3 pp 291ndash324 1989
[30] G Swarnalatha G Prasanthi N Sirisha and CMadhusudhanaChetty ldquo14-Dihydropyridines a multtifunctional moleculemdash areviewrdquo International Journal of ChemTech Research vol 3 no1 pp 75ndash89 2011
28 Oxidative Medicine and Cellular Longevity
[31] M Cataldi and F Bruno ldquo14-Dihydropyridines the multiplepersonalities of a blockbuster drug familyrdquo Translational Medi-cine UniSa vol 4 no 2 pp 12ndash26 2012 httpwwwncbinlmnihgovpmcarticlesPMC3728803
[32] R Vitolina A Krauze G Duburs and A Velena ldquoAspects ofthe amlodipine pleiotropy in biochemistry pharmacology andclinicsrdquo International Journal of Pharmaceutical Sciences andResearch vol 3 no 5 pp 1215ndash1232 2012
[33] D Grover S N Mokale and M T Shete ldquoDihydropyridinea novel pharmacophorerdquo International Journal of Pharmaceu-tical Erudition vol 1 no 2 pp 16ndash29 2011 httppharmaeru-ditionorgContentPaper20111-RV-320Final2016-29pdf
[34] A M Vijesh A M Isloor S K Peethambar K N ShivanandaT Arulmoli and N A Isloor ldquoHantzsch reaction synthesis andcharacterization of somenew 14-dihydropyridine derivatives aspotent antimicrobial and antioxidant agentsrdquo European Journalof Medicinal Chemistry vol 46 no 11 pp 5591ndash5597 2011
[35] P Mehta and P Verma ldquoAntimicrobial activity of some deriva-tives of 14-dihydropyridinesrdquo Journal of Chemistry vol 2013Article ID 865128 4 pages 2013
[36] P Olejnıkova L Svorc D Olsovska et al ldquoAntimicrobialactivity of novel C2-substituted 14-dihydropyridine analoguesrdquoScientia Pharmaceutica vol 82 no 2 pp 221ndash232 2014
[37] S Sepehri H Perez Sanchez and A Fassihi ldquoHantzsch-typedihydropyridines and biginelli-type tetra-hydropyrimidinesa review of their chemotherapeutic activitiesrdquo Journal of Phar-macy amp Pharmaceutical Sciences vol 18 no 1 pp 1ndash52 2015httpsejournalslibraryualbertacaindexphpJPPSarticleview2383617863
[38] S A Khedkar and P B Auti ldquo14-Dihydropyridines a classof pharmacologically important moleculesrdquo Mini-Reviews inMedicinal Chemistry vol 14 no 3 pp 282ndash290 2014
[39] G D Tirzit and G Ya Duburs ldquo14-dihydropyridines as inhi-bitors of free-radical reactionsrdquo Chemistry of Heterocyclic Com-pounds vol 8 no 1 pp 126ndash127 1972 Translated from KhimiyaGeterotsiklicheskikh Soedinenii no1 pp 133ndash134 1972 (Rus-sian)
[40] I Bogeski R Kappl C Kummerow R Gulaboski M Hothand B A Niemeyer ldquoRedox regulation of calcium ion channelschemical and physiological aspectsrdquoCell Calcium vol 50 no 5pp 407ndash423 2011
[41] S A Giller G Y Dubur Y R Uldrikis et al ldquoDiludine [Themethod to obtain 35-dicarbonylderivatives of 26-dimethyl-14-dihydropyridines]rdquo Authors certificate of USSR no 3004651971 [Byull Izobret no13 p 95 1971] and following patentsPatent of England no 1294650 1973 Patent of France no2055458 1971 Patent of Japan no 702883 1973 Patent ofHolland no 149787 1976 Patent of Italy no 969022 1974 Patentof FRG no 2036403 1978 US Patent no 3883673 1975 USPatent no 3948924 1976
[42] S A Giller G Y Dubur Y R Uldrikis et al ldquoImprovementsin or relating to the stabilization of carotenerdquo GB Patent no1294650 1972
[43] S A Giller G Y Dubur Y R Uldrikis et al ldquoStabilization ofcarotenerdquo US Patent no 3883673 1975 Chemical Abstracts vol83 Article ID 95193 1975
[44] Yu A Zilber G Ya Dubur K K Kumsar and A Kh VelenaldquoThe effect of antioxidants on the peroxidation of bimole-cular phospholipid membranesrdquo Latvijas PSR ZA Vestis Izves-tia Akademii Nauk Latviyskoy SSR vol 6 pp 80ndash82 1971(Russian) translated from the original Russian Doc Accesion
No AD0771751 distributed by NTIS US Department of Com-merce httpwwwdticmildtictrfulltextu2771751pdf
[45] G Ya Dubur Yu A Zilbers A Kh Velena A O Kumerovaand G D Tirzitis ldquoMultistage study of regulation of peroxida-tion processes in biological membranes by antioxidants of 14-dihydropyridine grouprdquo Izvestiya Akademii Nauk LatviyskoySSR vol 336 no 7 pp 65ndash68 1975 (Russian)
[46] R P Mason and M W Trumbore ldquoDifferential membraneinteractions of calcium channel blockers Implications forantioxidant activityrdquo Biochemical Pharmacology vol 51 no 5pp 653ndash660 1996
[47] R P Mason M F Walter M W Trumbore E G Olmstead Jrand P E Mason ldquoMembrane antioxidant effects of the chargeddihydropyridine calcium antagonist amlodipinerdquo Journal ofMolecular and Cellular Cardiology vol 31 no 1 pp 275ndash2811999
[48] R PMason I T MakMW Trumbore and P EMason ldquoAnti-oxidant properties of calcium antagonists related to membranebiophysical interactionsrdquo American Journal of Cardiology vol84 no 4 pp 16ndash22 1999
[49] R PMasonMW Trumbore and P EMason ldquoMembrane bio-physical interaction of amlodipine and antioxidant propertiesrdquoDrugs vol 59 no 2 pp 9ndash16 2000 (French)
[50] R P Mason P Marche and T H Hintze ldquoNovel vascularbiology of third-generation L-type calcium channel antagonistsAncillary actions of amlodipinerdquo Arteriosclerosis Thrombosisand Vascular Biology vol 23 no 12 pp 2155ndash2163 2003
[51] A Augustyniak G Bartosz A Cipak et al ldquoNatural andsynthetic antioxidants an updated overviewrdquo Free RadicalResearch vol 44 no 10 pp 1216ndash1262 2010
[52] T Grune N Zarkovic and K Kostelidou ldquoLipid peroxidationresearch in Europe and the COST B35 action lsquoLipid Peroxida-tion Associated Disordersrsquordquo Free Radical Research vol 44 no10 pp 1095ndash1097 2010
[53] E Carosati P Ioan M Micucci et al ldquo14-Dihydropyridinescaffold in medicinal chemistry the story so far and perspec-tives (part 2) action in other targets and antitargetsrdquo CurrentMedicinal Chemistry vol 19 no 25 pp 4306ndash4323 2012
[54] U Eisner and J Kuthan ldquoThe chemistry of dihydropyridinesrdquoChemical Reviews vol 72 no 1 pp 1ndash42 1972 httpwwwsci-encemadnessorgtalkfilesphppid=138742ampaid=6475
[55] J Kuthan and A Kurfurst ldquoDevelopment in dihydropyri-dine chemistryrdquo Industrial amp Engineering Chemistry ProductResearch and Development vol 21 no 2 pp 191ndash261 1982
[56] A Sausins and G Duburs ldquoSynthesis of 14-dihydropyridinesby cyclocondensation reactionsrdquo Heterocycles vol 27 no 1 pp269ndash289 1988
[57] A E Sausins and G Y Duburs ldquoSynthesis of 14-dihydro-pyridines in cyclocondensation reactions (review)rdquo Chemistryof Heterocyclic Compounds vol 28 no 4 pp 363ndash391 1992Translated from Khimiya Geterotsiklicheskikh Soedinenii no 4pp 435ndash467 1992 (Russian)
[58] S Kazda ldquoTwenty years of dihydropyridinesrdquo in Dihydropy-ridines Progress in Pharmacology and Therapy W-D Busse BGarthoff and F Seuter Eds pp 1ndash12 Springer Verlag BerlinGermany 1993
[59] J-P Wan and Y Liu ldquoRecent advances in new multicomponentsynthesis of structurally diversified 14-dihydropyridinesrdquo RSCAdvances vol 2 no 26 pp 9763ndash9777 2012
[61] Reaxys Database[62] J Tuttle ldquoStructure mechanism and reactivity of hantzsch
estersrdquo in MacMillan Lab Group Meeting (082504) p 332004 httpwwwprincetoneduchemistrymacmillangroup-meetingsJBT20Hantzschpdf
[63] A Saini S Kumar and J S Sandhu ldquoHantzsch reaction recentadvances in Hantzsch 14-dihydropyridinesrdquo Journal of Sci-entific amp Industrial Research vol 67 pp 95ndash111 2008
[64] L LW Cheung S A Styler and A P Dicks ldquoRapid and conve-nient synthesis of the 14-dihydropyridine privileged structurerdquoJournal of Chemical Education vol 87 no 6 pp 628ndash630 2010
[65] A Kumar R A Maurya S Sharma M Kumar and G BhatialdquoSynthesis and biological evaluation of N-aryl-14-dihydro-pyridines as novel antidyslipidemic and antioxidant agentsrdquoEuropean Journal of Medicinal Chemistry vol 45 no 2 pp 501ndash509 2010
[66] R S Kumar A Idhayadhulla A J Abdul Nasser and J SelvinldquoSynthesis and anticoagulant activity of a new series of 14-dihydropyridine derivativesrdquo European Journal of MedicinalChemistry vol 46 no 2 pp 804ndash810 2011
[67] H A Stefani C B Oliveira R B Almeida et al ldquoDihydro-pyrimidin-(2H)-ones obtained by ultrasound irradiation anew class of potential antioxidant agentsrdquo European Journal ofMedicinal Chemistry vol 41 no 4 pp 513ndash518 2006
[68] H Sun C Shang L Jin and J Zhang ldquoSynthesis and antiox-idant activity of a series of novel 3-chalcone-substituted 14-dihydropyridine derivativesrdquoHeterocyclic Communications vol18 no 5-6 pp 239ndash243 2012
[69] D B Tikhonov and B S Zhorov ldquoStructural model for dihy-dropyridine binding to L-type calcium channelsrdquo The Journalof Biological Chemistry vol 284 no 28 pp 19006ndash19017 2009
[70] G Y Dubur and Y R Uldrikis ldquoThe oxidation of 14-dihydro-pyridinesrdquo Chemistry of Heterocyclic Compounds vol 6 no 1pp 80ndash84 1970 Translated from Khimiya GeterotsiklicheskikhSoedinenii no 1 pp 83ndash88 1970 (Russian)
[71] G Ya Duburs A O Kumerova and Ya R Uldrikis ldquoEnzymicoxidation of hydrogenated pyridines with peroxidase-hydrogenperoxide systemrdquoLatvijas PSRZAVestis vol 73 no 7 pp 73ndash771970 (Russian) Chemical Abstracts vol 73 Article ID 94913g1970
[72] K Xie Y-C Liu Y Cui J-GWang Y Fu andT CWMak ldquoN-methyl-(R)-3-(tert-butyl)-sulfinyl-14-dihydropyridine a novelNADHmodel compoundrdquoMolecules vol 12 no 3 pp 415ndash4222007
[73] S Tamagaki T Mimura and W Tagaki ldquoMetal-ion-facilitatedoxidations of dihydropyridines with molecular oxygen andhydrogen peroxiderdquo Journal of the Chemical Society PerkinTransactions 2 no 10 pp 1645ndash1650 1990
[74] D Tirzite G Tirzitis andD Antipova ldquoReductive ability of 14-dihydropyridine derivatives in relation to ions of trivalent ironrdquoChemistry of Heterocyclic Compounds vol 35 no 5 pp 592ndash594 1999
[76] J Ogle J Stradins and L Baumane ldquoFormation and decay offree cation-radicals in the course of electro-oxidation of 12- and14-dihydropyridines (Hantzsch esters)rdquo Electrochimica Actavol 39 no 1 pp 73ndash79 1994
[77] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for the
synthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts C Wittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Berlin Germany 2010
[78] WDu and Zh Yu ldquoBiomimetic in situ regeneration of cofactorsNAD(P)+ and NAD(P)H models hantzsch esters and dihy-drophenanthridinerdquo Synlett vol 23 no 9 pp 1300ndash1304 2012
[79] H K Chenault and G M Whitesides ldquoRegeneration ofnicotinamide cofactors for use in organic synthesisrdquo AppliedBiochemistry and Biotechnology vol 14 no 2 pp 147ndash197 1987
[80] Y R Uldrikis A A Zidermane E A Biseniex I E Preisa GY Dubur and G D Tirzit ldquoEsters of 26-dimethyl-14-dihydro-pyridine-35-dicarboxylic acid and method of obtainingthereofrdquo WO 8000345 A1 1978 httpworldwideespacenetcompublicationDetailsbiblioDB=EPODOCampII=1ampND=3ampadjacent=trueamplocale=en EPampFT=Dampdate=19800306ampCC=WOampNR=8000345A1ampKC=A1
[81] Y Sambongi H Nitta K Ichihashi M Futai and I Ueda ldquoAnovel water-soluble Hantzsch 14-dihydropyridine compoundthat functions in biological processes through NADH regener-ationrdquo Journal of Organic Chemistry vol 67 no 10 pp 3499ndash3501 2002
[82] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for thesynthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts ChWittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Verlag Berlin Germany 2010
[83] T Okamura T Kikuchi A Nagamine et al ldquoAn approach formeasuring in vivo cerebral redox states using the oxidative con-version of dihydropyridine to pyridinium ion and themetabolictrapping principlerdquo Free Radical Biology and Medicine vol 38no 9 pp 1197ndash1205 2005
[84] K A Schellenberg and F H Westheimer ldquoA free-radicaloxidation of a dihydropyridine1ardquo The Journal of OrganicChemistry vol 30 no 6 pp 1859ndash1862 1965
[85] K A Schellenberg ldquoReaction of hydroxyl radical with thymi-dine Scavenging by a dihydropyridinerdquo Federation Proceedingsvol 38 no 3 I p 1433 1979
[86] E S Huyser J A K Harmony and F L McMillian ldquoPeroxideoxidations of dihydropyridine derivativesrdquo Journal of the Amer-ican Chemical Society vol 94 no 9 pp 3176ndash3180 1972
[87] A Sakamoto S T Ohnishi and R Ogawa ldquoInhibition of lipidperoxidation by some dihydropyridine derivativesrdquo Journal ofAnesthesia vol 7 no 2 pp 193ndash197 1993
[88] R Hardeland ldquoReview Neuroprotection by radical avoidancesearch for suitable agentsrdquo Molecules vol 14 no 12 pp 5054ndash5102 2009
[89] G Ya Dubur A Kh Velena V M Gukasov and Yu AVladimirov ldquoRegulation of peroxidation of mitochondrialmembrane lipids initiated by Fe2+ ions by antoxidants of the14-dihydropyridine series in experiments in vitrordquo Biomed-itsinskaya Khimiya vol 22 no 5 pp 665ndash673 1976 (Russian)Chemical Abstracts vol 88 Article ID 2640 1977
[90] G RMMHaenenM J T J Arts A Bast andMD ColemanldquoStructure and activity in assessing antioxidant activity in vitroand in vivo a critical appraisal illustrated with the flavonoidsrdquoEnvironmental Toxicology and Pharmacology vol 21 no 2 pp191ndash198 2006
[91] G Tirzitis and G Bartosz ldquoDetermination of antiradical andantioxidant activity basic principles and new insightsrdquo ActaBiochimica Polonica vol 57 no 2 pp 139ndash142 2010
30 Oxidative Medicine and Cellular Longevity
[92] G R Buettner and R P Mason ldquoSpin-trapping methods fordetecting superoxide and hydroxyl free radicals in vitro and invivordquo inCritical Reviews of Oxidative Stress and Aging Advancesin Basic Science Diagnostics and Intervention R G Cutler andH Rodriguez Eds vol 1 chapter 2 pp 27ndash38World ScientificLondon UK 2003
[93] M M Tarpey and I Fridovich ldquoMethods of detection ofvascular reactive species Nitric oxide superoxide hydrogenperoxide and peroxynitriterdquo Circulation Research vol 89 no3 pp 224ndash236 2001
[94] E Y Kazush E I Sagun G D Tirzit and G Y DaburldquoQuenching of singlet oxygen by electron donating derivativesof 14-dihydropyridinerdquo Chemistry of Heterocyclic Compoundsvol 30 no 5 pp 562ndash563 1994
[95] G Tirzitis E Kazush and G Duburs ldquoReaction of 14-dihydropyridine derivatives with peroxynitrite anionrdquo Chem-istry of Heterocyclic Compounds vol 34 no 3 pp 321ndash3231998 (Russian) Translated from Khimiya GeterotsiklicheskikhSoedinenii no 3 pp 355ndash357 1998
[96] L J Nunez-Vergara C Lopez-Alarcon P A Navarrete-EncinaA M Atria C Camargo and J A Squella ldquoElectrochemicaland EPR characterization of 14-dihydropyridines Reactivitytowards alkyl radicalsrdquo Free Radical Research vol 37 no 1 pp109ndash120 2003
[97] D Tirzite A Krauze A Zubareva G Tirzitis and G DubursldquoSynthesis and antiradical activity of 5-acetyl-2-alkylthio-4-aryl-6-methyl-14-dihydropyridine-3-carboxylic acid nitrilesrdquoChemistry of Heterocyclic Compounds vol 38 no 7 pp 795ndash800 2002
[98] H Ohkawa N Ohishi and K Yagi ldquoAssay for lipid peroxidesin animal tissues by thiobarbituric acid reactionrdquo AnalyticalBiochemistry vol 95 no 2 pp 351ndash358 1979
[99] N Zarkovic ldquo4-Hydroxynonenal as a bioactive marker ofpathophysiological processesrdquo Molecular Aspects of Medicinevol 24 no 4-5 pp 281ndash291 2003
[100] M Parola G Bellomo G Robino G Barrera and M UDianzani ldquo4-Hydroxynonenal as a biological signal molecularbasis and pathophysiological implicationsrdquo Antioxidants andRedox Signaling vol 1 no 3 pp 255ndash284 1999
[101] T Lovakovic M Poljak-Blazi G Duburs et al ldquoGrowthmodulation of human cells in vitro by mild oxidative stressand 14-dihydropyridine derivative antioxidantsrdquo CollegiumAntropologicum vol 35 no 1 pp 137ndash141 2011
[102] R van den Berg G R M M Haenen H van den Bergand A Bast ldquoApplicability of an improved Trolox equivalentantioxidant capacity (TEAC) assay for evaluation of antioxidantcapacity measurements of mixturesrdquo Food Chemistry vol 66no 4 pp 511ndash517 1999
[103] C Lopez-Alarcon P Navarrete C Camargo J A Squella andL J Nunez-Vergara ldquoReactivity of 14-dihydropyridines towardalkyl alkylperoxyl radicals and ABTS radical cationrdquo ChemicalResearch in Toxicology vol 16 no 2 pp 208ndash215 2003
[104] V Valenzuela P Santander C Camargo J A Squella C Lopez-Alarcon and L J Nunez-Vergara ldquo14-Dihydropyridines reac-tivity of nitrosoaryl and nitroaryl derivatives with alkylperoxylradicals andABTS radical cationrdquo Free Radical Research vol 38no 7 pp 715ndash727 2004
[105] L G Tsetlin N A Chebotareva B I Kurganov A K VelenaG Y Dubur and V Z Lankin ldquoStudy of 14-dihydropyridinesas lipoxygenase inhibitors with the use of hydrated reversedmicellesrdquo Pharmaceutical Chemistry Journal vol 22 no 6 pp425ndash428 1988 (Russian)
[106] J Panek Z Reblova L Kocirkova et al ldquoAntioxidant activityof dihydropyridine derivativesrdquo Czech Journal of Food Sciencesvol 18 pp 144ndash145 2000
[107] G Tirzitis I Kirule and G Duburs ldquoAntioxidationsaktivitatder 35-dicarbonylderivate des 26-demethyl-14-dihydropyri-dinsrdquo Fett Wissenschaft TechnologieFat Science Technology vol90 no 10 pp 411ndash413 1988
[108] M Plotniece G Tirzitis Y Uldrikis et al ldquoSynthesis of 14-dihydropyridine derivatives having an oxy- alkoxy- or dimeth-ylaminophenyl substituent in the 4 position their antioxidantactivity and their binding to phospholipid membranesrdquo Chem-istry of Heterocyclic Compounds vol 32 no 10 pp 1166ndash11721996 Translated from Khimiya Geterotsiklicheskikh Soedineniino 10(352) pp 1358ndash1365 1996 (Russian)
[109] D Y Rubene V S Sharov V I Olenev G D Tirzit G Y Duburand Y A Vladimirov ldquoUse of chemiluminescent method forthe evaluation of antioxidant activity of some derivatives of 14-dihydropyridinerdquo Russian Journal of Physical Chemistry A vol55 no 2 pp 511ndash512 1981 (Russian)
[110] M C R Symons and JM C Gutteridge Free Radicals and IronChemistry Biology and Medicine Oxford Science PublicationsOxford University Press Oxford UK 1998
[111] M Repetto J Semprine and A Boveris ldquoLipid peroxidationchemical mechanism biological implications and analyticaldeterminationrdquo in Lipid Peroxidation A Catala Ed Section ILipid Peroxidation Chemical Mechanisms Antioxidants Bio-logical Implications of Biochemistry Genetics and MolecularBiology chapter 1 pp 3ndash30 InTech Rijeka Croatia 2012
[112] A Velena J Zilbers and G Duburs ldquoDerivatives of 14-dihydropyridines asmodulators of ascorbate-induced lipid per-oxidation and high-amplitude swelling ofmitochondria causedby ascorbate sodium linoleate and sodiumpyrophosphaterdquoCellBiochemistry and Function vol 17 no 4 pp 237ndash252 1999
[113] M V Bilenko L N Shelenkova G Y Dubur and A K VelenaldquoUse of antioxidants to prevent renal damage during acuteischemia and reperfusionrdquo Bulletin of Experimental Biology andMedicine vol 96 no 3 pp 1195ndash1198 1983 Translated fromByulletenrsquo Eksperimentalrsquonoi Biologii i Meditsiny vol 96 no 9pp 8ndash11 1983 (Russian)
[114] R Toniolo F Tubaro F Ursini and G Bontempelli ldquoAn elec-troanalytical investigation on the redox properties of calciumantagonist dihydropyridinesrdquo Electroanalysis vol 15 no 10 pp855ndash861 2003
[115] L Kourimska J Pokorny and G Tirzitis ldquoThe antioxidant aci-tivity of 26-dimethyl-35-diethoxycarbonyl-14-dihydropyri-dine in edible oilsrdquo Nahrung vol 37 no 1 pp 91ndash93 1993
[116] C Lopez-Alarcon H Speisky J A Squella C Olea-Azar CCamargo and L J Nunez-Vergara ldquoReactivity of 14-dihydro-pyridines toward SIN-1-derived peroxynitriterdquo PharmaceuticalResearch vol 21 no 10 pp 1750ndash1757 2004
[117] R A Olek W Ziolkowski J J Kaczor L Greci J Popinigisand J Antosiewicz ldquoAntioxidant activity of NADH and its ana-loguemdashan in vitro studyrdquo Journal of Biochemistry andMolecularBiology vol 37 no 4 pp 416ndash421 2004
[118] E Niki N Noguchi and N Gotoh ldquoInhibition of oxidativemodification of low density lipoprotein by antioxidantsrdquo Jour-nal of Nutritional Science andVitaminology vol 39 supplementpp S1ndashS8 1993
[119] N Rojstaczer and D J Triggle ldquoStructure-function relation-ships of calcium antagonists effect on oxidative modificationof low density lipoproteinrdquo Biochemical Pharmacology vol 51no 2 pp 141ndash150 1996
Oxidative Medicine and Cellular Longevity 31
[120] A Sevanian L Shen and FUrsini ldquoInhibition of LDLoxidationand oxidized LDL-induced cytotoxicity by dihydropyridinecalcium antagonistsrdquo Pharmaceutical Research vol 17 no 8 pp999ndash1006 2000
[121] A Negre-Salvayre and R Salvayre ldquoProtection by Ca2+ channelblockers (nifedipine diltiazem and verapamil) against the tox-icity of oxidized low density lipoprotein to cultured lymphoidcellsrdquo British Journal of Pharmacology vol 107 no 3 pp 738ndash744 1992
[122] A Negre-Salvayre G FitoussiM Troly and R Salvayre ldquoCom-parative cytoprotective effect of dihydropyridine calcium chan-nel blockers against the toxicity of oxidized low density lipopro-tein for cultured lymphoid cellsrdquo Biochemical Pharmacologyvol 44 no 12 pp 2379ndash2386 1992
[123] L Cominacini A F Pasini U Garbin et al ldquoAntioxidant activ-ity of different dihydropyridinesrdquo Biochemical and BiophysicalResearch Communications vol 302 no 4 pp 679ndash684 2003
[124] L Cominacini U Garbin A Fratta Pasini et al ldquoOxidized low-density lipoprotein increases the production of intracellularreactive oxygen species in endothelial cells inhibitory effect oflacidipinerdquo Journal of Hypertension vol 16 no 12 part 2 pp1913ndash1919 1998
[125] H M Lander ldquoAn essential role for free radicals and derivedspecies in signal transductionrdquo The FASEB Journal vol 11 no2 pp 118ndash124 1997
[126] M L L Martinez E Rizzi M M Castro et al ldquoLercanidipinedecreases vascular matrix metalloproteinase-2 activity andprotects against vascular dysfunction in diabetic ratsrdquo EuropeanJournal of Pharmacology vol 599 no 1ndash3 pp 110ndash116 2008
[127] P Lesnik C Dachet L Petit et al ldquoImpact of a combinationof a calcium antagonist and a 120573-blocker on cell- and copper-mediated oxidation of LDL and on the accumulation and effluxof cholesterol in human macrophages and murine J774 cellsrdquoArteriosclerosis Thrombosis and Vascular Biology vol 17 no 5pp 979ndash988 1997
[128] G Sobal E J Menzel and H Sinzinger ldquoCalcium antagonistsas inhibitors of in vitro low density lipoprotein oxidation andglycationrdquoBiochemical Pharmacology vol 61 no 3 pp 373ndash3792001
[129] E Lupo R Locher B Weisser and W Vetter ldquoIn vitro antiox-idant activity of calcium antagonists against LDL oxidationcompared with 120572-tocopherolrdquo Biochemical and BiophysicalResearch Communications vol 203 no 3 pp 1803ndash1808 1994
[130] J Zou Y Li H-Q Fan and J-G Wang ldquoEffects of dihydropy-ridine calcium channel blockers on oxidized low-density lipo-protein induced proliferation and oxidative stress of vascularsmooth muscle cellsrdquo BMC Research Notes vol 5 article 1682012
[131] C Napoli S Salomone T Godfraind et al ldquo14-Dihydro-pyridine calcium channel blockers inhibit plasma and LDL oxi-dation and formation of oxidation-specific epitopes in the arte-rial wall and prolong survival in stroke-prone spontaneouslyhypertensive ratsrdquo Stroke vol 30 no 9 pp 1907ndash1915 1999
[132] G Zernig I Graziadei T Moshammer C Zech N Reider andH Glossmann ldquoMitochondrial Ca2+ antagonist binding sitesare associated with an inner mitochondrial membrane anionchannelrdquo Molecular Pharmacology vol 38 no 3 pp 362ndash3691990
[133] F E Hunter Jr A Scott P E Hochstein et al ldquoStudies of themechanism of ascorbate-induced swelling and lysis of isolatedliver mitochondriardquo The Journal of Biological Chemistry vol239 pp 604ndash613 1964
[134] D R Janero B Burghardt and R Lopez ldquoProtection of cardiacmembrane phospholipid against oxidative injury by calciumantagonistsrdquoBiochemical Pharmacology vol 37 no 21 pp 4197ndash4203 1988
[135] A Karadag B Ozcelik and S S Saner ldquoReview of methods todetermine antioxidant capacitiesrdquo FoodAnalyticalMethods vol2 no 1 pp 41ndash60 2009
[136] Y I Gubskiı N V Litvinova and E V Shnurko-TabakovaldquoAntioxidant and antiradical activity of various classes of antiox-idantsrdquo Ukrainskiı Biokhimicheskiı Zhurnal vol 66 no 4 pp114ndash116 1994 (Russian)
[137] M Takei M Hiramatsu and A Mori ldquoInhibitory effects ofcalcium antagonists onmitochondrial swelling induced by lipidperoxidation or arachidonic acid in the rat brain in vitrordquoNeurochemical Research vol 19 no 9 pp 1199ndash1206 1994
[138] M Takei M Hiramatsu R Edamatsu and A Mori ldquoFreeradical scavenging by calcium antagonistsrdquo Neurosciences vol20 no 2 pp 75ndash82 1994
[139] Ya P Stradin G Ya Dubur Yu A Beilis Ya R Uldrikis andA F Korotkova ldquoVoltammetry of 14-dihydropyridine deriva-tives I Potentials of electrochemical oxidation of 35-diacyl-and 35-di(alkoxycarbonyl)-14-dihydropyridines in acetoni-trilerdquo Chemistry of Heterocyclic Compounds no 1 pp 84ndash871972 (Russian)
[140] E V Ivanov T V Ponomarjova G N Merkusev et al ldquoEinneuer Haut-Radioprotektor Diethon (experimentelle Unter-suchung)rdquo Radiobiologia Radiotherapia vol 31 no 1 pp 69ndash78 1990
[141] E V Ivanov T V Ponomareva G N Merkushev et al ldquoRadia-tion modulating properties of derivates of 14-dihydropyridineand 12345678910-decahydroacridine-18 dionerdquo Radiat-sionnaia Biologiia Radioecologiia vol 44 no 5 pp 550ndash5592004 (Russian)
[142] R O Vitolinia D A Berzinia A K Velena I A Vutsina A AKimenis and G Y Duburs ldquoThe protective effects of the cal-cium antagonist foridon in acute myocardial ischaemiardquo Kardi-ologiya vol 27 no 3 pp 90ndash93 1987 (Russian)
[143] A H Velena G Ya Duburs R O Vitolina et al ldquoEffect ofryodipine on electromechanical parameters of heart and vesselscAMP phosphodiesterase activity and swelling-contractioncycle of mitochondriardquo Arzneimittelforschung vol 35 no 6 pp907ndash914 1985
[144] L I Utno Z E Lipsberga A A Silova M I Girgensone EA Bisenieks and G I Ia ldquoCardioprotective properties of a 14-dihydropyridine derivative glutapyrone in deep hypothermiardquoBiulletenrsquo Eksperimentalrsquonoı Biologii i Meditsiny vol 108 no 11pp 558ndash561 1989 (Russian)
[145] M A S FernandesM S Santos J A F Vicente et al ldquoEffects of14-dihydropyridine derivatives (cerebrocrast gammapyroneglutapyrone and diethone) onmitochondrial bioenergetics andoxidative stress a comparative studyrdquoMitochondrion vol 3 no1 pp 47ndash59 2003
[146] M A S Fernandes M S Santos A J M Moreno et al ldquoEffectsof 5-acetyl(carbamoyl)-6-methylsulfanyl-14-dihydropyridine-5-carbonitriles on rat liver mitochondrial functionrdquo Toxicologyin Vitro vol 23 no 7 pp 1333ndash1341 2009
[147] L Klimaviciusa A Kalda A Kaasik et al ldquoNeuroprotectiveactivity of 14-dihydropyridine derivatives structure determi-nantsrdquo Proceedings of the Latvian Academy of Sciences BNatural Exact and Applied Sciences vol 61 no 1-2 pp 33ndash372007
32 Oxidative Medicine and Cellular Longevity
[148] L Klimaviciusa M A S Fernandes N Lencberga et alldquoTargeting the mitochondria by novel adamantane-containing14-dihydropyridine compoundsrdquo in Bioenergetics K B ClarkEd pp 257ndash272 InTech 2012
[149] V Klusa L Klimaviciusa G Duburs J Poikans and AZharkovsky ldquoAnti-neurotoxic effects of tauropyrone a taurineanaloguerdquo Advances in Experimental Medicine and Biology vol583 pp 499ndash508 2006
[150] N Sampson P Berger and Ch Zenzmaier ldquoRedox signalingas a therapeutic target to inhibit myofibroblast activation indegenerative fibrotic diseaserdquo BioMed Research Internationalvol 2014 Article ID 131737 14 pages 2014
[151] T L Leto and M Geiszt ldquoRole of Nox family NADPH oxidasesin host defenserdquoAntioxidantsampRedox Signaling vol 8 no 9-10pp 1549ndash1561 2006
[152] K K Griendling D Sorescu and M Ushio-Fukai ldquoNAD(P)Hoxidase role in cardiovascular biology and diseaserdquo CirculationResearch vol 86 no 5 pp 494ndash501 2000
[153] H Chen Y S Song and P H Chan ldquoInhibition of NADPHoxi-dase is neuroprotective after ischemia-reperfusionrdquo Journal ofCerebral Blood Flow and Metabolism vol 29 no 7 pp 1262ndash1272 2009
[154] P Hochstein and L Ernster ldquoADP-activated lipid peroxidationcoupled to the TPNH oxidase system of microsomesrdquo Biochem-ical and Biophysical Research Communications vol 12 no 5 pp388ndash394 1963
[155] I I Gubskiı AGGoriushkoNV Litvinova et al ldquoAntioxidantproperties and membranotropic effect of certain derivatives of14-dihydropyridinerdquo Ukrainskiı Biokhimicheskiı Zhurnal vol71 no 4 pp 35ndash39 1999 (Russian)
[156] F Engineer and R Sridhar ldquoInhibition of rat heart andliver microsomal lipid peroxidation by nifedipinerdquo BiochemicalPharmacology vol 38 no 8 pp 1279ndash1285 1989
[157] T Goncalves A P Carvalho and C R Oliveira ldquoAntioxidanteffect of calcium antagonists on microsomai membranes iso-lated from different brain areasrdquo European Journal of Pharma-cology vol 204 no 3 pp 315ndash322 1991
[158] M E Letelier P Izquierdo L Godoy A M Lepe and MFaundez ldquoLiver microsomal biotransformation of nitro-aryldrugs mechanism for potential oxidative stress inductionrdquoJournal of Applied Toxicology vol 24 no 6 pp 519ndash525 2004
[159] M E Letelier P Entrala C Lopez-Alarcon et al ldquoNitroaryl-14-dihydropyridines as antioxidants against rat liver microsomesoxidation induced by ironascorbate Nitrofurantoin and naph-thalenerdquo Toxicology in Vitro vol 21 no 8 pp 1610ndash1618 2007
[160] F P Guengerich W R Brian M Iwasaki M-A Sari CBaarnhielm and P Berntsson ldquoOxidation of dihydropyridinecalcium channel blockers and analogues by human liver cyto-chrome P-450 IIIA4rdquo Journal of Medicinal Chemistry vol 34no 6 pp 1838ndash1844 1991
[161] S H Park S-W RhaW-Y Shin et al ldquoAS-160 Calcium channelblockers of dihydropyridine class reduce the antiplatelet effectof Clopidogrel what is clinical impactrdquo The American Journalof Cardiology vol 107 no 8 supplement p 47A 2011
[162] C Asma and D M Reda ldquoEvaluation of dihydropyridinecalcium antagonist effects on the stress bioindicator orga-nism Saccharomyces cerevisiaerdquo Annals of Biological Researchvol 4 no 10 pp 40ndash46 2013 httpscholarsresearchlibrarycomABR-vol4-iss10ABR-2013-4-10-40-46pdf
[163] G Gaviraghi A M Pastorino E Ratti and D G TristldquoCalcium channel blockers with antioxidant activityrdquo in Free
Radicals Lipoprotein Oxidation andAtherosclerosis G BellomoG Finardi E Maggi and E Rice-Evans Eds pp 431ndash456Richelieu Press London UK 1995
[164] G Gaviraghi AM Pastorino E Ratti and D G Trist ldquoAntiox-idant dihydropyridines a new and comprehensive therapy forfree radical-induced cardiovascular diseasesrdquo in Free Radicalsin Biology and Environment F Minisci Ed vol 27 of NATOASI Series pp 193ndash221 Springer Dordrecht The Netherlands1997
[165] P D Henry ldquoAntiperoxidative actions of calcium antagonistsand atherogenesisrdquo Journal of Cardiovascular Pharmacologyvol 18 supplement 1 pp S6ndashS10 1991
[166] F Kouoh B Gressier T Dine et al ldquoAntioxidant effects andanti-elastase activity of the calcium antagonist nicardipine onactivated human and rabbit neutrophilsmdasha potential antiath-erosclerotic property of calcium antagonistsrdquo CardiovascularDrugs andTherapy vol 16 no 6 pp 515ndash520 2002
[167] S Parthasarathy D Litvinov K Selvarajan and M GarelnabildquoLipid peroxidation and decompositionmdashconflicting roles inplaque vulnerability and stabilityrdquo Biochimica et BiophysicaActa vol 1781 no 5 pp 221ndash231 2008
[168] D-Q Liu Z-Q Pang D-H Zhao and B-H Sheng ldquoEffects offuryl-dihydropyridines I on lipid peroxides of ischemic myo-cardium and ATPases activity of erythrocyte membranes inratsrdquo Acta Pharmacologica Sinica vol 12 no 3 pp 253ndash2561991
[169] V Lukic-Panin T Kamiya H Zhang et al ldquoPrevention of neu-ronal damage by calcium channel blockers with antioxidativeeffects after transient focal ischemia in ratsrdquo Brain Research vol1176 no 1 pp 143ndash150 2007
[170] Y Allanore D Borderie H Lemarechal O G Ekindjian andA Kahan ldquoAcute and sustained effects of dihydropyridine-typecalcium channel antagonists on oxidative stress in systemicsclerosisrdquo American Journal of Medicine vol 116 no 9 pp 595ndash600 2004
[171] I Casetta V Govoni and E Granieri ldquoOxidative stress antioxi-dants and neurodegenerative diseasesrdquo Current PharmaceuticalDesign vol 11 no 16 pp 2033ndash2052 2005
[172] M J T J Arts Assessing antioxidant activity [PhD the-sis] Maastricht University Maastricht The Netherlands 2007httparnounimaasnlshowcgifid=8676
[173] G Dıaz-Araya L Godoy L Naranjo A Squella M E Letelierand L J Nunez-Vergara ldquoAntioxidant effects of 14-dihydro-pyridine and nitroso aryl derivatives on the Fe+3ascorbate-stimulated lipid peroxidation in rat brain slicesrdquo General Phar-macology The Vascular System vol 31 no 3 pp 385ndash391 1998
[174] Y Fukuhara K Tsuchiya Y Horinouchi et al ldquoProtectiveeffect of photodegradation product of nifedipine against tumornecrosis factor 120572-induced oxidative stress in human glomerularendothelial cellsrdquo Journal of Medical Investigation vol 58 no1-2 pp 118ndash126 2011
[175] W Stengel M Jainz and K Andreas ldquoDifferent potencies ofdihydropyridine derivatives in blocking T-type but not L-typeCa2+ channels in neuroblastoma-glioma hybrid cellsrdquo EuropeanJournal of Pharmacology vol 342 no 2-3 pp 339ndash345 1998
[176] O M Panasenko D J Tirzite G D Tirzitis and G J DubursldquoEffect of some 14-dihydropyridine derivatives on structuralorganization of erythrocyte membranesrdquo Biologicheskie Mem-brany (Biochemistry (Moscow) Series A Membrane and CellBiology) vol 1 pp 919ndash925 1984 (Russian)
[177] L G Herbette Y M H Vant Erve and D G Rhodes ldquoInter-action of 14 dihydropyridine calcium channel antagonists with
Oxidative Medicine and Cellular Longevity 33
biological membranes lipid bilayer partitioning could occurbefore drug binding to receptorsrdquo Journal of Molecular andCellular Cardiology vol 21 no 2 pp 187ndash201 1989
[178] L G Herbette P E Mason G Gaviraghi T N Tulenko andR P Mason ldquoThe molecular basis for lacidipinersquos unique phar-macokinetics optimal hydrophobicity results in membraneinteractions that may facilitate the treatment of atherosclerosisrdquoJournal of Cardiovascular Pharmacology vol 23 supplement 5pp S16ndashS25 1994
[179] G V Belevitch G Y Dubur G E Dobretsov N K Kurek andM M Spirin ldquoCalcium antagonists riodipine nifedipine andverapamil binding to model and biological membranes fluore-scence analysisrdquo Biologicheskie Membrany (Biochemistry(Moscow) Series A Membrane and Cell Biology) vol 5 pp768ndash776 1988 (Russian)
[180] R P Mason G E Gonye D W Chester and L G HerbetteldquoPartitioning and location of Bay K 8644 14-dihydropyridinecalcium channel agonist in model and biological membranesrdquoBiophysical Journal vol 55 no 4 pp 769ndash778 1989
[181] M Cindric A Cipak J Serly et al ldquoReversal of multidrugresistance inmurine lymphoma cells by amphiphilic dihydropy-ridine antioxidant derivativerdquo Anticancer Research vol 30 no10 pp 4063ndash4070 2010
[182] F Shekari H Sadeghpour K Javidnia et al ldquoCytotoxic andmultidrug resistance reversal activities of novel 14-dihydro-pyridines against human cancer cellsrdquo European Journal ofPharmacology vol 746 no 1 pp 233ndash244 2015
[183] X-F Zhou Q Shao R A Coburn and M E Morris ldquoQuanti-tative structure-activity relationship and quantitative structure-pharmacokinetics relationship of 14-dihydropyridines andpyridines as multidrug resistance modulatorsrdquo PharmaceuticalResearch vol 22 no 12 pp 1989ndash1996 2005
[184] R Berkels T Breitenbach H Bartels et al ldquoDifferent antioxida-tive potencies of dihydropyridine calcium channel modulatorsin various modelsrdquo Vascular Pharmacology vol 42 no 4 pp145ndash152 2005
[185] S Borovic G Tirzitis D Tirzite et al ldquoBioactive 14-dihydro-isonicotinic acid derivatives prevent oxidative damage of livercellsrdquo European Journal of Pharmacology vol 537 no 1ndash3 pp12ndash19 2006
[186] D Ya Rubene G D Tirzitis and G Ya Duburs ldquoInteractionof some 14-dihydropyridine derivatives with Fentonrsquos reagentrdquoLatvijas PSRZinatnuAkademijas Vestis Kimijas Serija Proceed-ings of the Latvian SSR Academy of Sciences Chemistry Seriespp 212ndash216 1982 (Russian)
[187] K Ondrias V Misık D Gergel and A Stasko ldquoLipid per-oxidation of phosphatidylcholine liposomes depressed by thecalcium channel blockers nifedipine and verapamil and bythe antiarrhythmic-antihypoxic drug stobadinerdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1003 no 3pp 238ndash245 1989
[188] I T Mak and W B Weglicki ldquoComparative antioxidant acti-vities of propranolol nifedipine verapamil and diltiazemagainst sarcolemmal membrane lipid peroxidationrdquoCirculationResearch vol 66 no 5 pp 1449ndash1452 1990
[189] I T Mak P Boehme and W B Weglicki ldquoProtective effects ofcalcium channel blockers against free radical-impaired endo-thelial cell proliferationrdquo Biochemical Pharmacology vol 50 no9 pp 1531ndash1534 1995
[190] S Ray S Mondal and N Dana ldquoEvaluation of protective roleof nifedipine on lipid peroxidation using reduced glutathione as
model markerrdquo Oxidants and Antioxidants in Medical Sciencevol 1 no 2 pp 97ndash100 2012
[191] M Yamato T Shiba T Ide Y Honda K-I Yamada andH Tsutsui ldquoNifedipine treatment reduces brain damage aftertransient focal ischemia possibly through its antioxidativeeffectsrdquoHypertension Research vol 34 no 7 pp 840ndash845 2011
[192] V Chander and K Chopra ldquoNifedipine attenuates changes innitric oxide levels renal oxidative stress and nephrotoxicityinduced by cyclosporinerdquo Renal Failure vol 27 no 4 pp 441ndash450 2005
[193] K M Gaafa M M Badawy and A A Hamza ldquoThe protectiveeffects of ascorbic acid cimetidine and nifedipine on diethyl-dithiocarbamate-induced hepatic toxicity in albino ratsrdquo Drugand Chemical Toxicology vol 34 no 4 pp 405ndash419 2011
[194] H Sugawara K Tobise and S Onodera ldquoAbsence of antiox-idant effects of nifedipine and diltiazem on myocardial mem-brane lipid peroxidation in contrast with those of nisoldipineand propranololrdquo Biochemical Pharmacology vol 47 no 5 pp887ndash892 1994
[195] I E Kirule D Y Rubene E A Bisenieks G D Tirzit and GY Dubur ldquo4-Nitrophenyl-14-dihydropyridinesmdasha new groupof inhibitors of peroxide oxidationrdquo Chemistry of HeterocyclicCompounds vol 18 no 3 p 316 1982
[196] G D Tirzit I E Kirule L K Baumane R A Gavar Y PStradynrsquo andG YDubur ldquoMechanism of the antioxidant actionof 26-dimethyl-35-dimethoxy-carbonyl-4-(2-nitrophenyl)14-dihydropyridinerdquoChemistry ofHeterocyclic Compounds vol 20no 8 pp 915ndash918 1984
[197] C Yanez C Lopez-Alarcon C Camargo V Valenzuela J ASquella and L J Nunez-Vergara ldquoStructural effects on thereactivity 14-dihydropyridines with alkylperoxyl radicals andABTS radical cationrdquo Bioorganic and Medicinal Chemistry vol12 no 9 pp 2459ndash2468 2004
[198] VMisik A J Stasko D Gergel and K Ondrias ldquoSpin-trappingand antioxidant properties of illuminated and nonilluminatednifedipine and nimodipine in heart homogenate and modelsystemrdquo Molecular Pharmacology vol 40 no 3 pp 435ndash4391991
[199] K Ondrias V Misık A Stasko D Gergelrsquo and M HromadovaldquoComparison of antioxidant properties of nifedipine and illu-minated nifedipine with nitroso spin traps in low densitylipoproteins and phosphatidylcholine liposomesrdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1211 no 1pp 114ndash119 1994
[200] A Stasko V Brezova S Biskupic K Ondrias and V MisıkldquoReactive radical intermediates formed from illuminated nife-dipinerdquoFree Radical Biology andMedicine vol 17 no 6 pp 545ndash556 1994
[201] K Ishizawa Y Izawa-Ishizawa N Yamano et al ldquoNitrosoni-fedipine ameliorates the progression of type 2 diabetic nephro-pathy by exerting antioxidative effectsrdquo PLoS ONE vol 9 no 1Article ID e86335 2014
[202] H Fujii and L J Berliner ldquoIn vivo EPR evidence for free radicaladducts of nifedipinerdquoMagnetic Resonance in Medicine vol 42no 4 pp 691ndash694 1999
[203] S Bollo S Finger J C Sturm L J Nunez-Vergara and JA Squella ldquoCyclic voltammetry and scanning electrochemicalmicroscopy studies of the heterogeneous electron transferreaction of some nitrosoaromatic compoundsrdquo ElectrochimicaActa vol 52 no 15 pp 4892ndash4898 2007
34 Oxidative Medicine and Cellular Longevity
[204] F Ursini ldquoTissue protection by lacidipine insight from redoxbehaviorrdquo Journal of Cardiovascular Pharmacology vol 30supplement 2 pp S28ndashS30 1997
[205] P G Cristofori F A Crivellente I Faustinelli et al ldquoInvolve-ment of the nitric oxide system in the anti-atheroscleroticpotential of lacidipine in the apoE-deficient mouse a mor-phological functional and electrochemical studyrdquo ToxicologicPathology vol 32 no 4 pp 493ndash499 2004
[206] X-P Zhang E L Kit S Mital S Chahwala and T HHintze ldquoParadoxical release of nitric oxide by an L-type calciumchannel antagonist the R+ enantiomer of amlodipinerdquo Journalof Cardiovascular Pharmacology vol 39 no 2 pp 208ndash2142002
[207] F Franzoni G Santoro F Regoli et al ldquoAn in vitro study of theperoxyl and hydroxyl radical scavenging capacity of the calciumantagonist amlodipinerdquo Biomedicine and Pharmacotherapy vol58 no 8 pp 423ndash426 2004
[208] S V Gatsura ldquoOxygen-dependent mechanisms underlying theantiischemic effect of verapamil and amlodipinerdquo Bulletin ofExperimental Biology and Medicine vol 137 no 1 pp 40ndash422004
[209] Y Hirooka Y Kimura M Nozoe Y Sagara K Ito and KSunagawa ldquoAmlodipine-induced reduction of oxidative stressin the brain is associated with sympatho-inhibitory effects instroke-prone spontaneously hypertensive ratsrdquo HypertensionResearch vol 29 no 1 pp 49ndash56 2006
[210] B Tomlinson and I F F Benzie ldquoAntioxidant effect of lercani-dipine (note)rdquo Hypertension vol 42 no 4 pp e10ndashe11 2003
[211] A A Faraqui ldquoNeurochemical aspects of 4-hydroxynonenalrdquoin Lipid Mediators and Their Metabolism in the Brain A AFaraqui Ed chapter 6 pp 159ndash191 Springer New York NYUSA 2011
[212] V S NascimentoM S DrsquoAlva A AOliveira et al ldquoAntioxidanteffect of nimodipine in young rats after pilocarpine-inducedseizuresrdquo Pharmacology Biochemistry and Behavior vol 82 no1 pp 11ndash16 2005
[213] O Ismailoglu P Atilla S Palaoglu et al ldquoThe therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjuryrdquo Turkish Neurosurgery vol 22 no 6 pp 740ndash746 2012
[214] M Matsubara and K Hasegawa ldquoBenidipine a dihydropy-ridine-calcium channel blocker prevents lysophosphatidyl-choline-induced injury and reactive oxygen species productionin human aortic endothelial cellsrdquo Atherosclerosis vol 178 no1 pp 57ndash66 2005
[215] M Matsubara K Yao and K Hasegawa ldquoBenidipine adihydropyridine-calcium channel blocker inhibits lysophos-phatidylcholine-induced endothelial injury via stimulation ofnitric oxide releaserdquo Pharmacological Research vol 53 no 1 pp35ndash43 2006
[216] MMatsubara and K Hasegawa ldquoEffects of benidipine a dihyd-ropyridine-Ca2+ channel blocker on expression of cytokine-induced adhesion molecules and chemoattractants in humanaortic endothelial cellsrdquo European Journal of Pharmacology vol498 no 1ndash3 pp 303ndash314 2004
[217] M Matsubara O Akizuki J-I Ikeda K Saeki K Yao and KSasaki ldquoBenidipine an anti-hypertensive drug inhibits reactiveoxygen species production in polymorphonuclear leukocytesand oxidative stress in salt-loaded stroke-prone spontaneouslyhypertensive ratsrdquo European Journal of Pharmacology vol 580no 1-2 pp 201ndash213 2008
[218] A C Rosenkranz H Lob T Breitenbach R Berkels and RRoesen ldquoEndothelial antioxidant actions of dihydropyridines
and angiotensin converting enzyme inhibitorsrdquo European Jour-nal of Pharmacology vol 529 no 1ndash3 pp 55ndash62 2006
[219] V Kain S Kumar and S L Sitasawad ldquoAzelnidipine preventscardiac dysfunction in streptozotocin-diabetic rats by reducingintracellular calcium accumulation oxidative stress and apop-tosisrdquo Cardiovascular Diabetology vol 10 article 97 2011
[220] K Nakamura S Yamagishi and H Inoue ldquoUnique atheropro-tective property of azelnidipine a dihydropyridine-based cal-cium antagonistrdquoMedical Hypotheses vol 65 no 1 pp 155ndash1572005
[221] TMatsui S Yamagishi K Nakamura S Kikuchi andH InoueldquoAzelnidipine a dihydropyridine-based calcium antagonistinhibits angiotensin II-induced oxidative stress generation anddownregulation of pigment epithelium-derived factor mRNAlevels in microvascular endothelial cellsrdquo Drugs under Experi-mental and Clinical Research vol 31 no 5-6 pp 215ndash219 2005
[222] C Ohmura H Watada T Shimizu et al ldquoCalcium channelblocker azelnidipine reduces lipid hydroperoxides in patientswith type 2 diabetes independent of blood pressurerdquo EndocrineJournal vol 54 no 5 pp 805ndash811 2007
[223] H Daikuhara F Kikuchi and T Ishida ldquoThe combination ofOLmesartan and a CAlcium channel blocker (azelnidipine) orcandesartan and a calcium channel blocker (amlodipine) intype 2 diabetic hypertensive patients theOLCA studyrdquoDiabetesand Vascular Disease Research vol 9 no 4 pp 280ndash286 2012
[224] MAbe NMaruyama KOkada SMatsumoto KMatsumotoand M Soma ldquoAdditive antioxidative effects of azelnidipine onangiotensin receptor blocker olmesartan treatment for type 2diabetic patients with albuminuriardquoHypertension Research vol34 no 8 pp 935ndash941 2011
[225] K Mizushige ldquoAntioxidative activities of thiazolidinedionesand dihydropyridine-type calcium antagonistsrdquo IRYOmdashJapa-nese Journal of National Medical Services vol 59 no 11 pp 581ndash592 2005
[226] S Manabe T Okura T Fukuoka and J Higaki ldquoAntioxidativeeffects of azelnidipine on mesangial cell proliferation inducedby highly concentrated insulinrdquo European Journal of Pharma-cology vol 567 no 3 pp 252ndash257 2007
[227] Y Koyama Y Takeishi H Takahashi et al ldquoAzelnidipine inhi-bits H
2O2-induced cell death in neonatal rat cardiomyocytesrdquo
CardiovascularDrugs andTherapy vol 21 no 1 pp 69ndash72 2007[228] K Shinomiya K Mizushige M Fukunaga et al ldquoAntioxidant
effect of a new calcium antagonist azelnipidine in culturedhuman arterial endothelial cellsrdquo Journal of International Med-ical Research vol 32 no 2 pp 170ndash175 2004
[229] T Ohyama K Sato K Kishimoto et al ldquoAzelnidipine is acalcium blocker that attenuates liver fibrosis and may increaseantioxidant defencerdquo British Journal of Pharmacology vol 165no 4 pp 1173ndash1187 2012
[230] L A Calo F Zaghetto E Pagnin P A Davis A Sempliciniand A C Pessina ldquoEffect of manidipine on gene expressionand protein level of oxidative stress-related proteins p22phoxand HO-1 Relevance for antihypertensive and anti-remodelingeffectsrdquo Journal of Cardiovascular Pharmacology vol 43 no 4pp 531ndash538 2004
[231] R Ghyasi G Sepehri M Mohammadi R Badalzadeh and AGhyasi ldquoEffect of mebudipine on oxidative stress and lipid per-oxidation in myocardial ischemic-reperfusion injury in maleratrdquo Journal of Research in Medical Sciences vol 17 no 12 pp1150ndash1155 2012
Oxidative Medicine and Cellular Longevity 35
[232] DCAndersson J Fauconnier T Yamada et al ldquoMitochondrialproduction of reactive oxygen species contributes to the 120573-adrenergic stimulation of mouse cardiomycytesrdquoThe Journal ofPhysiology vol 589 no 7 pp 1791ndash1801 2011
[233] A F Ceylan-Isik N Ari M Stefek et al ldquoEffects of a long-term treatment with an antioxidant pyridoindole on vascularresponsiveness in diabetes-induced aging ratsrdquo Current AgingScience vol 4 no 2 pp 150ndash157 2011
[234] S Saponara G Sgaragli and F Fusi ldquoQuercetin antagonismof Bay K 8644 effects on rat tail artery L-type Ca2+ channelsrdquoEuropean Journal of Pharmacology vol 598 no 1ndash3 pp 75ndash802008
[235] D A Sica ldquoInteraction of grapefruit juice and calcium channelblockersrdquo American Journal of Hypertension vol 19 no 7 pp768ndash773 2006
[236] P Mulder G Litwinienko S Lin P D MacLean L R CBarclay and K U Ingold ldquoThe L-type calcium channel block-ers Hantzsch 14-dihydropyridines are not peroxyl radical-trapping chain-breaking antioxidantsrdquo Chemical Research inToxicology vol 19 no 1 pp 79ndash85 2006
[237] L J Nunez-Vergara R Salazar C Camargo et al ldquoOxidation ofC4-hydroxyphenyl 14-dihydropyridines in dimethylsulfoxideand its reactivity towards alkylperoxyl radicals in aqueousmediumrdquo Bioorganic and Medicinal Chemistry vol 15 no 12pp 4318ndash4326 2007
[238] M E Ortiz L J Nunez-Vergara and J A Squella ldquoRelativereactivity of dihydropyridine derivatives to electrogeneratedsuperoxide ion in DMSO solutions a voltammetric approachrdquoPharmaceutical Research vol 20 no 2 pp 292ndash296 2003
[239] M E Ortiz L J Nunez-Vergara C Camargo and J A SquellaldquoOxidation of Hantzsch 14-dihydropyridines of pharmacolog-ical significance by electrogenerated superoxiderdquo Pharmaceuti-cal Research vol 21 no 3 pp 428ndash435 2004
[240] R S Raghuvanshi and K N Singh ldquoSuperoxide induced oxida-tive aromatization of Hantzsch 14-dihydropyridinesrdquo IndianJournal of Chemistry Section B Organic and Medicinal Chem-istry vol 47 no 11 pp 1735ndash1738 2008
[241] I Kruk A Kladna K Lichszteld et al ldquoAntioxidant activityof 4-flavonil-14-dihydropyridine derivativesrdquo Biopolymers vol62 no 3 pp 163ndash167 2001
[242] G D Tirzit I M Byteva K I Salokhiddinov G P Gurinovichand G Y Dubur ldquo14-Dihydropyridine derivatives as deactiva-tors of singlet oxygenrdquo Chemistry of Heterocyclic Compoundsvol 17 no 7 pp 682ndash684 1981
[243] G D Tirzit E Y Kazush and G Y Dubur ldquoInfluence of14-dihydropyridine derivatives on the generation of hydroxylradicalsrdquo Chemistry of Heterocyclic Compounds vol 28 no 4pp 435ndash437 1992
[244] N A Pizarro-Urzua and L J Nunez-Vergara ldquoNifedipine andnitrendipine reactivity toward singlet oxygenrdquo Journal of Photo-chemistry and Photobiology A Chemistry vol 175 no 2-3 pp129ndash137 2005
[245] L-F Wang H-Y Zhang L Konga Z-W Chena and J-G ShildquoDFT calculations indicate that 14-dihydropyridine is a promis-ing lead antioxidantrdquo Helvetica Chimica Acta vol 87 no 6 pp1515ndash1521 2004
[246] P Mulder H-G Korth and K U Ingold ldquoWhy quantum-thermochemical calculations must be used with caution toindicate lsquoa promising lead antioxidantrsquordquoHelvetica Chimica Actavol 88 no 2 pp 370ndash374 2005
[247] K Yao Y Ina K Nagashima K Ohmori and T Ohno ldquoAntiox-idant effects of calcium antagonists in rat brain homogenatesrdquo
Biological and Pharmaceutical Bulletin vol 23 no 6 pp 766ndash769 2000
[248] T Matsui S-I Yamagishi K Nakamura and H Inoue ldquoBayw 9798 a dihydropyridine structurally related to nifedipinewith no calcium channel-blocking properties inhibits tumournecrosis factor-120572-induced vascular cell adhesion molecule-1expression in endothelial cells by suppressing reactive oxygenspecies generationrdquo Journal of International Medical Researchvol 35 no 6 pp 886ndash891 2007
[249] K AMitrega B VargheseM Porc and T F Krzeminski ldquoAnti-arrhythmic and hemodynamic effects of oxy nifedipine oxynimodipine oxy nitrendipine and oxy nisoldipinerdquo Pharmaco-logical Research vol 66 no 4 pp 300ndash308 2012
[250] V Herbert ldquoSymposium prooxidant effects of antioxidantvitamins Introductionrdquo The Journal of Nutrition vol 126 no4 supplement pp 1197Sndash1200S 1996 httpjnnutritionorgcontent1264 Suppl1197Sfullpdf
[251] B Halliwell ldquoAre polyphenols antioxidants or pro-oxidantsWhat do we learn from cell culture and in vivo studiesrdquoArchives of Biochemistry and Biophysics vol 476 no 2 pp 107ndash112 2008
[252] C Winterbourn Pro-Oxidants or Antioxidants ChristchurchSchool of Medicine Depatment of Pathology Free RadicalSchool SFRBMUniversity of Otago San Francisco Calif USA2009 httpwwwsfrbmorgfrsWinterbournpdf
[253] A Morakinyo B Iranloye and O Adegoke ldquoCalcium antag-onists modulate oxidative stress and acrosomal reaction in ratspermatozoardquo Archives of Medical Science vol 7 no 4 pp 613ndash618 2011
[254] The Alpha-Tocopherol Beta Carotene Cancer Prevention StudyGroup ldquoThe effect of vitamin E and beta carotene on theincidence of lung cancer and other cancers in male smokersrdquoTheNew England Journal of Medicine vol 330 no 15 pp 1029ndash1035 1994
[255] B Poljsak ldquoStrategies for reducing or preventing the generationof oxidative stressrdquo Oxidative Medicine and Cellular Longevityvol 2011 Article ID 194586 15 pages 2011
[256] B Poljsak and I Milisav ldquoThe neglected significance of lsquoanti-oxidative stressrsquordquoOxidativeMedicine and Cellular Longevity vol2012 Article ID 480895 12 pages 2012
[257] T Godfraind and S Salomone ldquoAmbiguities in dietary antiox-idant supplementation compared to calcium channel blockerstherapyrdquo Frontiers in Pharmacology vol 6 article 10 2015
[258] H Wagner H Norr and H Winterhoff ldquoDrugs with adap-togenic effects for strengthening the powers of resistancerdquoZeitschrift fur Phytotherapie vol 13 no 2 pp 42ndash54 1992
22 Oxidative Medicine and Cellular Longevity
ability Furthermore it has been recently found that serumlevels of monocyte chemoattractant protein-1 a biomarkerfor subclinical atherosclerosis were significantly decreased bythe AZL treatment in patients with essential hypertension Inthis paper [220] authors hypothesize that due to its uniqueTNF-120572 signalmodulatory activity and antioxidative propertyazelnidipine may be a promising DHP for targeting diabetesand cardiovascular diseases in hypertensive patients withmetabolic syndrome
Shinomiya et al [228] evaluated its AOA in culturedhuman arterial EC under OS Azelnidipine has shown apotent antioxidative effect that could be of significant clinicalbenefit when combined with its long-lasting antihypertensiveaction and low incidence of tachycardia
Azelnidipine inhibited TGF-1205731 and angiotensin II- (AngII-) activated 1205721(I) collagen mRNA expression in hepaticstellate cells (HSCs) (Ohyama et al [229]) FurthermoreTGF-1205731- and Ang II-induced OS and TGF-1205731-induced p38and JNK phosphorylation were reduced inHSCs treated withAZL Azelnidipine significantly decreased inflammatory cellinfiltration profibrotic genes expression HSC activation LPoxidative DNA damage and fibrosis in liver of CCl
4- or
TAA-treated mice Finally AZL prevented decrease of theexpression of some AO enzymes and accelerated regressionof liver fibrosis in CCl
4-treated mice Hence the antifibrotic
mechanism of AZL against CCl4-induced liver fibrosis in
mice may have been due to an increased level of AO defenseAs azelnidipine is widely used in clinical practice withoutserious adverse effects it may provide an effective newstrategy for antifibrotic therapy
358 Manidipine Manidipine (2-[4-(diphenylmethyl)pip-erazin-1-yl]ethyl methyl 26-dimethyl-4-(3-nitrophenyl)-14-dihydropyridine-35-dicarboxylate) is a DHP CCB withreported nephroprotective properties Calo et al [230] stud-ied effect of manidipine on gene expression and proteinlevel of OS related proteins p22(phox) (human neutrophilcytochrome b light chain (CYBA)) and heme oxygenase-1HO-1 Relevance for antihypertensive effects was revealedThe study assessed the effect of manidipine on normalsubjectsrsquo monocyte gene and protein expression of OS relatedproteins such as p22phox a NADPH oxidase system subunitcritical in generating O
2
∙minus and HO-1 induced by and pro-tective against OS Manidipine was compared with the ACEinhibitor captopril and the CCB nifedipine in the presenceand in the absence of sodiumarsenite (NaAsO
2) as an inducer
of OS Monocyte p22phox (CYBA) mRNA production wasreduced by both manidipine and captopril while no changeswere induced by nifedipine Manidipine increased monocyteHO-1 mRNA production while nifedipine and captoprilshowed no effect The effects of manidipine on p22phoxand HO-1 gene expression in the presence of OS were alsoconfirmed at the protein level Thus manidipine seems tosuppress p22phox and to increase the HO-1 mRNA produc-tion and protein level The manidipine-induced increase ofHO-1 gene and protein expression seems to be a peculiareffect of this drug since it is not observed with captopriland nifedipine This effect together with the reduction of
p22phoxmRNAproduction could play a role in its protectivemechanism against OS
359 Mebudipine The protective effect of mebudipine (14-dihydro-26-dimethyl-4-(3-nitrophenyl)-35-pyridinedicar-boxylic acid 3-methyl-5-tert-butyl ester BAY-n-6391) wasrevealed on OS and LP (MDA decrease SOD GPX andcatalase increase) in myocardial ischemic-reperfusion injuryin male rats (Ghyasi et al [231])
There are articles about other commercial and experi-mental DHPs on OS but we have reviewed only the mostcommonly studied compounds Effects of other commercialCA DHPs on OS are also mentioned in several parts of thisreview
36 14-DHPs Ca Agonists andTheir AOA and ARA For themost popular calcium agonist DHP Bay K 8644 no reactionwith peroxyl radicals was registered (Toniolo et al [114])However interactionwith other compounds possessing AOAand ARA (quercetin) was found
Opposite to that AON-acetylcysteine (NAC) diminishedincrease in Ca2+ transient amplitude and cell shorteninginduced by ISO and forskolin whereas NAC had no effecton the (S)-(minus)-methyl-14-dihydro-26-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylatemdash(minus)-BayK 8644-induced increases (Andersson et al [232])
Increased vasoconstriction responses to Bay K 8644 (3 times10minus7ndash3times 10minus5M)were significantly decreased by pyridoindoleantioxidant stobadine treatment in diabetes (Ceylan-Isik etal [233])
The functional interaction between two L-type Ca2+channel activators quercetin and Bay K 8644 has beeninvestigated in vascular smooth muscle cells Biological ARAcompound quercetin at nutritionally meaningful concen-trations limited the responsiveness of vascular L-type Ca2+channels to the pharmacological stimulation operated by BayK 8644 These data contribute to a better understanding ofquercetin effects on experimental in vivo cardioprotection(Saponara et al [234]) Thus these findings indicated thatalthough Bay K 8644 does not exert potent and direct AOAyet acting as calcium agonist it may affect efficiency of AOsubstances and vice versa
Interaction of grapefruit juice (containing quercetin andits analogues) with DHPs CA diminished effectiveness of CAaction of DHPs (Sica [235])
37 Interpretations of the Mechanism(s) of RadicalScavenging and AOA by DHPs
371 Molecular Mechanism(s) of Radical Scavenging andAOA of DHPs in the Model Systems 35-Dicarbonyl-14-di-hydropyridine derivatives possess powerful bis-120573-carbony-lvinyl-amino conjugation and for that reason cannot be con-sidered as ordinary amino antioxidants The electron andorH donation from DHPs ensures their reductant role andresults in AOA and ARA Oxidation reaction from DHPsresults in production of corresponding heteroaromatic pyri-dine derivatives
Oxidative Medicine and Cellular Longevity 23
Detailed studies were made about substituent in DHPring positions 14- namely 4-unsubstituted- 4-substituted4-alkyl- 4-aryl- 4-alkylaryl- ao 26- 35- (diacetyl ordialkoxycarbonyl chain ao) electronic and steric effects onAOA and ARA of DHPs [44 45 51] see Sections 331and 35 The bell-shaped dependence of DHPs AOA onthe 35-dialkoxycarbonyl- chain length was observed [4445 107 109 112] with the maximum activity at C
2H5ndash
C4H9 Decrease of AOA and incorporation into liposomes for
DHPs with alkyl chains longer than R gt C4H9further were
clarified as probable tendency to self-aggregation of thesecompounds ([51] and citation number 245 therein) Electronacceptorelectron donor properties are relevant for expres-sion of AOA or ARA of 35-disubstituted DHPs 35-Diacyl-substituted and 35-dicarbanilido- and 35-dipyridylamido-substituted DHPs are more active as AOs as their 35-dicyano-substituted analogues which have electron acceptorproperties [186]
Dubur et al [89] observed overwhelming steric influenceof substituents in position 4 of the DHP ring Gaviraghiet al [163 164] proposed that AO activity of DHPs ispartly dependent on capacity of the 14-DHP ring to donateelectrons to the propagating radical (ROO∙ or RO∙) and toreduce it to a less reactive form The abstraction (donation)of electron andor H in the oxidation and LP reactionstakes place from all 35-dicarbonyl-14-DHP systems andresults in the formation of corresponding pyridine derivatives(Augustyniak et al [51]) The physicochemical mechanism ofARA and AOA of 14-DHP has been extensively studied anddiscussed (Mulder et al [236]) but precise mechanisms oftheir activity need further clarification
The reactivity of C-4 substituted 14-DHPs possessingeither secondary or tertiary nitrogen atom in the DHP ringtoward alkyl alkylperoxyl radicals and ABTS radical cationwas determined in aqueous media at pH 74 [103] Thesecompounds reacted faster toward alkylperoxyl radicals andABTS radical cation than alkyl ones N-Ethyl-substitutedDHPs showed the lowest reactivity
The 4-methyl substituted DHP was the most reac-tive compound in previously mentioned reactions (Lopez-Alarcon et al [103]) However it was less active (068versus 10) than Trolox-C DHPs having electron-donatingsubstituents (4-Me-DHP and p-MeO-Phe-DHP) showed thehighest kinetic rate constants toward ABTS radical cation p-nitro-Phe-DHP a compound with an electron-withdrawingsubstituent showed a lower kinetic rate constant and N-alkyl-DHP compounds show kinetic rate constants lowerthan the -NH-DHP
Hydrogen at the 1-position of the DHP ring was revealedaccording to the deuteriumkinetic isotope effect studies to beinvolved in the proposedARAmechanismThis fact ismostlynoticeable in the case of alkyl radicals N-Ethyl-substitutedDHPs show the lowest reactivity when compared to Troloxor nisoldipine In all cases the respective pyridine derivativewas detected as the main product of the reaction (Lopez-Alarcon et al [103]) Authors indicate that the kinetic rateconstants toward alkyl alkylperoxyl andABTS radical cationdepend on the nature of the substituents in the C-4 positionof DHP and the presence of the secondary amine group in the
dihydropyridine ring that is the presence of the hydrogen in1-position
Yanez et al [197] have studied the reactivity of 11derivatives of 14-DHPs (including commercial CA) withalkylperoxyl radicals and ABTS radical cation The tested14-DHPs were 83-fold more reactive towards alkylperoxylradicals than to the ABTS cation radical All commercial14-DHP type CCBs were weaker than Trolox-C The par-ticipation of the hydrogen atom in the 1-position appearsto be very relevant for exhibited reactivity Hantzsch ester(diludine)was again found to be themost active compound inthe reaction with alkylperoxyl radicals 23-fold more activethan Trolox The photodegradation product of nifedipine(nitrosophenyl derivative of pyridine) also showed a highactivity Kinetic rate constants for the reaction between 14-DHP compounds and alkylperoxyl radicals exhibited a fairlygood linear correlation with the oxidation peak potentialof DHP derivatives However the activity of tested 14-DHPs towards ABTS radical cation showed an independencebetween kinetic rate constants and oxidation peak potentials
Kirule et al [195] andTirzit et al [196] studiedmechanismof AOA of 4-nitrophenyl-14-DHPs nifedipine and its ana-logues involving formation of 4-(21015840-nitrosophenyl)-pyridinederivative (as active principle) as a result of intramolecularredox reaction using chemical electrochemical and bio-chemical approaches (see Sections 331 and 351)
Nunez-Vergara et al [237] reported the electrochemicaloxidation of C4-hydroxyphenyl-substituted 14-DHP deriva-tives The oxidation proceeds via formation of the unstabledihydropyridyl radical as confirmed by controlled-potentialelectrolysis (CPE) and ESR experiments This type of 14-DHPs has significant activity towards the radicals even whencompared with commercial 14-DHP drugs with well-knownantioxidant ability
It was observed that nicardipine preferentially targets RO∙radicals and is inactive against ROO∙ Lacidipine on theother hand is equally active towards both types of radicals(Gaviraghi et al [164]) The cytoprotective effect againstexposure to H
2O2was more significant for lacidipine (ID
50=
14 nM its log119875 = 54 membrane partition = 136000 assumesposition located 7 A near to the membrane center otherless lipophilic DHPs located 12ndash16 A far from the center)as compared to amlodipine nifedipine and nicardipine insmooth muscle cell culture (Gaviraghi et al [164]) Oxidativeeffect of H
2O2shifts the Ca channel toward an open state
Thus the redox property of CCBs DHPs may augment theirCCB properties
Oxidation of pharmacologically active Hantzsch 14-dihydropyridines was found by electrogenerated superoxideusing a voltammetric approach in DMSO solutions (Ortiz etal [238] and Ortiz et al [239]) Raghuvanshi and Singh [240]have also reported oxidative aromatization of these DHPsinduced by superoxide
Chemiluminescence (CL) was used in the studies ana-lyzing the antioxidant activity of 12 various 4-flavonil-14-dihydropyridine derivatives (Kruk et al [241]) on a chemicalsystem involving a superoxide radical anion These deriva-tives showed structural similarity to flavonoids with respectto the presence of rings A B and C The results obtained in
24 Oxidative Medicine and Cellular Longevity
this study indicate that the tested derivatives may catalyzeconversion of superoxide radicals through mimicking theactivity of superoxide dismutase by delivering H+ for reac-tion
O2
minus∙+O2
minus∙+ 2H+ 997888rarr H
2O2+1O2
(3)
The enhanced emission of the light in the presence oftested compounds was significant and related to stimulatedproduction ofH
2O2and 1O
2fromO
2
∙The latter specieswereremoved from the reactionmixture by the following sequenceof reactions
H+
O2
minus∙997888rarr HO
2
∙
HO2
∙+O2
∙minus997888rarr HO
2
minus+1O2
2HO2
∙997888rarr H
2O2+1O2
2 (1O2) 997888rarr (O
2)2+ h]lowast
(4)
or to take part in spontaneous dismutation of H2O2
2H2O2997888rarr 2H
2O + 1O
2(5)
The authors have offered an original concept of action for 4-flavonil-14-dihydropyridine derivatives unrelated to that ofO2
∙ radical-trapping chain-breaking antioxidants Insteadthey showed that these compounds act similar to superoxidedismutases converting O
2
∙ to H2O2 Hydrogen peroxide
is less toxic for cells than O2
∙ because it is predominantlyremoved by peroxidases and catalases Finally AO effect ofthese DHPs differed from those mediated by flavonoids witha catechol structure of ring B which are well-known 1O
2
quenchersMulder and collaborators came to similar conclusions
especially related to molecular mechanisms of antioxidativeactivity of DHPs [236]TheAOproperties of Hantzsch 14-di-hydropyridine esters and two dibenzo-14-dihydropyridines910-dihydroacridine (DHAC) and N-methyl-910-dihydro-acridine (N-Me-DHAC) have been explored by determin-ing the autoxidation of styrene or cumene at 30∘C Theseexperiments showed that Hantzsch esters are virtually inac-tive as chain-breaking antioxidants (CB-AOs) contrary tothe findings observed by Lopez-Alarcon et al [103] whoused CB-AOA in aqueous media at pH 74 Their reactivitytoward peroxyl radicals was shown to be some 5 orders ofmagnitude lower than that of the excellent CB-AO 22578-pentamethyl-6-hydroxy-chroman (PMHC)
DHAC was found to be sim10 times less reactive thanPMHC kinetic measurements using DHAC N-deuterio-DHAC and N-Me-DHAC pointing out the abstraction ofN-H hydrogen in DHAC by peroxyl radicals despite the factthat the calculated C-H bond dissociation enthalpy (BDE) inDHAC is about 11 kcalmol lower than the N-H BDE Therates of hydrogen atom abstraction by the 22-diphenyl-1-picrylhydrazyl radical (DPPH∙) have also been determined
for the same series of compounds The trends in the peroxyl∙and DPPH∙ rate constants were found to be similar [236]
Tirzit et al [242] have observed quenching of singletoxygen by DHPs This observation paved the ground forfurther research related to reactions of DHPs with hydroxylradicals (Tirzit et al [243]) singlet oxygen (Kazush etal [94]) and mechanisms of action A series of 14-DHPderivatives in NAD-H-Cu2+-H
2O2system inhibited forming
of the hydroxyl radical (HO∙) while 14-DHP derivativeswith electron donor substituents in the molecule were shownto be capable themselves of generating HO∙ in the presenceof Cu2+ and H
2O2 Rubene et al [186] also described
interaction of 14-DHP derivatives with Fentonrsquos reagentwhich produces hydroxyl radical (HO∙) Rate constants ofthe DHPs reaction (1st order) with HO∙ radical were highin the range 109 L times mol times secminus1 close to that of NADHcysteine and thiourea 35-Diacetyl- derivatives reacted fastercompared to 35-dialkoxycarbonyl- ones The reaction ratedecrease was observed in the case of substitution at position4 as compared to 4-unsubstituted DHPs Some DHPs havingelectron donor -COOminus groups in the 35- or 26- positionsof DHP ring reacted immediately (having rate constantshigher as 109 L times mol times secminus1) Rate constants with HO
2
∙
and O2
∙minus radicals were of lower degree Thus DHPs actingas oxygen radical scavengers could effectively inhibit ROSrelated reactions of LP initiation stage
Nifedipine and nitrendipine reactivity toward singletoxygen was also studied [244] Nifedipine was shown tobe a good scavenger of excited oxygen mainly via physicaldeactivation with values of the total rate constant rangingfrom 208 times 105Mminus1 sminus1 (in dioxane) to 930 times 105Mminus1 sminus1(in propylene carbonate)The less reactive pathway generateda photooxidation product For that reason a mechanisminvolving a perepoxide-like encounter complex in the firststep of the reaction path was proposed (see [244] Figures8 and 9 therein) The dependence was observed on solventmicroscopic parameters of the total rate constant for the reac-tion between singlet oxygen and 14-DHPs These findingsshow that nifedipine possesses stronger protective activity inbiological systems than nitrendipine
Density-functional-theory (DFT) calculations made byWang et al [245] confirmed the former experimental obser-vations that Hantzsch ester diludine is potent antioxi-dant with high H atom-donating ability and relatively lowprooxidant activity Possible reaction pathways for radicalsderived from 14-dihydropyridine and the resonance modesfor radical species were given [245]
Moreover two ethoxycarbonyl (EtOCO) substituentsat C(2) and C(6) should further enhance Hantzsch esterdiludine H-atom-donating ability due to resonance effectsHowever DHPs should be used in nonpolar rather than inpolar solvents since in the latter not H-atom but electrontransfer is preferred in the radical scavenging process [245]
Mulder et al [246] proposed that quantum-thermochem-ical calculations must be used with caution to indicate ldquoapromising lead antioxidantrdquo as they criticized the density-functional-theory (DFT) calculations made by Wang et al[245]
Oxidative Medicine and Cellular Longevity 25
372 Possible Mechanisms of DHPs ARA and AOA in the Bio-logical Systems Interaction with Other OSModifiers Some ofthese mechanisms were already described (Sections 331 (2)-(b) 331 (2)-(c) 331 (3)-(b) 35)
Enzymatic sources of ROSwith confirmed functional rolein hypertension are NADPH oxidase NO synthase (NOS)xanthine oxidase and cyclooxygenase Godfraind [3] hasreviewed AO effects and protective action of calcium channelblockers (CCBs) Yao et al [247] observed antioxidant effects(as inhibition of LP) for cardio- and neuroprotective CCBs(3ndash300 120583molL) including 7 DHPs in homogenates of ratbrain IC
50values (120583M) were as follows nifedipine (515) gt
barnidipine (586) gt benidipine (712) gt nicardipine (1293)gt amlodipine (1355) gt nilvadipine (1673) gt nitrendipine(2521) gt diltiazem (gt300) = verapamil (gt300) There arealso research articles describing the AO properties of CCBsthrough direct scavenging effect or through preservationof the endogenous SOD activity These findings indicatethat CCBs may also act by reducing the production ofvasoconstrictors angiotensin and endothelin
When present in concentrations that can be achievedin plasma CCBs may inhibit LP formation [3] This AOactivity seems to be typical for high lipophilic CCBs becausetheir chemical structure facilitates proton-donating andresonance-stabilization mechanisms that quench the freeradical reaction Their insertion in the membrane nearpolyunsaturated fatty acids at relatively high concentrationspotentiates proton donation (or atomary H) to lipid peroxidemolecules thereby blocking the peroxidation process Theremaining unpaired free electron associated with the CCBmolecule can be stabilized in well-defined resonance struc-tures associated with the DHP ring (Mason et al [48])
The radical reaction (according to Godfraind [3]) thatdescribes the AO effects of a DHP CCBs is LOOlowast + DHPrarr LOOH + DHPlowast (where LOOlowast is lipid peroxide radical)which in general is reaction (7) of the LP reaction cascadeconsisting of sim10 reactions (Scheme 2) [89]
As the rate constants of in vitro interaction of 4-substituted DHPs with peroxyl radicals are three ordersof magnitude lower than that of the vitamin E derivativethese DHPs must be considered as weak AO (Ursini [204])However due to partition coefficient of DHPs in membranesand in case of specific binding high local concentration ofDHPs may be obtained
DHPs without CCB properties for instance Bay w 9798although structurally related to nifedipine inhibit TNF-120572-induced vascular cell adhesion molecule-1 expression inendothelial cells by suppressing reactive oxygen speciesgeneration [248]
Mitrega et al [249] have discovered that antiarrhythmicand hemodynamic effects of oxidized heteroaromatic DHPsoxy nifedipine oxy nimodipine oxy nitrendipine and oxynisoldipine suggest that CCB DHPs and their metabolitescould act at least in two ways targeting OS related eventsas reductants (see Section 351 (1)) andor bypassing OSrelatedmetabolic routes Authors postulated that contrary tocurrent belief NIF metabolites are pharmacologically activeATP sensitive potassium channels were mentioned as a tar-get
38 DHPs Anti- or Prooxidants Several substances (ascorbicacid being the most commonly studied) can serve either asantioxidants or as prooxidants depending on given condi-tions (Herbert [250]) Therefore Halliwell [251] has reporteddilemma related to polyphenols as possible antioxidantsand prooxidants causing experimental artifacts (about 25)by oxidation of antioxidant compounds in the cell culturemedia Nevertheless it is generally accepted opinion thatpolyphenols act as antioxidants in vivo Studies on DHPs alsoface such a dilemmaThe exact roles (anti- or prooxidative) ofany specific DHP depend on its structure appliedachievedconcentration and specificity of the targetexperimentaltesting system
This situation resembles the case of antioxidative effectsof tocopherol which depends on the fate of the secondaryradical as proposed by Winterbourn [252] The question wasldquoVitamin E - Pro- or Antioxidantrdquo
997888rarr chain termination of lipid peroxidation
(6)
Prooxidant
Toc∙ + Lipid-H 997888rarr Lipid∙ (in LDL particles) (7)
This example shows that generally speaking any AO mustfulfil several criteria to be considered as an effective com-pound physiologically
(i) It must be able to functionally interact with endoge-nous scavengers even at low concentrations
(ii) It must affect endogenous pathways of OS(iii) It should not have undesirable adverse effect(iv) It should manifest the antioxidant efficacy dependent
on the oxidant(v) It must discriminate among different strategies
needed for 1-electron and 2-electron processes(vi) Radical scavengers can be prooxidant unless linked to
a radical sink (Winterbourn [252])
According to these statements DHPs could be effective asAO under physiological conditions in vivo (Godfraind [3]and others [30 31 38]) and in vitro in various experimentalsystems (cell and tissue) (see Sections 33 34 35)
Hence calcium antagonists appeared to disrupt thefine balance between the production and scavenging ofROS Nifedipine verapamil and diltiazem were shown toinduce significant oxidative stress in the epididymal sperm(increased MDA and decreased catalase and superoxidedismutase activity) This may be the reason for the inductionof male infertility [253]
The dualism of 14-DHP effects has been recorded asinhibition or promotion of LP as quenching or initiating
26 Oxidative Medicine and Cellular Longevity
oxygen and nitrogen free radical chain reactions radiopro-tecting or radiosensitizing antagonizing or synergizing Ca2+in electromechanical coupling as well as in the membranestabilization or labilization
39 Could DHPs Be Involved in Antioxidative Stress Beforebeing applied in vivo the optimal dose and optimal timeintervals forDHPs applicationmust be knownNamely whileROS have been traditionally considered as toxic byproductsof aerobic metabolism we know nowadays that ROS may actas essential signaling molecules needed for the control ofmany different physiological processes Whether the role ofROS will be damaging protective or signaling depends onthe delicate equilibrium between time- and location-specificROS production and scavenging Accordingly the imbalanceof the increased AO potential so-called antioxidative stresscould be dangerous similar to chronic OS in particular incase of extended exposure Inappropriate interventions inthe oxidative homeostasis by excessive antioxidants especiallyin case of chronic exposure to antioxidants might havevery negative effects as was published in the ATBC studyshowing an increased cancer incidence in smokers treatedby excessive beta-carotene [254] Therefore overconsump-tion of any natural or synthetic AO including DHPs asdietary supplements or drugs must be avoided in order tosuppress oxidative damage and must not disrupt the well-integrated antioxidant defense network (Poljsak [255] andPoljsak and Milisav [256]) This is especially important whenadministrating lipid-soluble antioxidants that can be storedin biomembranes thus not only attenuating or preventing LPbut also affecting physiological effects of the natural antiox-idants in particular tocopherol The interrelationship withthe status of endogenous antioxidantsprooxidants should befollowed
DHPs primarily suppress the initiation stages of LPprocessThey do not entirely stop the LP propagation Actingsynergistically with tocopherol diludine may prevent patho-logical excess of ROS production within the lipid moiety ofthe cellular membranes and LDL However due to its lowsolubility and fast metabolism its concentration in the cellsis low For that reason it cannot cause antioxidative stresseven if used for an extended period of time Thus diludine(diethone) could be only a mild antioxidant it has potentialfor restoring the pool of natural antioxidants (as synergist of120572-tocopherol and polyphenols) in the cells
Moreover DHPs CA used for cardioprotection andvasodilatation as commercial drugs in low concentrationsare fast metabolized via CYP3A4 and for that reason theirapplication does not induce cellular AO stress [53 160]However Godfraind and Salomone [257] have postulated noevidence that allows recommending dietary supplementationwith antioxidants for the primary or secondary prevention ofcardiovascular disease
So far there are no reports on antioxidative stress causedby some DHPs diludine and its analogues Diludine andits analogues therefore could act as adaptogens supportinghormetic effects of mild oxidative stress These compoundsmay act as potential multisided modulators of Yin-Yang
cycles of redox and cell functions (the electroplasmic cycle)(Wagner et al [258])
4 Conclusions
14-Dihydropyridines (14-DHPs) have broad spectrum ofOS modulating activities DHPs have reducing and lipidperoxidation inhibitor properties act as reductants in simplechemical systems and stabilize various biological systems(LDL mitochondria microsomes cells and tissues) againstOS Examples and peculiarities and mechanisms of antiox-idant activity (AOA) and antiradical activity (ARA) as wellas stress-protective effect of DHPs including commercialcalcium antagonists (CA) were highlighted These activitiesdepend on various structural parameters related to DHPs(presence and character of substituents) lipophilicity anddepth of the incorporation in the biologicalmembranesTheyalso depend on the experimental model system for exploringthe lipid peroxidation or oxidative stress Stress-protectiveeffect of some metabolites of CA (nifedipine) is reviewedAlthough some DHPs including CA have prooxidant prop-erties (on epididymal sperm cells) they can generally beconsidered as potent antioxidants Therefore comparisonof the AOA and ARA of different DHPs (mutually andwith other AOs) was described in detail According to thedata presented the DHPs might be considered as bellwetheramong synthetic compounds targeting OS and as a kind ofpharmacological measure for respective field of organic andmedicinal chemistry
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
Authors from Latvian IOS acknowledge ESF 201300021DP1112013APIAVIAA011 and National Research Pro-gramme PUBLIC HEALTHBiomedicine of the Republicof Latvia for financial support administration of the Insti-tute for technical support and Rufus Smits PhD for con-sultations in English The support of Cooperation in Euro-pean System of Science and Technology (COST) Domain ofChemistry Molecular Sciences and Technologies (CMST)was of highest importance for preparation of this paper
[2] D J Triggle ldquo14-Dihydropyridines as calcium channel ligandsand privileged structuresrdquoCellular andMolecular Neurobiologyvol 23 no 3 pp 293ndash303 2003
[3] T Godfraind ldquoAntioxidant effects and the therapeutic modeof action of calcium channel blockers in hypertension andatherosclerosisrdquo Philosophical Transactions of the Royal SocietyB Biological Sciences vol 360 no 1464 pp 2259ndash2272 2005
[4] E Cadenas ldquoMitochondrial free radical production and cellsignalingrdquoMolecular Aspects of Medicine vol 25 no 1-2 pp 17ndash26 2004
[5] E Cadenas ldquoFree radicals oxidative stress and diseasesrdquo inLecture PSC 616 p 38 Missouri University of Science andTechnology Rolla Mo USA httpwwwcarnicominstituteorgarticlesenrique cadenaspdf
[6] K Rahman ldquoStudies on free radicals antioxidants and co-fac-torsrdquo Clinical Interventions in Aging vol 2 no 2 pp 219ndash2362007
[7] V Bocci and G Valacchi ldquoFree radicals and antioxidants howto reestablish redox homeostasis in chronic diseasesrdquo CurrentMedicinal Chemistry vol 20 no 27 pp 3397ndash3415 2013
[8] M Valko C J Rhodes J Moncol M Izakovic and M MazurldquoFree radicals metals and antioxidants in oxidative stress-induced cancerrdquo Chemico-Biological Interactions vol 160 no 1pp 1ndash40 2006
[9] G Bartosz ldquoReactive oxygen species destroyers or messen-gersrdquo Biochemical Pharmacology vol 77 no 8 pp 1303ndash13152009
[10] R Visconti and D Grieco ldquoNew insights on oxidative stress incancerrdquo Current Opinion in Drug Discovery and Developmentvol 12 no 2 pp 240ndash245 2009
[11] R N Kujundzic N Zarkovic and K G Troselj ldquoPyridinenucleotides in regulation of cell death and survival by redoxand non-redox reactionsrdquo Critical Reviews in Eukaryotic GeneExpression vol 24 no 4 pp 287ndash309 2014
[12] B Halliwell and J M C Gutteridge ldquoThe definition and mea-surement of antioxidants in biological systemsrdquo Free RadicalBiology and Medicine vol 18 no 1 pp 125ndash126 1995
[13] V D Kancheva and O T Kasaikina ldquoBio-antioxidantsmdashachemical base of their antioxidant activity and beneficial effect
on human healthrdquo Current Medicinal Chemistry vol 20 no 37pp 4784ndash4805 2013
[14] H V Panglossi Ed Frontiers in Antioxidants Research NovaScience Publishers New York NY USA 2006
[15] E B Burlakova E M Molochkina and G A NikiforovldquoHybrid antioxidantsrdquo Oxidation Communications vol 31 no4 pp 739ndash757 2008 httpmembraneustceducnpaperpdfHybrid20Antioxidantspdf
[16] A Bast and G R M M Haenen ldquoTen misconceptions aboutantioxidantsrdquo Trends in Pharmacological Sciences vol 34 no 8pp 430ndash436 2013
[17] E B Burlakova A V 0lesenko E M Molochkina N PPalmina and N G Khrapova Bioantioxidants for RadiationDamage and Malignant Growth Nauka Moscow Russia 1975(Russian)
[18] J Fang T Seki and H Maeda ldquoTherapeutic strategies by mod-ulating oxygen stress in cancer and inflammationrdquo AdvancedDrug Delivery Reviews vol 61 no 4 pp 290ndash302 2009
[19] M Valko D Leibfritz J Moncol M T D Cronin M Mazurand J Telser ldquoFree radicals and antioxidants in normal physi-ological functions and human diseaserdquo International Journal ofBiochemistry and Cell Biology vol 39 no 1 pp 44ndash84 2007
[20] M Jimenez-Del-Rio and C Velez-Pardo ldquoThe bad the goodand the ugly about oxidative stressrdquo Oxidative Medicine andCellular Longevity vol 2012 Article ID 163913 13 pages 2012
[21] C D Kamat S Gadal M Mhatre K S Williamson Q N Pyeand K Hensley ldquoAntioxidants in central nervous system dis-eases preclinical promise and translational challengesrdquo Journalof Alzheimerrsquos Disease vol 15 no 3 pp 473ndash493 2008
[22] A Pompella H Sies R Wacker et al ldquoThe use of totalantioxidant capacity as surrogate marker for food quality andits effect on health is to be discouragedrdquo Nutrition vol 30 no7-8 pp 791ndash793 2014
[23] Z Ye and H Song ldquoAntioxidant vitamins intake and the risk ofcoronary heart disease meta-analysis of cohort studiesrdquo Euro-pean Journal of Cardiovascular Prevention and Rehabilitationvol 15 no 1 pp 26ndash34 2008
[24] P Knekt J Ritz M A Pereira et al ldquoAntioxidant vitamins andcoronary heart disease risk a pooled analysis of 9 cohortsrdquoTheAmerican Journal of Clinical Nutrition vol 80 no 6 pp 1508ndash1520 2004
[25] A C Carr and M C M Vissers ldquoSynthetic or food-derivedvitamin Cmdashare they equally bioavailablerdquo Nutrients vol 5 no11 pp 4284ndash4304 2013
[26] R Tabrizchi ldquoEdaravoneMitsubishi-TokyordquoCurrentOpinion inInvestigational Drugs vol 1 no 3 pp 347ndash354 2000
[27] K Kikuchi S Tancharoen N Takeshige et al ldquoThe efficacy ofedaravone (radicut) a free radical scavenger for cardiovasculardiseaserdquo International Journal of Molecular Sciences vol 14 no7 pp 13909ndash13930 2013
[28] D Mauzerall and F H Westheimer ldquo1-Benzyldihydronicoti-namidemdasha model for reduced DPNrdquo Journal of the AmericanChemical Society vol 77 no 8 pp 2261ndash2264 1955 ChemicalAbstracts vol 50 Article ID 2588i 1956
[29] F Bossert and W Vater ldquo14-Dihydropyridinesmdasha basis fordeveloping new drugsrdquo Medicinal Research Reviews vol 9 no3 pp 291ndash324 1989
[30] G Swarnalatha G Prasanthi N Sirisha and CMadhusudhanaChetty ldquo14-Dihydropyridines a multtifunctional moleculemdash areviewrdquo International Journal of ChemTech Research vol 3 no1 pp 75ndash89 2011
28 Oxidative Medicine and Cellular Longevity
[31] M Cataldi and F Bruno ldquo14-Dihydropyridines the multiplepersonalities of a blockbuster drug familyrdquo Translational Medi-cine UniSa vol 4 no 2 pp 12ndash26 2012 httpwwwncbinlmnihgovpmcarticlesPMC3728803
[32] R Vitolina A Krauze G Duburs and A Velena ldquoAspects ofthe amlodipine pleiotropy in biochemistry pharmacology andclinicsrdquo International Journal of Pharmaceutical Sciences andResearch vol 3 no 5 pp 1215ndash1232 2012
[33] D Grover S N Mokale and M T Shete ldquoDihydropyridinea novel pharmacophorerdquo International Journal of Pharmaceu-tical Erudition vol 1 no 2 pp 16ndash29 2011 httppharmaeru-ditionorgContentPaper20111-RV-320Final2016-29pdf
[34] A M Vijesh A M Isloor S K Peethambar K N ShivanandaT Arulmoli and N A Isloor ldquoHantzsch reaction synthesis andcharacterization of somenew 14-dihydropyridine derivatives aspotent antimicrobial and antioxidant agentsrdquo European Journalof Medicinal Chemistry vol 46 no 11 pp 5591ndash5597 2011
[35] P Mehta and P Verma ldquoAntimicrobial activity of some deriva-tives of 14-dihydropyridinesrdquo Journal of Chemistry vol 2013Article ID 865128 4 pages 2013
[36] P Olejnıkova L Svorc D Olsovska et al ldquoAntimicrobialactivity of novel C2-substituted 14-dihydropyridine analoguesrdquoScientia Pharmaceutica vol 82 no 2 pp 221ndash232 2014
[37] S Sepehri H Perez Sanchez and A Fassihi ldquoHantzsch-typedihydropyridines and biginelli-type tetra-hydropyrimidinesa review of their chemotherapeutic activitiesrdquo Journal of Phar-macy amp Pharmaceutical Sciences vol 18 no 1 pp 1ndash52 2015httpsejournalslibraryualbertacaindexphpJPPSarticleview2383617863
[38] S A Khedkar and P B Auti ldquo14-Dihydropyridines a classof pharmacologically important moleculesrdquo Mini-Reviews inMedicinal Chemistry vol 14 no 3 pp 282ndash290 2014
[39] G D Tirzit and G Ya Duburs ldquo14-dihydropyridines as inhi-bitors of free-radical reactionsrdquo Chemistry of Heterocyclic Com-pounds vol 8 no 1 pp 126ndash127 1972 Translated from KhimiyaGeterotsiklicheskikh Soedinenii no1 pp 133ndash134 1972 (Rus-sian)
[40] I Bogeski R Kappl C Kummerow R Gulaboski M Hothand B A Niemeyer ldquoRedox regulation of calcium ion channelschemical and physiological aspectsrdquoCell Calcium vol 50 no 5pp 407ndash423 2011
[41] S A Giller G Y Dubur Y R Uldrikis et al ldquoDiludine [Themethod to obtain 35-dicarbonylderivatives of 26-dimethyl-14-dihydropyridines]rdquo Authors certificate of USSR no 3004651971 [Byull Izobret no13 p 95 1971] and following patentsPatent of England no 1294650 1973 Patent of France no2055458 1971 Patent of Japan no 702883 1973 Patent ofHolland no 149787 1976 Patent of Italy no 969022 1974 Patentof FRG no 2036403 1978 US Patent no 3883673 1975 USPatent no 3948924 1976
[42] S A Giller G Y Dubur Y R Uldrikis et al ldquoImprovementsin or relating to the stabilization of carotenerdquo GB Patent no1294650 1972
[43] S A Giller G Y Dubur Y R Uldrikis et al ldquoStabilization ofcarotenerdquo US Patent no 3883673 1975 Chemical Abstracts vol83 Article ID 95193 1975
[44] Yu A Zilber G Ya Dubur K K Kumsar and A Kh VelenaldquoThe effect of antioxidants on the peroxidation of bimole-cular phospholipid membranesrdquo Latvijas PSR ZA Vestis Izves-tia Akademii Nauk Latviyskoy SSR vol 6 pp 80ndash82 1971(Russian) translated from the original Russian Doc Accesion
No AD0771751 distributed by NTIS US Department of Com-merce httpwwwdticmildtictrfulltextu2771751pdf
[45] G Ya Dubur Yu A Zilbers A Kh Velena A O Kumerovaand G D Tirzitis ldquoMultistage study of regulation of peroxida-tion processes in biological membranes by antioxidants of 14-dihydropyridine grouprdquo Izvestiya Akademii Nauk LatviyskoySSR vol 336 no 7 pp 65ndash68 1975 (Russian)
[46] R P Mason and M W Trumbore ldquoDifferential membraneinteractions of calcium channel blockers Implications forantioxidant activityrdquo Biochemical Pharmacology vol 51 no 5pp 653ndash660 1996
[47] R P Mason M F Walter M W Trumbore E G Olmstead Jrand P E Mason ldquoMembrane antioxidant effects of the chargeddihydropyridine calcium antagonist amlodipinerdquo Journal ofMolecular and Cellular Cardiology vol 31 no 1 pp 275ndash2811999
[48] R PMason I T MakMW Trumbore and P EMason ldquoAnti-oxidant properties of calcium antagonists related to membranebiophysical interactionsrdquo American Journal of Cardiology vol84 no 4 pp 16ndash22 1999
[49] R PMasonMW Trumbore and P EMason ldquoMembrane bio-physical interaction of amlodipine and antioxidant propertiesrdquoDrugs vol 59 no 2 pp 9ndash16 2000 (French)
[50] R P Mason P Marche and T H Hintze ldquoNovel vascularbiology of third-generation L-type calcium channel antagonistsAncillary actions of amlodipinerdquo Arteriosclerosis Thrombosisand Vascular Biology vol 23 no 12 pp 2155ndash2163 2003
[51] A Augustyniak G Bartosz A Cipak et al ldquoNatural andsynthetic antioxidants an updated overviewrdquo Free RadicalResearch vol 44 no 10 pp 1216ndash1262 2010
[52] T Grune N Zarkovic and K Kostelidou ldquoLipid peroxidationresearch in Europe and the COST B35 action lsquoLipid Peroxida-tion Associated Disordersrsquordquo Free Radical Research vol 44 no10 pp 1095ndash1097 2010
[53] E Carosati P Ioan M Micucci et al ldquo14-Dihydropyridinescaffold in medicinal chemistry the story so far and perspec-tives (part 2) action in other targets and antitargetsrdquo CurrentMedicinal Chemistry vol 19 no 25 pp 4306ndash4323 2012
[54] U Eisner and J Kuthan ldquoThe chemistry of dihydropyridinesrdquoChemical Reviews vol 72 no 1 pp 1ndash42 1972 httpwwwsci-encemadnessorgtalkfilesphppid=138742ampaid=6475
[55] J Kuthan and A Kurfurst ldquoDevelopment in dihydropyri-dine chemistryrdquo Industrial amp Engineering Chemistry ProductResearch and Development vol 21 no 2 pp 191ndash261 1982
[56] A Sausins and G Duburs ldquoSynthesis of 14-dihydropyridinesby cyclocondensation reactionsrdquo Heterocycles vol 27 no 1 pp269ndash289 1988
[57] A E Sausins and G Y Duburs ldquoSynthesis of 14-dihydro-pyridines in cyclocondensation reactions (review)rdquo Chemistryof Heterocyclic Compounds vol 28 no 4 pp 363ndash391 1992Translated from Khimiya Geterotsiklicheskikh Soedinenii no 4pp 435ndash467 1992 (Russian)
[58] S Kazda ldquoTwenty years of dihydropyridinesrdquo in Dihydropy-ridines Progress in Pharmacology and Therapy W-D Busse BGarthoff and F Seuter Eds pp 1ndash12 Springer Verlag BerlinGermany 1993
[59] J-P Wan and Y Liu ldquoRecent advances in new multicomponentsynthesis of structurally diversified 14-dihydropyridinesrdquo RSCAdvances vol 2 no 26 pp 9763ndash9777 2012
[61] Reaxys Database[62] J Tuttle ldquoStructure mechanism and reactivity of hantzsch
estersrdquo in MacMillan Lab Group Meeting (082504) p 332004 httpwwwprincetoneduchemistrymacmillangroup-meetingsJBT20Hantzschpdf
[63] A Saini S Kumar and J S Sandhu ldquoHantzsch reaction recentadvances in Hantzsch 14-dihydropyridinesrdquo Journal of Sci-entific amp Industrial Research vol 67 pp 95ndash111 2008
[64] L LW Cheung S A Styler and A P Dicks ldquoRapid and conve-nient synthesis of the 14-dihydropyridine privileged structurerdquoJournal of Chemical Education vol 87 no 6 pp 628ndash630 2010
[65] A Kumar R A Maurya S Sharma M Kumar and G BhatialdquoSynthesis and biological evaluation of N-aryl-14-dihydro-pyridines as novel antidyslipidemic and antioxidant agentsrdquoEuropean Journal of Medicinal Chemistry vol 45 no 2 pp 501ndash509 2010
[66] R S Kumar A Idhayadhulla A J Abdul Nasser and J SelvinldquoSynthesis and anticoagulant activity of a new series of 14-dihydropyridine derivativesrdquo European Journal of MedicinalChemistry vol 46 no 2 pp 804ndash810 2011
[67] H A Stefani C B Oliveira R B Almeida et al ldquoDihydro-pyrimidin-(2H)-ones obtained by ultrasound irradiation anew class of potential antioxidant agentsrdquo European Journal ofMedicinal Chemistry vol 41 no 4 pp 513ndash518 2006
[68] H Sun C Shang L Jin and J Zhang ldquoSynthesis and antiox-idant activity of a series of novel 3-chalcone-substituted 14-dihydropyridine derivativesrdquoHeterocyclic Communications vol18 no 5-6 pp 239ndash243 2012
[69] D B Tikhonov and B S Zhorov ldquoStructural model for dihy-dropyridine binding to L-type calcium channelsrdquo The Journalof Biological Chemistry vol 284 no 28 pp 19006ndash19017 2009
[70] G Y Dubur and Y R Uldrikis ldquoThe oxidation of 14-dihydro-pyridinesrdquo Chemistry of Heterocyclic Compounds vol 6 no 1pp 80ndash84 1970 Translated from Khimiya GeterotsiklicheskikhSoedinenii no 1 pp 83ndash88 1970 (Russian)
[71] G Ya Duburs A O Kumerova and Ya R Uldrikis ldquoEnzymicoxidation of hydrogenated pyridines with peroxidase-hydrogenperoxide systemrdquoLatvijas PSRZAVestis vol 73 no 7 pp 73ndash771970 (Russian) Chemical Abstracts vol 73 Article ID 94913g1970
[72] K Xie Y-C Liu Y Cui J-GWang Y Fu andT CWMak ldquoN-methyl-(R)-3-(tert-butyl)-sulfinyl-14-dihydropyridine a novelNADHmodel compoundrdquoMolecules vol 12 no 3 pp 415ndash4222007
[73] S Tamagaki T Mimura and W Tagaki ldquoMetal-ion-facilitatedoxidations of dihydropyridines with molecular oxygen andhydrogen peroxiderdquo Journal of the Chemical Society PerkinTransactions 2 no 10 pp 1645ndash1650 1990
[74] D Tirzite G Tirzitis andD Antipova ldquoReductive ability of 14-dihydropyridine derivatives in relation to ions of trivalent ironrdquoChemistry of Heterocyclic Compounds vol 35 no 5 pp 592ndash594 1999
[76] J Ogle J Stradins and L Baumane ldquoFormation and decay offree cation-radicals in the course of electro-oxidation of 12- and14-dihydropyridines (Hantzsch esters)rdquo Electrochimica Actavol 39 no 1 pp 73ndash79 1994
[77] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for the
synthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts C Wittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Berlin Germany 2010
[78] WDu and Zh Yu ldquoBiomimetic in situ regeneration of cofactorsNAD(P)+ and NAD(P)H models hantzsch esters and dihy-drophenanthridinerdquo Synlett vol 23 no 9 pp 1300ndash1304 2012
[79] H K Chenault and G M Whitesides ldquoRegeneration ofnicotinamide cofactors for use in organic synthesisrdquo AppliedBiochemistry and Biotechnology vol 14 no 2 pp 147ndash197 1987
[80] Y R Uldrikis A A Zidermane E A Biseniex I E Preisa GY Dubur and G D Tirzit ldquoEsters of 26-dimethyl-14-dihydro-pyridine-35-dicarboxylic acid and method of obtainingthereofrdquo WO 8000345 A1 1978 httpworldwideespacenetcompublicationDetailsbiblioDB=EPODOCampII=1ampND=3ampadjacent=trueamplocale=en EPampFT=Dampdate=19800306ampCC=WOampNR=8000345A1ampKC=A1
[81] Y Sambongi H Nitta K Ichihashi M Futai and I Ueda ldquoAnovel water-soluble Hantzsch 14-dihydropyridine compoundthat functions in biological processes through NADH regener-ationrdquo Journal of Organic Chemistry vol 67 no 10 pp 3499ndash3501 2002
[82] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for thesynthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts ChWittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Verlag Berlin Germany 2010
[83] T Okamura T Kikuchi A Nagamine et al ldquoAn approach formeasuring in vivo cerebral redox states using the oxidative con-version of dihydropyridine to pyridinium ion and themetabolictrapping principlerdquo Free Radical Biology and Medicine vol 38no 9 pp 1197ndash1205 2005
[84] K A Schellenberg and F H Westheimer ldquoA free-radicaloxidation of a dihydropyridine1ardquo The Journal of OrganicChemistry vol 30 no 6 pp 1859ndash1862 1965
[85] K A Schellenberg ldquoReaction of hydroxyl radical with thymi-dine Scavenging by a dihydropyridinerdquo Federation Proceedingsvol 38 no 3 I p 1433 1979
[86] E S Huyser J A K Harmony and F L McMillian ldquoPeroxideoxidations of dihydropyridine derivativesrdquo Journal of the Amer-ican Chemical Society vol 94 no 9 pp 3176ndash3180 1972
[87] A Sakamoto S T Ohnishi and R Ogawa ldquoInhibition of lipidperoxidation by some dihydropyridine derivativesrdquo Journal ofAnesthesia vol 7 no 2 pp 193ndash197 1993
[88] R Hardeland ldquoReview Neuroprotection by radical avoidancesearch for suitable agentsrdquo Molecules vol 14 no 12 pp 5054ndash5102 2009
[89] G Ya Dubur A Kh Velena V M Gukasov and Yu AVladimirov ldquoRegulation of peroxidation of mitochondrialmembrane lipids initiated by Fe2+ ions by antoxidants of the14-dihydropyridine series in experiments in vitrordquo Biomed-itsinskaya Khimiya vol 22 no 5 pp 665ndash673 1976 (Russian)Chemical Abstracts vol 88 Article ID 2640 1977
[90] G RMMHaenenM J T J Arts A Bast andMD ColemanldquoStructure and activity in assessing antioxidant activity in vitroand in vivo a critical appraisal illustrated with the flavonoidsrdquoEnvironmental Toxicology and Pharmacology vol 21 no 2 pp191ndash198 2006
[91] G Tirzitis and G Bartosz ldquoDetermination of antiradical andantioxidant activity basic principles and new insightsrdquo ActaBiochimica Polonica vol 57 no 2 pp 139ndash142 2010
30 Oxidative Medicine and Cellular Longevity
[92] G R Buettner and R P Mason ldquoSpin-trapping methods fordetecting superoxide and hydroxyl free radicals in vitro and invivordquo inCritical Reviews of Oxidative Stress and Aging Advancesin Basic Science Diagnostics and Intervention R G Cutler andH Rodriguez Eds vol 1 chapter 2 pp 27ndash38World ScientificLondon UK 2003
[93] M M Tarpey and I Fridovich ldquoMethods of detection ofvascular reactive species Nitric oxide superoxide hydrogenperoxide and peroxynitriterdquo Circulation Research vol 89 no3 pp 224ndash236 2001
[94] E Y Kazush E I Sagun G D Tirzit and G Y DaburldquoQuenching of singlet oxygen by electron donating derivativesof 14-dihydropyridinerdquo Chemistry of Heterocyclic Compoundsvol 30 no 5 pp 562ndash563 1994
[95] G Tirzitis E Kazush and G Duburs ldquoReaction of 14-dihydropyridine derivatives with peroxynitrite anionrdquo Chem-istry of Heterocyclic Compounds vol 34 no 3 pp 321ndash3231998 (Russian) Translated from Khimiya GeterotsiklicheskikhSoedinenii no 3 pp 355ndash357 1998
[96] L J Nunez-Vergara C Lopez-Alarcon P A Navarrete-EncinaA M Atria C Camargo and J A Squella ldquoElectrochemicaland EPR characterization of 14-dihydropyridines Reactivitytowards alkyl radicalsrdquo Free Radical Research vol 37 no 1 pp109ndash120 2003
[97] D Tirzite A Krauze A Zubareva G Tirzitis and G DubursldquoSynthesis and antiradical activity of 5-acetyl-2-alkylthio-4-aryl-6-methyl-14-dihydropyridine-3-carboxylic acid nitrilesrdquoChemistry of Heterocyclic Compounds vol 38 no 7 pp 795ndash800 2002
[98] H Ohkawa N Ohishi and K Yagi ldquoAssay for lipid peroxidesin animal tissues by thiobarbituric acid reactionrdquo AnalyticalBiochemistry vol 95 no 2 pp 351ndash358 1979
[99] N Zarkovic ldquo4-Hydroxynonenal as a bioactive marker ofpathophysiological processesrdquo Molecular Aspects of Medicinevol 24 no 4-5 pp 281ndash291 2003
[100] M Parola G Bellomo G Robino G Barrera and M UDianzani ldquo4-Hydroxynonenal as a biological signal molecularbasis and pathophysiological implicationsrdquo Antioxidants andRedox Signaling vol 1 no 3 pp 255ndash284 1999
[101] T Lovakovic M Poljak-Blazi G Duburs et al ldquoGrowthmodulation of human cells in vitro by mild oxidative stressand 14-dihydropyridine derivative antioxidantsrdquo CollegiumAntropologicum vol 35 no 1 pp 137ndash141 2011
[102] R van den Berg G R M M Haenen H van den Bergand A Bast ldquoApplicability of an improved Trolox equivalentantioxidant capacity (TEAC) assay for evaluation of antioxidantcapacity measurements of mixturesrdquo Food Chemistry vol 66no 4 pp 511ndash517 1999
[103] C Lopez-Alarcon P Navarrete C Camargo J A Squella andL J Nunez-Vergara ldquoReactivity of 14-dihydropyridines towardalkyl alkylperoxyl radicals and ABTS radical cationrdquo ChemicalResearch in Toxicology vol 16 no 2 pp 208ndash215 2003
[104] V Valenzuela P Santander C Camargo J A Squella C Lopez-Alarcon and L J Nunez-Vergara ldquo14-Dihydropyridines reac-tivity of nitrosoaryl and nitroaryl derivatives with alkylperoxylradicals andABTS radical cationrdquo Free Radical Research vol 38no 7 pp 715ndash727 2004
[105] L G Tsetlin N A Chebotareva B I Kurganov A K VelenaG Y Dubur and V Z Lankin ldquoStudy of 14-dihydropyridinesas lipoxygenase inhibitors with the use of hydrated reversedmicellesrdquo Pharmaceutical Chemistry Journal vol 22 no 6 pp425ndash428 1988 (Russian)
[106] J Panek Z Reblova L Kocirkova et al ldquoAntioxidant activityof dihydropyridine derivativesrdquo Czech Journal of Food Sciencesvol 18 pp 144ndash145 2000
[107] G Tirzitis I Kirule and G Duburs ldquoAntioxidationsaktivitatder 35-dicarbonylderivate des 26-demethyl-14-dihydropyri-dinsrdquo Fett Wissenschaft TechnologieFat Science Technology vol90 no 10 pp 411ndash413 1988
[108] M Plotniece G Tirzitis Y Uldrikis et al ldquoSynthesis of 14-dihydropyridine derivatives having an oxy- alkoxy- or dimeth-ylaminophenyl substituent in the 4 position their antioxidantactivity and their binding to phospholipid membranesrdquo Chem-istry of Heterocyclic Compounds vol 32 no 10 pp 1166ndash11721996 Translated from Khimiya Geterotsiklicheskikh Soedineniino 10(352) pp 1358ndash1365 1996 (Russian)
[109] D Y Rubene V S Sharov V I Olenev G D Tirzit G Y Duburand Y A Vladimirov ldquoUse of chemiluminescent method forthe evaluation of antioxidant activity of some derivatives of 14-dihydropyridinerdquo Russian Journal of Physical Chemistry A vol55 no 2 pp 511ndash512 1981 (Russian)
[110] M C R Symons and JM C Gutteridge Free Radicals and IronChemistry Biology and Medicine Oxford Science PublicationsOxford University Press Oxford UK 1998
[111] M Repetto J Semprine and A Boveris ldquoLipid peroxidationchemical mechanism biological implications and analyticaldeterminationrdquo in Lipid Peroxidation A Catala Ed Section ILipid Peroxidation Chemical Mechanisms Antioxidants Bio-logical Implications of Biochemistry Genetics and MolecularBiology chapter 1 pp 3ndash30 InTech Rijeka Croatia 2012
[112] A Velena J Zilbers and G Duburs ldquoDerivatives of 14-dihydropyridines asmodulators of ascorbate-induced lipid per-oxidation and high-amplitude swelling ofmitochondria causedby ascorbate sodium linoleate and sodiumpyrophosphaterdquoCellBiochemistry and Function vol 17 no 4 pp 237ndash252 1999
[113] M V Bilenko L N Shelenkova G Y Dubur and A K VelenaldquoUse of antioxidants to prevent renal damage during acuteischemia and reperfusionrdquo Bulletin of Experimental Biology andMedicine vol 96 no 3 pp 1195ndash1198 1983 Translated fromByulletenrsquo Eksperimentalrsquonoi Biologii i Meditsiny vol 96 no 9pp 8ndash11 1983 (Russian)
[114] R Toniolo F Tubaro F Ursini and G Bontempelli ldquoAn elec-troanalytical investigation on the redox properties of calciumantagonist dihydropyridinesrdquo Electroanalysis vol 15 no 10 pp855ndash861 2003
[115] L Kourimska J Pokorny and G Tirzitis ldquoThe antioxidant aci-tivity of 26-dimethyl-35-diethoxycarbonyl-14-dihydropyri-dine in edible oilsrdquo Nahrung vol 37 no 1 pp 91ndash93 1993
[116] C Lopez-Alarcon H Speisky J A Squella C Olea-Azar CCamargo and L J Nunez-Vergara ldquoReactivity of 14-dihydro-pyridines toward SIN-1-derived peroxynitriterdquo PharmaceuticalResearch vol 21 no 10 pp 1750ndash1757 2004
[117] R A Olek W Ziolkowski J J Kaczor L Greci J Popinigisand J Antosiewicz ldquoAntioxidant activity of NADH and its ana-loguemdashan in vitro studyrdquo Journal of Biochemistry andMolecularBiology vol 37 no 4 pp 416ndash421 2004
[118] E Niki N Noguchi and N Gotoh ldquoInhibition of oxidativemodification of low density lipoprotein by antioxidantsrdquo Jour-nal of Nutritional Science andVitaminology vol 39 supplementpp S1ndashS8 1993
[119] N Rojstaczer and D J Triggle ldquoStructure-function relation-ships of calcium antagonists effect on oxidative modificationof low density lipoproteinrdquo Biochemical Pharmacology vol 51no 2 pp 141ndash150 1996
Oxidative Medicine and Cellular Longevity 31
[120] A Sevanian L Shen and FUrsini ldquoInhibition of LDLoxidationand oxidized LDL-induced cytotoxicity by dihydropyridinecalcium antagonistsrdquo Pharmaceutical Research vol 17 no 8 pp999ndash1006 2000
[121] A Negre-Salvayre and R Salvayre ldquoProtection by Ca2+ channelblockers (nifedipine diltiazem and verapamil) against the tox-icity of oxidized low density lipoprotein to cultured lymphoidcellsrdquo British Journal of Pharmacology vol 107 no 3 pp 738ndash744 1992
[122] A Negre-Salvayre G FitoussiM Troly and R Salvayre ldquoCom-parative cytoprotective effect of dihydropyridine calcium chan-nel blockers against the toxicity of oxidized low density lipopro-tein for cultured lymphoid cellsrdquo Biochemical Pharmacologyvol 44 no 12 pp 2379ndash2386 1992
[123] L Cominacini A F Pasini U Garbin et al ldquoAntioxidant activ-ity of different dihydropyridinesrdquo Biochemical and BiophysicalResearch Communications vol 302 no 4 pp 679ndash684 2003
[124] L Cominacini U Garbin A Fratta Pasini et al ldquoOxidized low-density lipoprotein increases the production of intracellularreactive oxygen species in endothelial cells inhibitory effect oflacidipinerdquo Journal of Hypertension vol 16 no 12 part 2 pp1913ndash1919 1998
[125] H M Lander ldquoAn essential role for free radicals and derivedspecies in signal transductionrdquo The FASEB Journal vol 11 no2 pp 118ndash124 1997
[126] M L L Martinez E Rizzi M M Castro et al ldquoLercanidipinedecreases vascular matrix metalloproteinase-2 activity andprotects against vascular dysfunction in diabetic ratsrdquo EuropeanJournal of Pharmacology vol 599 no 1ndash3 pp 110ndash116 2008
[127] P Lesnik C Dachet L Petit et al ldquoImpact of a combinationof a calcium antagonist and a 120573-blocker on cell- and copper-mediated oxidation of LDL and on the accumulation and effluxof cholesterol in human macrophages and murine J774 cellsrdquoArteriosclerosis Thrombosis and Vascular Biology vol 17 no 5pp 979ndash988 1997
[128] G Sobal E J Menzel and H Sinzinger ldquoCalcium antagonistsas inhibitors of in vitro low density lipoprotein oxidation andglycationrdquoBiochemical Pharmacology vol 61 no 3 pp 373ndash3792001
[129] E Lupo R Locher B Weisser and W Vetter ldquoIn vitro antiox-idant activity of calcium antagonists against LDL oxidationcompared with 120572-tocopherolrdquo Biochemical and BiophysicalResearch Communications vol 203 no 3 pp 1803ndash1808 1994
[130] J Zou Y Li H-Q Fan and J-G Wang ldquoEffects of dihydropy-ridine calcium channel blockers on oxidized low-density lipo-protein induced proliferation and oxidative stress of vascularsmooth muscle cellsrdquo BMC Research Notes vol 5 article 1682012
[131] C Napoli S Salomone T Godfraind et al ldquo14-Dihydro-pyridine calcium channel blockers inhibit plasma and LDL oxi-dation and formation of oxidation-specific epitopes in the arte-rial wall and prolong survival in stroke-prone spontaneouslyhypertensive ratsrdquo Stroke vol 30 no 9 pp 1907ndash1915 1999
[132] G Zernig I Graziadei T Moshammer C Zech N Reider andH Glossmann ldquoMitochondrial Ca2+ antagonist binding sitesare associated with an inner mitochondrial membrane anionchannelrdquo Molecular Pharmacology vol 38 no 3 pp 362ndash3691990
[133] F E Hunter Jr A Scott P E Hochstein et al ldquoStudies of themechanism of ascorbate-induced swelling and lysis of isolatedliver mitochondriardquo The Journal of Biological Chemistry vol239 pp 604ndash613 1964
[134] D R Janero B Burghardt and R Lopez ldquoProtection of cardiacmembrane phospholipid against oxidative injury by calciumantagonistsrdquoBiochemical Pharmacology vol 37 no 21 pp 4197ndash4203 1988
[135] A Karadag B Ozcelik and S S Saner ldquoReview of methods todetermine antioxidant capacitiesrdquo FoodAnalyticalMethods vol2 no 1 pp 41ndash60 2009
[136] Y I Gubskiı N V Litvinova and E V Shnurko-TabakovaldquoAntioxidant and antiradical activity of various classes of antiox-idantsrdquo Ukrainskiı Biokhimicheskiı Zhurnal vol 66 no 4 pp114ndash116 1994 (Russian)
[137] M Takei M Hiramatsu and A Mori ldquoInhibitory effects ofcalcium antagonists onmitochondrial swelling induced by lipidperoxidation or arachidonic acid in the rat brain in vitrordquoNeurochemical Research vol 19 no 9 pp 1199ndash1206 1994
[138] M Takei M Hiramatsu R Edamatsu and A Mori ldquoFreeradical scavenging by calcium antagonistsrdquo Neurosciences vol20 no 2 pp 75ndash82 1994
[139] Ya P Stradin G Ya Dubur Yu A Beilis Ya R Uldrikis andA F Korotkova ldquoVoltammetry of 14-dihydropyridine deriva-tives I Potentials of electrochemical oxidation of 35-diacyl-and 35-di(alkoxycarbonyl)-14-dihydropyridines in acetoni-trilerdquo Chemistry of Heterocyclic Compounds no 1 pp 84ndash871972 (Russian)
[140] E V Ivanov T V Ponomarjova G N Merkusev et al ldquoEinneuer Haut-Radioprotektor Diethon (experimentelle Unter-suchung)rdquo Radiobiologia Radiotherapia vol 31 no 1 pp 69ndash78 1990
[141] E V Ivanov T V Ponomareva G N Merkushev et al ldquoRadia-tion modulating properties of derivates of 14-dihydropyridineand 12345678910-decahydroacridine-18 dionerdquo Radiat-sionnaia Biologiia Radioecologiia vol 44 no 5 pp 550ndash5592004 (Russian)
[142] R O Vitolinia D A Berzinia A K Velena I A Vutsina A AKimenis and G Y Duburs ldquoThe protective effects of the cal-cium antagonist foridon in acute myocardial ischaemiardquo Kardi-ologiya vol 27 no 3 pp 90ndash93 1987 (Russian)
[143] A H Velena G Ya Duburs R O Vitolina et al ldquoEffect ofryodipine on electromechanical parameters of heart and vesselscAMP phosphodiesterase activity and swelling-contractioncycle of mitochondriardquo Arzneimittelforschung vol 35 no 6 pp907ndash914 1985
[144] L I Utno Z E Lipsberga A A Silova M I Girgensone EA Bisenieks and G I Ia ldquoCardioprotective properties of a 14-dihydropyridine derivative glutapyrone in deep hypothermiardquoBiulletenrsquo Eksperimentalrsquonoı Biologii i Meditsiny vol 108 no 11pp 558ndash561 1989 (Russian)
[145] M A S FernandesM S Santos J A F Vicente et al ldquoEffects of14-dihydropyridine derivatives (cerebrocrast gammapyroneglutapyrone and diethone) onmitochondrial bioenergetics andoxidative stress a comparative studyrdquoMitochondrion vol 3 no1 pp 47ndash59 2003
[146] M A S Fernandes M S Santos A J M Moreno et al ldquoEffectsof 5-acetyl(carbamoyl)-6-methylsulfanyl-14-dihydropyridine-5-carbonitriles on rat liver mitochondrial functionrdquo Toxicologyin Vitro vol 23 no 7 pp 1333ndash1341 2009
[147] L Klimaviciusa A Kalda A Kaasik et al ldquoNeuroprotectiveactivity of 14-dihydropyridine derivatives structure determi-nantsrdquo Proceedings of the Latvian Academy of Sciences BNatural Exact and Applied Sciences vol 61 no 1-2 pp 33ndash372007
32 Oxidative Medicine and Cellular Longevity
[148] L Klimaviciusa M A S Fernandes N Lencberga et alldquoTargeting the mitochondria by novel adamantane-containing14-dihydropyridine compoundsrdquo in Bioenergetics K B ClarkEd pp 257ndash272 InTech 2012
[149] V Klusa L Klimaviciusa G Duburs J Poikans and AZharkovsky ldquoAnti-neurotoxic effects of tauropyrone a taurineanaloguerdquo Advances in Experimental Medicine and Biology vol583 pp 499ndash508 2006
[150] N Sampson P Berger and Ch Zenzmaier ldquoRedox signalingas a therapeutic target to inhibit myofibroblast activation indegenerative fibrotic diseaserdquo BioMed Research Internationalvol 2014 Article ID 131737 14 pages 2014
[151] T L Leto and M Geiszt ldquoRole of Nox family NADPH oxidasesin host defenserdquoAntioxidantsampRedox Signaling vol 8 no 9-10pp 1549ndash1561 2006
[152] K K Griendling D Sorescu and M Ushio-Fukai ldquoNAD(P)Hoxidase role in cardiovascular biology and diseaserdquo CirculationResearch vol 86 no 5 pp 494ndash501 2000
[153] H Chen Y S Song and P H Chan ldquoInhibition of NADPHoxi-dase is neuroprotective after ischemia-reperfusionrdquo Journal ofCerebral Blood Flow and Metabolism vol 29 no 7 pp 1262ndash1272 2009
[154] P Hochstein and L Ernster ldquoADP-activated lipid peroxidationcoupled to the TPNH oxidase system of microsomesrdquo Biochem-ical and Biophysical Research Communications vol 12 no 5 pp388ndash394 1963
[155] I I Gubskiı AGGoriushkoNV Litvinova et al ldquoAntioxidantproperties and membranotropic effect of certain derivatives of14-dihydropyridinerdquo Ukrainskiı Biokhimicheskiı Zhurnal vol71 no 4 pp 35ndash39 1999 (Russian)
[156] F Engineer and R Sridhar ldquoInhibition of rat heart andliver microsomal lipid peroxidation by nifedipinerdquo BiochemicalPharmacology vol 38 no 8 pp 1279ndash1285 1989
[157] T Goncalves A P Carvalho and C R Oliveira ldquoAntioxidanteffect of calcium antagonists on microsomai membranes iso-lated from different brain areasrdquo European Journal of Pharma-cology vol 204 no 3 pp 315ndash322 1991
[158] M E Letelier P Izquierdo L Godoy A M Lepe and MFaundez ldquoLiver microsomal biotransformation of nitro-aryldrugs mechanism for potential oxidative stress inductionrdquoJournal of Applied Toxicology vol 24 no 6 pp 519ndash525 2004
[159] M E Letelier P Entrala C Lopez-Alarcon et al ldquoNitroaryl-14-dihydropyridines as antioxidants against rat liver microsomesoxidation induced by ironascorbate Nitrofurantoin and naph-thalenerdquo Toxicology in Vitro vol 21 no 8 pp 1610ndash1618 2007
[160] F P Guengerich W R Brian M Iwasaki M-A Sari CBaarnhielm and P Berntsson ldquoOxidation of dihydropyridinecalcium channel blockers and analogues by human liver cyto-chrome P-450 IIIA4rdquo Journal of Medicinal Chemistry vol 34no 6 pp 1838ndash1844 1991
[161] S H Park S-W RhaW-Y Shin et al ldquoAS-160 Calcium channelblockers of dihydropyridine class reduce the antiplatelet effectof Clopidogrel what is clinical impactrdquo The American Journalof Cardiology vol 107 no 8 supplement p 47A 2011
[162] C Asma and D M Reda ldquoEvaluation of dihydropyridinecalcium antagonist effects on the stress bioindicator orga-nism Saccharomyces cerevisiaerdquo Annals of Biological Researchvol 4 no 10 pp 40ndash46 2013 httpscholarsresearchlibrarycomABR-vol4-iss10ABR-2013-4-10-40-46pdf
[163] G Gaviraghi A M Pastorino E Ratti and D G TristldquoCalcium channel blockers with antioxidant activityrdquo in Free
Radicals Lipoprotein Oxidation andAtherosclerosis G BellomoG Finardi E Maggi and E Rice-Evans Eds pp 431ndash456Richelieu Press London UK 1995
[164] G Gaviraghi AM Pastorino E Ratti and D G Trist ldquoAntiox-idant dihydropyridines a new and comprehensive therapy forfree radical-induced cardiovascular diseasesrdquo in Free Radicalsin Biology and Environment F Minisci Ed vol 27 of NATOASI Series pp 193ndash221 Springer Dordrecht The Netherlands1997
[165] P D Henry ldquoAntiperoxidative actions of calcium antagonistsand atherogenesisrdquo Journal of Cardiovascular Pharmacologyvol 18 supplement 1 pp S6ndashS10 1991
[166] F Kouoh B Gressier T Dine et al ldquoAntioxidant effects andanti-elastase activity of the calcium antagonist nicardipine onactivated human and rabbit neutrophilsmdasha potential antiath-erosclerotic property of calcium antagonistsrdquo CardiovascularDrugs andTherapy vol 16 no 6 pp 515ndash520 2002
[167] S Parthasarathy D Litvinov K Selvarajan and M GarelnabildquoLipid peroxidation and decompositionmdashconflicting roles inplaque vulnerability and stabilityrdquo Biochimica et BiophysicaActa vol 1781 no 5 pp 221ndash231 2008
[168] D-Q Liu Z-Q Pang D-H Zhao and B-H Sheng ldquoEffects offuryl-dihydropyridines I on lipid peroxides of ischemic myo-cardium and ATPases activity of erythrocyte membranes inratsrdquo Acta Pharmacologica Sinica vol 12 no 3 pp 253ndash2561991
[169] V Lukic-Panin T Kamiya H Zhang et al ldquoPrevention of neu-ronal damage by calcium channel blockers with antioxidativeeffects after transient focal ischemia in ratsrdquo Brain Research vol1176 no 1 pp 143ndash150 2007
[170] Y Allanore D Borderie H Lemarechal O G Ekindjian andA Kahan ldquoAcute and sustained effects of dihydropyridine-typecalcium channel antagonists on oxidative stress in systemicsclerosisrdquo American Journal of Medicine vol 116 no 9 pp 595ndash600 2004
[171] I Casetta V Govoni and E Granieri ldquoOxidative stress antioxi-dants and neurodegenerative diseasesrdquo Current PharmaceuticalDesign vol 11 no 16 pp 2033ndash2052 2005
[172] M J T J Arts Assessing antioxidant activity [PhD the-sis] Maastricht University Maastricht The Netherlands 2007httparnounimaasnlshowcgifid=8676
[173] G Dıaz-Araya L Godoy L Naranjo A Squella M E Letelierand L J Nunez-Vergara ldquoAntioxidant effects of 14-dihydro-pyridine and nitroso aryl derivatives on the Fe+3ascorbate-stimulated lipid peroxidation in rat brain slicesrdquo General Phar-macology The Vascular System vol 31 no 3 pp 385ndash391 1998
[174] Y Fukuhara K Tsuchiya Y Horinouchi et al ldquoProtectiveeffect of photodegradation product of nifedipine against tumornecrosis factor 120572-induced oxidative stress in human glomerularendothelial cellsrdquo Journal of Medical Investigation vol 58 no1-2 pp 118ndash126 2011
[175] W Stengel M Jainz and K Andreas ldquoDifferent potencies ofdihydropyridine derivatives in blocking T-type but not L-typeCa2+ channels in neuroblastoma-glioma hybrid cellsrdquo EuropeanJournal of Pharmacology vol 342 no 2-3 pp 339ndash345 1998
[176] O M Panasenko D J Tirzite G D Tirzitis and G J DubursldquoEffect of some 14-dihydropyridine derivatives on structuralorganization of erythrocyte membranesrdquo Biologicheskie Mem-brany (Biochemistry (Moscow) Series A Membrane and CellBiology) vol 1 pp 919ndash925 1984 (Russian)
[177] L G Herbette Y M H Vant Erve and D G Rhodes ldquoInter-action of 14 dihydropyridine calcium channel antagonists with
Oxidative Medicine and Cellular Longevity 33
biological membranes lipid bilayer partitioning could occurbefore drug binding to receptorsrdquo Journal of Molecular andCellular Cardiology vol 21 no 2 pp 187ndash201 1989
[178] L G Herbette P E Mason G Gaviraghi T N Tulenko andR P Mason ldquoThe molecular basis for lacidipinersquos unique phar-macokinetics optimal hydrophobicity results in membraneinteractions that may facilitate the treatment of atherosclerosisrdquoJournal of Cardiovascular Pharmacology vol 23 supplement 5pp S16ndashS25 1994
[179] G V Belevitch G Y Dubur G E Dobretsov N K Kurek andM M Spirin ldquoCalcium antagonists riodipine nifedipine andverapamil binding to model and biological membranes fluore-scence analysisrdquo Biologicheskie Membrany (Biochemistry(Moscow) Series A Membrane and Cell Biology) vol 5 pp768ndash776 1988 (Russian)
[180] R P Mason G E Gonye D W Chester and L G HerbetteldquoPartitioning and location of Bay K 8644 14-dihydropyridinecalcium channel agonist in model and biological membranesrdquoBiophysical Journal vol 55 no 4 pp 769ndash778 1989
[181] M Cindric A Cipak J Serly et al ldquoReversal of multidrugresistance inmurine lymphoma cells by amphiphilic dihydropy-ridine antioxidant derivativerdquo Anticancer Research vol 30 no10 pp 4063ndash4070 2010
[182] F Shekari H Sadeghpour K Javidnia et al ldquoCytotoxic andmultidrug resistance reversal activities of novel 14-dihydro-pyridines against human cancer cellsrdquo European Journal ofPharmacology vol 746 no 1 pp 233ndash244 2015
[183] X-F Zhou Q Shao R A Coburn and M E Morris ldquoQuanti-tative structure-activity relationship and quantitative structure-pharmacokinetics relationship of 14-dihydropyridines andpyridines as multidrug resistance modulatorsrdquo PharmaceuticalResearch vol 22 no 12 pp 1989ndash1996 2005
[184] R Berkels T Breitenbach H Bartels et al ldquoDifferent antioxida-tive potencies of dihydropyridine calcium channel modulatorsin various modelsrdquo Vascular Pharmacology vol 42 no 4 pp145ndash152 2005
[185] S Borovic G Tirzitis D Tirzite et al ldquoBioactive 14-dihydro-isonicotinic acid derivatives prevent oxidative damage of livercellsrdquo European Journal of Pharmacology vol 537 no 1ndash3 pp12ndash19 2006
[186] D Ya Rubene G D Tirzitis and G Ya Duburs ldquoInteractionof some 14-dihydropyridine derivatives with Fentonrsquos reagentrdquoLatvijas PSRZinatnuAkademijas Vestis Kimijas Serija Proceed-ings of the Latvian SSR Academy of Sciences Chemistry Seriespp 212ndash216 1982 (Russian)
[187] K Ondrias V Misık D Gergel and A Stasko ldquoLipid per-oxidation of phosphatidylcholine liposomes depressed by thecalcium channel blockers nifedipine and verapamil and bythe antiarrhythmic-antihypoxic drug stobadinerdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1003 no 3pp 238ndash245 1989
[188] I T Mak and W B Weglicki ldquoComparative antioxidant acti-vities of propranolol nifedipine verapamil and diltiazemagainst sarcolemmal membrane lipid peroxidationrdquoCirculationResearch vol 66 no 5 pp 1449ndash1452 1990
[189] I T Mak P Boehme and W B Weglicki ldquoProtective effects ofcalcium channel blockers against free radical-impaired endo-thelial cell proliferationrdquo Biochemical Pharmacology vol 50 no9 pp 1531ndash1534 1995
[190] S Ray S Mondal and N Dana ldquoEvaluation of protective roleof nifedipine on lipid peroxidation using reduced glutathione as
model markerrdquo Oxidants and Antioxidants in Medical Sciencevol 1 no 2 pp 97ndash100 2012
[191] M Yamato T Shiba T Ide Y Honda K-I Yamada andH Tsutsui ldquoNifedipine treatment reduces brain damage aftertransient focal ischemia possibly through its antioxidativeeffectsrdquoHypertension Research vol 34 no 7 pp 840ndash845 2011
[192] V Chander and K Chopra ldquoNifedipine attenuates changes innitric oxide levels renal oxidative stress and nephrotoxicityinduced by cyclosporinerdquo Renal Failure vol 27 no 4 pp 441ndash450 2005
[193] K M Gaafa M M Badawy and A A Hamza ldquoThe protectiveeffects of ascorbic acid cimetidine and nifedipine on diethyl-dithiocarbamate-induced hepatic toxicity in albino ratsrdquo Drugand Chemical Toxicology vol 34 no 4 pp 405ndash419 2011
[194] H Sugawara K Tobise and S Onodera ldquoAbsence of antiox-idant effects of nifedipine and diltiazem on myocardial mem-brane lipid peroxidation in contrast with those of nisoldipineand propranololrdquo Biochemical Pharmacology vol 47 no 5 pp887ndash892 1994
[195] I E Kirule D Y Rubene E A Bisenieks G D Tirzit and GY Dubur ldquo4-Nitrophenyl-14-dihydropyridinesmdasha new groupof inhibitors of peroxide oxidationrdquo Chemistry of HeterocyclicCompounds vol 18 no 3 p 316 1982
[196] G D Tirzit I E Kirule L K Baumane R A Gavar Y PStradynrsquo andG YDubur ldquoMechanism of the antioxidant actionof 26-dimethyl-35-dimethoxy-carbonyl-4-(2-nitrophenyl)14-dihydropyridinerdquoChemistry ofHeterocyclic Compounds vol 20no 8 pp 915ndash918 1984
[197] C Yanez C Lopez-Alarcon C Camargo V Valenzuela J ASquella and L J Nunez-Vergara ldquoStructural effects on thereactivity 14-dihydropyridines with alkylperoxyl radicals andABTS radical cationrdquo Bioorganic and Medicinal Chemistry vol12 no 9 pp 2459ndash2468 2004
[198] VMisik A J Stasko D Gergel and K Ondrias ldquoSpin-trappingand antioxidant properties of illuminated and nonilluminatednifedipine and nimodipine in heart homogenate and modelsystemrdquo Molecular Pharmacology vol 40 no 3 pp 435ndash4391991
[199] K Ondrias V Misık A Stasko D Gergelrsquo and M HromadovaldquoComparison of antioxidant properties of nifedipine and illu-minated nifedipine with nitroso spin traps in low densitylipoproteins and phosphatidylcholine liposomesrdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1211 no 1pp 114ndash119 1994
[200] A Stasko V Brezova S Biskupic K Ondrias and V MisıkldquoReactive radical intermediates formed from illuminated nife-dipinerdquoFree Radical Biology andMedicine vol 17 no 6 pp 545ndash556 1994
[201] K Ishizawa Y Izawa-Ishizawa N Yamano et al ldquoNitrosoni-fedipine ameliorates the progression of type 2 diabetic nephro-pathy by exerting antioxidative effectsrdquo PLoS ONE vol 9 no 1Article ID e86335 2014
[202] H Fujii and L J Berliner ldquoIn vivo EPR evidence for free radicaladducts of nifedipinerdquoMagnetic Resonance in Medicine vol 42no 4 pp 691ndash694 1999
[203] S Bollo S Finger J C Sturm L J Nunez-Vergara and JA Squella ldquoCyclic voltammetry and scanning electrochemicalmicroscopy studies of the heterogeneous electron transferreaction of some nitrosoaromatic compoundsrdquo ElectrochimicaActa vol 52 no 15 pp 4892ndash4898 2007
34 Oxidative Medicine and Cellular Longevity
[204] F Ursini ldquoTissue protection by lacidipine insight from redoxbehaviorrdquo Journal of Cardiovascular Pharmacology vol 30supplement 2 pp S28ndashS30 1997
[205] P G Cristofori F A Crivellente I Faustinelli et al ldquoInvolve-ment of the nitric oxide system in the anti-atheroscleroticpotential of lacidipine in the apoE-deficient mouse a mor-phological functional and electrochemical studyrdquo ToxicologicPathology vol 32 no 4 pp 493ndash499 2004
[206] X-P Zhang E L Kit S Mital S Chahwala and T HHintze ldquoParadoxical release of nitric oxide by an L-type calciumchannel antagonist the R+ enantiomer of amlodipinerdquo Journalof Cardiovascular Pharmacology vol 39 no 2 pp 208ndash2142002
[207] F Franzoni G Santoro F Regoli et al ldquoAn in vitro study of theperoxyl and hydroxyl radical scavenging capacity of the calciumantagonist amlodipinerdquo Biomedicine and Pharmacotherapy vol58 no 8 pp 423ndash426 2004
[208] S V Gatsura ldquoOxygen-dependent mechanisms underlying theantiischemic effect of verapamil and amlodipinerdquo Bulletin ofExperimental Biology and Medicine vol 137 no 1 pp 40ndash422004
[209] Y Hirooka Y Kimura M Nozoe Y Sagara K Ito and KSunagawa ldquoAmlodipine-induced reduction of oxidative stressin the brain is associated with sympatho-inhibitory effects instroke-prone spontaneously hypertensive ratsrdquo HypertensionResearch vol 29 no 1 pp 49ndash56 2006
[210] B Tomlinson and I F F Benzie ldquoAntioxidant effect of lercani-dipine (note)rdquo Hypertension vol 42 no 4 pp e10ndashe11 2003
[211] A A Faraqui ldquoNeurochemical aspects of 4-hydroxynonenalrdquoin Lipid Mediators and Their Metabolism in the Brain A AFaraqui Ed chapter 6 pp 159ndash191 Springer New York NYUSA 2011
[212] V S NascimentoM S DrsquoAlva A AOliveira et al ldquoAntioxidanteffect of nimodipine in young rats after pilocarpine-inducedseizuresrdquo Pharmacology Biochemistry and Behavior vol 82 no1 pp 11ndash16 2005
[213] O Ismailoglu P Atilla S Palaoglu et al ldquoThe therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjuryrdquo Turkish Neurosurgery vol 22 no 6 pp 740ndash746 2012
[214] M Matsubara and K Hasegawa ldquoBenidipine a dihydropy-ridine-calcium channel blocker prevents lysophosphatidyl-choline-induced injury and reactive oxygen species productionin human aortic endothelial cellsrdquo Atherosclerosis vol 178 no1 pp 57ndash66 2005
[215] M Matsubara K Yao and K Hasegawa ldquoBenidipine adihydropyridine-calcium channel blocker inhibits lysophos-phatidylcholine-induced endothelial injury via stimulation ofnitric oxide releaserdquo Pharmacological Research vol 53 no 1 pp35ndash43 2006
[216] MMatsubara and K Hasegawa ldquoEffects of benidipine a dihyd-ropyridine-Ca2+ channel blocker on expression of cytokine-induced adhesion molecules and chemoattractants in humanaortic endothelial cellsrdquo European Journal of Pharmacology vol498 no 1ndash3 pp 303ndash314 2004
[217] M Matsubara O Akizuki J-I Ikeda K Saeki K Yao and KSasaki ldquoBenidipine an anti-hypertensive drug inhibits reactiveoxygen species production in polymorphonuclear leukocytesand oxidative stress in salt-loaded stroke-prone spontaneouslyhypertensive ratsrdquo European Journal of Pharmacology vol 580no 1-2 pp 201ndash213 2008
[218] A C Rosenkranz H Lob T Breitenbach R Berkels and RRoesen ldquoEndothelial antioxidant actions of dihydropyridines
and angiotensin converting enzyme inhibitorsrdquo European Jour-nal of Pharmacology vol 529 no 1ndash3 pp 55ndash62 2006
[219] V Kain S Kumar and S L Sitasawad ldquoAzelnidipine preventscardiac dysfunction in streptozotocin-diabetic rats by reducingintracellular calcium accumulation oxidative stress and apop-tosisrdquo Cardiovascular Diabetology vol 10 article 97 2011
[220] K Nakamura S Yamagishi and H Inoue ldquoUnique atheropro-tective property of azelnidipine a dihydropyridine-based cal-cium antagonistrdquoMedical Hypotheses vol 65 no 1 pp 155ndash1572005
[221] TMatsui S Yamagishi K Nakamura S Kikuchi andH InoueldquoAzelnidipine a dihydropyridine-based calcium antagonistinhibits angiotensin II-induced oxidative stress generation anddownregulation of pigment epithelium-derived factor mRNAlevels in microvascular endothelial cellsrdquo Drugs under Experi-mental and Clinical Research vol 31 no 5-6 pp 215ndash219 2005
[222] C Ohmura H Watada T Shimizu et al ldquoCalcium channelblocker azelnidipine reduces lipid hydroperoxides in patientswith type 2 diabetes independent of blood pressurerdquo EndocrineJournal vol 54 no 5 pp 805ndash811 2007
[223] H Daikuhara F Kikuchi and T Ishida ldquoThe combination ofOLmesartan and a CAlcium channel blocker (azelnidipine) orcandesartan and a calcium channel blocker (amlodipine) intype 2 diabetic hypertensive patients theOLCA studyrdquoDiabetesand Vascular Disease Research vol 9 no 4 pp 280ndash286 2012
[224] MAbe NMaruyama KOkada SMatsumoto KMatsumotoand M Soma ldquoAdditive antioxidative effects of azelnidipine onangiotensin receptor blocker olmesartan treatment for type 2diabetic patients with albuminuriardquoHypertension Research vol34 no 8 pp 935ndash941 2011
[225] K Mizushige ldquoAntioxidative activities of thiazolidinedionesand dihydropyridine-type calcium antagonistsrdquo IRYOmdashJapa-nese Journal of National Medical Services vol 59 no 11 pp 581ndash592 2005
[226] S Manabe T Okura T Fukuoka and J Higaki ldquoAntioxidativeeffects of azelnidipine on mesangial cell proliferation inducedby highly concentrated insulinrdquo European Journal of Pharma-cology vol 567 no 3 pp 252ndash257 2007
[227] Y Koyama Y Takeishi H Takahashi et al ldquoAzelnidipine inhi-bits H
2O2-induced cell death in neonatal rat cardiomyocytesrdquo
CardiovascularDrugs andTherapy vol 21 no 1 pp 69ndash72 2007[228] K Shinomiya K Mizushige M Fukunaga et al ldquoAntioxidant
effect of a new calcium antagonist azelnipidine in culturedhuman arterial endothelial cellsrdquo Journal of International Med-ical Research vol 32 no 2 pp 170ndash175 2004
[229] T Ohyama K Sato K Kishimoto et al ldquoAzelnidipine is acalcium blocker that attenuates liver fibrosis and may increaseantioxidant defencerdquo British Journal of Pharmacology vol 165no 4 pp 1173ndash1187 2012
[230] L A Calo F Zaghetto E Pagnin P A Davis A Sempliciniand A C Pessina ldquoEffect of manidipine on gene expressionand protein level of oxidative stress-related proteins p22phoxand HO-1 Relevance for antihypertensive and anti-remodelingeffectsrdquo Journal of Cardiovascular Pharmacology vol 43 no 4pp 531ndash538 2004
[231] R Ghyasi G Sepehri M Mohammadi R Badalzadeh and AGhyasi ldquoEffect of mebudipine on oxidative stress and lipid per-oxidation in myocardial ischemic-reperfusion injury in maleratrdquo Journal of Research in Medical Sciences vol 17 no 12 pp1150ndash1155 2012
Oxidative Medicine and Cellular Longevity 35
[232] DCAndersson J Fauconnier T Yamada et al ldquoMitochondrialproduction of reactive oxygen species contributes to the 120573-adrenergic stimulation of mouse cardiomycytesrdquoThe Journal ofPhysiology vol 589 no 7 pp 1791ndash1801 2011
[233] A F Ceylan-Isik N Ari M Stefek et al ldquoEffects of a long-term treatment with an antioxidant pyridoindole on vascularresponsiveness in diabetes-induced aging ratsrdquo Current AgingScience vol 4 no 2 pp 150ndash157 2011
[234] S Saponara G Sgaragli and F Fusi ldquoQuercetin antagonismof Bay K 8644 effects on rat tail artery L-type Ca2+ channelsrdquoEuropean Journal of Pharmacology vol 598 no 1ndash3 pp 75ndash802008
[235] D A Sica ldquoInteraction of grapefruit juice and calcium channelblockersrdquo American Journal of Hypertension vol 19 no 7 pp768ndash773 2006
[236] P Mulder G Litwinienko S Lin P D MacLean L R CBarclay and K U Ingold ldquoThe L-type calcium channel block-ers Hantzsch 14-dihydropyridines are not peroxyl radical-trapping chain-breaking antioxidantsrdquo Chemical Research inToxicology vol 19 no 1 pp 79ndash85 2006
[237] L J Nunez-Vergara R Salazar C Camargo et al ldquoOxidation ofC4-hydroxyphenyl 14-dihydropyridines in dimethylsulfoxideand its reactivity towards alkylperoxyl radicals in aqueousmediumrdquo Bioorganic and Medicinal Chemistry vol 15 no 12pp 4318ndash4326 2007
[238] M E Ortiz L J Nunez-Vergara and J A Squella ldquoRelativereactivity of dihydropyridine derivatives to electrogeneratedsuperoxide ion in DMSO solutions a voltammetric approachrdquoPharmaceutical Research vol 20 no 2 pp 292ndash296 2003
[239] M E Ortiz L J Nunez-Vergara C Camargo and J A SquellaldquoOxidation of Hantzsch 14-dihydropyridines of pharmacolog-ical significance by electrogenerated superoxiderdquo Pharmaceuti-cal Research vol 21 no 3 pp 428ndash435 2004
[240] R S Raghuvanshi and K N Singh ldquoSuperoxide induced oxida-tive aromatization of Hantzsch 14-dihydropyridinesrdquo IndianJournal of Chemistry Section B Organic and Medicinal Chem-istry vol 47 no 11 pp 1735ndash1738 2008
[241] I Kruk A Kladna K Lichszteld et al ldquoAntioxidant activityof 4-flavonil-14-dihydropyridine derivativesrdquo Biopolymers vol62 no 3 pp 163ndash167 2001
[242] G D Tirzit I M Byteva K I Salokhiddinov G P Gurinovichand G Y Dubur ldquo14-Dihydropyridine derivatives as deactiva-tors of singlet oxygenrdquo Chemistry of Heterocyclic Compoundsvol 17 no 7 pp 682ndash684 1981
[243] G D Tirzit E Y Kazush and G Y Dubur ldquoInfluence of14-dihydropyridine derivatives on the generation of hydroxylradicalsrdquo Chemistry of Heterocyclic Compounds vol 28 no 4pp 435ndash437 1992
[244] N A Pizarro-Urzua and L J Nunez-Vergara ldquoNifedipine andnitrendipine reactivity toward singlet oxygenrdquo Journal of Photo-chemistry and Photobiology A Chemistry vol 175 no 2-3 pp129ndash137 2005
[245] L-F Wang H-Y Zhang L Konga Z-W Chena and J-G ShildquoDFT calculations indicate that 14-dihydropyridine is a promis-ing lead antioxidantrdquo Helvetica Chimica Acta vol 87 no 6 pp1515ndash1521 2004
[246] P Mulder H-G Korth and K U Ingold ldquoWhy quantum-thermochemical calculations must be used with caution toindicate lsquoa promising lead antioxidantrsquordquoHelvetica Chimica Actavol 88 no 2 pp 370ndash374 2005
[247] K Yao Y Ina K Nagashima K Ohmori and T Ohno ldquoAntiox-idant effects of calcium antagonists in rat brain homogenatesrdquo
Biological and Pharmaceutical Bulletin vol 23 no 6 pp 766ndash769 2000
[248] T Matsui S-I Yamagishi K Nakamura and H Inoue ldquoBayw 9798 a dihydropyridine structurally related to nifedipinewith no calcium channel-blocking properties inhibits tumournecrosis factor-120572-induced vascular cell adhesion molecule-1expression in endothelial cells by suppressing reactive oxygenspecies generationrdquo Journal of International Medical Researchvol 35 no 6 pp 886ndash891 2007
[249] K AMitrega B VargheseM Porc and T F Krzeminski ldquoAnti-arrhythmic and hemodynamic effects of oxy nifedipine oxynimodipine oxy nitrendipine and oxy nisoldipinerdquo Pharmaco-logical Research vol 66 no 4 pp 300ndash308 2012
[250] V Herbert ldquoSymposium prooxidant effects of antioxidantvitamins Introductionrdquo The Journal of Nutrition vol 126 no4 supplement pp 1197Sndash1200S 1996 httpjnnutritionorgcontent1264 Suppl1197Sfullpdf
[251] B Halliwell ldquoAre polyphenols antioxidants or pro-oxidantsWhat do we learn from cell culture and in vivo studiesrdquoArchives of Biochemistry and Biophysics vol 476 no 2 pp 107ndash112 2008
[252] C Winterbourn Pro-Oxidants or Antioxidants ChristchurchSchool of Medicine Depatment of Pathology Free RadicalSchool SFRBMUniversity of Otago San Francisco Calif USA2009 httpwwwsfrbmorgfrsWinterbournpdf
[253] A Morakinyo B Iranloye and O Adegoke ldquoCalcium antag-onists modulate oxidative stress and acrosomal reaction in ratspermatozoardquo Archives of Medical Science vol 7 no 4 pp 613ndash618 2011
[254] The Alpha-Tocopherol Beta Carotene Cancer Prevention StudyGroup ldquoThe effect of vitamin E and beta carotene on theincidence of lung cancer and other cancers in male smokersrdquoTheNew England Journal of Medicine vol 330 no 15 pp 1029ndash1035 1994
[255] B Poljsak ldquoStrategies for reducing or preventing the generationof oxidative stressrdquo Oxidative Medicine and Cellular Longevityvol 2011 Article ID 194586 15 pages 2011
[256] B Poljsak and I Milisav ldquoThe neglected significance of lsquoanti-oxidative stressrsquordquoOxidativeMedicine and Cellular Longevity vol2012 Article ID 480895 12 pages 2012
[257] T Godfraind and S Salomone ldquoAmbiguities in dietary antiox-idant supplementation compared to calcium channel blockerstherapyrdquo Frontiers in Pharmacology vol 6 article 10 2015
[258] H Wagner H Norr and H Winterhoff ldquoDrugs with adap-togenic effects for strengthening the powers of resistancerdquoZeitschrift fur Phytotherapie vol 13 no 2 pp 42ndash54 1992
Oxidative Medicine and Cellular Longevity 23
Detailed studies were made about substituent in DHPring positions 14- namely 4-unsubstituted- 4-substituted4-alkyl- 4-aryl- 4-alkylaryl- ao 26- 35- (diacetyl ordialkoxycarbonyl chain ao) electronic and steric effects onAOA and ARA of DHPs [44 45 51] see Sections 331and 35 The bell-shaped dependence of DHPs AOA onthe 35-dialkoxycarbonyl- chain length was observed [4445 107 109 112] with the maximum activity at C
2H5ndash
C4H9 Decrease of AOA and incorporation into liposomes for
DHPs with alkyl chains longer than R gt C4H9further were
clarified as probable tendency to self-aggregation of thesecompounds ([51] and citation number 245 therein) Electronacceptorelectron donor properties are relevant for expres-sion of AOA or ARA of 35-disubstituted DHPs 35-Diacyl-substituted and 35-dicarbanilido- and 35-dipyridylamido-substituted DHPs are more active as AOs as their 35-dicyano-substituted analogues which have electron acceptorproperties [186]
Dubur et al [89] observed overwhelming steric influenceof substituents in position 4 of the DHP ring Gaviraghiet al [163 164] proposed that AO activity of DHPs ispartly dependent on capacity of the 14-DHP ring to donateelectrons to the propagating radical (ROO∙ or RO∙) and toreduce it to a less reactive form The abstraction (donation)of electron andor H in the oxidation and LP reactionstakes place from all 35-dicarbonyl-14-DHP systems andresults in the formation of corresponding pyridine derivatives(Augustyniak et al [51]) The physicochemical mechanism ofARA and AOA of 14-DHP has been extensively studied anddiscussed (Mulder et al [236]) but precise mechanisms oftheir activity need further clarification
The reactivity of C-4 substituted 14-DHPs possessingeither secondary or tertiary nitrogen atom in the DHP ringtoward alkyl alkylperoxyl radicals and ABTS radical cationwas determined in aqueous media at pH 74 [103] Thesecompounds reacted faster toward alkylperoxyl radicals andABTS radical cation than alkyl ones N-Ethyl-substitutedDHPs showed the lowest reactivity
The 4-methyl substituted DHP was the most reac-tive compound in previously mentioned reactions (Lopez-Alarcon et al [103]) However it was less active (068versus 10) than Trolox-C DHPs having electron-donatingsubstituents (4-Me-DHP and p-MeO-Phe-DHP) showed thehighest kinetic rate constants toward ABTS radical cation p-nitro-Phe-DHP a compound with an electron-withdrawingsubstituent showed a lower kinetic rate constant and N-alkyl-DHP compounds show kinetic rate constants lowerthan the -NH-DHP
Hydrogen at the 1-position of the DHP ring was revealedaccording to the deuteriumkinetic isotope effect studies to beinvolved in the proposedARAmechanismThis fact ismostlynoticeable in the case of alkyl radicals N-Ethyl-substitutedDHPs show the lowest reactivity when compared to Troloxor nisoldipine In all cases the respective pyridine derivativewas detected as the main product of the reaction (Lopez-Alarcon et al [103]) Authors indicate that the kinetic rateconstants toward alkyl alkylperoxyl andABTS radical cationdepend on the nature of the substituents in the C-4 positionof DHP and the presence of the secondary amine group in the
dihydropyridine ring that is the presence of the hydrogen in1-position
Yanez et al [197] have studied the reactivity of 11derivatives of 14-DHPs (including commercial CA) withalkylperoxyl radicals and ABTS radical cation The tested14-DHPs were 83-fold more reactive towards alkylperoxylradicals than to the ABTS cation radical All commercial14-DHP type CCBs were weaker than Trolox-C The par-ticipation of the hydrogen atom in the 1-position appearsto be very relevant for exhibited reactivity Hantzsch ester(diludine)was again found to be themost active compound inthe reaction with alkylperoxyl radicals 23-fold more activethan Trolox The photodegradation product of nifedipine(nitrosophenyl derivative of pyridine) also showed a highactivity Kinetic rate constants for the reaction between 14-DHP compounds and alkylperoxyl radicals exhibited a fairlygood linear correlation with the oxidation peak potentialof DHP derivatives However the activity of tested 14-DHPs towards ABTS radical cation showed an independencebetween kinetic rate constants and oxidation peak potentials
Kirule et al [195] andTirzit et al [196] studiedmechanismof AOA of 4-nitrophenyl-14-DHPs nifedipine and its ana-logues involving formation of 4-(21015840-nitrosophenyl)-pyridinederivative (as active principle) as a result of intramolecularredox reaction using chemical electrochemical and bio-chemical approaches (see Sections 331 and 351)
Nunez-Vergara et al [237] reported the electrochemicaloxidation of C4-hydroxyphenyl-substituted 14-DHP deriva-tives The oxidation proceeds via formation of the unstabledihydropyridyl radical as confirmed by controlled-potentialelectrolysis (CPE) and ESR experiments This type of 14-DHPs has significant activity towards the radicals even whencompared with commercial 14-DHP drugs with well-knownantioxidant ability
It was observed that nicardipine preferentially targets RO∙radicals and is inactive against ROO∙ Lacidipine on theother hand is equally active towards both types of radicals(Gaviraghi et al [164]) The cytoprotective effect againstexposure to H
2O2was more significant for lacidipine (ID
50=
14 nM its log119875 = 54 membrane partition = 136000 assumesposition located 7 A near to the membrane center otherless lipophilic DHPs located 12ndash16 A far from the center)as compared to amlodipine nifedipine and nicardipine insmooth muscle cell culture (Gaviraghi et al [164]) Oxidativeeffect of H
2O2shifts the Ca channel toward an open state
Thus the redox property of CCBs DHPs may augment theirCCB properties
Oxidation of pharmacologically active Hantzsch 14-dihydropyridines was found by electrogenerated superoxideusing a voltammetric approach in DMSO solutions (Ortiz etal [238] and Ortiz et al [239]) Raghuvanshi and Singh [240]have also reported oxidative aromatization of these DHPsinduced by superoxide
Chemiluminescence (CL) was used in the studies ana-lyzing the antioxidant activity of 12 various 4-flavonil-14-dihydropyridine derivatives (Kruk et al [241]) on a chemicalsystem involving a superoxide radical anion These deriva-tives showed structural similarity to flavonoids with respectto the presence of rings A B and C The results obtained in
24 Oxidative Medicine and Cellular Longevity
this study indicate that the tested derivatives may catalyzeconversion of superoxide radicals through mimicking theactivity of superoxide dismutase by delivering H+ for reac-tion
O2
minus∙+O2
minus∙+ 2H+ 997888rarr H
2O2+1O2
(3)
The enhanced emission of the light in the presence oftested compounds was significant and related to stimulatedproduction ofH
2O2and 1O
2fromO
2
∙The latter specieswereremoved from the reactionmixture by the following sequenceof reactions
H+
O2
minus∙997888rarr HO
2
∙
HO2
∙+O2
∙minus997888rarr HO
2
minus+1O2
2HO2
∙997888rarr H
2O2+1O2
2 (1O2) 997888rarr (O
2)2+ h]lowast
(4)
or to take part in spontaneous dismutation of H2O2
2H2O2997888rarr 2H
2O + 1O
2(5)
The authors have offered an original concept of action for 4-flavonil-14-dihydropyridine derivatives unrelated to that ofO2
∙ radical-trapping chain-breaking antioxidants Insteadthey showed that these compounds act similar to superoxidedismutases converting O
2
∙ to H2O2 Hydrogen peroxide
is less toxic for cells than O2
∙ because it is predominantlyremoved by peroxidases and catalases Finally AO effect ofthese DHPs differed from those mediated by flavonoids witha catechol structure of ring B which are well-known 1O
2
quenchersMulder and collaborators came to similar conclusions
especially related to molecular mechanisms of antioxidativeactivity of DHPs [236]TheAOproperties of Hantzsch 14-di-hydropyridine esters and two dibenzo-14-dihydropyridines910-dihydroacridine (DHAC) and N-methyl-910-dihydro-acridine (N-Me-DHAC) have been explored by determin-ing the autoxidation of styrene or cumene at 30∘C Theseexperiments showed that Hantzsch esters are virtually inac-tive as chain-breaking antioxidants (CB-AOs) contrary tothe findings observed by Lopez-Alarcon et al [103] whoused CB-AOA in aqueous media at pH 74 Their reactivitytoward peroxyl radicals was shown to be some 5 orders ofmagnitude lower than that of the excellent CB-AO 22578-pentamethyl-6-hydroxy-chroman (PMHC)
DHAC was found to be sim10 times less reactive thanPMHC kinetic measurements using DHAC N-deuterio-DHAC and N-Me-DHAC pointing out the abstraction ofN-H hydrogen in DHAC by peroxyl radicals despite the factthat the calculated C-H bond dissociation enthalpy (BDE) inDHAC is about 11 kcalmol lower than the N-H BDE Therates of hydrogen atom abstraction by the 22-diphenyl-1-picrylhydrazyl radical (DPPH∙) have also been determined
for the same series of compounds The trends in the peroxyl∙and DPPH∙ rate constants were found to be similar [236]
Tirzit et al [242] have observed quenching of singletoxygen by DHPs This observation paved the ground forfurther research related to reactions of DHPs with hydroxylradicals (Tirzit et al [243]) singlet oxygen (Kazush etal [94]) and mechanisms of action A series of 14-DHPderivatives in NAD-H-Cu2+-H
2O2system inhibited forming
of the hydroxyl radical (HO∙) while 14-DHP derivativeswith electron donor substituents in the molecule were shownto be capable themselves of generating HO∙ in the presenceof Cu2+ and H
2O2 Rubene et al [186] also described
interaction of 14-DHP derivatives with Fentonrsquos reagentwhich produces hydroxyl radical (HO∙) Rate constants ofthe DHPs reaction (1st order) with HO∙ radical were highin the range 109 L times mol times secminus1 close to that of NADHcysteine and thiourea 35-Diacetyl- derivatives reacted fastercompared to 35-dialkoxycarbonyl- ones The reaction ratedecrease was observed in the case of substitution at position4 as compared to 4-unsubstituted DHPs Some DHPs havingelectron donor -COOminus groups in the 35- or 26- positionsof DHP ring reacted immediately (having rate constantshigher as 109 L times mol times secminus1) Rate constants with HO
2
∙
and O2
∙minus radicals were of lower degree Thus DHPs actingas oxygen radical scavengers could effectively inhibit ROSrelated reactions of LP initiation stage
Nifedipine and nitrendipine reactivity toward singletoxygen was also studied [244] Nifedipine was shown tobe a good scavenger of excited oxygen mainly via physicaldeactivation with values of the total rate constant rangingfrom 208 times 105Mminus1 sminus1 (in dioxane) to 930 times 105Mminus1 sminus1(in propylene carbonate)The less reactive pathway generateda photooxidation product For that reason a mechanisminvolving a perepoxide-like encounter complex in the firststep of the reaction path was proposed (see [244] Figures8 and 9 therein) The dependence was observed on solventmicroscopic parameters of the total rate constant for the reac-tion between singlet oxygen and 14-DHPs These findingsshow that nifedipine possesses stronger protective activity inbiological systems than nitrendipine
Density-functional-theory (DFT) calculations made byWang et al [245] confirmed the former experimental obser-vations that Hantzsch ester diludine is potent antioxi-dant with high H atom-donating ability and relatively lowprooxidant activity Possible reaction pathways for radicalsderived from 14-dihydropyridine and the resonance modesfor radical species were given [245]
Moreover two ethoxycarbonyl (EtOCO) substituentsat C(2) and C(6) should further enhance Hantzsch esterdiludine H-atom-donating ability due to resonance effectsHowever DHPs should be used in nonpolar rather than inpolar solvents since in the latter not H-atom but electrontransfer is preferred in the radical scavenging process [245]
Mulder et al [246] proposed that quantum-thermochem-ical calculations must be used with caution to indicate ldquoapromising lead antioxidantrdquo as they criticized the density-functional-theory (DFT) calculations made by Wang et al[245]
Oxidative Medicine and Cellular Longevity 25
372 Possible Mechanisms of DHPs ARA and AOA in the Bio-logical Systems Interaction with Other OSModifiers Some ofthese mechanisms were already described (Sections 331 (2)-(b) 331 (2)-(c) 331 (3)-(b) 35)
Enzymatic sources of ROSwith confirmed functional rolein hypertension are NADPH oxidase NO synthase (NOS)xanthine oxidase and cyclooxygenase Godfraind [3] hasreviewed AO effects and protective action of calcium channelblockers (CCBs) Yao et al [247] observed antioxidant effects(as inhibition of LP) for cardio- and neuroprotective CCBs(3ndash300 120583molL) including 7 DHPs in homogenates of ratbrain IC
50values (120583M) were as follows nifedipine (515) gt
barnidipine (586) gt benidipine (712) gt nicardipine (1293)gt amlodipine (1355) gt nilvadipine (1673) gt nitrendipine(2521) gt diltiazem (gt300) = verapamil (gt300) There arealso research articles describing the AO properties of CCBsthrough direct scavenging effect or through preservationof the endogenous SOD activity These findings indicatethat CCBs may also act by reducing the production ofvasoconstrictors angiotensin and endothelin
When present in concentrations that can be achievedin plasma CCBs may inhibit LP formation [3] This AOactivity seems to be typical for high lipophilic CCBs becausetheir chemical structure facilitates proton-donating andresonance-stabilization mechanisms that quench the freeradical reaction Their insertion in the membrane nearpolyunsaturated fatty acids at relatively high concentrationspotentiates proton donation (or atomary H) to lipid peroxidemolecules thereby blocking the peroxidation process Theremaining unpaired free electron associated with the CCBmolecule can be stabilized in well-defined resonance struc-tures associated with the DHP ring (Mason et al [48])
The radical reaction (according to Godfraind [3]) thatdescribes the AO effects of a DHP CCBs is LOOlowast + DHPrarr LOOH + DHPlowast (where LOOlowast is lipid peroxide radical)which in general is reaction (7) of the LP reaction cascadeconsisting of sim10 reactions (Scheme 2) [89]
As the rate constants of in vitro interaction of 4-substituted DHPs with peroxyl radicals are three ordersof magnitude lower than that of the vitamin E derivativethese DHPs must be considered as weak AO (Ursini [204])However due to partition coefficient of DHPs in membranesand in case of specific binding high local concentration ofDHPs may be obtained
DHPs without CCB properties for instance Bay w 9798although structurally related to nifedipine inhibit TNF-120572-induced vascular cell adhesion molecule-1 expression inendothelial cells by suppressing reactive oxygen speciesgeneration [248]
Mitrega et al [249] have discovered that antiarrhythmicand hemodynamic effects of oxidized heteroaromatic DHPsoxy nifedipine oxy nimodipine oxy nitrendipine and oxynisoldipine suggest that CCB DHPs and their metabolitescould act at least in two ways targeting OS related eventsas reductants (see Section 351 (1)) andor bypassing OSrelatedmetabolic routes Authors postulated that contrary tocurrent belief NIF metabolites are pharmacologically activeATP sensitive potassium channels were mentioned as a tar-get
38 DHPs Anti- or Prooxidants Several substances (ascorbicacid being the most commonly studied) can serve either asantioxidants or as prooxidants depending on given condi-tions (Herbert [250]) Therefore Halliwell [251] has reporteddilemma related to polyphenols as possible antioxidantsand prooxidants causing experimental artifacts (about 25)by oxidation of antioxidant compounds in the cell culturemedia Nevertheless it is generally accepted opinion thatpolyphenols act as antioxidants in vivo Studies on DHPs alsoface such a dilemmaThe exact roles (anti- or prooxidative) ofany specific DHP depend on its structure appliedachievedconcentration and specificity of the targetexperimentaltesting system
This situation resembles the case of antioxidative effectsof tocopherol which depends on the fate of the secondaryradical as proposed by Winterbourn [252] The question wasldquoVitamin E - Pro- or Antioxidantrdquo
997888rarr chain termination of lipid peroxidation
(6)
Prooxidant
Toc∙ + Lipid-H 997888rarr Lipid∙ (in LDL particles) (7)
This example shows that generally speaking any AO mustfulfil several criteria to be considered as an effective com-pound physiologically
(i) It must be able to functionally interact with endoge-nous scavengers even at low concentrations
(ii) It must affect endogenous pathways of OS(iii) It should not have undesirable adverse effect(iv) It should manifest the antioxidant efficacy dependent
on the oxidant(v) It must discriminate among different strategies
needed for 1-electron and 2-electron processes(vi) Radical scavengers can be prooxidant unless linked to
a radical sink (Winterbourn [252])
According to these statements DHPs could be effective asAO under physiological conditions in vivo (Godfraind [3]and others [30 31 38]) and in vitro in various experimentalsystems (cell and tissue) (see Sections 33 34 35)
Hence calcium antagonists appeared to disrupt thefine balance between the production and scavenging ofROS Nifedipine verapamil and diltiazem were shown toinduce significant oxidative stress in the epididymal sperm(increased MDA and decreased catalase and superoxidedismutase activity) This may be the reason for the inductionof male infertility [253]
The dualism of 14-DHP effects has been recorded asinhibition or promotion of LP as quenching or initiating
26 Oxidative Medicine and Cellular Longevity
oxygen and nitrogen free radical chain reactions radiopro-tecting or radiosensitizing antagonizing or synergizing Ca2+in electromechanical coupling as well as in the membranestabilization or labilization
39 Could DHPs Be Involved in Antioxidative Stress Beforebeing applied in vivo the optimal dose and optimal timeintervals forDHPs applicationmust be knownNamely whileROS have been traditionally considered as toxic byproductsof aerobic metabolism we know nowadays that ROS may actas essential signaling molecules needed for the control ofmany different physiological processes Whether the role ofROS will be damaging protective or signaling depends onthe delicate equilibrium between time- and location-specificROS production and scavenging Accordingly the imbalanceof the increased AO potential so-called antioxidative stresscould be dangerous similar to chronic OS in particular incase of extended exposure Inappropriate interventions inthe oxidative homeostasis by excessive antioxidants especiallyin case of chronic exposure to antioxidants might havevery negative effects as was published in the ATBC studyshowing an increased cancer incidence in smokers treatedby excessive beta-carotene [254] Therefore overconsump-tion of any natural or synthetic AO including DHPs asdietary supplements or drugs must be avoided in order tosuppress oxidative damage and must not disrupt the well-integrated antioxidant defense network (Poljsak [255] andPoljsak and Milisav [256]) This is especially important whenadministrating lipid-soluble antioxidants that can be storedin biomembranes thus not only attenuating or preventing LPbut also affecting physiological effects of the natural antiox-idants in particular tocopherol The interrelationship withthe status of endogenous antioxidantsprooxidants should befollowed
DHPs primarily suppress the initiation stages of LPprocessThey do not entirely stop the LP propagation Actingsynergistically with tocopherol diludine may prevent patho-logical excess of ROS production within the lipid moiety ofthe cellular membranes and LDL However due to its lowsolubility and fast metabolism its concentration in the cellsis low For that reason it cannot cause antioxidative stresseven if used for an extended period of time Thus diludine(diethone) could be only a mild antioxidant it has potentialfor restoring the pool of natural antioxidants (as synergist of120572-tocopherol and polyphenols) in the cells
Moreover DHPs CA used for cardioprotection andvasodilatation as commercial drugs in low concentrationsare fast metabolized via CYP3A4 and for that reason theirapplication does not induce cellular AO stress [53 160]However Godfraind and Salomone [257] have postulated noevidence that allows recommending dietary supplementationwith antioxidants for the primary or secondary prevention ofcardiovascular disease
So far there are no reports on antioxidative stress causedby some DHPs diludine and its analogues Diludine andits analogues therefore could act as adaptogens supportinghormetic effects of mild oxidative stress These compoundsmay act as potential multisided modulators of Yin-Yang
cycles of redox and cell functions (the electroplasmic cycle)(Wagner et al [258])
4 Conclusions
14-Dihydropyridines (14-DHPs) have broad spectrum ofOS modulating activities DHPs have reducing and lipidperoxidation inhibitor properties act as reductants in simplechemical systems and stabilize various biological systems(LDL mitochondria microsomes cells and tissues) againstOS Examples and peculiarities and mechanisms of antiox-idant activity (AOA) and antiradical activity (ARA) as wellas stress-protective effect of DHPs including commercialcalcium antagonists (CA) were highlighted These activitiesdepend on various structural parameters related to DHPs(presence and character of substituents) lipophilicity anddepth of the incorporation in the biologicalmembranesTheyalso depend on the experimental model system for exploringthe lipid peroxidation or oxidative stress Stress-protectiveeffect of some metabolites of CA (nifedipine) is reviewedAlthough some DHPs including CA have prooxidant prop-erties (on epididymal sperm cells) they can generally beconsidered as potent antioxidants Therefore comparisonof the AOA and ARA of different DHPs (mutually andwith other AOs) was described in detail According to thedata presented the DHPs might be considered as bellwetheramong synthetic compounds targeting OS and as a kind ofpharmacological measure for respective field of organic andmedicinal chemistry
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
Authors from Latvian IOS acknowledge ESF 201300021DP1112013APIAVIAA011 and National Research Pro-gramme PUBLIC HEALTHBiomedicine of the Republicof Latvia for financial support administration of the Insti-tute for technical support and Rufus Smits PhD for con-sultations in English The support of Cooperation in Euro-pean System of Science and Technology (COST) Domain ofChemistry Molecular Sciences and Technologies (CMST)was of highest importance for preparation of this paper
[2] D J Triggle ldquo14-Dihydropyridines as calcium channel ligandsand privileged structuresrdquoCellular andMolecular Neurobiologyvol 23 no 3 pp 293ndash303 2003
[3] T Godfraind ldquoAntioxidant effects and the therapeutic modeof action of calcium channel blockers in hypertension andatherosclerosisrdquo Philosophical Transactions of the Royal SocietyB Biological Sciences vol 360 no 1464 pp 2259ndash2272 2005
[4] E Cadenas ldquoMitochondrial free radical production and cellsignalingrdquoMolecular Aspects of Medicine vol 25 no 1-2 pp 17ndash26 2004
[5] E Cadenas ldquoFree radicals oxidative stress and diseasesrdquo inLecture PSC 616 p 38 Missouri University of Science andTechnology Rolla Mo USA httpwwwcarnicominstituteorgarticlesenrique cadenaspdf
[6] K Rahman ldquoStudies on free radicals antioxidants and co-fac-torsrdquo Clinical Interventions in Aging vol 2 no 2 pp 219ndash2362007
[7] V Bocci and G Valacchi ldquoFree radicals and antioxidants howto reestablish redox homeostasis in chronic diseasesrdquo CurrentMedicinal Chemistry vol 20 no 27 pp 3397ndash3415 2013
[8] M Valko C J Rhodes J Moncol M Izakovic and M MazurldquoFree radicals metals and antioxidants in oxidative stress-induced cancerrdquo Chemico-Biological Interactions vol 160 no 1pp 1ndash40 2006
[9] G Bartosz ldquoReactive oxygen species destroyers or messen-gersrdquo Biochemical Pharmacology vol 77 no 8 pp 1303ndash13152009
[10] R Visconti and D Grieco ldquoNew insights on oxidative stress incancerrdquo Current Opinion in Drug Discovery and Developmentvol 12 no 2 pp 240ndash245 2009
[11] R N Kujundzic N Zarkovic and K G Troselj ldquoPyridinenucleotides in regulation of cell death and survival by redoxand non-redox reactionsrdquo Critical Reviews in Eukaryotic GeneExpression vol 24 no 4 pp 287ndash309 2014
[12] B Halliwell and J M C Gutteridge ldquoThe definition and mea-surement of antioxidants in biological systemsrdquo Free RadicalBiology and Medicine vol 18 no 1 pp 125ndash126 1995
[13] V D Kancheva and O T Kasaikina ldquoBio-antioxidantsmdashachemical base of their antioxidant activity and beneficial effect
on human healthrdquo Current Medicinal Chemistry vol 20 no 37pp 4784ndash4805 2013
[14] H V Panglossi Ed Frontiers in Antioxidants Research NovaScience Publishers New York NY USA 2006
[15] E B Burlakova E M Molochkina and G A NikiforovldquoHybrid antioxidantsrdquo Oxidation Communications vol 31 no4 pp 739ndash757 2008 httpmembraneustceducnpaperpdfHybrid20Antioxidantspdf
[16] A Bast and G R M M Haenen ldquoTen misconceptions aboutantioxidantsrdquo Trends in Pharmacological Sciences vol 34 no 8pp 430ndash436 2013
[17] E B Burlakova A V 0lesenko E M Molochkina N PPalmina and N G Khrapova Bioantioxidants for RadiationDamage and Malignant Growth Nauka Moscow Russia 1975(Russian)
[18] J Fang T Seki and H Maeda ldquoTherapeutic strategies by mod-ulating oxygen stress in cancer and inflammationrdquo AdvancedDrug Delivery Reviews vol 61 no 4 pp 290ndash302 2009
[19] M Valko D Leibfritz J Moncol M T D Cronin M Mazurand J Telser ldquoFree radicals and antioxidants in normal physi-ological functions and human diseaserdquo International Journal ofBiochemistry and Cell Biology vol 39 no 1 pp 44ndash84 2007
[20] M Jimenez-Del-Rio and C Velez-Pardo ldquoThe bad the goodand the ugly about oxidative stressrdquo Oxidative Medicine andCellular Longevity vol 2012 Article ID 163913 13 pages 2012
[21] C D Kamat S Gadal M Mhatre K S Williamson Q N Pyeand K Hensley ldquoAntioxidants in central nervous system dis-eases preclinical promise and translational challengesrdquo Journalof Alzheimerrsquos Disease vol 15 no 3 pp 473ndash493 2008
[22] A Pompella H Sies R Wacker et al ldquoThe use of totalantioxidant capacity as surrogate marker for food quality andits effect on health is to be discouragedrdquo Nutrition vol 30 no7-8 pp 791ndash793 2014
[23] Z Ye and H Song ldquoAntioxidant vitamins intake and the risk ofcoronary heart disease meta-analysis of cohort studiesrdquo Euro-pean Journal of Cardiovascular Prevention and Rehabilitationvol 15 no 1 pp 26ndash34 2008
[24] P Knekt J Ritz M A Pereira et al ldquoAntioxidant vitamins andcoronary heart disease risk a pooled analysis of 9 cohortsrdquoTheAmerican Journal of Clinical Nutrition vol 80 no 6 pp 1508ndash1520 2004
[25] A C Carr and M C M Vissers ldquoSynthetic or food-derivedvitamin Cmdashare they equally bioavailablerdquo Nutrients vol 5 no11 pp 4284ndash4304 2013
[26] R Tabrizchi ldquoEdaravoneMitsubishi-TokyordquoCurrentOpinion inInvestigational Drugs vol 1 no 3 pp 347ndash354 2000
[27] K Kikuchi S Tancharoen N Takeshige et al ldquoThe efficacy ofedaravone (radicut) a free radical scavenger for cardiovasculardiseaserdquo International Journal of Molecular Sciences vol 14 no7 pp 13909ndash13930 2013
[28] D Mauzerall and F H Westheimer ldquo1-Benzyldihydronicoti-namidemdasha model for reduced DPNrdquo Journal of the AmericanChemical Society vol 77 no 8 pp 2261ndash2264 1955 ChemicalAbstracts vol 50 Article ID 2588i 1956
[29] F Bossert and W Vater ldquo14-Dihydropyridinesmdasha basis fordeveloping new drugsrdquo Medicinal Research Reviews vol 9 no3 pp 291ndash324 1989
[30] G Swarnalatha G Prasanthi N Sirisha and CMadhusudhanaChetty ldquo14-Dihydropyridines a multtifunctional moleculemdash areviewrdquo International Journal of ChemTech Research vol 3 no1 pp 75ndash89 2011
28 Oxidative Medicine and Cellular Longevity
[31] M Cataldi and F Bruno ldquo14-Dihydropyridines the multiplepersonalities of a blockbuster drug familyrdquo Translational Medi-cine UniSa vol 4 no 2 pp 12ndash26 2012 httpwwwncbinlmnihgovpmcarticlesPMC3728803
[32] R Vitolina A Krauze G Duburs and A Velena ldquoAspects ofthe amlodipine pleiotropy in biochemistry pharmacology andclinicsrdquo International Journal of Pharmaceutical Sciences andResearch vol 3 no 5 pp 1215ndash1232 2012
[33] D Grover S N Mokale and M T Shete ldquoDihydropyridinea novel pharmacophorerdquo International Journal of Pharmaceu-tical Erudition vol 1 no 2 pp 16ndash29 2011 httppharmaeru-ditionorgContentPaper20111-RV-320Final2016-29pdf
[34] A M Vijesh A M Isloor S K Peethambar K N ShivanandaT Arulmoli and N A Isloor ldquoHantzsch reaction synthesis andcharacterization of somenew 14-dihydropyridine derivatives aspotent antimicrobial and antioxidant agentsrdquo European Journalof Medicinal Chemistry vol 46 no 11 pp 5591ndash5597 2011
[35] P Mehta and P Verma ldquoAntimicrobial activity of some deriva-tives of 14-dihydropyridinesrdquo Journal of Chemistry vol 2013Article ID 865128 4 pages 2013
[36] P Olejnıkova L Svorc D Olsovska et al ldquoAntimicrobialactivity of novel C2-substituted 14-dihydropyridine analoguesrdquoScientia Pharmaceutica vol 82 no 2 pp 221ndash232 2014
[37] S Sepehri H Perez Sanchez and A Fassihi ldquoHantzsch-typedihydropyridines and biginelli-type tetra-hydropyrimidinesa review of their chemotherapeutic activitiesrdquo Journal of Phar-macy amp Pharmaceutical Sciences vol 18 no 1 pp 1ndash52 2015httpsejournalslibraryualbertacaindexphpJPPSarticleview2383617863
[38] S A Khedkar and P B Auti ldquo14-Dihydropyridines a classof pharmacologically important moleculesrdquo Mini-Reviews inMedicinal Chemistry vol 14 no 3 pp 282ndash290 2014
[39] G D Tirzit and G Ya Duburs ldquo14-dihydropyridines as inhi-bitors of free-radical reactionsrdquo Chemistry of Heterocyclic Com-pounds vol 8 no 1 pp 126ndash127 1972 Translated from KhimiyaGeterotsiklicheskikh Soedinenii no1 pp 133ndash134 1972 (Rus-sian)
[40] I Bogeski R Kappl C Kummerow R Gulaboski M Hothand B A Niemeyer ldquoRedox regulation of calcium ion channelschemical and physiological aspectsrdquoCell Calcium vol 50 no 5pp 407ndash423 2011
[41] S A Giller G Y Dubur Y R Uldrikis et al ldquoDiludine [Themethod to obtain 35-dicarbonylderivatives of 26-dimethyl-14-dihydropyridines]rdquo Authors certificate of USSR no 3004651971 [Byull Izobret no13 p 95 1971] and following patentsPatent of England no 1294650 1973 Patent of France no2055458 1971 Patent of Japan no 702883 1973 Patent ofHolland no 149787 1976 Patent of Italy no 969022 1974 Patentof FRG no 2036403 1978 US Patent no 3883673 1975 USPatent no 3948924 1976
[42] S A Giller G Y Dubur Y R Uldrikis et al ldquoImprovementsin or relating to the stabilization of carotenerdquo GB Patent no1294650 1972
[43] S A Giller G Y Dubur Y R Uldrikis et al ldquoStabilization ofcarotenerdquo US Patent no 3883673 1975 Chemical Abstracts vol83 Article ID 95193 1975
[44] Yu A Zilber G Ya Dubur K K Kumsar and A Kh VelenaldquoThe effect of antioxidants on the peroxidation of bimole-cular phospholipid membranesrdquo Latvijas PSR ZA Vestis Izves-tia Akademii Nauk Latviyskoy SSR vol 6 pp 80ndash82 1971(Russian) translated from the original Russian Doc Accesion
No AD0771751 distributed by NTIS US Department of Com-merce httpwwwdticmildtictrfulltextu2771751pdf
[45] G Ya Dubur Yu A Zilbers A Kh Velena A O Kumerovaand G D Tirzitis ldquoMultistage study of regulation of peroxida-tion processes in biological membranes by antioxidants of 14-dihydropyridine grouprdquo Izvestiya Akademii Nauk LatviyskoySSR vol 336 no 7 pp 65ndash68 1975 (Russian)
[46] R P Mason and M W Trumbore ldquoDifferential membraneinteractions of calcium channel blockers Implications forantioxidant activityrdquo Biochemical Pharmacology vol 51 no 5pp 653ndash660 1996
[47] R P Mason M F Walter M W Trumbore E G Olmstead Jrand P E Mason ldquoMembrane antioxidant effects of the chargeddihydropyridine calcium antagonist amlodipinerdquo Journal ofMolecular and Cellular Cardiology vol 31 no 1 pp 275ndash2811999
[48] R PMason I T MakMW Trumbore and P EMason ldquoAnti-oxidant properties of calcium antagonists related to membranebiophysical interactionsrdquo American Journal of Cardiology vol84 no 4 pp 16ndash22 1999
[49] R PMasonMW Trumbore and P EMason ldquoMembrane bio-physical interaction of amlodipine and antioxidant propertiesrdquoDrugs vol 59 no 2 pp 9ndash16 2000 (French)
[50] R P Mason P Marche and T H Hintze ldquoNovel vascularbiology of third-generation L-type calcium channel antagonistsAncillary actions of amlodipinerdquo Arteriosclerosis Thrombosisand Vascular Biology vol 23 no 12 pp 2155ndash2163 2003
[51] A Augustyniak G Bartosz A Cipak et al ldquoNatural andsynthetic antioxidants an updated overviewrdquo Free RadicalResearch vol 44 no 10 pp 1216ndash1262 2010
[52] T Grune N Zarkovic and K Kostelidou ldquoLipid peroxidationresearch in Europe and the COST B35 action lsquoLipid Peroxida-tion Associated Disordersrsquordquo Free Radical Research vol 44 no10 pp 1095ndash1097 2010
[53] E Carosati P Ioan M Micucci et al ldquo14-Dihydropyridinescaffold in medicinal chemistry the story so far and perspec-tives (part 2) action in other targets and antitargetsrdquo CurrentMedicinal Chemistry vol 19 no 25 pp 4306ndash4323 2012
[54] U Eisner and J Kuthan ldquoThe chemistry of dihydropyridinesrdquoChemical Reviews vol 72 no 1 pp 1ndash42 1972 httpwwwsci-encemadnessorgtalkfilesphppid=138742ampaid=6475
[55] J Kuthan and A Kurfurst ldquoDevelopment in dihydropyri-dine chemistryrdquo Industrial amp Engineering Chemistry ProductResearch and Development vol 21 no 2 pp 191ndash261 1982
[56] A Sausins and G Duburs ldquoSynthesis of 14-dihydropyridinesby cyclocondensation reactionsrdquo Heterocycles vol 27 no 1 pp269ndash289 1988
[57] A E Sausins and G Y Duburs ldquoSynthesis of 14-dihydro-pyridines in cyclocondensation reactions (review)rdquo Chemistryof Heterocyclic Compounds vol 28 no 4 pp 363ndash391 1992Translated from Khimiya Geterotsiklicheskikh Soedinenii no 4pp 435ndash467 1992 (Russian)
[58] S Kazda ldquoTwenty years of dihydropyridinesrdquo in Dihydropy-ridines Progress in Pharmacology and Therapy W-D Busse BGarthoff and F Seuter Eds pp 1ndash12 Springer Verlag BerlinGermany 1993
[59] J-P Wan and Y Liu ldquoRecent advances in new multicomponentsynthesis of structurally diversified 14-dihydropyridinesrdquo RSCAdvances vol 2 no 26 pp 9763ndash9777 2012
[61] Reaxys Database[62] J Tuttle ldquoStructure mechanism and reactivity of hantzsch
estersrdquo in MacMillan Lab Group Meeting (082504) p 332004 httpwwwprincetoneduchemistrymacmillangroup-meetingsJBT20Hantzschpdf
[63] A Saini S Kumar and J S Sandhu ldquoHantzsch reaction recentadvances in Hantzsch 14-dihydropyridinesrdquo Journal of Sci-entific amp Industrial Research vol 67 pp 95ndash111 2008
[64] L LW Cheung S A Styler and A P Dicks ldquoRapid and conve-nient synthesis of the 14-dihydropyridine privileged structurerdquoJournal of Chemical Education vol 87 no 6 pp 628ndash630 2010
[65] A Kumar R A Maurya S Sharma M Kumar and G BhatialdquoSynthesis and biological evaluation of N-aryl-14-dihydro-pyridines as novel antidyslipidemic and antioxidant agentsrdquoEuropean Journal of Medicinal Chemistry vol 45 no 2 pp 501ndash509 2010
[66] R S Kumar A Idhayadhulla A J Abdul Nasser and J SelvinldquoSynthesis and anticoagulant activity of a new series of 14-dihydropyridine derivativesrdquo European Journal of MedicinalChemistry vol 46 no 2 pp 804ndash810 2011
[67] H A Stefani C B Oliveira R B Almeida et al ldquoDihydro-pyrimidin-(2H)-ones obtained by ultrasound irradiation anew class of potential antioxidant agentsrdquo European Journal ofMedicinal Chemistry vol 41 no 4 pp 513ndash518 2006
[68] H Sun C Shang L Jin and J Zhang ldquoSynthesis and antiox-idant activity of a series of novel 3-chalcone-substituted 14-dihydropyridine derivativesrdquoHeterocyclic Communications vol18 no 5-6 pp 239ndash243 2012
[69] D B Tikhonov and B S Zhorov ldquoStructural model for dihy-dropyridine binding to L-type calcium channelsrdquo The Journalof Biological Chemistry vol 284 no 28 pp 19006ndash19017 2009
[70] G Y Dubur and Y R Uldrikis ldquoThe oxidation of 14-dihydro-pyridinesrdquo Chemistry of Heterocyclic Compounds vol 6 no 1pp 80ndash84 1970 Translated from Khimiya GeterotsiklicheskikhSoedinenii no 1 pp 83ndash88 1970 (Russian)
[71] G Ya Duburs A O Kumerova and Ya R Uldrikis ldquoEnzymicoxidation of hydrogenated pyridines with peroxidase-hydrogenperoxide systemrdquoLatvijas PSRZAVestis vol 73 no 7 pp 73ndash771970 (Russian) Chemical Abstracts vol 73 Article ID 94913g1970
[72] K Xie Y-C Liu Y Cui J-GWang Y Fu andT CWMak ldquoN-methyl-(R)-3-(tert-butyl)-sulfinyl-14-dihydropyridine a novelNADHmodel compoundrdquoMolecules vol 12 no 3 pp 415ndash4222007
[73] S Tamagaki T Mimura and W Tagaki ldquoMetal-ion-facilitatedoxidations of dihydropyridines with molecular oxygen andhydrogen peroxiderdquo Journal of the Chemical Society PerkinTransactions 2 no 10 pp 1645ndash1650 1990
[74] D Tirzite G Tirzitis andD Antipova ldquoReductive ability of 14-dihydropyridine derivatives in relation to ions of trivalent ironrdquoChemistry of Heterocyclic Compounds vol 35 no 5 pp 592ndash594 1999
[76] J Ogle J Stradins and L Baumane ldquoFormation and decay offree cation-radicals in the course of electro-oxidation of 12- and14-dihydropyridines (Hantzsch esters)rdquo Electrochimica Actavol 39 no 1 pp 73ndash79 1994
[77] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for the
synthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts C Wittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Berlin Germany 2010
[78] WDu and Zh Yu ldquoBiomimetic in situ regeneration of cofactorsNAD(P)+ and NAD(P)H models hantzsch esters and dihy-drophenanthridinerdquo Synlett vol 23 no 9 pp 1300ndash1304 2012
[79] H K Chenault and G M Whitesides ldquoRegeneration ofnicotinamide cofactors for use in organic synthesisrdquo AppliedBiochemistry and Biotechnology vol 14 no 2 pp 147ndash197 1987
[80] Y R Uldrikis A A Zidermane E A Biseniex I E Preisa GY Dubur and G D Tirzit ldquoEsters of 26-dimethyl-14-dihydro-pyridine-35-dicarboxylic acid and method of obtainingthereofrdquo WO 8000345 A1 1978 httpworldwideespacenetcompublicationDetailsbiblioDB=EPODOCampII=1ampND=3ampadjacent=trueamplocale=en EPampFT=Dampdate=19800306ampCC=WOampNR=8000345A1ampKC=A1
[81] Y Sambongi H Nitta K Ichihashi M Futai and I Ueda ldquoAnovel water-soluble Hantzsch 14-dihydropyridine compoundthat functions in biological processes through NADH regener-ationrdquo Journal of Organic Chemistry vol 67 no 10 pp 3499ndash3501 2002
[82] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for thesynthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts ChWittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Verlag Berlin Germany 2010
[83] T Okamura T Kikuchi A Nagamine et al ldquoAn approach formeasuring in vivo cerebral redox states using the oxidative con-version of dihydropyridine to pyridinium ion and themetabolictrapping principlerdquo Free Radical Biology and Medicine vol 38no 9 pp 1197ndash1205 2005
[84] K A Schellenberg and F H Westheimer ldquoA free-radicaloxidation of a dihydropyridine1ardquo The Journal of OrganicChemistry vol 30 no 6 pp 1859ndash1862 1965
[85] K A Schellenberg ldquoReaction of hydroxyl radical with thymi-dine Scavenging by a dihydropyridinerdquo Federation Proceedingsvol 38 no 3 I p 1433 1979
[86] E S Huyser J A K Harmony and F L McMillian ldquoPeroxideoxidations of dihydropyridine derivativesrdquo Journal of the Amer-ican Chemical Society vol 94 no 9 pp 3176ndash3180 1972
[87] A Sakamoto S T Ohnishi and R Ogawa ldquoInhibition of lipidperoxidation by some dihydropyridine derivativesrdquo Journal ofAnesthesia vol 7 no 2 pp 193ndash197 1993
[88] R Hardeland ldquoReview Neuroprotection by radical avoidancesearch for suitable agentsrdquo Molecules vol 14 no 12 pp 5054ndash5102 2009
[89] G Ya Dubur A Kh Velena V M Gukasov and Yu AVladimirov ldquoRegulation of peroxidation of mitochondrialmembrane lipids initiated by Fe2+ ions by antoxidants of the14-dihydropyridine series in experiments in vitrordquo Biomed-itsinskaya Khimiya vol 22 no 5 pp 665ndash673 1976 (Russian)Chemical Abstracts vol 88 Article ID 2640 1977
[90] G RMMHaenenM J T J Arts A Bast andMD ColemanldquoStructure and activity in assessing antioxidant activity in vitroand in vivo a critical appraisal illustrated with the flavonoidsrdquoEnvironmental Toxicology and Pharmacology vol 21 no 2 pp191ndash198 2006
[91] G Tirzitis and G Bartosz ldquoDetermination of antiradical andantioxidant activity basic principles and new insightsrdquo ActaBiochimica Polonica vol 57 no 2 pp 139ndash142 2010
30 Oxidative Medicine and Cellular Longevity
[92] G R Buettner and R P Mason ldquoSpin-trapping methods fordetecting superoxide and hydroxyl free radicals in vitro and invivordquo inCritical Reviews of Oxidative Stress and Aging Advancesin Basic Science Diagnostics and Intervention R G Cutler andH Rodriguez Eds vol 1 chapter 2 pp 27ndash38World ScientificLondon UK 2003
[93] M M Tarpey and I Fridovich ldquoMethods of detection ofvascular reactive species Nitric oxide superoxide hydrogenperoxide and peroxynitriterdquo Circulation Research vol 89 no3 pp 224ndash236 2001
[94] E Y Kazush E I Sagun G D Tirzit and G Y DaburldquoQuenching of singlet oxygen by electron donating derivativesof 14-dihydropyridinerdquo Chemistry of Heterocyclic Compoundsvol 30 no 5 pp 562ndash563 1994
[95] G Tirzitis E Kazush and G Duburs ldquoReaction of 14-dihydropyridine derivatives with peroxynitrite anionrdquo Chem-istry of Heterocyclic Compounds vol 34 no 3 pp 321ndash3231998 (Russian) Translated from Khimiya GeterotsiklicheskikhSoedinenii no 3 pp 355ndash357 1998
[96] L J Nunez-Vergara C Lopez-Alarcon P A Navarrete-EncinaA M Atria C Camargo and J A Squella ldquoElectrochemicaland EPR characterization of 14-dihydropyridines Reactivitytowards alkyl radicalsrdquo Free Radical Research vol 37 no 1 pp109ndash120 2003
[97] D Tirzite A Krauze A Zubareva G Tirzitis and G DubursldquoSynthesis and antiradical activity of 5-acetyl-2-alkylthio-4-aryl-6-methyl-14-dihydropyridine-3-carboxylic acid nitrilesrdquoChemistry of Heterocyclic Compounds vol 38 no 7 pp 795ndash800 2002
[98] H Ohkawa N Ohishi and K Yagi ldquoAssay for lipid peroxidesin animal tissues by thiobarbituric acid reactionrdquo AnalyticalBiochemistry vol 95 no 2 pp 351ndash358 1979
[99] N Zarkovic ldquo4-Hydroxynonenal as a bioactive marker ofpathophysiological processesrdquo Molecular Aspects of Medicinevol 24 no 4-5 pp 281ndash291 2003
[100] M Parola G Bellomo G Robino G Barrera and M UDianzani ldquo4-Hydroxynonenal as a biological signal molecularbasis and pathophysiological implicationsrdquo Antioxidants andRedox Signaling vol 1 no 3 pp 255ndash284 1999
[101] T Lovakovic M Poljak-Blazi G Duburs et al ldquoGrowthmodulation of human cells in vitro by mild oxidative stressand 14-dihydropyridine derivative antioxidantsrdquo CollegiumAntropologicum vol 35 no 1 pp 137ndash141 2011
[102] R van den Berg G R M M Haenen H van den Bergand A Bast ldquoApplicability of an improved Trolox equivalentantioxidant capacity (TEAC) assay for evaluation of antioxidantcapacity measurements of mixturesrdquo Food Chemistry vol 66no 4 pp 511ndash517 1999
[103] C Lopez-Alarcon P Navarrete C Camargo J A Squella andL J Nunez-Vergara ldquoReactivity of 14-dihydropyridines towardalkyl alkylperoxyl radicals and ABTS radical cationrdquo ChemicalResearch in Toxicology vol 16 no 2 pp 208ndash215 2003
[104] V Valenzuela P Santander C Camargo J A Squella C Lopez-Alarcon and L J Nunez-Vergara ldquo14-Dihydropyridines reac-tivity of nitrosoaryl and nitroaryl derivatives with alkylperoxylradicals andABTS radical cationrdquo Free Radical Research vol 38no 7 pp 715ndash727 2004
[105] L G Tsetlin N A Chebotareva B I Kurganov A K VelenaG Y Dubur and V Z Lankin ldquoStudy of 14-dihydropyridinesas lipoxygenase inhibitors with the use of hydrated reversedmicellesrdquo Pharmaceutical Chemistry Journal vol 22 no 6 pp425ndash428 1988 (Russian)
[106] J Panek Z Reblova L Kocirkova et al ldquoAntioxidant activityof dihydropyridine derivativesrdquo Czech Journal of Food Sciencesvol 18 pp 144ndash145 2000
[107] G Tirzitis I Kirule and G Duburs ldquoAntioxidationsaktivitatder 35-dicarbonylderivate des 26-demethyl-14-dihydropyri-dinsrdquo Fett Wissenschaft TechnologieFat Science Technology vol90 no 10 pp 411ndash413 1988
[108] M Plotniece G Tirzitis Y Uldrikis et al ldquoSynthesis of 14-dihydropyridine derivatives having an oxy- alkoxy- or dimeth-ylaminophenyl substituent in the 4 position their antioxidantactivity and their binding to phospholipid membranesrdquo Chem-istry of Heterocyclic Compounds vol 32 no 10 pp 1166ndash11721996 Translated from Khimiya Geterotsiklicheskikh Soedineniino 10(352) pp 1358ndash1365 1996 (Russian)
[109] D Y Rubene V S Sharov V I Olenev G D Tirzit G Y Duburand Y A Vladimirov ldquoUse of chemiluminescent method forthe evaluation of antioxidant activity of some derivatives of 14-dihydropyridinerdquo Russian Journal of Physical Chemistry A vol55 no 2 pp 511ndash512 1981 (Russian)
[110] M C R Symons and JM C Gutteridge Free Radicals and IronChemistry Biology and Medicine Oxford Science PublicationsOxford University Press Oxford UK 1998
[111] M Repetto J Semprine and A Boveris ldquoLipid peroxidationchemical mechanism biological implications and analyticaldeterminationrdquo in Lipid Peroxidation A Catala Ed Section ILipid Peroxidation Chemical Mechanisms Antioxidants Bio-logical Implications of Biochemistry Genetics and MolecularBiology chapter 1 pp 3ndash30 InTech Rijeka Croatia 2012
[112] A Velena J Zilbers and G Duburs ldquoDerivatives of 14-dihydropyridines asmodulators of ascorbate-induced lipid per-oxidation and high-amplitude swelling ofmitochondria causedby ascorbate sodium linoleate and sodiumpyrophosphaterdquoCellBiochemistry and Function vol 17 no 4 pp 237ndash252 1999
[113] M V Bilenko L N Shelenkova G Y Dubur and A K VelenaldquoUse of antioxidants to prevent renal damage during acuteischemia and reperfusionrdquo Bulletin of Experimental Biology andMedicine vol 96 no 3 pp 1195ndash1198 1983 Translated fromByulletenrsquo Eksperimentalrsquonoi Biologii i Meditsiny vol 96 no 9pp 8ndash11 1983 (Russian)
[114] R Toniolo F Tubaro F Ursini and G Bontempelli ldquoAn elec-troanalytical investigation on the redox properties of calciumantagonist dihydropyridinesrdquo Electroanalysis vol 15 no 10 pp855ndash861 2003
[115] L Kourimska J Pokorny and G Tirzitis ldquoThe antioxidant aci-tivity of 26-dimethyl-35-diethoxycarbonyl-14-dihydropyri-dine in edible oilsrdquo Nahrung vol 37 no 1 pp 91ndash93 1993
[116] C Lopez-Alarcon H Speisky J A Squella C Olea-Azar CCamargo and L J Nunez-Vergara ldquoReactivity of 14-dihydro-pyridines toward SIN-1-derived peroxynitriterdquo PharmaceuticalResearch vol 21 no 10 pp 1750ndash1757 2004
[117] R A Olek W Ziolkowski J J Kaczor L Greci J Popinigisand J Antosiewicz ldquoAntioxidant activity of NADH and its ana-loguemdashan in vitro studyrdquo Journal of Biochemistry andMolecularBiology vol 37 no 4 pp 416ndash421 2004
[118] E Niki N Noguchi and N Gotoh ldquoInhibition of oxidativemodification of low density lipoprotein by antioxidantsrdquo Jour-nal of Nutritional Science andVitaminology vol 39 supplementpp S1ndashS8 1993
[119] N Rojstaczer and D J Triggle ldquoStructure-function relation-ships of calcium antagonists effect on oxidative modificationof low density lipoproteinrdquo Biochemical Pharmacology vol 51no 2 pp 141ndash150 1996
Oxidative Medicine and Cellular Longevity 31
[120] A Sevanian L Shen and FUrsini ldquoInhibition of LDLoxidationand oxidized LDL-induced cytotoxicity by dihydropyridinecalcium antagonistsrdquo Pharmaceutical Research vol 17 no 8 pp999ndash1006 2000
[121] A Negre-Salvayre and R Salvayre ldquoProtection by Ca2+ channelblockers (nifedipine diltiazem and verapamil) against the tox-icity of oxidized low density lipoprotein to cultured lymphoidcellsrdquo British Journal of Pharmacology vol 107 no 3 pp 738ndash744 1992
[122] A Negre-Salvayre G FitoussiM Troly and R Salvayre ldquoCom-parative cytoprotective effect of dihydropyridine calcium chan-nel blockers against the toxicity of oxidized low density lipopro-tein for cultured lymphoid cellsrdquo Biochemical Pharmacologyvol 44 no 12 pp 2379ndash2386 1992
[123] L Cominacini A F Pasini U Garbin et al ldquoAntioxidant activ-ity of different dihydropyridinesrdquo Biochemical and BiophysicalResearch Communications vol 302 no 4 pp 679ndash684 2003
[124] L Cominacini U Garbin A Fratta Pasini et al ldquoOxidized low-density lipoprotein increases the production of intracellularreactive oxygen species in endothelial cells inhibitory effect oflacidipinerdquo Journal of Hypertension vol 16 no 12 part 2 pp1913ndash1919 1998
[125] H M Lander ldquoAn essential role for free radicals and derivedspecies in signal transductionrdquo The FASEB Journal vol 11 no2 pp 118ndash124 1997
[126] M L L Martinez E Rizzi M M Castro et al ldquoLercanidipinedecreases vascular matrix metalloproteinase-2 activity andprotects against vascular dysfunction in diabetic ratsrdquo EuropeanJournal of Pharmacology vol 599 no 1ndash3 pp 110ndash116 2008
[127] P Lesnik C Dachet L Petit et al ldquoImpact of a combinationof a calcium antagonist and a 120573-blocker on cell- and copper-mediated oxidation of LDL and on the accumulation and effluxof cholesterol in human macrophages and murine J774 cellsrdquoArteriosclerosis Thrombosis and Vascular Biology vol 17 no 5pp 979ndash988 1997
[128] G Sobal E J Menzel and H Sinzinger ldquoCalcium antagonistsas inhibitors of in vitro low density lipoprotein oxidation andglycationrdquoBiochemical Pharmacology vol 61 no 3 pp 373ndash3792001
[129] E Lupo R Locher B Weisser and W Vetter ldquoIn vitro antiox-idant activity of calcium antagonists against LDL oxidationcompared with 120572-tocopherolrdquo Biochemical and BiophysicalResearch Communications vol 203 no 3 pp 1803ndash1808 1994
[130] J Zou Y Li H-Q Fan and J-G Wang ldquoEffects of dihydropy-ridine calcium channel blockers on oxidized low-density lipo-protein induced proliferation and oxidative stress of vascularsmooth muscle cellsrdquo BMC Research Notes vol 5 article 1682012
[131] C Napoli S Salomone T Godfraind et al ldquo14-Dihydro-pyridine calcium channel blockers inhibit plasma and LDL oxi-dation and formation of oxidation-specific epitopes in the arte-rial wall and prolong survival in stroke-prone spontaneouslyhypertensive ratsrdquo Stroke vol 30 no 9 pp 1907ndash1915 1999
[132] G Zernig I Graziadei T Moshammer C Zech N Reider andH Glossmann ldquoMitochondrial Ca2+ antagonist binding sitesare associated with an inner mitochondrial membrane anionchannelrdquo Molecular Pharmacology vol 38 no 3 pp 362ndash3691990
[133] F E Hunter Jr A Scott P E Hochstein et al ldquoStudies of themechanism of ascorbate-induced swelling and lysis of isolatedliver mitochondriardquo The Journal of Biological Chemistry vol239 pp 604ndash613 1964
[134] D R Janero B Burghardt and R Lopez ldquoProtection of cardiacmembrane phospholipid against oxidative injury by calciumantagonistsrdquoBiochemical Pharmacology vol 37 no 21 pp 4197ndash4203 1988
[135] A Karadag B Ozcelik and S S Saner ldquoReview of methods todetermine antioxidant capacitiesrdquo FoodAnalyticalMethods vol2 no 1 pp 41ndash60 2009
[136] Y I Gubskiı N V Litvinova and E V Shnurko-TabakovaldquoAntioxidant and antiradical activity of various classes of antiox-idantsrdquo Ukrainskiı Biokhimicheskiı Zhurnal vol 66 no 4 pp114ndash116 1994 (Russian)
[137] M Takei M Hiramatsu and A Mori ldquoInhibitory effects ofcalcium antagonists onmitochondrial swelling induced by lipidperoxidation or arachidonic acid in the rat brain in vitrordquoNeurochemical Research vol 19 no 9 pp 1199ndash1206 1994
[138] M Takei M Hiramatsu R Edamatsu and A Mori ldquoFreeradical scavenging by calcium antagonistsrdquo Neurosciences vol20 no 2 pp 75ndash82 1994
[139] Ya P Stradin G Ya Dubur Yu A Beilis Ya R Uldrikis andA F Korotkova ldquoVoltammetry of 14-dihydropyridine deriva-tives I Potentials of electrochemical oxidation of 35-diacyl-and 35-di(alkoxycarbonyl)-14-dihydropyridines in acetoni-trilerdquo Chemistry of Heterocyclic Compounds no 1 pp 84ndash871972 (Russian)
[140] E V Ivanov T V Ponomarjova G N Merkusev et al ldquoEinneuer Haut-Radioprotektor Diethon (experimentelle Unter-suchung)rdquo Radiobiologia Radiotherapia vol 31 no 1 pp 69ndash78 1990
[141] E V Ivanov T V Ponomareva G N Merkushev et al ldquoRadia-tion modulating properties of derivates of 14-dihydropyridineand 12345678910-decahydroacridine-18 dionerdquo Radiat-sionnaia Biologiia Radioecologiia vol 44 no 5 pp 550ndash5592004 (Russian)
[142] R O Vitolinia D A Berzinia A K Velena I A Vutsina A AKimenis and G Y Duburs ldquoThe protective effects of the cal-cium antagonist foridon in acute myocardial ischaemiardquo Kardi-ologiya vol 27 no 3 pp 90ndash93 1987 (Russian)
[143] A H Velena G Ya Duburs R O Vitolina et al ldquoEffect ofryodipine on electromechanical parameters of heart and vesselscAMP phosphodiesterase activity and swelling-contractioncycle of mitochondriardquo Arzneimittelforschung vol 35 no 6 pp907ndash914 1985
[144] L I Utno Z E Lipsberga A A Silova M I Girgensone EA Bisenieks and G I Ia ldquoCardioprotective properties of a 14-dihydropyridine derivative glutapyrone in deep hypothermiardquoBiulletenrsquo Eksperimentalrsquonoı Biologii i Meditsiny vol 108 no 11pp 558ndash561 1989 (Russian)
[145] M A S FernandesM S Santos J A F Vicente et al ldquoEffects of14-dihydropyridine derivatives (cerebrocrast gammapyroneglutapyrone and diethone) onmitochondrial bioenergetics andoxidative stress a comparative studyrdquoMitochondrion vol 3 no1 pp 47ndash59 2003
[146] M A S Fernandes M S Santos A J M Moreno et al ldquoEffectsof 5-acetyl(carbamoyl)-6-methylsulfanyl-14-dihydropyridine-5-carbonitriles on rat liver mitochondrial functionrdquo Toxicologyin Vitro vol 23 no 7 pp 1333ndash1341 2009
[147] L Klimaviciusa A Kalda A Kaasik et al ldquoNeuroprotectiveactivity of 14-dihydropyridine derivatives structure determi-nantsrdquo Proceedings of the Latvian Academy of Sciences BNatural Exact and Applied Sciences vol 61 no 1-2 pp 33ndash372007
32 Oxidative Medicine and Cellular Longevity
[148] L Klimaviciusa M A S Fernandes N Lencberga et alldquoTargeting the mitochondria by novel adamantane-containing14-dihydropyridine compoundsrdquo in Bioenergetics K B ClarkEd pp 257ndash272 InTech 2012
[149] V Klusa L Klimaviciusa G Duburs J Poikans and AZharkovsky ldquoAnti-neurotoxic effects of tauropyrone a taurineanaloguerdquo Advances in Experimental Medicine and Biology vol583 pp 499ndash508 2006
[150] N Sampson P Berger and Ch Zenzmaier ldquoRedox signalingas a therapeutic target to inhibit myofibroblast activation indegenerative fibrotic diseaserdquo BioMed Research Internationalvol 2014 Article ID 131737 14 pages 2014
[151] T L Leto and M Geiszt ldquoRole of Nox family NADPH oxidasesin host defenserdquoAntioxidantsampRedox Signaling vol 8 no 9-10pp 1549ndash1561 2006
[152] K K Griendling D Sorescu and M Ushio-Fukai ldquoNAD(P)Hoxidase role in cardiovascular biology and diseaserdquo CirculationResearch vol 86 no 5 pp 494ndash501 2000
[153] H Chen Y S Song and P H Chan ldquoInhibition of NADPHoxi-dase is neuroprotective after ischemia-reperfusionrdquo Journal ofCerebral Blood Flow and Metabolism vol 29 no 7 pp 1262ndash1272 2009
[154] P Hochstein and L Ernster ldquoADP-activated lipid peroxidationcoupled to the TPNH oxidase system of microsomesrdquo Biochem-ical and Biophysical Research Communications vol 12 no 5 pp388ndash394 1963
[155] I I Gubskiı AGGoriushkoNV Litvinova et al ldquoAntioxidantproperties and membranotropic effect of certain derivatives of14-dihydropyridinerdquo Ukrainskiı Biokhimicheskiı Zhurnal vol71 no 4 pp 35ndash39 1999 (Russian)
[156] F Engineer and R Sridhar ldquoInhibition of rat heart andliver microsomal lipid peroxidation by nifedipinerdquo BiochemicalPharmacology vol 38 no 8 pp 1279ndash1285 1989
[157] T Goncalves A P Carvalho and C R Oliveira ldquoAntioxidanteffect of calcium antagonists on microsomai membranes iso-lated from different brain areasrdquo European Journal of Pharma-cology vol 204 no 3 pp 315ndash322 1991
[158] M E Letelier P Izquierdo L Godoy A M Lepe and MFaundez ldquoLiver microsomal biotransformation of nitro-aryldrugs mechanism for potential oxidative stress inductionrdquoJournal of Applied Toxicology vol 24 no 6 pp 519ndash525 2004
[159] M E Letelier P Entrala C Lopez-Alarcon et al ldquoNitroaryl-14-dihydropyridines as antioxidants against rat liver microsomesoxidation induced by ironascorbate Nitrofurantoin and naph-thalenerdquo Toxicology in Vitro vol 21 no 8 pp 1610ndash1618 2007
[160] F P Guengerich W R Brian M Iwasaki M-A Sari CBaarnhielm and P Berntsson ldquoOxidation of dihydropyridinecalcium channel blockers and analogues by human liver cyto-chrome P-450 IIIA4rdquo Journal of Medicinal Chemistry vol 34no 6 pp 1838ndash1844 1991
[161] S H Park S-W RhaW-Y Shin et al ldquoAS-160 Calcium channelblockers of dihydropyridine class reduce the antiplatelet effectof Clopidogrel what is clinical impactrdquo The American Journalof Cardiology vol 107 no 8 supplement p 47A 2011
[162] C Asma and D M Reda ldquoEvaluation of dihydropyridinecalcium antagonist effects on the stress bioindicator orga-nism Saccharomyces cerevisiaerdquo Annals of Biological Researchvol 4 no 10 pp 40ndash46 2013 httpscholarsresearchlibrarycomABR-vol4-iss10ABR-2013-4-10-40-46pdf
[163] G Gaviraghi A M Pastorino E Ratti and D G TristldquoCalcium channel blockers with antioxidant activityrdquo in Free
Radicals Lipoprotein Oxidation andAtherosclerosis G BellomoG Finardi E Maggi and E Rice-Evans Eds pp 431ndash456Richelieu Press London UK 1995
[164] G Gaviraghi AM Pastorino E Ratti and D G Trist ldquoAntiox-idant dihydropyridines a new and comprehensive therapy forfree radical-induced cardiovascular diseasesrdquo in Free Radicalsin Biology and Environment F Minisci Ed vol 27 of NATOASI Series pp 193ndash221 Springer Dordrecht The Netherlands1997
[165] P D Henry ldquoAntiperoxidative actions of calcium antagonistsand atherogenesisrdquo Journal of Cardiovascular Pharmacologyvol 18 supplement 1 pp S6ndashS10 1991
[166] F Kouoh B Gressier T Dine et al ldquoAntioxidant effects andanti-elastase activity of the calcium antagonist nicardipine onactivated human and rabbit neutrophilsmdasha potential antiath-erosclerotic property of calcium antagonistsrdquo CardiovascularDrugs andTherapy vol 16 no 6 pp 515ndash520 2002
[167] S Parthasarathy D Litvinov K Selvarajan and M GarelnabildquoLipid peroxidation and decompositionmdashconflicting roles inplaque vulnerability and stabilityrdquo Biochimica et BiophysicaActa vol 1781 no 5 pp 221ndash231 2008
[168] D-Q Liu Z-Q Pang D-H Zhao and B-H Sheng ldquoEffects offuryl-dihydropyridines I on lipid peroxides of ischemic myo-cardium and ATPases activity of erythrocyte membranes inratsrdquo Acta Pharmacologica Sinica vol 12 no 3 pp 253ndash2561991
[169] V Lukic-Panin T Kamiya H Zhang et al ldquoPrevention of neu-ronal damage by calcium channel blockers with antioxidativeeffects after transient focal ischemia in ratsrdquo Brain Research vol1176 no 1 pp 143ndash150 2007
[170] Y Allanore D Borderie H Lemarechal O G Ekindjian andA Kahan ldquoAcute and sustained effects of dihydropyridine-typecalcium channel antagonists on oxidative stress in systemicsclerosisrdquo American Journal of Medicine vol 116 no 9 pp 595ndash600 2004
[171] I Casetta V Govoni and E Granieri ldquoOxidative stress antioxi-dants and neurodegenerative diseasesrdquo Current PharmaceuticalDesign vol 11 no 16 pp 2033ndash2052 2005
[172] M J T J Arts Assessing antioxidant activity [PhD the-sis] Maastricht University Maastricht The Netherlands 2007httparnounimaasnlshowcgifid=8676
[173] G Dıaz-Araya L Godoy L Naranjo A Squella M E Letelierand L J Nunez-Vergara ldquoAntioxidant effects of 14-dihydro-pyridine and nitroso aryl derivatives on the Fe+3ascorbate-stimulated lipid peroxidation in rat brain slicesrdquo General Phar-macology The Vascular System vol 31 no 3 pp 385ndash391 1998
[174] Y Fukuhara K Tsuchiya Y Horinouchi et al ldquoProtectiveeffect of photodegradation product of nifedipine against tumornecrosis factor 120572-induced oxidative stress in human glomerularendothelial cellsrdquo Journal of Medical Investigation vol 58 no1-2 pp 118ndash126 2011
[175] W Stengel M Jainz and K Andreas ldquoDifferent potencies ofdihydropyridine derivatives in blocking T-type but not L-typeCa2+ channels in neuroblastoma-glioma hybrid cellsrdquo EuropeanJournal of Pharmacology vol 342 no 2-3 pp 339ndash345 1998
[176] O M Panasenko D J Tirzite G D Tirzitis and G J DubursldquoEffect of some 14-dihydropyridine derivatives on structuralorganization of erythrocyte membranesrdquo Biologicheskie Mem-brany (Biochemistry (Moscow) Series A Membrane and CellBiology) vol 1 pp 919ndash925 1984 (Russian)
[177] L G Herbette Y M H Vant Erve and D G Rhodes ldquoInter-action of 14 dihydropyridine calcium channel antagonists with
Oxidative Medicine and Cellular Longevity 33
biological membranes lipid bilayer partitioning could occurbefore drug binding to receptorsrdquo Journal of Molecular andCellular Cardiology vol 21 no 2 pp 187ndash201 1989
[178] L G Herbette P E Mason G Gaviraghi T N Tulenko andR P Mason ldquoThe molecular basis for lacidipinersquos unique phar-macokinetics optimal hydrophobicity results in membraneinteractions that may facilitate the treatment of atherosclerosisrdquoJournal of Cardiovascular Pharmacology vol 23 supplement 5pp S16ndashS25 1994
[179] G V Belevitch G Y Dubur G E Dobretsov N K Kurek andM M Spirin ldquoCalcium antagonists riodipine nifedipine andverapamil binding to model and biological membranes fluore-scence analysisrdquo Biologicheskie Membrany (Biochemistry(Moscow) Series A Membrane and Cell Biology) vol 5 pp768ndash776 1988 (Russian)
[180] R P Mason G E Gonye D W Chester and L G HerbetteldquoPartitioning and location of Bay K 8644 14-dihydropyridinecalcium channel agonist in model and biological membranesrdquoBiophysical Journal vol 55 no 4 pp 769ndash778 1989
[181] M Cindric A Cipak J Serly et al ldquoReversal of multidrugresistance inmurine lymphoma cells by amphiphilic dihydropy-ridine antioxidant derivativerdquo Anticancer Research vol 30 no10 pp 4063ndash4070 2010
[182] F Shekari H Sadeghpour K Javidnia et al ldquoCytotoxic andmultidrug resistance reversal activities of novel 14-dihydro-pyridines against human cancer cellsrdquo European Journal ofPharmacology vol 746 no 1 pp 233ndash244 2015
[183] X-F Zhou Q Shao R A Coburn and M E Morris ldquoQuanti-tative structure-activity relationship and quantitative structure-pharmacokinetics relationship of 14-dihydropyridines andpyridines as multidrug resistance modulatorsrdquo PharmaceuticalResearch vol 22 no 12 pp 1989ndash1996 2005
[184] R Berkels T Breitenbach H Bartels et al ldquoDifferent antioxida-tive potencies of dihydropyridine calcium channel modulatorsin various modelsrdquo Vascular Pharmacology vol 42 no 4 pp145ndash152 2005
[185] S Borovic G Tirzitis D Tirzite et al ldquoBioactive 14-dihydro-isonicotinic acid derivatives prevent oxidative damage of livercellsrdquo European Journal of Pharmacology vol 537 no 1ndash3 pp12ndash19 2006
[186] D Ya Rubene G D Tirzitis and G Ya Duburs ldquoInteractionof some 14-dihydropyridine derivatives with Fentonrsquos reagentrdquoLatvijas PSRZinatnuAkademijas Vestis Kimijas Serija Proceed-ings of the Latvian SSR Academy of Sciences Chemistry Seriespp 212ndash216 1982 (Russian)
[187] K Ondrias V Misık D Gergel and A Stasko ldquoLipid per-oxidation of phosphatidylcholine liposomes depressed by thecalcium channel blockers nifedipine and verapamil and bythe antiarrhythmic-antihypoxic drug stobadinerdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1003 no 3pp 238ndash245 1989
[188] I T Mak and W B Weglicki ldquoComparative antioxidant acti-vities of propranolol nifedipine verapamil and diltiazemagainst sarcolemmal membrane lipid peroxidationrdquoCirculationResearch vol 66 no 5 pp 1449ndash1452 1990
[189] I T Mak P Boehme and W B Weglicki ldquoProtective effects ofcalcium channel blockers against free radical-impaired endo-thelial cell proliferationrdquo Biochemical Pharmacology vol 50 no9 pp 1531ndash1534 1995
[190] S Ray S Mondal and N Dana ldquoEvaluation of protective roleof nifedipine on lipid peroxidation using reduced glutathione as
model markerrdquo Oxidants and Antioxidants in Medical Sciencevol 1 no 2 pp 97ndash100 2012
[191] M Yamato T Shiba T Ide Y Honda K-I Yamada andH Tsutsui ldquoNifedipine treatment reduces brain damage aftertransient focal ischemia possibly through its antioxidativeeffectsrdquoHypertension Research vol 34 no 7 pp 840ndash845 2011
[192] V Chander and K Chopra ldquoNifedipine attenuates changes innitric oxide levels renal oxidative stress and nephrotoxicityinduced by cyclosporinerdquo Renal Failure vol 27 no 4 pp 441ndash450 2005
[193] K M Gaafa M M Badawy and A A Hamza ldquoThe protectiveeffects of ascorbic acid cimetidine and nifedipine on diethyl-dithiocarbamate-induced hepatic toxicity in albino ratsrdquo Drugand Chemical Toxicology vol 34 no 4 pp 405ndash419 2011
[194] H Sugawara K Tobise and S Onodera ldquoAbsence of antiox-idant effects of nifedipine and diltiazem on myocardial mem-brane lipid peroxidation in contrast with those of nisoldipineand propranololrdquo Biochemical Pharmacology vol 47 no 5 pp887ndash892 1994
[195] I E Kirule D Y Rubene E A Bisenieks G D Tirzit and GY Dubur ldquo4-Nitrophenyl-14-dihydropyridinesmdasha new groupof inhibitors of peroxide oxidationrdquo Chemistry of HeterocyclicCompounds vol 18 no 3 p 316 1982
[196] G D Tirzit I E Kirule L K Baumane R A Gavar Y PStradynrsquo andG YDubur ldquoMechanism of the antioxidant actionof 26-dimethyl-35-dimethoxy-carbonyl-4-(2-nitrophenyl)14-dihydropyridinerdquoChemistry ofHeterocyclic Compounds vol 20no 8 pp 915ndash918 1984
[197] C Yanez C Lopez-Alarcon C Camargo V Valenzuela J ASquella and L J Nunez-Vergara ldquoStructural effects on thereactivity 14-dihydropyridines with alkylperoxyl radicals andABTS radical cationrdquo Bioorganic and Medicinal Chemistry vol12 no 9 pp 2459ndash2468 2004
[198] VMisik A J Stasko D Gergel and K Ondrias ldquoSpin-trappingand antioxidant properties of illuminated and nonilluminatednifedipine and nimodipine in heart homogenate and modelsystemrdquo Molecular Pharmacology vol 40 no 3 pp 435ndash4391991
[199] K Ondrias V Misık A Stasko D Gergelrsquo and M HromadovaldquoComparison of antioxidant properties of nifedipine and illu-minated nifedipine with nitroso spin traps in low densitylipoproteins and phosphatidylcholine liposomesrdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1211 no 1pp 114ndash119 1994
[200] A Stasko V Brezova S Biskupic K Ondrias and V MisıkldquoReactive radical intermediates formed from illuminated nife-dipinerdquoFree Radical Biology andMedicine vol 17 no 6 pp 545ndash556 1994
[201] K Ishizawa Y Izawa-Ishizawa N Yamano et al ldquoNitrosoni-fedipine ameliorates the progression of type 2 diabetic nephro-pathy by exerting antioxidative effectsrdquo PLoS ONE vol 9 no 1Article ID e86335 2014
[202] H Fujii and L J Berliner ldquoIn vivo EPR evidence for free radicaladducts of nifedipinerdquoMagnetic Resonance in Medicine vol 42no 4 pp 691ndash694 1999
[203] S Bollo S Finger J C Sturm L J Nunez-Vergara and JA Squella ldquoCyclic voltammetry and scanning electrochemicalmicroscopy studies of the heterogeneous electron transferreaction of some nitrosoaromatic compoundsrdquo ElectrochimicaActa vol 52 no 15 pp 4892ndash4898 2007
34 Oxidative Medicine and Cellular Longevity
[204] F Ursini ldquoTissue protection by lacidipine insight from redoxbehaviorrdquo Journal of Cardiovascular Pharmacology vol 30supplement 2 pp S28ndashS30 1997
[205] P G Cristofori F A Crivellente I Faustinelli et al ldquoInvolve-ment of the nitric oxide system in the anti-atheroscleroticpotential of lacidipine in the apoE-deficient mouse a mor-phological functional and electrochemical studyrdquo ToxicologicPathology vol 32 no 4 pp 493ndash499 2004
[206] X-P Zhang E L Kit S Mital S Chahwala and T HHintze ldquoParadoxical release of nitric oxide by an L-type calciumchannel antagonist the R+ enantiomer of amlodipinerdquo Journalof Cardiovascular Pharmacology vol 39 no 2 pp 208ndash2142002
[207] F Franzoni G Santoro F Regoli et al ldquoAn in vitro study of theperoxyl and hydroxyl radical scavenging capacity of the calciumantagonist amlodipinerdquo Biomedicine and Pharmacotherapy vol58 no 8 pp 423ndash426 2004
[208] S V Gatsura ldquoOxygen-dependent mechanisms underlying theantiischemic effect of verapamil and amlodipinerdquo Bulletin ofExperimental Biology and Medicine vol 137 no 1 pp 40ndash422004
[209] Y Hirooka Y Kimura M Nozoe Y Sagara K Ito and KSunagawa ldquoAmlodipine-induced reduction of oxidative stressin the brain is associated with sympatho-inhibitory effects instroke-prone spontaneously hypertensive ratsrdquo HypertensionResearch vol 29 no 1 pp 49ndash56 2006
[210] B Tomlinson and I F F Benzie ldquoAntioxidant effect of lercani-dipine (note)rdquo Hypertension vol 42 no 4 pp e10ndashe11 2003
[211] A A Faraqui ldquoNeurochemical aspects of 4-hydroxynonenalrdquoin Lipid Mediators and Their Metabolism in the Brain A AFaraqui Ed chapter 6 pp 159ndash191 Springer New York NYUSA 2011
[212] V S NascimentoM S DrsquoAlva A AOliveira et al ldquoAntioxidanteffect of nimodipine in young rats after pilocarpine-inducedseizuresrdquo Pharmacology Biochemistry and Behavior vol 82 no1 pp 11ndash16 2005
[213] O Ismailoglu P Atilla S Palaoglu et al ldquoThe therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjuryrdquo Turkish Neurosurgery vol 22 no 6 pp 740ndash746 2012
[214] M Matsubara and K Hasegawa ldquoBenidipine a dihydropy-ridine-calcium channel blocker prevents lysophosphatidyl-choline-induced injury and reactive oxygen species productionin human aortic endothelial cellsrdquo Atherosclerosis vol 178 no1 pp 57ndash66 2005
[215] M Matsubara K Yao and K Hasegawa ldquoBenidipine adihydropyridine-calcium channel blocker inhibits lysophos-phatidylcholine-induced endothelial injury via stimulation ofnitric oxide releaserdquo Pharmacological Research vol 53 no 1 pp35ndash43 2006
[216] MMatsubara and K Hasegawa ldquoEffects of benidipine a dihyd-ropyridine-Ca2+ channel blocker on expression of cytokine-induced adhesion molecules and chemoattractants in humanaortic endothelial cellsrdquo European Journal of Pharmacology vol498 no 1ndash3 pp 303ndash314 2004
[217] M Matsubara O Akizuki J-I Ikeda K Saeki K Yao and KSasaki ldquoBenidipine an anti-hypertensive drug inhibits reactiveoxygen species production in polymorphonuclear leukocytesand oxidative stress in salt-loaded stroke-prone spontaneouslyhypertensive ratsrdquo European Journal of Pharmacology vol 580no 1-2 pp 201ndash213 2008
[218] A C Rosenkranz H Lob T Breitenbach R Berkels and RRoesen ldquoEndothelial antioxidant actions of dihydropyridines
and angiotensin converting enzyme inhibitorsrdquo European Jour-nal of Pharmacology vol 529 no 1ndash3 pp 55ndash62 2006
[219] V Kain S Kumar and S L Sitasawad ldquoAzelnidipine preventscardiac dysfunction in streptozotocin-diabetic rats by reducingintracellular calcium accumulation oxidative stress and apop-tosisrdquo Cardiovascular Diabetology vol 10 article 97 2011
[220] K Nakamura S Yamagishi and H Inoue ldquoUnique atheropro-tective property of azelnidipine a dihydropyridine-based cal-cium antagonistrdquoMedical Hypotheses vol 65 no 1 pp 155ndash1572005
[221] TMatsui S Yamagishi K Nakamura S Kikuchi andH InoueldquoAzelnidipine a dihydropyridine-based calcium antagonistinhibits angiotensin II-induced oxidative stress generation anddownregulation of pigment epithelium-derived factor mRNAlevels in microvascular endothelial cellsrdquo Drugs under Experi-mental and Clinical Research vol 31 no 5-6 pp 215ndash219 2005
[222] C Ohmura H Watada T Shimizu et al ldquoCalcium channelblocker azelnidipine reduces lipid hydroperoxides in patientswith type 2 diabetes independent of blood pressurerdquo EndocrineJournal vol 54 no 5 pp 805ndash811 2007
[223] H Daikuhara F Kikuchi and T Ishida ldquoThe combination ofOLmesartan and a CAlcium channel blocker (azelnidipine) orcandesartan and a calcium channel blocker (amlodipine) intype 2 diabetic hypertensive patients theOLCA studyrdquoDiabetesand Vascular Disease Research vol 9 no 4 pp 280ndash286 2012
[224] MAbe NMaruyama KOkada SMatsumoto KMatsumotoand M Soma ldquoAdditive antioxidative effects of azelnidipine onangiotensin receptor blocker olmesartan treatment for type 2diabetic patients with albuminuriardquoHypertension Research vol34 no 8 pp 935ndash941 2011
[225] K Mizushige ldquoAntioxidative activities of thiazolidinedionesand dihydropyridine-type calcium antagonistsrdquo IRYOmdashJapa-nese Journal of National Medical Services vol 59 no 11 pp 581ndash592 2005
[226] S Manabe T Okura T Fukuoka and J Higaki ldquoAntioxidativeeffects of azelnidipine on mesangial cell proliferation inducedby highly concentrated insulinrdquo European Journal of Pharma-cology vol 567 no 3 pp 252ndash257 2007
[227] Y Koyama Y Takeishi H Takahashi et al ldquoAzelnidipine inhi-bits H
2O2-induced cell death in neonatal rat cardiomyocytesrdquo
CardiovascularDrugs andTherapy vol 21 no 1 pp 69ndash72 2007[228] K Shinomiya K Mizushige M Fukunaga et al ldquoAntioxidant
effect of a new calcium antagonist azelnipidine in culturedhuman arterial endothelial cellsrdquo Journal of International Med-ical Research vol 32 no 2 pp 170ndash175 2004
[229] T Ohyama K Sato K Kishimoto et al ldquoAzelnidipine is acalcium blocker that attenuates liver fibrosis and may increaseantioxidant defencerdquo British Journal of Pharmacology vol 165no 4 pp 1173ndash1187 2012
[230] L A Calo F Zaghetto E Pagnin P A Davis A Sempliciniand A C Pessina ldquoEffect of manidipine on gene expressionand protein level of oxidative stress-related proteins p22phoxand HO-1 Relevance for antihypertensive and anti-remodelingeffectsrdquo Journal of Cardiovascular Pharmacology vol 43 no 4pp 531ndash538 2004
[231] R Ghyasi G Sepehri M Mohammadi R Badalzadeh and AGhyasi ldquoEffect of mebudipine on oxidative stress and lipid per-oxidation in myocardial ischemic-reperfusion injury in maleratrdquo Journal of Research in Medical Sciences vol 17 no 12 pp1150ndash1155 2012
Oxidative Medicine and Cellular Longevity 35
[232] DCAndersson J Fauconnier T Yamada et al ldquoMitochondrialproduction of reactive oxygen species contributes to the 120573-adrenergic stimulation of mouse cardiomycytesrdquoThe Journal ofPhysiology vol 589 no 7 pp 1791ndash1801 2011
[233] A F Ceylan-Isik N Ari M Stefek et al ldquoEffects of a long-term treatment with an antioxidant pyridoindole on vascularresponsiveness in diabetes-induced aging ratsrdquo Current AgingScience vol 4 no 2 pp 150ndash157 2011
[234] S Saponara G Sgaragli and F Fusi ldquoQuercetin antagonismof Bay K 8644 effects on rat tail artery L-type Ca2+ channelsrdquoEuropean Journal of Pharmacology vol 598 no 1ndash3 pp 75ndash802008
[235] D A Sica ldquoInteraction of grapefruit juice and calcium channelblockersrdquo American Journal of Hypertension vol 19 no 7 pp768ndash773 2006
[236] P Mulder G Litwinienko S Lin P D MacLean L R CBarclay and K U Ingold ldquoThe L-type calcium channel block-ers Hantzsch 14-dihydropyridines are not peroxyl radical-trapping chain-breaking antioxidantsrdquo Chemical Research inToxicology vol 19 no 1 pp 79ndash85 2006
[237] L J Nunez-Vergara R Salazar C Camargo et al ldquoOxidation ofC4-hydroxyphenyl 14-dihydropyridines in dimethylsulfoxideand its reactivity towards alkylperoxyl radicals in aqueousmediumrdquo Bioorganic and Medicinal Chemistry vol 15 no 12pp 4318ndash4326 2007
[238] M E Ortiz L J Nunez-Vergara and J A Squella ldquoRelativereactivity of dihydropyridine derivatives to electrogeneratedsuperoxide ion in DMSO solutions a voltammetric approachrdquoPharmaceutical Research vol 20 no 2 pp 292ndash296 2003
[239] M E Ortiz L J Nunez-Vergara C Camargo and J A SquellaldquoOxidation of Hantzsch 14-dihydropyridines of pharmacolog-ical significance by electrogenerated superoxiderdquo Pharmaceuti-cal Research vol 21 no 3 pp 428ndash435 2004
[240] R S Raghuvanshi and K N Singh ldquoSuperoxide induced oxida-tive aromatization of Hantzsch 14-dihydropyridinesrdquo IndianJournal of Chemistry Section B Organic and Medicinal Chem-istry vol 47 no 11 pp 1735ndash1738 2008
[241] I Kruk A Kladna K Lichszteld et al ldquoAntioxidant activityof 4-flavonil-14-dihydropyridine derivativesrdquo Biopolymers vol62 no 3 pp 163ndash167 2001
[242] G D Tirzit I M Byteva K I Salokhiddinov G P Gurinovichand G Y Dubur ldquo14-Dihydropyridine derivatives as deactiva-tors of singlet oxygenrdquo Chemistry of Heterocyclic Compoundsvol 17 no 7 pp 682ndash684 1981
[243] G D Tirzit E Y Kazush and G Y Dubur ldquoInfluence of14-dihydropyridine derivatives on the generation of hydroxylradicalsrdquo Chemistry of Heterocyclic Compounds vol 28 no 4pp 435ndash437 1992
[244] N A Pizarro-Urzua and L J Nunez-Vergara ldquoNifedipine andnitrendipine reactivity toward singlet oxygenrdquo Journal of Photo-chemistry and Photobiology A Chemistry vol 175 no 2-3 pp129ndash137 2005
[245] L-F Wang H-Y Zhang L Konga Z-W Chena and J-G ShildquoDFT calculations indicate that 14-dihydropyridine is a promis-ing lead antioxidantrdquo Helvetica Chimica Acta vol 87 no 6 pp1515ndash1521 2004
[246] P Mulder H-G Korth and K U Ingold ldquoWhy quantum-thermochemical calculations must be used with caution toindicate lsquoa promising lead antioxidantrsquordquoHelvetica Chimica Actavol 88 no 2 pp 370ndash374 2005
[247] K Yao Y Ina K Nagashima K Ohmori and T Ohno ldquoAntiox-idant effects of calcium antagonists in rat brain homogenatesrdquo
Biological and Pharmaceutical Bulletin vol 23 no 6 pp 766ndash769 2000
[248] T Matsui S-I Yamagishi K Nakamura and H Inoue ldquoBayw 9798 a dihydropyridine structurally related to nifedipinewith no calcium channel-blocking properties inhibits tumournecrosis factor-120572-induced vascular cell adhesion molecule-1expression in endothelial cells by suppressing reactive oxygenspecies generationrdquo Journal of International Medical Researchvol 35 no 6 pp 886ndash891 2007
[249] K AMitrega B VargheseM Porc and T F Krzeminski ldquoAnti-arrhythmic and hemodynamic effects of oxy nifedipine oxynimodipine oxy nitrendipine and oxy nisoldipinerdquo Pharmaco-logical Research vol 66 no 4 pp 300ndash308 2012
[250] V Herbert ldquoSymposium prooxidant effects of antioxidantvitamins Introductionrdquo The Journal of Nutrition vol 126 no4 supplement pp 1197Sndash1200S 1996 httpjnnutritionorgcontent1264 Suppl1197Sfullpdf
[251] B Halliwell ldquoAre polyphenols antioxidants or pro-oxidantsWhat do we learn from cell culture and in vivo studiesrdquoArchives of Biochemistry and Biophysics vol 476 no 2 pp 107ndash112 2008
[252] C Winterbourn Pro-Oxidants or Antioxidants ChristchurchSchool of Medicine Depatment of Pathology Free RadicalSchool SFRBMUniversity of Otago San Francisco Calif USA2009 httpwwwsfrbmorgfrsWinterbournpdf
[253] A Morakinyo B Iranloye and O Adegoke ldquoCalcium antag-onists modulate oxidative stress and acrosomal reaction in ratspermatozoardquo Archives of Medical Science vol 7 no 4 pp 613ndash618 2011
[254] The Alpha-Tocopherol Beta Carotene Cancer Prevention StudyGroup ldquoThe effect of vitamin E and beta carotene on theincidence of lung cancer and other cancers in male smokersrdquoTheNew England Journal of Medicine vol 330 no 15 pp 1029ndash1035 1994
[255] B Poljsak ldquoStrategies for reducing or preventing the generationof oxidative stressrdquo Oxidative Medicine and Cellular Longevityvol 2011 Article ID 194586 15 pages 2011
[256] B Poljsak and I Milisav ldquoThe neglected significance of lsquoanti-oxidative stressrsquordquoOxidativeMedicine and Cellular Longevity vol2012 Article ID 480895 12 pages 2012
[257] T Godfraind and S Salomone ldquoAmbiguities in dietary antiox-idant supplementation compared to calcium channel blockerstherapyrdquo Frontiers in Pharmacology vol 6 article 10 2015
[258] H Wagner H Norr and H Winterhoff ldquoDrugs with adap-togenic effects for strengthening the powers of resistancerdquoZeitschrift fur Phytotherapie vol 13 no 2 pp 42ndash54 1992
24 Oxidative Medicine and Cellular Longevity
this study indicate that the tested derivatives may catalyzeconversion of superoxide radicals through mimicking theactivity of superoxide dismutase by delivering H+ for reac-tion
O2
minus∙+O2
minus∙+ 2H+ 997888rarr H
2O2+1O2
(3)
The enhanced emission of the light in the presence oftested compounds was significant and related to stimulatedproduction ofH
2O2and 1O
2fromO
2
∙The latter specieswereremoved from the reactionmixture by the following sequenceof reactions
H+
O2
minus∙997888rarr HO
2
∙
HO2
∙+O2
∙minus997888rarr HO
2
minus+1O2
2HO2
∙997888rarr H
2O2+1O2
2 (1O2) 997888rarr (O
2)2+ h]lowast
(4)
or to take part in spontaneous dismutation of H2O2
2H2O2997888rarr 2H
2O + 1O
2(5)
The authors have offered an original concept of action for 4-flavonil-14-dihydropyridine derivatives unrelated to that ofO2
∙ radical-trapping chain-breaking antioxidants Insteadthey showed that these compounds act similar to superoxidedismutases converting O
2
∙ to H2O2 Hydrogen peroxide
is less toxic for cells than O2
∙ because it is predominantlyremoved by peroxidases and catalases Finally AO effect ofthese DHPs differed from those mediated by flavonoids witha catechol structure of ring B which are well-known 1O
2
quenchersMulder and collaborators came to similar conclusions
especially related to molecular mechanisms of antioxidativeactivity of DHPs [236]TheAOproperties of Hantzsch 14-di-hydropyridine esters and two dibenzo-14-dihydropyridines910-dihydroacridine (DHAC) and N-methyl-910-dihydro-acridine (N-Me-DHAC) have been explored by determin-ing the autoxidation of styrene or cumene at 30∘C Theseexperiments showed that Hantzsch esters are virtually inac-tive as chain-breaking antioxidants (CB-AOs) contrary tothe findings observed by Lopez-Alarcon et al [103] whoused CB-AOA in aqueous media at pH 74 Their reactivitytoward peroxyl radicals was shown to be some 5 orders ofmagnitude lower than that of the excellent CB-AO 22578-pentamethyl-6-hydroxy-chroman (PMHC)
DHAC was found to be sim10 times less reactive thanPMHC kinetic measurements using DHAC N-deuterio-DHAC and N-Me-DHAC pointing out the abstraction ofN-H hydrogen in DHAC by peroxyl radicals despite the factthat the calculated C-H bond dissociation enthalpy (BDE) inDHAC is about 11 kcalmol lower than the N-H BDE Therates of hydrogen atom abstraction by the 22-diphenyl-1-picrylhydrazyl radical (DPPH∙) have also been determined
for the same series of compounds The trends in the peroxyl∙and DPPH∙ rate constants were found to be similar [236]
Tirzit et al [242] have observed quenching of singletoxygen by DHPs This observation paved the ground forfurther research related to reactions of DHPs with hydroxylradicals (Tirzit et al [243]) singlet oxygen (Kazush etal [94]) and mechanisms of action A series of 14-DHPderivatives in NAD-H-Cu2+-H
2O2system inhibited forming
of the hydroxyl radical (HO∙) while 14-DHP derivativeswith electron donor substituents in the molecule were shownto be capable themselves of generating HO∙ in the presenceof Cu2+ and H
2O2 Rubene et al [186] also described
interaction of 14-DHP derivatives with Fentonrsquos reagentwhich produces hydroxyl radical (HO∙) Rate constants ofthe DHPs reaction (1st order) with HO∙ radical were highin the range 109 L times mol times secminus1 close to that of NADHcysteine and thiourea 35-Diacetyl- derivatives reacted fastercompared to 35-dialkoxycarbonyl- ones The reaction ratedecrease was observed in the case of substitution at position4 as compared to 4-unsubstituted DHPs Some DHPs havingelectron donor -COOminus groups in the 35- or 26- positionsof DHP ring reacted immediately (having rate constantshigher as 109 L times mol times secminus1) Rate constants with HO
2
∙
and O2
∙minus radicals were of lower degree Thus DHPs actingas oxygen radical scavengers could effectively inhibit ROSrelated reactions of LP initiation stage
Nifedipine and nitrendipine reactivity toward singletoxygen was also studied [244] Nifedipine was shown tobe a good scavenger of excited oxygen mainly via physicaldeactivation with values of the total rate constant rangingfrom 208 times 105Mminus1 sminus1 (in dioxane) to 930 times 105Mminus1 sminus1(in propylene carbonate)The less reactive pathway generateda photooxidation product For that reason a mechanisminvolving a perepoxide-like encounter complex in the firststep of the reaction path was proposed (see [244] Figures8 and 9 therein) The dependence was observed on solventmicroscopic parameters of the total rate constant for the reac-tion between singlet oxygen and 14-DHPs These findingsshow that nifedipine possesses stronger protective activity inbiological systems than nitrendipine
Density-functional-theory (DFT) calculations made byWang et al [245] confirmed the former experimental obser-vations that Hantzsch ester diludine is potent antioxi-dant with high H atom-donating ability and relatively lowprooxidant activity Possible reaction pathways for radicalsderived from 14-dihydropyridine and the resonance modesfor radical species were given [245]
Moreover two ethoxycarbonyl (EtOCO) substituentsat C(2) and C(6) should further enhance Hantzsch esterdiludine H-atom-donating ability due to resonance effectsHowever DHPs should be used in nonpolar rather than inpolar solvents since in the latter not H-atom but electrontransfer is preferred in the radical scavenging process [245]
Mulder et al [246] proposed that quantum-thermochem-ical calculations must be used with caution to indicate ldquoapromising lead antioxidantrdquo as they criticized the density-functional-theory (DFT) calculations made by Wang et al[245]
Oxidative Medicine and Cellular Longevity 25
372 Possible Mechanisms of DHPs ARA and AOA in the Bio-logical Systems Interaction with Other OSModifiers Some ofthese mechanisms were already described (Sections 331 (2)-(b) 331 (2)-(c) 331 (3)-(b) 35)
Enzymatic sources of ROSwith confirmed functional rolein hypertension are NADPH oxidase NO synthase (NOS)xanthine oxidase and cyclooxygenase Godfraind [3] hasreviewed AO effects and protective action of calcium channelblockers (CCBs) Yao et al [247] observed antioxidant effects(as inhibition of LP) for cardio- and neuroprotective CCBs(3ndash300 120583molL) including 7 DHPs in homogenates of ratbrain IC
50values (120583M) were as follows nifedipine (515) gt
barnidipine (586) gt benidipine (712) gt nicardipine (1293)gt amlodipine (1355) gt nilvadipine (1673) gt nitrendipine(2521) gt diltiazem (gt300) = verapamil (gt300) There arealso research articles describing the AO properties of CCBsthrough direct scavenging effect or through preservationof the endogenous SOD activity These findings indicatethat CCBs may also act by reducing the production ofvasoconstrictors angiotensin and endothelin
When present in concentrations that can be achievedin plasma CCBs may inhibit LP formation [3] This AOactivity seems to be typical for high lipophilic CCBs becausetheir chemical structure facilitates proton-donating andresonance-stabilization mechanisms that quench the freeradical reaction Their insertion in the membrane nearpolyunsaturated fatty acids at relatively high concentrationspotentiates proton donation (or atomary H) to lipid peroxidemolecules thereby blocking the peroxidation process Theremaining unpaired free electron associated with the CCBmolecule can be stabilized in well-defined resonance struc-tures associated with the DHP ring (Mason et al [48])
The radical reaction (according to Godfraind [3]) thatdescribes the AO effects of a DHP CCBs is LOOlowast + DHPrarr LOOH + DHPlowast (where LOOlowast is lipid peroxide radical)which in general is reaction (7) of the LP reaction cascadeconsisting of sim10 reactions (Scheme 2) [89]
As the rate constants of in vitro interaction of 4-substituted DHPs with peroxyl radicals are three ordersof magnitude lower than that of the vitamin E derivativethese DHPs must be considered as weak AO (Ursini [204])However due to partition coefficient of DHPs in membranesand in case of specific binding high local concentration ofDHPs may be obtained
DHPs without CCB properties for instance Bay w 9798although structurally related to nifedipine inhibit TNF-120572-induced vascular cell adhesion molecule-1 expression inendothelial cells by suppressing reactive oxygen speciesgeneration [248]
Mitrega et al [249] have discovered that antiarrhythmicand hemodynamic effects of oxidized heteroaromatic DHPsoxy nifedipine oxy nimodipine oxy nitrendipine and oxynisoldipine suggest that CCB DHPs and their metabolitescould act at least in two ways targeting OS related eventsas reductants (see Section 351 (1)) andor bypassing OSrelatedmetabolic routes Authors postulated that contrary tocurrent belief NIF metabolites are pharmacologically activeATP sensitive potassium channels were mentioned as a tar-get
38 DHPs Anti- or Prooxidants Several substances (ascorbicacid being the most commonly studied) can serve either asantioxidants or as prooxidants depending on given condi-tions (Herbert [250]) Therefore Halliwell [251] has reporteddilemma related to polyphenols as possible antioxidantsand prooxidants causing experimental artifacts (about 25)by oxidation of antioxidant compounds in the cell culturemedia Nevertheless it is generally accepted opinion thatpolyphenols act as antioxidants in vivo Studies on DHPs alsoface such a dilemmaThe exact roles (anti- or prooxidative) ofany specific DHP depend on its structure appliedachievedconcentration and specificity of the targetexperimentaltesting system
This situation resembles the case of antioxidative effectsof tocopherol which depends on the fate of the secondaryradical as proposed by Winterbourn [252] The question wasldquoVitamin E - Pro- or Antioxidantrdquo
997888rarr chain termination of lipid peroxidation
(6)
Prooxidant
Toc∙ + Lipid-H 997888rarr Lipid∙ (in LDL particles) (7)
This example shows that generally speaking any AO mustfulfil several criteria to be considered as an effective com-pound physiologically
(i) It must be able to functionally interact with endoge-nous scavengers even at low concentrations
(ii) It must affect endogenous pathways of OS(iii) It should not have undesirable adverse effect(iv) It should manifest the antioxidant efficacy dependent
on the oxidant(v) It must discriminate among different strategies
needed for 1-electron and 2-electron processes(vi) Radical scavengers can be prooxidant unless linked to
a radical sink (Winterbourn [252])
According to these statements DHPs could be effective asAO under physiological conditions in vivo (Godfraind [3]and others [30 31 38]) and in vitro in various experimentalsystems (cell and tissue) (see Sections 33 34 35)
Hence calcium antagonists appeared to disrupt thefine balance between the production and scavenging ofROS Nifedipine verapamil and diltiazem were shown toinduce significant oxidative stress in the epididymal sperm(increased MDA and decreased catalase and superoxidedismutase activity) This may be the reason for the inductionof male infertility [253]
The dualism of 14-DHP effects has been recorded asinhibition or promotion of LP as quenching or initiating
26 Oxidative Medicine and Cellular Longevity
oxygen and nitrogen free radical chain reactions radiopro-tecting or radiosensitizing antagonizing or synergizing Ca2+in electromechanical coupling as well as in the membranestabilization or labilization
39 Could DHPs Be Involved in Antioxidative Stress Beforebeing applied in vivo the optimal dose and optimal timeintervals forDHPs applicationmust be knownNamely whileROS have been traditionally considered as toxic byproductsof aerobic metabolism we know nowadays that ROS may actas essential signaling molecules needed for the control ofmany different physiological processes Whether the role ofROS will be damaging protective or signaling depends onthe delicate equilibrium between time- and location-specificROS production and scavenging Accordingly the imbalanceof the increased AO potential so-called antioxidative stresscould be dangerous similar to chronic OS in particular incase of extended exposure Inappropriate interventions inthe oxidative homeostasis by excessive antioxidants especiallyin case of chronic exposure to antioxidants might havevery negative effects as was published in the ATBC studyshowing an increased cancer incidence in smokers treatedby excessive beta-carotene [254] Therefore overconsump-tion of any natural or synthetic AO including DHPs asdietary supplements or drugs must be avoided in order tosuppress oxidative damage and must not disrupt the well-integrated antioxidant defense network (Poljsak [255] andPoljsak and Milisav [256]) This is especially important whenadministrating lipid-soluble antioxidants that can be storedin biomembranes thus not only attenuating or preventing LPbut also affecting physiological effects of the natural antiox-idants in particular tocopherol The interrelationship withthe status of endogenous antioxidantsprooxidants should befollowed
DHPs primarily suppress the initiation stages of LPprocessThey do not entirely stop the LP propagation Actingsynergistically with tocopherol diludine may prevent patho-logical excess of ROS production within the lipid moiety ofthe cellular membranes and LDL However due to its lowsolubility and fast metabolism its concentration in the cellsis low For that reason it cannot cause antioxidative stresseven if used for an extended period of time Thus diludine(diethone) could be only a mild antioxidant it has potentialfor restoring the pool of natural antioxidants (as synergist of120572-tocopherol and polyphenols) in the cells
Moreover DHPs CA used for cardioprotection andvasodilatation as commercial drugs in low concentrationsare fast metabolized via CYP3A4 and for that reason theirapplication does not induce cellular AO stress [53 160]However Godfraind and Salomone [257] have postulated noevidence that allows recommending dietary supplementationwith antioxidants for the primary or secondary prevention ofcardiovascular disease
So far there are no reports on antioxidative stress causedby some DHPs diludine and its analogues Diludine andits analogues therefore could act as adaptogens supportinghormetic effects of mild oxidative stress These compoundsmay act as potential multisided modulators of Yin-Yang
cycles of redox and cell functions (the electroplasmic cycle)(Wagner et al [258])
4 Conclusions
14-Dihydropyridines (14-DHPs) have broad spectrum ofOS modulating activities DHPs have reducing and lipidperoxidation inhibitor properties act as reductants in simplechemical systems and stabilize various biological systems(LDL mitochondria microsomes cells and tissues) againstOS Examples and peculiarities and mechanisms of antiox-idant activity (AOA) and antiradical activity (ARA) as wellas stress-protective effect of DHPs including commercialcalcium antagonists (CA) were highlighted These activitiesdepend on various structural parameters related to DHPs(presence and character of substituents) lipophilicity anddepth of the incorporation in the biologicalmembranesTheyalso depend on the experimental model system for exploringthe lipid peroxidation or oxidative stress Stress-protectiveeffect of some metabolites of CA (nifedipine) is reviewedAlthough some DHPs including CA have prooxidant prop-erties (on epididymal sperm cells) they can generally beconsidered as potent antioxidants Therefore comparisonof the AOA and ARA of different DHPs (mutually andwith other AOs) was described in detail According to thedata presented the DHPs might be considered as bellwetheramong synthetic compounds targeting OS and as a kind ofpharmacological measure for respective field of organic andmedicinal chemistry
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
Authors from Latvian IOS acknowledge ESF 201300021DP1112013APIAVIAA011 and National Research Pro-gramme PUBLIC HEALTHBiomedicine of the Republicof Latvia for financial support administration of the Insti-tute for technical support and Rufus Smits PhD for con-sultations in English The support of Cooperation in Euro-pean System of Science and Technology (COST) Domain ofChemistry Molecular Sciences and Technologies (CMST)was of highest importance for preparation of this paper
[2] D J Triggle ldquo14-Dihydropyridines as calcium channel ligandsand privileged structuresrdquoCellular andMolecular Neurobiologyvol 23 no 3 pp 293ndash303 2003
[3] T Godfraind ldquoAntioxidant effects and the therapeutic modeof action of calcium channel blockers in hypertension andatherosclerosisrdquo Philosophical Transactions of the Royal SocietyB Biological Sciences vol 360 no 1464 pp 2259ndash2272 2005
[4] E Cadenas ldquoMitochondrial free radical production and cellsignalingrdquoMolecular Aspects of Medicine vol 25 no 1-2 pp 17ndash26 2004
[5] E Cadenas ldquoFree radicals oxidative stress and diseasesrdquo inLecture PSC 616 p 38 Missouri University of Science andTechnology Rolla Mo USA httpwwwcarnicominstituteorgarticlesenrique cadenaspdf
[6] K Rahman ldquoStudies on free radicals antioxidants and co-fac-torsrdquo Clinical Interventions in Aging vol 2 no 2 pp 219ndash2362007
[7] V Bocci and G Valacchi ldquoFree radicals and antioxidants howto reestablish redox homeostasis in chronic diseasesrdquo CurrentMedicinal Chemistry vol 20 no 27 pp 3397ndash3415 2013
[8] M Valko C J Rhodes J Moncol M Izakovic and M MazurldquoFree radicals metals and antioxidants in oxidative stress-induced cancerrdquo Chemico-Biological Interactions vol 160 no 1pp 1ndash40 2006
[9] G Bartosz ldquoReactive oxygen species destroyers or messen-gersrdquo Biochemical Pharmacology vol 77 no 8 pp 1303ndash13152009
[10] R Visconti and D Grieco ldquoNew insights on oxidative stress incancerrdquo Current Opinion in Drug Discovery and Developmentvol 12 no 2 pp 240ndash245 2009
[11] R N Kujundzic N Zarkovic and K G Troselj ldquoPyridinenucleotides in regulation of cell death and survival by redoxand non-redox reactionsrdquo Critical Reviews in Eukaryotic GeneExpression vol 24 no 4 pp 287ndash309 2014
[12] B Halliwell and J M C Gutteridge ldquoThe definition and mea-surement of antioxidants in biological systemsrdquo Free RadicalBiology and Medicine vol 18 no 1 pp 125ndash126 1995
[13] V D Kancheva and O T Kasaikina ldquoBio-antioxidantsmdashachemical base of their antioxidant activity and beneficial effect
on human healthrdquo Current Medicinal Chemistry vol 20 no 37pp 4784ndash4805 2013
[14] H V Panglossi Ed Frontiers in Antioxidants Research NovaScience Publishers New York NY USA 2006
[15] E B Burlakova E M Molochkina and G A NikiforovldquoHybrid antioxidantsrdquo Oxidation Communications vol 31 no4 pp 739ndash757 2008 httpmembraneustceducnpaperpdfHybrid20Antioxidantspdf
[16] A Bast and G R M M Haenen ldquoTen misconceptions aboutantioxidantsrdquo Trends in Pharmacological Sciences vol 34 no 8pp 430ndash436 2013
[17] E B Burlakova A V 0lesenko E M Molochkina N PPalmina and N G Khrapova Bioantioxidants for RadiationDamage and Malignant Growth Nauka Moscow Russia 1975(Russian)
[18] J Fang T Seki and H Maeda ldquoTherapeutic strategies by mod-ulating oxygen stress in cancer and inflammationrdquo AdvancedDrug Delivery Reviews vol 61 no 4 pp 290ndash302 2009
[19] M Valko D Leibfritz J Moncol M T D Cronin M Mazurand J Telser ldquoFree radicals and antioxidants in normal physi-ological functions and human diseaserdquo International Journal ofBiochemistry and Cell Biology vol 39 no 1 pp 44ndash84 2007
[20] M Jimenez-Del-Rio and C Velez-Pardo ldquoThe bad the goodand the ugly about oxidative stressrdquo Oxidative Medicine andCellular Longevity vol 2012 Article ID 163913 13 pages 2012
[21] C D Kamat S Gadal M Mhatre K S Williamson Q N Pyeand K Hensley ldquoAntioxidants in central nervous system dis-eases preclinical promise and translational challengesrdquo Journalof Alzheimerrsquos Disease vol 15 no 3 pp 473ndash493 2008
[22] A Pompella H Sies R Wacker et al ldquoThe use of totalantioxidant capacity as surrogate marker for food quality andits effect on health is to be discouragedrdquo Nutrition vol 30 no7-8 pp 791ndash793 2014
[23] Z Ye and H Song ldquoAntioxidant vitamins intake and the risk ofcoronary heart disease meta-analysis of cohort studiesrdquo Euro-pean Journal of Cardiovascular Prevention and Rehabilitationvol 15 no 1 pp 26ndash34 2008
[24] P Knekt J Ritz M A Pereira et al ldquoAntioxidant vitamins andcoronary heart disease risk a pooled analysis of 9 cohortsrdquoTheAmerican Journal of Clinical Nutrition vol 80 no 6 pp 1508ndash1520 2004
[25] A C Carr and M C M Vissers ldquoSynthetic or food-derivedvitamin Cmdashare they equally bioavailablerdquo Nutrients vol 5 no11 pp 4284ndash4304 2013
[26] R Tabrizchi ldquoEdaravoneMitsubishi-TokyordquoCurrentOpinion inInvestigational Drugs vol 1 no 3 pp 347ndash354 2000
[27] K Kikuchi S Tancharoen N Takeshige et al ldquoThe efficacy ofedaravone (radicut) a free radical scavenger for cardiovasculardiseaserdquo International Journal of Molecular Sciences vol 14 no7 pp 13909ndash13930 2013
[28] D Mauzerall and F H Westheimer ldquo1-Benzyldihydronicoti-namidemdasha model for reduced DPNrdquo Journal of the AmericanChemical Society vol 77 no 8 pp 2261ndash2264 1955 ChemicalAbstracts vol 50 Article ID 2588i 1956
[29] F Bossert and W Vater ldquo14-Dihydropyridinesmdasha basis fordeveloping new drugsrdquo Medicinal Research Reviews vol 9 no3 pp 291ndash324 1989
[30] G Swarnalatha G Prasanthi N Sirisha and CMadhusudhanaChetty ldquo14-Dihydropyridines a multtifunctional moleculemdash areviewrdquo International Journal of ChemTech Research vol 3 no1 pp 75ndash89 2011
28 Oxidative Medicine and Cellular Longevity
[31] M Cataldi and F Bruno ldquo14-Dihydropyridines the multiplepersonalities of a blockbuster drug familyrdquo Translational Medi-cine UniSa vol 4 no 2 pp 12ndash26 2012 httpwwwncbinlmnihgovpmcarticlesPMC3728803
[32] R Vitolina A Krauze G Duburs and A Velena ldquoAspects ofthe amlodipine pleiotropy in biochemistry pharmacology andclinicsrdquo International Journal of Pharmaceutical Sciences andResearch vol 3 no 5 pp 1215ndash1232 2012
[33] D Grover S N Mokale and M T Shete ldquoDihydropyridinea novel pharmacophorerdquo International Journal of Pharmaceu-tical Erudition vol 1 no 2 pp 16ndash29 2011 httppharmaeru-ditionorgContentPaper20111-RV-320Final2016-29pdf
[34] A M Vijesh A M Isloor S K Peethambar K N ShivanandaT Arulmoli and N A Isloor ldquoHantzsch reaction synthesis andcharacterization of somenew 14-dihydropyridine derivatives aspotent antimicrobial and antioxidant agentsrdquo European Journalof Medicinal Chemistry vol 46 no 11 pp 5591ndash5597 2011
[35] P Mehta and P Verma ldquoAntimicrobial activity of some deriva-tives of 14-dihydropyridinesrdquo Journal of Chemistry vol 2013Article ID 865128 4 pages 2013
[36] P Olejnıkova L Svorc D Olsovska et al ldquoAntimicrobialactivity of novel C2-substituted 14-dihydropyridine analoguesrdquoScientia Pharmaceutica vol 82 no 2 pp 221ndash232 2014
[37] S Sepehri H Perez Sanchez and A Fassihi ldquoHantzsch-typedihydropyridines and biginelli-type tetra-hydropyrimidinesa review of their chemotherapeutic activitiesrdquo Journal of Phar-macy amp Pharmaceutical Sciences vol 18 no 1 pp 1ndash52 2015httpsejournalslibraryualbertacaindexphpJPPSarticleview2383617863
[38] S A Khedkar and P B Auti ldquo14-Dihydropyridines a classof pharmacologically important moleculesrdquo Mini-Reviews inMedicinal Chemistry vol 14 no 3 pp 282ndash290 2014
[39] G D Tirzit and G Ya Duburs ldquo14-dihydropyridines as inhi-bitors of free-radical reactionsrdquo Chemistry of Heterocyclic Com-pounds vol 8 no 1 pp 126ndash127 1972 Translated from KhimiyaGeterotsiklicheskikh Soedinenii no1 pp 133ndash134 1972 (Rus-sian)
[40] I Bogeski R Kappl C Kummerow R Gulaboski M Hothand B A Niemeyer ldquoRedox regulation of calcium ion channelschemical and physiological aspectsrdquoCell Calcium vol 50 no 5pp 407ndash423 2011
[41] S A Giller G Y Dubur Y R Uldrikis et al ldquoDiludine [Themethod to obtain 35-dicarbonylderivatives of 26-dimethyl-14-dihydropyridines]rdquo Authors certificate of USSR no 3004651971 [Byull Izobret no13 p 95 1971] and following patentsPatent of England no 1294650 1973 Patent of France no2055458 1971 Patent of Japan no 702883 1973 Patent ofHolland no 149787 1976 Patent of Italy no 969022 1974 Patentof FRG no 2036403 1978 US Patent no 3883673 1975 USPatent no 3948924 1976
[42] S A Giller G Y Dubur Y R Uldrikis et al ldquoImprovementsin or relating to the stabilization of carotenerdquo GB Patent no1294650 1972
[43] S A Giller G Y Dubur Y R Uldrikis et al ldquoStabilization ofcarotenerdquo US Patent no 3883673 1975 Chemical Abstracts vol83 Article ID 95193 1975
[44] Yu A Zilber G Ya Dubur K K Kumsar and A Kh VelenaldquoThe effect of antioxidants on the peroxidation of bimole-cular phospholipid membranesrdquo Latvijas PSR ZA Vestis Izves-tia Akademii Nauk Latviyskoy SSR vol 6 pp 80ndash82 1971(Russian) translated from the original Russian Doc Accesion
No AD0771751 distributed by NTIS US Department of Com-merce httpwwwdticmildtictrfulltextu2771751pdf
[45] G Ya Dubur Yu A Zilbers A Kh Velena A O Kumerovaand G D Tirzitis ldquoMultistage study of regulation of peroxida-tion processes in biological membranes by antioxidants of 14-dihydropyridine grouprdquo Izvestiya Akademii Nauk LatviyskoySSR vol 336 no 7 pp 65ndash68 1975 (Russian)
[46] R P Mason and M W Trumbore ldquoDifferential membraneinteractions of calcium channel blockers Implications forantioxidant activityrdquo Biochemical Pharmacology vol 51 no 5pp 653ndash660 1996
[47] R P Mason M F Walter M W Trumbore E G Olmstead Jrand P E Mason ldquoMembrane antioxidant effects of the chargeddihydropyridine calcium antagonist amlodipinerdquo Journal ofMolecular and Cellular Cardiology vol 31 no 1 pp 275ndash2811999
[48] R PMason I T MakMW Trumbore and P EMason ldquoAnti-oxidant properties of calcium antagonists related to membranebiophysical interactionsrdquo American Journal of Cardiology vol84 no 4 pp 16ndash22 1999
[49] R PMasonMW Trumbore and P EMason ldquoMembrane bio-physical interaction of amlodipine and antioxidant propertiesrdquoDrugs vol 59 no 2 pp 9ndash16 2000 (French)
[50] R P Mason P Marche and T H Hintze ldquoNovel vascularbiology of third-generation L-type calcium channel antagonistsAncillary actions of amlodipinerdquo Arteriosclerosis Thrombosisand Vascular Biology vol 23 no 12 pp 2155ndash2163 2003
[51] A Augustyniak G Bartosz A Cipak et al ldquoNatural andsynthetic antioxidants an updated overviewrdquo Free RadicalResearch vol 44 no 10 pp 1216ndash1262 2010
[52] T Grune N Zarkovic and K Kostelidou ldquoLipid peroxidationresearch in Europe and the COST B35 action lsquoLipid Peroxida-tion Associated Disordersrsquordquo Free Radical Research vol 44 no10 pp 1095ndash1097 2010
[53] E Carosati P Ioan M Micucci et al ldquo14-Dihydropyridinescaffold in medicinal chemistry the story so far and perspec-tives (part 2) action in other targets and antitargetsrdquo CurrentMedicinal Chemistry vol 19 no 25 pp 4306ndash4323 2012
[54] U Eisner and J Kuthan ldquoThe chemistry of dihydropyridinesrdquoChemical Reviews vol 72 no 1 pp 1ndash42 1972 httpwwwsci-encemadnessorgtalkfilesphppid=138742ampaid=6475
[55] J Kuthan and A Kurfurst ldquoDevelopment in dihydropyri-dine chemistryrdquo Industrial amp Engineering Chemistry ProductResearch and Development vol 21 no 2 pp 191ndash261 1982
[56] A Sausins and G Duburs ldquoSynthesis of 14-dihydropyridinesby cyclocondensation reactionsrdquo Heterocycles vol 27 no 1 pp269ndash289 1988
[57] A E Sausins and G Y Duburs ldquoSynthesis of 14-dihydro-pyridines in cyclocondensation reactions (review)rdquo Chemistryof Heterocyclic Compounds vol 28 no 4 pp 363ndash391 1992Translated from Khimiya Geterotsiklicheskikh Soedinenii no 4pp 435ndash467 1992 (Russian)
[58] S Kazda ldquoTwenty years of dihydropyridinesrdquo in Dihydropy-ridines Progress in Pharmacology and Therapy W-D Busse BGarthoff and F Seuter Eds pp 1ndash12 Springer Verlag BerlinGermany 1993
[59] J-P Wan and Y Liu ldquoRecent advances in new multicomponentsynthesis of structurally diversified 14-dihydropyridinesrdquo RSCAdvances vol 2 no 26 pp 9763ndash9777 2012
[61] Reaxys Database[62] J Tuttle ldquoStructure mechanism and reactivity of hantzsch
estersrdquo in MacMillan Lab Group Meeting (082504) p 332004 httpwwwprincetoneduchemistrymacmillangroup-meetingsJBT20Hantzschpdf
[63] A Saini S Kumar and J S Sandhu ldquoHantzsch reaction recentadvances in Hantzsch 14-dihydropyridinesrdquo Journal of Sci-entific amp Industrial Research vol 67 pp 95ndash111 2008
[64] L LW Cheung S A Styler and A P Dicks ldquoRapid and conve-nient synthesis of the 14-dihydropyridine privileged structurerdquoJournal of Chemical Education vol 87 no 6 pp 628ndash630 2010
[65] A Kumar R A Maurya S Sharma M Kumar and G BhatialdquoSynthesis and biological evaluation of N-aryl-14-dihydro-pyridines as novel antidyslipidemic and antioxidant agentsrdquoEuropean Journal of Medicinal Chemistry vol 45 no 2 pp 501ndash509 2010
[66] R S Kumar A Idhayadhulla A J Abdul Nasser and J SelvinldquoSynthesis and anticoagulant activity of a new series of 14-dihydropyridine derivativesrdquo European Journal of MedicinalChemistry vol 46 no 2 pp 804ndash810 2011
[67] H A Stefani C B Oliveira R B Almeida et al ldquoDihydro-pyrimidin-(2H)-ones obtained by ultrasound irradiation anew class of potential antioxidant agentsrdquo European Journal ofMedicinal Chemistry vol 41 no 4 pp 513ndash518 2006
[68] H Sun C Shang L Jin and J Zhang ldquoSynthesis and antiox-idant activity of a series of novel 3-chalcone-substituted 14-dihydropyridine derivativesrdquoHeterocyclic Communications vol18 no 5-6 pp 239ndash243 2012
[69] D B Tikhonov and B S Zhorov ldquoStructural model for dihy-dropyridine binding to L-type calcium channelsrdquo The Journalof Biological Chemistry vol 284 no 28 pp 19006ndash19017 2009
[70] G Y Dubur and Y R Uldrikis ldquoThe oxidation of 14-dihydro-pyridinesrdquo Chemistry of Heterocyclic Compounds vol 6 no 1pp 80ndash84 1970 Translated from Khimiya GeterotsiklicheskikhSoedinenii no 1 pp 83ndash88 1970 (Russian)
[71] G Ya Duburs A O Kumerova and Ya R Uldrikis ldquoEnzymicoxidation of hydrogenated pyridines with peroxidase-hydrogenperoxide systemrdquoLatvijas PSRZAVestis vol 73 no 7 pp 73ndash771970 (Russian) Chemical Abstracts vol 73 Article ID 94913g1970
[72] K Xie Y-C Liu Y Cui J-GWang Y Fu andT CWMak ldquoN-methyl-(R)-3-(tert-butyl)-sulfinyl-14-dihydropyridine a novelNADHmodel compoundrdquoMolecules vol 12 no 3 pp 415ndash4222007
[73] S Tamagaki T Mimura and W Tagaki ldquoMetal-ion-facilitatedoxidations of dihydropyridines with molecular oxygen andhydrogen peroxiderdquo Journal of the Chemical Society PerkinTransactions 2 no 10 pp 1645ndash1650 1990
[74] D Tirzite G Tirzitis andD Antipova ldquoReductive ability of 14-dihydropyridine derivatives in relation to ions of trivalent ironrdquoChemistry of Heterocyclic Compounds vol 35 no 5 pp 592ndash594 1999
[76] J Ogle J Stradins and L Baumane ldquoFormation and decay offree cation-radicals in the course of electro-oxidation of 12- and14-dihydropyridines (Hantzsch esters)rdquo Electrochimica Actavol 39 no 1 pp 73ndash79 1994
[77] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for the
synthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts C Wittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Berlin Germany 2010
[78] WDu and Zh Yu ldquoBiomimetic in situ regeneration of cofactorsNAD(P)+ and NAD(P)H models hantzsch esters and dihy-drophenanthridinerdquo Synlett vol 23 no 9 pp 1300ndash1304 2012
[79] H K Chenault and G M Whitesides ldquoRegeneration ofnicotinamide cofactors for use in organic synthesisrdquo AppliedBiochemistry and Biotechnology vol 14 no 2 pp 147ndash197 1987
[80] Y R Uldrikis A A Zidermane E A Biseniex I E Preisa GY Dubur and G D Tirzit ldquoEsters of 26-dimethyl-14-dihydro-pyridine-35-dicarboxylic acid and method of obtainingthereofrdquo WO 8000345 A1 1978 httpworldwideespacenetcompublicationDetailsbiblioDB=EPODOCampII=1ampND=3ampadjacent=trueamplocale=en EPampFT=Dampdate=19800306ampCC=WOampNR=8000345A1ampKC=A1
[81] Y Sambongi H Nitta K Ichihashi M Futai and I Ueda ldquoAnovel water-soluble Hantzsch 14-dihydropyridine compoundthat functions in biological processes through NADH regener-ationrdquo Journal of Organic Chemistry vol 67 no 10 pp 3499ndash3501 2002
[82] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for thesynthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts ChWittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Verlag Berlin Germany 2010
[83] T Okamura T Kikuchi A Nagamine et al ldquoAn approach formeasuring in vivo cerebral redox states using the oxidative con-version of dihydropyridine to pyridinium ion and themetabolictrapping principlerdquo Free Radical Biology and Medicine vol 38no 9 pp 1197ndash1205 2005
[84] K A Schellenberg and F H Westheimer ldquoA free-radicaloxidation of a dihydropyridine1ardquo The Journal of OrganicChemistry vol 30 no 6 pp 1859ndash1862 1965
[85] K A Schellenberg ldquoReaction of hydroxyl radical with thymi-dine Scavenging by a dihydropyridinerdquo Federation Proceedingsvol 38 no 3 I p 1433 1979
[86] E S Huyser J A K Harmony and F L McMillian ldquoPeroxideoxidations of dihydropyridine derivativesrdquo Journal of the Amer-ican Chemical Society vol 94 no 9 pp 3176ndash3180 1972
[87] A Sakamoto S T Ohnishi and R Ogawa ldquoInhibition of lipidperoxidation by some dihydropyridine derivativesrdquo Journal ofAnesthesia vol 7 no 2 pp 193ndash197 1993
[88] R Hardeland ldquoReview Neuroprotection by radical avoidancesearch for suitable agentsrdquo Molecules vol 14 no 12 pp 5054ndash5102 2009
[89] G Ya Dubur A Kh Velena V M Gukasov and Yu AVladimirov ldquoRegulation of peroxidation of mitochondrialmembrane lipids initiated by Fe2+ ions by antoxidants of the14-dihydropyridine series in experiments in vitrordquo Biomed-itsinskaya Khimiya vol 22 no 5 pp 665ndash673 1976 (Russian)Chemical Abstracts vol 88 Article ID 2640 1977
[90] G RMMHaenenM J T J Arts A Bast andMD ColemanldquoStructure and activity in assessing antioxidant activity in vitroand in vivo a critical appraisal illustrated with the flavonoidsrdquoEnvironmental Toxicology and Pharmacology vol 21 no 2 pp191ndash198 2006
[91] G Tirzitis and G Bartosz ldquoDetermination of antiradical andantioxidant activity basic principles and new insightsrdquo ActaBiochimica Polonica vol 57 no 2 pp 139ndash142 2010
30 Oxidative Medicine and Cellular Longevity
[92] G R Buettner and R P Mason ldquoSpin-trapping methods fordetecting superoxide and hydroxyl free radicals in vitro and invivordquo inCritical Reviews of Oxidative Stress and Aging Advancesin Basic Science Diagnostics and Intervention R G Cutler andH Rodriguez Eds vol 1 chapter 2 pp 27ndash38World ScientificLondon UK 2003
[93] M M Tarpey and I Fridovich ldquoMethods of detection ofvascular reactive species Nitric oxide superoxide hydrogenperoxide and peroxynitriterdquo Circulation Research vol 89 no3 pp 224ndash236 2001
[94] E Y Kazush E I Sagun G D Tirzit and G Y DaburldquoQuenching of singlet oxygen by electron donating derivativesof 14-dihydropyridinerdquo Chemistry of Heterocyclic Compoundsvol 30 no 5 pp 562ndash563 1994
[95] G Tirzitis E Kazush and G Duburs ldquoReaction of 14-dihydropyridine derivatives with peroxynitrite anionrdquo Chem-istry of Heterocyclic Compounds vol 34 no 3 pp 321ndash3231998 (Russian) Translated from Khimiya GeterotsiklicheskikhSoedinenii no 3 pp 355ndash357 1998
[96] L J Nunez-Vergara C Lopez-Alarcon P A Navarrete-EncinaA M Atria C Camargo and J A Squella ldquoElectrochemicaland EPR characterization of 14-dihydropyridines Reactivitytowards alkyl radicalsrdquo Free Radical Research vol 37 no 1 pp109ndash120 2003
[97] D Tirzite A Krauze A Zubareva G Tirzitis and G DubursldquoSynthesis and antiradical activity of 5-acetyl-2-alkylthio-4-aryl-6-methyl-14-dihydropyridine-3-carboxylic acid nitrilesrdquoChemistry of Heterocyclic Compounds vol 38 no 7 pp 795ndash800 2002
[98] H Ohkawa N Ohishi and K Yagi ldquoAssay for lipid peroxidesin animal tissues by thiobarbituric acid reactionrdquo AnalyticalBiochemistry vol 95 no 2 pp 351ndash358 1979
[99] N Zarkovic ldquo4-Hydroxynonenal as a bioactive marker ofpathophysiological processesrdquo Molecular Aspects of Medicinevol 24 no 4-5 pp 281ndash291 2003
[100] M Parola G Bellomo G Robino G Barrera and M UDianzani ldquo4-Hydroxynonenal as a biological signal molecularbasis and pathophysiological implicationsrdquo Antioxidants andRedox Signaling vol 1 no 3 pp 255ndash284 1999
[101] T Lovakovic M Poljak-Blazi G Duburs et al ldquoGrowthmodulation of human cells in vitro by mild oxidative stressand 14-dihydropyridine derivative antioxidantsrdquo CollegiumAntropologicum vol 35 no 1 pp 137ndash141 2011
[102] R van den Berg G R M M Haenen H van den Bergand A Bast ldquoApplicability of an improved Trolox equivalentantioxidant capacity (TEAC) assay for evaluation of antioxidantcapacity measurements of mixturesrdquo Food Chemistry vol 66no 4 pp 511ndash517 1999
[103] C Lopez-Alarcon P Navarrete C Camargo J A Squella andL J Nunez-Vergara ldquoReactivity of 14-dihydropyridines towardalkyl alkylperoxyl radicals and ABTS radical cationrdquo ChemicalResearch in Toxicology vol 16 no 2 pp 208ndash215 2003
[104] V Valenzuela P Santander C Camargo J A Squella C Lopez-Alarcon and L J Nunez-Vergara ldquo14-Dihydropyridines reac-tivity of nitrosoaryl and nitroaryl derivatives with alkylperoxylradicals andABTS radical cationrdquo Free Radical Research vol 38no 7 pp 715ndash727 2004
[105] L G Tsetlin N A Chebotareva B I Kurganov A K VelenaG Y Dubur and V Z Lankin ldquoStudy of 14-dihydropyridinesas lipoxygenase inhibitors with the use of hydrated reversedmicellesrdquo Pharmaceutical Chemistry Journal vol 22 no 6 pp425ndash428 1988 (Russian)
[106] J Panek Z Reblova L Kocirkova et al ldquoAntioxidant activityof dihydropyridine derivativesrdquo Czech Journal of Food Sciencesvol 18 pp 144ndash145 2000
[107] G Tirzitis I Kirule and G Duburs ldquoAntioxidationsaktivitatder 35-dicarbonylderivate des 26-demethyl-14-dihydropyri-dinsrdquo Fett Wissenschaft TechnologieFat Science Technology vol90 no 10 pp 411ndash413 1988
[108] M Plotniece G Tirzitis Y Uldrikis et al ldquoSynthesis of 14-dihydropyridine derivatives having an oxy- alkoxy- or dimeth-ylaminophenyl substituent in the 4 position their antioxidantactivity and their binding to phospholipid membranesrdquo Chem-istry of Heterocyclic Compounds vol 32 no 10 pp 1166ndash11721996 Translated from Khimiya Geterotsiklicheskikh Soedineniino 10(352) pp 1358ndash1365 1996 (Russian)
[109] D Y Rubene V S Sharov V I Olenev G D Tirzit G Y Duburand Y A Vladimirov ldquoUse of chemiluminescent method forthe evaluation of antioxidant activity of some derivatives of 14-dihydropyridinerdquo Russian Journal of Physical Chemistry A vol55 no 2 pp 511ndash512 1981 (Russian)
[110] M C R Symons and JM C Gutteridge Free Radicals and IronChemistry Biology and Medicine Oxford Science PublicationsOxford University Press Oxford UK 1998
[111] M Repetto J Semprine and A Boveris ldquoLipid peroxidationchemical mechanism biological implications and analyticaldeterminationrdquo in Lipid Peroxidation A Catala Ed Section ILipid Peroxidation Chemical Mechanisms Antioxidants Bio-logical Implications of Biochemistry Genetics and MolecularBiology chapter 1 pp 3ndash30 InTech Rijeka Croatia 2012
[112] A Velena J Zilbers and G Duburs ldquoDerivatives of 14-dihydropyridines asmodulators of ascorbate-induced lipid per-oxidation and high-amplitude swelling ofmitochondria causedby ascorbate sodium linoleate and sodiumpyrophosphaterdquoCellBiochemistry and Function vol 17 no 4 pp 237ndash252 1999
[113] M V Bilenko L N Shelenkova G Y Dubur and A K VelenaldquoUse of antioxidants to prevent renal damage during acuteischemia and reperfusionrdquo Bulletin of Experimental Biology andMedicine vol 96 no 3 pp 1195ndash1198 1983 Translated fromByulletenrsquo Eksperimentalrsquonoi Biologii i Meditsiny vol 96 no 9pp 8ndash11 1983 (Russian)
[114] R Toniolo F Tubaro F Ursini and G Bontempelli ldquoAn elec-troanalytical investigation on the redox properties of calciumantagonist dihydropyridinesrdquo Electroanalysis vol 15 no 10 pp855ndash861 2003
[115] L Kourimska J Pokorny and G Tirzitis ldquoThe antioxidant aci-tivity of 26-dimethyl-35-diethoxycarbonyl-14-dihydropyri-dine in edible oilsrdquo Nahrung vol 37 no 1 pp 91ndash93 1993
[116] C Lopez-Alarcon H Speisky J A Squella C Olea-Azar CCamargo and L J Nunez-Vergara ldquoReactivity of 14-dihydro-pyridines toward SIN-1-derived peroxynitriterdquo PharmaceuticalResearch vol 21 no 10 pp 1750ndash1757 2004
[117] R A Olek W Ziolkowski J J Kaczor L Greci J Popinigisand J Antosiewicz ldquoAntioxidant activity of NADH and its ana-loguemdashan in vitro studyrdquo Journal of Biochemistry andMolecularBiology vol 37 no 4 pp 416ndash421 2004
[118] E Niki N Noguchi and N Gotoh ldquoInhibition of oxidativemodification of low density lipoprotein by antioxidantsrdquo Jour-nal of Nutritional Science andVitaminology vol 39 supplementpp S1ndashS8 1993
[119] N Rojstaczer and D J Triggle ldquoStructure-function relation-ships of calcium antagonists effect on oxidative modificationof low density lipoproteinrdquo Biochemical Pharmacology vol 51no 2 pp 141ndash150 1996
Oxidative Medicine and Cellular Longevity 31
[120] A Sevanian L Shen and FUrsini ldquoInhibition of LDLoxidationand oxidized LDL-induced cytotoxicity by dihydropyridinecalcium antagonistsrdquo Pharmaceutical Research vol 17 no 8 pp999ndash1006 2000
[121] A Negre-Salvayre and R Salvayre ldquoProtection by Ca2+ channelblockers (nifedipine diltiazem and verapamil) against the tox-icity of oxidized low density lipoprotein to cultured lymphoidcellsrdquo British Journal of Pharmacology vol 107 no 3 pp 738ndash744 1992
[122] A Negre-Salvayre G FitoussiM Troly and R Salvayre ldquoCom-parative cytoprotective effect of dihydropyridine calcium chan-nel blockers against the toxicity of oxidized low density lipopro-tein for cultured lymphoid cellsrdquo Biochemical Pharmacologyvol 44 no 12 pp 2379ndash2386 1992
[123] L Cominacini A F Pasini U Garbin et al ldquoAntioxidant activ-ity of different dihydropyridinesrdquo Biochemical and BiophysicalResearch Communications vol 302 no 4 pp 679ndash684 2003
[124] L Cominacini U Garbin A Fratta Pasini et al ldquoOxidized low-density lipoprotein increases the production of intracellularreactive oxygen species in endothelial cells inhibitory effect oflacidipinerdquo Journal of Hypertension vol 16 no 12 part 2 pp1913ndash1919 1998
[125] H M Lander ldquoAn essential role for free radicals and derivedspecies in signal transductionrdquo The FASEB Journal vol 11 no2 pp 118ndash124 1997
[126] M L L Martinez E Rizzi M M Castro et al ldquoLercanidipinedecreases vascular matrix metalloproteinase-2 activity andprotects against vascular dysfunction in diabetic ratsrdquo EuropeanJournal of Pharmacology vol 599 no 1ndash3 pp 110ndash116 2008
[127] P Lesnik C Dachet L Petit et al ldquoImpact of a combinationof a calcium antagonist and a 120573-blocker on cell- and copper-mediated oxidation of LDL and on the accumulation and effluxof cholesterol in human macrophages and murine J774 cellsrdquoArteriosclerosis Thrombosis and Vascular Biology vol 17 no 5pp 979ndash988 1997
[128] G Sobal E J Menzel and H Sinzinger ldquoCalcium antagonistsas inhibitors of in vitro low density lipoprotein oxidation andglycationrdquoBiochemical Pharmacology vol 61 no 3 pp 373ndash3792001
[129] E Lupo R Locher B Weisser and W Vetter ldquoIn vitro antiox-idant activity of calcium antagonists against LDL oxidationcompared with 120572-tocopherolrdquo Biochemical and BiophysicalResearch Communications vol 203 no 3 pp 1803ndash1808 1994
[130] J Zou Y Li H-Q Fan and J-G Wang ldquoEffects of dihydropy-ridine calcium channel blockers on oxidized low-density lipo-protein induced proliferation and oxidative stress of vascularsmooth muscle cellsrdquo BMC Research Notes vol 5 article 1682012
[131] C Napoli S Salomone T Godfraind et al ldquo14-Dihydro-pyridine calcium channel blockers inhibit plasma and LDL oxi-dation and formation of oxidation-specific epitopes in the arte-rial wall and prolong survival in stroke-prone spontaneouslyhypertensive ratsrdquo Stroke vol 30 no 9 pp 1907ndash1915 1999
[132] G Zernig I Graziadei T Moshammer C Zech N Reider andH Glossmann ldquoMitochondrial Ca2+ antagonist binding sitesare associated with an inner mitochondrial membrane anionchannelrdquo Molecular Pharmacology vol 38 no 3 pp 362ndash3691990
[133] F E Hunter Jr A Scott P E Hochstein et al ldquoStudies of themechanism of ascorbate-induced swelling and lysis of isolatedliver mitochondriardquo The Journal of Biological Chemistry vol239 pp 604ndash613 1964
[134] D R Janero B Burghardt and R Lopez ldquoProtection of cardiacmembrane phospholipid against oxidative injury by calciumantagonistsrdquoBiochemical Pharmacology vol 37 no 21 pp 4197ndash4203 1988
[135] A Karadag B Ozcelik and S S Saner ldquoReview of methods todetermine antioxidant capacitiesrdquo FoodAnalyticalMethods vol2 no 1 pp 41ndash60 2009
[136] Y I Gubskiı N V Litvinova and E V Shnurko-TabakovaldquoAntioxidant and antiradical activity of various classes of antiox-idantsrdquo Ukrainskiı Biokhimicheskiı Zhurnal vol 66 no 4 pp114ndash116 1994 (Russian)
[137] M Takei M Hiramatsu and A Mori ldquoInhibitory effects ofcalcium antagonists onmitochondrial swelling induced by lipidperoxidation or arachidonic acid in the rat brain in vitrordquoNeurochemical Research vol 19 no 9 pp 1199ndash1206 1994
[138] M Takei M Hiramatsu R Edamatsu and A Mori ldquoFreeradical scavenging by calcium antagonistsrdquo Neurosciences vol20 no 2 pp 75ndash82 1994
[139] Ya P Stradin G Ya Dubur Yu A Beilis Ya R Uldrikis andA F Korotkova ldquoVoltammetry of 14-dihydropyridine deriva-tives I Potentials of electrochemical oxidation of 35-diacyl-and 35-di(alkoxycarbonyl)-14-dihydropyridines in acetoni-trilerdquo Chemistry of Heterocyclic Compounds no 1 pp 84ndash871972 (Russian)
[140] E V Ivanov T V Ponomarjova G N Merkusev et al ldquoEinneuer Haut-Radioprotektor Diethon (experimentelle Unter-suchung)rdquo Radiobiologia Radiotherapia vol 31 no 1 pp 69ndash78 1990
[141] E V Ivanov T V Ponomareva G N Merkushev et al ldquoRadia-tion modulating properties of derivates of 14-dihydropyridineand 12345678910-decahydroacridine-18 dionerdquo Radiat-sionnaia Biologiia Radioecologiia vol 44 no 5 pp 550ndash5592004 (Russian)
[142] R O Vitolinia D A Berzinia A K Velena I A Vutsina A AKimenis and G Y Duburs ldquoThe protective effects of the cal-cium antagonist foridon in acute myocardial ischaemiardquo Kardi-ologiya vol 27 no 3 pp 90ndash93 1987 (Russian)
[143] A H Velena G Ya Duburs R O Vitolina et al ldquoEffect ofryodipine on electromechanical parameters of heart and vesselscAMP phosphodiesterase activity and swelling-contractioncycle of mitochondriardquo Arzneimittelforschung vol 35 no 6 pp907ndash914 1985
[144] L I Utno Z E Lipsberga A A Silova M I Girgensone EA Bisenieks and G I Ia ldquoCardioprotective properties of a 14-dihydropyridine derivative glutapyrone in deep hypothermiardquoBiulletenrsquo Eksperimentalrsquonoı Biologii i Meditsiny vol 108 no 11pp 558ndash561 1989 (Russian)
[145] M A S FernandesM S Santos J A F Vicente et al ldquoEffects of14-dihydropyridine derivatives (cerebrocrast gammapyroneglutapyrone and diethone) onmitochondrial bioenergetics andoxidative stress a comparative studyrdquoMitochondrion vol 3 no1 pp 47ndash59 2003
[146] M A S Fernandes M S Santos A J M Moreno et al ldquoEffectsof 5-acetyl(carbamoyl)-6-methylsulfanyl-14-dihydropyridine-5-carbonitriles on rat liver mitochondrial functionrdquo Toxicologyin Vitro vol 23 no 7 pp 1333ndash1341 2009
[147] L Klimaviciusa A Kalda A Kaasik et al ldquoNeuroprotectiveactivity of 14-dihydropyridine derivatives structure determi-nantsrdquo Proceedings of the Latvian Academy of Sciences BNatural Exact and Applied Sciences vol 61 no 1-2 pp 33ndash372007
32 Oxidative Medicine and Cellular Longevity
[148] L Klimaviciusa M A S Fernandes N Lencberga et alldquoTargeting the mitochondria by novel adamantane-containing14-dihydropyridine compoundsrdquo in Bioenergetics K B ClarkEd pp 257ndash272 InTech 2012
[149] V Klusa L Klimaviciusa G Duburs J Poikans and AZharkovsky ldquoAnti-neurotoxic effects of tauropyrone a taurineanaloguerdquo Advances in Experimental Medicine and Biology vol583 pp 499ndash508 2006
[150] N Sampson P Berger and Ch Zenzmaier ldquoRedox signalingas a therapeutic target to inhibit myofibroblast activation indegenerative fibrotic diseaserdquo BioMed Research Internationalvol 2014 Article ID 131737 14 pages 2014
[151] T L Leto and M Geiszt ldquoRole of Nox family NADPH oxidasesin host defenserdquoAntioxidantsampRedox Signaling vol 8 no 9-10pp 1549ndash1561 2006
[152] K K Griendling D Sorescu and M Ushio-Fukai ldquoNAD(P)Hoxidase role in cardiovascular biology and diseaserdquo CirculationResearch vol 86 no 5 pp 494ndash501 2000
[153] H Chen Y S Song and P H Chan ldquoInhibition of NADPHoxi-dase is neuroprotective after ischemia-reperfusionrdquo Journal ofCerebral Blood Flow and Metabolism vol 29 no 7 pp 1262ndash1272 2009
[154] P Hochstein and L Ernster ldquoADP-activated lipid peroxidationcoupled to the TPNH oxidase system of microsomesrdquo Biochem-ical and Biophysical Research Communications vol 12 no 5 pp388ndash394 1963
[155] I I Gubskiı AGGoriushkoNV Litvinova et al ldquoAntioxidantproperties and membranotropic effect of certain derivatives of14-dihydropyridinerdquo Ukrainskiı Biokhimicheskiı Zhurnal vol71 no 4 pp 35ndash39 1999 (Russian)
[156] F Engineer and R Sridhar ldquoInhibition of rat heart andliver microsomal lipid peroxidation by nifedipinerdquo BiochemicalPharmacology vol 38 no 8 pp 1279ndash1285 1989
[157] T Goncalves A P Carvalho and C R Oliveira ldquoAntioxidanteffect of calcium antagonists on microsomai membranes iso-lated from different brain areasrdquo European Journal of Pharma-cology vol 204 no 3 pp 315ndash322 1991
[158] M E Letelier P Izquierdo L Godoy A M Lepe and MFaundez ldquoLiver microsomal biotransformation of nitro-aryldrugs mechanism for potential oxidative stress inductionrdquoJournal of Applied Toxicology vol 24 no 6 pp 519ndash525 2004
[159] M E Letelier P Entrala C Lopez-Alarcon et al ldquoNitroaryl-14-dihydropyridines as antioxidants against rat liver microsomesoxidation induced by ironascorbate Nitrofurantoin and naph-thalenerdquo Toxicology in Vitro vol 21 no 8 pp 1610ndash1618 2007
[160] F P Guengerich W R Brian M Iwasaki M-A Sari CBaarnhielm and P Berntsson ldquoOxidation of dihydropyridinecalcium channel blockers and analogues by human liver cyto-chrome P-450 IIIA4rdquo Journal of Medicinal Chemistry vol 34no 6 pp 1838ndash1844 1991
[161] S H Park S-W RhaW-Y Shin et al ldquoAS-160 Calcium channelblockers of dihydropyridine class reduce the antiplatelet effectof Clopidogrel what is clinical impactrdquo The American Journalof Cardiology vol 107 no 8 supplement p 47A 2011
[162] C Asma and D M Reda ldquoEvaluation of dihydropyridinecalcium antagonist effects on the stress bioindicator orga-nism Saccharomyces cerevisiaerdquo Annals of Biological Researchvol 4 no 10 pp 40ndash46 2013 httpscholarsresearchlibrarycomABR-vol4-iss10ABR-2013-4-10-40-46pdf
[163] G Gaviraghi A M Pastorino E Ratti and D G TristldquoCalcium channel blockers with antioxidant activityrdquo in Free
Radicals Lipoprotein Oxidation andAtherosclerosis G BellomoG Finardi E Maggi and E Rice-Evans Eds pp 431ndash456Richelieu Press London UK 1995
[164] G Gaviraghi AM Pastorino E Ratti and D G Trist ldquoAntiox-idant dihydropyridines a new and comprehensive therapy forfree radical-induced cardiovascular diseasesrdquo in Free Radicalsin Biology and Environment F Minisci Ed vol 27 of NATOASI Series pp 193ndash221 Springer Dordrecht The Netherlands1997
[165] P D Henry ldquoAntiperoxidative actions of calcium antagonistsand atherogenesisrdquo Journal of Cardiovascular Pharmacologyvol 18 supplement 1 pp S6ndashS10 1991
[166] F Kouoh B Gressier T Dine et al ldquoAntioxidant effects andanti-elastase activity of the calcium antagonist nicardipine onactivated human and rabbit neutrophilsmdasha potential antiath-erosclerotic property of calcium antagonistsrdquo CardiovascularDrugs andTherapy vol 16 no 6 pp 515ndash520 2002
[167] S Parthasarathy D Litvinov K Selvarajan and M GarelnabildquoLipid peroxidation and decompositionmdashconflicting roles inplaque vulnerability and stabilityrdquo Biochimica et BiophysicaActa vol 1781 no 5 pp 221ndash231 2008
[168] D-Q Liu Z-Q Pang D-H Zhao and B-H Sheng ldquoEffects offuryl-dihydropyridines I on lipid peroxides of ischemic myo-cardium and ATPases activity of erythrocyte membranes inratsrdquo Acta Pharmacologica Sinica vol 12 no 3 pp 253ndash2561991
[169] V Lukic-Panin T Kamiya H Zhang et al ldquoPrevention of neu-ronal damage by calcium channel blockers with antioxidativeeffects after transient focal ischemia in ratsrdquo Brain Research vol1176 no 1 pp 143ndash150 2007
[170] Y Allanore D Borderie H Lemarechal O G Ekindjian andA Kahan ldquoAcute and sustained effects of dihydropyridine-typecalcium channel antagonists on oxidative stress in systemicsclerosisrdquo American Journal of Medicine vol 116 no 9 pp 595ndash600 2004
[171] I Casetta V Govoni and E Granieri ldquoOxidative stress antioxi-dants and neurodegenerative diseasesrdquo Current PharmaceuticalDesign vol 11 no 16 pp 2033ndash2052 2005
[172] M J T J Arts Assessing antioxidant activity [PhD the-sis] Maastricht University Maastricht The Netherlands 2007httparnounimaasnlshowcgifid=8676
[173] G Dıaz-Araya L Godoy L Naranjo A Squella M E Letelierand L J Nunez-Vergara ldquoAntioxidant effects of 14-dihydro-pyridine and nitroso aryl derivatives on the Fe+3ascorbate-stimulated lipid peroxidation in rat brain slicesrdquo General Phar-macology The Vascular System vol 31 no 3 pp 385ndash391 1998
[174] Y Fukuhara K Tsuchiya Y Horinouchi et al ldquoProtectiveeffect of photodegradation product of nifedipine against tumornecrosis factor 120572-induced oxidative stress in human glomerularendothelial cellsrdquo Journal of Medical Investigation vol 58 no1-2 pp 118ndash126 2011
[175] W Stengel M Jainz and K Andreas ldquoDifferent potencies ofdihydropyridine derivatives in blocking T-type but not L-typeCa2+ channels in neuroblastoma-glioma hybrid cellsrdquo EuropeanJournal of Pharmacology vol 342 no 2-3 pp 339ndash345 1998
[176] O M Panasenko D J Tirzite G D Tirzitis and G J DubursldquoEffect of some 14-dihydropyridine derivatives on structuralorganization of erythrocyte membranesrdquo Biologicheskie Mem-brany (Biochemistry (Moscow) Series A Membrane and CellBiology) vol 1 pp 919ndash925 1984 (Russian)
[177] L G Herbette Y M H Vant Erve and D G Rhodes ldquoInter-action of 14 dihydropyridine calcium channel antagonists with
Oxidative Medicine and Cellular Longevity 33
biological membranes lipid bilayer partitioning could occurbefore drug binding to receptorsrdquo Journal of Molecular andCellular Cardiology vol 21 no 2 pp 187ndash201 1989
[178] L G Herbette P E Mason G Gaviraghi T N Tulenko andR P Mason ldquoThe molecular basis for lacidipinersquos unique phar-macokinetics optimal hydrophobicity results in membraneinteractions that may facilitate the treatment of atherosclerosisrdquoJournal of Cardiovascular Pharmacology vol 23 supplement 5pp S16ndashS25 1994
[179] G V Belevitch G Y Dubur G E Dobretsov N K Kurek andM M Spirin ldquoCalcium antagonists riodipine nifedipine andverapamil binding to model and biological membranes fluore-scence analysisrdquo Biologicheskie Membrany (Biochemistry(Moscow) Series A Membrane and Cell Biology) vol 5 pp768ndash776 1988 (Russian)
[180] R P Mason G E Gonye D W Chester and L G HerbetteldquoPartitioning and location of Bay K 8644 14-dihydropyridinecalcium channel agonist in model and biological membranesrdquoBiophysical Journal vol 55 no 4 pp 769ndash778 1989
[181] M Cindric A Cipak J Serly et al ldquoReversal of multidrugresistance inmurine lymphoma cells by amphiphilic dihydropy-ridine antioxidant derivativerdquo Anticancer Research vol 30 no10 pp 4063ndash4070 2010
[182] F Shekari H Sadeghpour K Javidnia et al ldquoCytotoxic andmultidrug resistance reversal activities of novel 14-dihydro-pyridines against human cancer cellsrdquo European Journal ofPharmacology vol 746 no 1 pp 233ndash244 2015
[183] X-F Zhou Q Shao R A Coburn and M E Morris ldquoQuanti-tative structure-activity relationship and quantitative structure-pharmacokinetics relationship of 14-dihydropyridines andpyridines as multidrug resistance modulatorsrdquo PharmaceuticalResearch vol 22 no 12 pp 1989ndash1996 2005
[184] R Berkels T Breitenbach H Bartels et al ldquoDifferent antioxida-tive potencies of dihydropyridine calcium channel modulatorsin various modelsrdquo Vascular Pharmacology vol 42 no 4 pp145ndash152 2005
[185] S Borovic G Tirzitis D Tirzite et al ldquoBioactive 14-dihydro-isonicotinic acid derivatives prevent oxidative damage of livercellsrdquo European Journal of Pharmacology vol 537 no 1ndash3 pp12ndash19 2006
[186] D Ya Rubene G D Tirzitis and G Ya Duburs ldquoInteractionof some 14-dihydropyridine derivatives with Fentonrsquos reagentrdquoLatvijas PSRZinatnuAkademijas Vestis Kimijas Serija Proceed-ings of the Latvian SSR Academy of Sciences Chemistry Seriespp 212ndash216 1982 (Russian)
[187] K Ondrias V Misık D Gergel and A Stasko ldquoLipid per-oxidation of phosphatidylcholine liposomes depressed by thecalcium channel blockers nifedipine and verapamil and bythe antiarrhythmic-antihypoxic drug stobadinerdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1003 no 3pp 238ndash245 1989
[188] I T Mak and W B Weglicki ldquoComparative antioxidant acti-vities of propranolol nifedipine verapamil and diltiazemagainst sarcolemmal membrane lipid peroxidationrdquoCirculationResearch vol 66 no 5 pp 1449ndash1452 1990
[189] I T Mak P Boehme and W B Weglicki ldquoProtective effects ofcalcium channel blockers against free radical-impaired endo-thelial cell proliferationrdquo Biochemical Pharmacology vol 50 no9 pp 1531ndash1534 1995
[190] S Ray S Mondal and N Dana ldquoEvaluation of protective roleof nifedipine on lipid peroxidation using reduced glutathione as
model markerrdquo Oxidants and Antioxidants in Medical Sciencevol 1 no 2 pp 97ndash100 2012
[191] M Yamato T Shiba T Ide Y Honda K-I Yamada andH Tsutsui ldquoNifedipine treatment reduces brain damage aftertransient focal ischemia possibly through its antioxidativeeffectsrdquoHypertension Research vol 34 no 7 pp 840ndash845 2011
[192] V Chander and K Chopra ldquoNifedipine attenuates changes innitric oxide levels renal oxidative stress and nephrotoxicityinduced by cyclosporinerdquo Renal Failure vol 27 no 4 pp 441ndash450 2005
[193] K M Gaafa M M Badawy and A A Hamza ldquoThe protectiveeffects of ascorbic acid cimetidine and nifedipine on diethyl-dithiocarbamate-induced hepatic toxicity in albino ratsrdquo Drugand Chemical Toxicology vol 34 no 4 pp 405ndash419 2011
[194] H Sugawara K Tobise and S Onodera ldquoAbsence of antiox-idant effects of nifedipine and diltiazem on myocardial mem-brane lipid peroxidation in contrast with those of nisoldipineand propranololrdquo Biochemical Pharmacology vol 47 no 5 pp887ndash892 1994
[195] I E Kirule D Y Rubene E A Bisenieks G D Tirzit and GY Dubur ldquo4-Nitrophenyl-14-dihydropyridinesmdasha new groupof inhibitors of peroxide oxidationrdquo Chemistry of HeterocyclicCompounds vol 18 no 3 p 316 1982
[196] G D Tirzit I E Kirule L K Baumane R A Gavar Y PStradynrsquo andG YDubur ldquoMechanism of the antioxidant actionof 26-dimethyl-35-dimethoxy-carbonyl-4-(2-nitrophenyl)14-dihydropyridinerdquoChemistry ofHeterocyclic Compounds vol 20no 8 pp 915ndash918 1984
[197] C Yanez C Lopez-Alarcon C Camargo V Valenzuela J ASquella and L J Nunez-Vergara ldquoStructural effects on thereactivity 14-dihydropyridines with alkylperoxyl radicals andABTS radical cationrdquo Bioorganic and Medicinal Chemistry vol12 no 9 pp 2459ndash2468 2004
[198] VMisik A J Stasko D Gergel and K Ondrias ldquoSpin-trappingand antioxidant properties of illuminated and nonilluminatednifedipine and nimodipine in heart homogenate and modelsystemrdquo Molecular Pharmacology vol 40 no 3 pp 435ndash4391991
[199] K Ondrias V Misık A Stasko D Gergelrsquo and M HromadovaldquoComparison of antioxidant properties of nifedipine and illu-minated nifedipine with nitroso spin traps in low densitylipoproteins and phosphatidylcholine liposomesrdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1211 no 1pp 114ndash119 1994
[200] A Stasko V Brezova S Biskupic K Ondrias and V MisıkldquoReactive radical intermediates formed from illuminated nife-dipinerdquoFree Radical Biology andMedicine vol 17 no 6 pp 545ndash556 1994
[201] K Ishizawa Y Izawa-Ishizawa N Yamano et al ldquoNitrosoni-fedipine ameliorates the progression of type 2 diabetic nephro-pathy by exerting antioxidative effectsrdquo PLoS ONE vol 9 no 1Article ID e86335 2014
[202] H Fujii and L J Berliner ldquoIn vivo EPR evidence for free radicaladducts of nifedipinerdquoMagnetic Resonance in Medicine vol 42no 4 pp 691ndash694 1999
[203] S Bollo S Finger J C Sturm L J Nunez-Vergara and JA Squella ldquoCyclic voltammetry and scanning electrochemicalmicroscopy studies of the heterogeneous electron transferreaction of some nitrosoaromatic compoundsrdquo ElectrochimicaActa vol 52 no 15 pp 4892ndash4898 2007
34 Oxidative Medicine and Cellular Longevity
[204] F Ursini ldquoTissue protection by lacidipine insight from redoxbehaviorrdquo Journal of Cardiovascular Pharmacology vol 30supplement 2 pp S28ndashS30 1997
[205] P G Cristofori F A Crivellente I Faustinelli et al ldquoInvolve-ment of the nitric oxide system in the anti-atheroscleroticpotential of lacidipine in the apoE-deficient mouse a mor-phological functional and electrochemical studyrdquo ToxicologicPathology vol 32 no 4 pp 493ndash499 2004
[206] X-P Zhang E L Kit S Mital S Chahwala and T HHintze ldquoParadoxical release of nitric oxide by an L-type calciumchannel antagonist the R+ enantiomer of amlodipinerdquo Journalof Cardiovascular Pharmacology vol 39 no 2 pp 208ndash2142002
[207] F Franzoni G Santoro F Regoli et al ldquoAn in vitro study of theperoxyl and hydroxyl radical scavenging capacity of the calciumantagonist amlodipinerdquo Biomedicine and Pharmacotherapy vol58 no 8 pp 423ndash426 2004
[208] S V Gatsura ldquoOxygen-dependent mechanisms underlying theantiischemic effect of verapamil and amlodipinerdquo Bulletin ofExperimental Biology and Medicine vol 137 no 1 pp 40ndash422004
[209] Y Hirooka Y Kimura M Nozoe Y Sagara K Ito and KSunagawa ldquoAmlodipine-induced reduction of oxidative stressin the brain is associated with sympatho-inhibitory effects instroke-prone spontaneously hypertensive ratsrdquo HypertensionResearch vol 29 no 1 pp 49ndash56 2006
[210] B Tomlinson and I F F Benzie ldquoAntioxidant effect of lercani-dipine (note)rdquo Hypertension vol 42 no 4 pp e10ndashe11 2003
[211] A A Faraqui ldquoNeurochemical aspects of 4-hydroxynonenalrdquoin Lipid Mediators and Their Metabolism in the Brain A AFaraqui Ed chapter 6 pp 159ndash191 Springer New York NYUSA 2011
[212] V S NascimentoM S DrsquoAlva A AOliveira et al ldquoAntioxidanteffect of nimodipine in young rats after pilocarpine-inducedseizuresrdquo Pharmacology Biochemistry and Behavior vol 82 no1 pp 11ndash16 2005
[213] O Ismailoglu P Atilla S Palaoglu et al ldquoThe therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjuryrdquo Turkish Neurosurgery vol 22 no 6 pp 740ndash746 2012
[214] M Matsubara and K Hasegawa ldquoBenidipine a dihydropy-ridine-calcium channel blocker prevents lysophosphatidyl-choline-induced injury and reactive oxygen species productionin human aortic endothelial cellsrdquo Atherosclerosis vol 178 no1 pp 57ndash66 2005
[215] M Matsubara K Yao and K Hasegawa ldquoBenidipine adihydropyridine-calcium channel blocker inhibits lysophos-phatidylcholine-induced endothelial injury via stimulation ofnitric oxide releaserdquo Pharmacological Research vol 53 no 1 pp35ndash43 2006
[216] MMatsubara and K Hasegawa ldquoEffects of benidipine a dihyd-ropyridine-Ca2+ channel blocker on expression of cytokine-induced adhesion molecules and chemoattractants in humanaortic endothelial cellsrdquo European Journal of Pharmacology vol498 no 1ndash3 pp 303ndash314 2004
[217] M Matsubara O Akizuki J-I Ikeda K Saeki K Yao and KSasaki ldquoBenidipine an anti-hypertensive drug inhibits reactiveoxygen species production in polymorphonuclear leukocytesand oxidative stress in salt-loaded stroke-prone spontaneouslyhypertensive ratsrdquo European Journal of Pharmacology vol 580no 1-2 pp 201ndash213 2008
[218] A C Rosenkranz H Lob T Breitenbach R Berkels and RRoesen ldquoEndothelial antioxidant actions of dihydropyridines
and angiotensin converting enzyme inhibitorsrdquo European Jour-nal of Pharmacology vol 529 no 1ndash3 pp 55ndash62 2006
[219] V Kain S Kumar and S L Sitasawad ldquoAzelnidipine preventscardiac dysfunction in streptozotocin-diabetic rats by reducingintracellular calcium accumulation oxidative stress and apop-tosisrdquo Cardiovascular Diabetology vol 10 article 97 2011
[220] K Nakamura S Yamagishi and H Inoue ldquoUnique atheropro-tective property of azelnidipine a dihydropyridine-based cal-cium antagonistrdquoMedical Hypotheses vol 65 no 1 pp 155ndash1572005
[221] TMatsui S Yamagishi K Nakamura S Kikuchi andH InoueldquoAzelnidipine a dihydropyridine-based calcium antagonistinhibits angiotensin II-induced oxidative stress generation anddownregulation of pigment epithelium-derived factor mRNAlevels in microvascular endothelial cellsrdquo Drugs under Experi-mental and Clinical Research vol 31 no 5-6 pp 215ndash219 2005
[222] C Ohmura H Watada T Shimizu et al ldquoCalcium channelblocker azelnidipine reduces lipid hydroperoxides in patientswith type 2 diabetes independent of blood pressurerdquo EndocrineJournal vol 54 no 5 pp 805ndash811 2007
[223] H Daikuhara F Kikuchi and T Ishida ldquoThe combination ofOLmesartan and a CAlcium channel blocker (azelnidipine) orcandesartan and a calcium channel blocker (amlodipine) intype 2 diabetic hypertensive patients theOLCA studyrdquoDiabetesand Vascular Disease Research vol 9 no 4 pp 280ndash286 2012
[224] MAbe NMaruyama KOkada SMatsumoto KMatsumotoand M Soma ldquoAdditive antioxidative effects of azelnidipine onangiotensin receptor blocker olmesartan treatment for type 2diabetic patients with albuminuriardquoHypertension Research vol34 no 8 pp 935ndash941 2011
[225] K Mizushige ldquoAntioxidative activities of thiazolidinedionesand dihydropyridine-type calcium antagonistsrdquo IRYOmdashJapa-nese Journal of National Medical Services vol 59 no 11 pp 581ndash592 2005
[226] S Manabe T Okura T Fukuoka and J Higaki ldquoAntioxidativeeffects of azelnidipine on mesangial cell proliferation inducedby highly concentrated insulinrdquo European Journal of Pharma-cology vol 567 no 3 pp 252ndash257 2007
[227] Y Koyama Y Takeishi H Takahashi et al ldquoAzelnidipine inhi-bits H
2O2-induced cell death in neonatal rat cardiomyocytesrdquo
CardiovascularDrugs andTherapy vol 21 no 1 pp 69ndash72 2007[228] K Shinomiya K Mizushige M Fukunaga et al ldquoAntioxidant
effect of a new calcium antagonist azelnipidine in culturedhuman arterial endothelial cellsrdquo Journal of International Med-ical Research vol 32 no 2 pp 170ndash175 2004
[229] T Ohyama K Sato K Kishimoto et al ldquoAzelnidipine is acalcium blocker that attenuates liver fibrosis and may increaseantioxidant defencerdquo British Journal of Pharmacology vol 165no 4 pp 1173ndash1187 2012
[230] L A Calo F Zaghetto E Pagnin P A Davis A Sempliciniand A C Pessina ldquoEffect of manidipine on gene expressionand protein level of oxidative stress-related proteins p22phoxand HO-1 Relevance for antihypertensive and anti-remodelingeffectsrdquo Journal of Cardiovascular Pharmacology vol 43 no 4pp 531ndash538 2004
[231] R Ghyasi G Sepehri M Mohammadi R Badalzadeh and AGhyasi ldquoEffect of mebudipine on oxidative stress and lipid per-oxidation in myocardial ischemic-reperfusion injury in maleratrdquo Journal of Research in Medical Sciences vol 17 no 12 pp1150ndash1155 2012
Oxidative Medicine and Cellular Longevity 35
[232] DCAndersson J Fauconnier T Yamada et al ldquoMitochondrialproduction of reactive oxygen species contributes to the 120573-adrenergic stimulation of mouse cardiomycytesrdquoThe Journal ofPhysiology vol 589 no 7 pp 1791ndash1801 2011
[233] A F Ceylan-Isik N Ari M Stefek et al ldquoEffects of a long-term treatment with an antioxidant pyridoindole on vascularresponsiveness in diabetes-induced aging ratsrdquo Current AgingScience vol 4 no 2 pp 150ndash157 2011
[234] S Saponara G Sgaragli and F Fusi ldquoQuercetin antagonismof Bay K 8644 effects on rat tail artery L-type Ca2+ channelsrdquoEuropean Journal of Pharmacology vol 598 no 1ndash3 pp 75ndash802008
[235] D A Sica ldquoInteraction of grapefruit juice and calcium channelblockersrdquo American Journal of Hypertension vol 19 no 7 pp768ndash773 2006
[236] P Mulder G Litwinienko S Lin P D MacLean L R CBarclay and K U Ingold ldquoThe L-type calcium channel block-ers Hantzsch 14-dihydropyridines are not peroxyl radical-trapping chain-breaking antioxidantsrdquo Chemical Research inToxicology vol 19 no 1 pp 79ndash85 2006
[237] L J Nunez-Vergara R Salazar C Camargo et al ldquoOxidation ofC4-hydroxyphenyl 14-dihydropyridines in dimethylsulfoxideand its reactivity towards alkylperoxyl radicals in aqueousmediumrdquo Bioorganic and Medicinal Chemistry vol 15 no 12pp 4318ndash4326 2007
[238] M E Ortiz L J Nunez-Vergara and J A Squella ldquoRelativereactivity of dihydropyridine derivatives to electrogeneratedsuperoxide ion in DMSO solutions a voltammetric approachrdquoPharmaceutical Research vol 20 no 2 pp 292ndash296 2003
[239] M E Ortiz L J Nunez-Vergara C Camargo and J A SquellaldquoOxidation of Hantzsch 14-dihydropyridines of pharmacolog-ical significance by electrogenerated superoxiderdquo Pharmaceuti-cal Research vol 21 no 3 pp 428ndash435 2004
[240] R S Raghuvanshi and K N Singh ldquoSuperoxide induced oxida-tive aromatization of Hantzsch 14-dihydropyridinesrdquo IndianJournal of Chemistry Section B Organic and Medicinal Chem-istry vol 47 no 11 pp 1735ndash1738 2008
[241] I Kruk A Kladna K Lichszteld et al ldquoAntioxidant activityof 4-flavonil-14-dihydropyridine derivativesrdquo Biopolymers vol62 no 3 pp 163ndash167 2001
[242] G D Tirzit I M Byteva K I Salokhiddinov G P Gurinovichand G Y Dubur ldquo14-Dihydropyridine derivatives as deactiva-tors of singlet oxygenrdquo Chemistry of Heterocyclic Compoundsvol 17 no 7 pp 682ndash684 1981
[243] G D Tirzit E Y Kazush and G Y Dubur ldquoInfluence of14-dihydropyridine derivatives on the generation of hydroxylradicalsrdquo Chemistry of Heterocyclic Compounds vol 28 no 4pp 435ndash437 1992
[244] N A Pizarro-Urzua and L J Nunez-Vergara ldquoNifedipine andnitrendipine reactivity toward singlet oxygenrdquo Journal of Photo-chemistry and Photobiology A Chemistry vol 175 no 2-3 pp129ndash137 2005
[245] L-F Wang H-Y Zhang L Konga Z-W Chena and J-G ShildquoDFT calculations indicate that 14-dihydropyridine is a promis-ing lead antioxidantrdquo Helvetica Chimica Acta vol 87 no 6 pp1515ndash1521 2004
[246] P Mulder H-G Korth and K U Ingold ldquoWhy quantum-thermochemical calculations must be used with caution toindicate lsquoa promising lead antioxidantrsquordquoHelvetica Chimica Actavol 88 no 2 pp 370ndash374 2005
[247] K Yao Y Ina K Nagashima K Ohmori and T Ohno ldquoAntiox-idant effects of calcium antagonists in rat brain homogenatesrdquo
Biological and Pharmaceutical Bulletin vol 23 no 6 pp 766ndash769 2000
[248] T Matsui S-I Yamagishi K Nakamura and H Inoue ldquoBayw 9798 a dihydropyridine structurally related to nifedipinewith no calcium channel-blocking properties inhibits tumournecrosis factor-120572-induced vascular cell adhesion molecule-1expression in endothelial cells by suppressing reactive oxygenspecies generationrdquo Journal of International Medical Researchvol 35 no 6 pp 886ndash891 2007
[249] K AMitrega B VargheseM Porc and T F Krzeminski ldquoAnti-arrhythmic and hemodynamic effects of oxy nifedipine oxynimodipine oxy nitrendipine and oxy nisoldipinerdquo Pharmaco-logical Research vol 66 no 4 pp 300ndash308 2012
[250] V Herbert ldquoSymposium prooxidant effects of antioxidantvitamins Introductionrdquo The Journal of Nutrition vol 126 no4 supplement pp 1197Sndash1200S 1996 httpjnnutritionorgcontent1264 Suppl1197Sfullpdf
[251] B Halliwell ldquoAre polyphenols antioxidants or pro-oxidantsWhat do we learn from cell culture and in vivo studiesrdquoArchives of Biochemistry and Biophysics vol 476 no 2 pp 107ndash112 2008
[252] C Winterbourn Pro-Oxidants or Antioxidants ChristchurchSchool of Medicine Depatment of Pathology Free RadicalSchool SFRBMUniversity of Otago San Francisco Calif USA2009 httpwwwsfrbmorgfrsWinterbournpdf
[253] A Morakinyo B Iranloye and O Adegoke ldquoCalcium antag-onists modulate oxidative stress and acrosomal reaction in ratspermatozoardquo Archives of Medical Science vol 7 no 4 pp 613ndash618 2011
[254] The Alpha-Tocopherol Beta Carotene Cancer Prevention StudyGroup ldquoThe effect of vitamin E and beta carotene on theincidence of lung cancer and other cancers in male smokersrdquoTheNew England Journal of Medicine vol 330 no 15 pp 1029ndash1035 1994
[255] B Poljsak ldquoStrategies for reducing or preventing the generationof oxidative stressrdquo Oxidative Medicine and Cellular Longevityvol 2011 Article ID 194586 15 pages 2011
[256] B Poljsak and I Milisav ldquoThe neglected significance of lsquoanti-oxidative stressrsquordquoOxidativeMedicine and Cellular Longevity vol2012 Article ID 480895 12 pages 2012
[257] T Godfraind and S Salomone ldquoAmbiguities in dietary antiox-idant supplementation compared to calcium channel blockerstherapyrdquo Frontiers in Pharmacology vol 6 article 10 2015
[258] H Wagner H Norr and H Winterhoff ldquoDrugs with adap-togenic effects for strengthening the powers of resistancerdquoZeitschrift fur Phytotherapie vol 13 no 2 pp 42ndash54 1992
Oxidative Medicine and Cellular Longevity 25
372 Possible Mechanisms of DHPs ARA and AOA in the Bio-logical Systems Interaction with Other OSModifiers Some ofthese mechanisms were already described (Sections 331 (2)-(b) 331 (2)-(c) 331 (3)-(b) 35)
Enzymatic sources of ROSwith confirmed functional rolein hypertension are NADPH oxidase NO synthase (NOS)xanthine oxidase and cyclooxygenase Godfraind [3] hasreviewed AO effects and protective action of calcium channelblockers (CCBs) Yao et al [247] observed antioxidant effects(as inhibition of LP) for cardio- and neuroprotective CCBs(3ndash300 120583molL) including 7 DHPs in homogenates of ratbrain IC
50values (120583M) were as follows nifedipine (515) gt
barnidipine (586) gt benidipine (712) gt nicardipine (1293)gt amlodipine (1355) gt nilvadipine (1673) gt nitrendipine(2521) gt diltiazem (gt300) = verapamil (gt300) There arealso research articles describing the AO properties of CCBsthrough direct scavenging effect or through preservationof the endogenous SOD activity These findings indicatethat CCBs may also act by reducing the production ofvasoconstrictors angiotensin and endothelin
When present in concentrations that can be achievedin plasma CCBs may inhibit LP formation [3] This AOactivity seems to be typical for high lipophilic CCBs becausetheir chemical structure facilitates proton-donating andresonance-stabilization mechanisms that quench the freeradical reaction Their insertion in the membrane nearpolyunsaturated fatty acids at relatively high concentrationspotentiates proton donation (or atomary H) to lipid peroxidemolecules thereby blocking the peroxidation process Theremaining unpaired free electron associated with the CCBmolecule can be stabilized in well-defined resonance struc-tures associated with the DHP ring (Mason et al [48])
The radical reaction (according to Godfraind [3]) thatdescribes the AO effects of a DHP CCBs is LOOlowast + DHPrarr LOOH + DHPlowast (where LOOlowast is lipid peroxide radical)which in general is reaction (7) of the LP reaction cascadeconsisting of sim10 reactions (Scheme 2) [89]
As the rate constants of in vitro interaction of 4-substituted DHPs with peroxyl radicals are three ordersof magnitude lower than that of the vitamin E derivativethese DHPs must be considered as weak AO (Ursini [204])However due to partition coefficient of DHPs in membranesand in case of specific binding high local concentration ofDHPs may be obtained
DHPs without CCB properties for instance Bay w 9798although structurally related to nifedipine inhibit TNF-120572-induced vascular cell adhesion molecule-1 expression inendothelial cells by suppressing reactive oxygen speciesgeneration [248]
Mitrega et al [249] have discovered that antiarrhythmicand hemodynamic effects of oxidized heteroaromatic DHPsoxy nifedipine oxy nimodipine oxy nitrendipine and oxynisoldipine suggest that CCB DHPs and their metabolitescould act at least in two ways targeting OS related eventsas reductants (see Section 351 (1)) andor bypassing OSrelatedmetabolic routes Authors postulated that contrary tocurrent belief NIF metabolites are pharmacologically activeATP sensitive potassium channels were mentioned as a tar-get
38 DHPs Anti- or Prooxidants Several substances (ascorbicacid being the most commonly studied) can serve either asantioxidants or as prooxidants depending on given condi-tions (Herbert [250]) Therefore Halliwell [251] has reporteddilemma related to polyphenols as possible antioxidantsand prooxidants causing experimental artifacts (about 25)by oxidation of antioxidant compounds in the cell culturemedia Nevertheless it is generally accepted opinion thatpolyphenols act as antioxidants in vivo Studies on DHPs alsoface such a dilemmaThe exact roles (anti- or prooxidative) ofany specific DHP depend on its structure appliedachievedconcentration and specificity of the targetexperimentaltesting system
This situation resembles the case of antioxidative effectsof tocopherol which depends on the fate of the secondaryradical as proposed by Winterbourn [252] The question wasldquoVitamin E - Pro- or Antioxidantrdquo
997888rarr chain termination of lipid peroxidation
(6)
Prooxidant
Toc∙ + Lipid-H 997888rarr Lipid∙ (in LDL particles) (7)
This example shows that generally speaking any AO mustfulfil several criteria to be considered as an effective com-pound physiologically
(i) It must be able to functionally interact with endoge-nous scavengers even at low concentrations
(ii) It must affect endogenous pathways of OS(iii) It should not have undesirable adverse effect(iv) It should manifest the antioxidant efficacy dependent
on the oxidant(v) It must discriminate among different strategies
needed for 1-electron and 2-electron processes(vi) Radical scavengers can be prooxidant unless linked to
a radical sink (Winterbourn [252])
According to these statements DHPs could be effective asAO under physiological conditions in vivo (Godfraind [3]and others [30 31 38]) and in vitro in various experimentalsystems (cell and tissue) (see Sections 33 34 35)
Hence calcium antagonists appeared to disrupt thefine balance between the production and scavenging ofROS Nifedipine verapamil and diltiazem were shown toinduce significant oxidative stress in the epididymal sperm(increased MDA and decreased catalase and superoxidedismutase activity) This may be the reason for the inductionof male infertility [253]
The dualism of 14-DHP effects has been recorded asinhibition or promotion of LP as quenching or initiating
26 Oxidative Medicine and Cellular Longevity
oxygen and nitrogen free radical chain reactions radiopro-tecting or radiosensitizing antagonizing or synergizing Ca2+in electromechanical coupling as well as in the membranestabilization or labilization
39 Could DHPs Be Involved in Antioxidative Stress Beforebeing applied in vivo the optimal dose and optimal timeintervals forDHPs applicationmust be knownNamely whileROS have been traditionally considered as toxic byproductsof aerobic metabolism we know nowadays that ROS may actas essential signaling molecules needed for the control ofmany different physiological processes Whether the role ofROS will be damaging protective or signaling depends onthe delicate equilibrium between time- and location-specificROS production and scavenging Accordingly the imbalanceof the increased AO potential so-called antioxidative stresscould be dangerous similar to chronic OS in particular incase of extended exposure Inappropriate interventions inthe oxidative homeostasis by excessive antioxidants especiallyin case of chronic exposure to antioxidants might havevery negative effects as was published in the ATBC studyshowing an increased cancer incidence in smokers treatedby excessive beta-carotene [254] Therefore overconsump-tion of any natural or synthetic AO including DHPs asdietary supplements or drugs must be avoided in order tosuppress oxidative damage and must not disrupt the well-integrated antioxidant defense network (Poljsak [255] andPoljsak and Milisav [256]) This is especially important whenadministrating lipid-soluble antioxidants that can be storedin biomembranes thus not only attenuating or preventing LPbut also affecting physiological effects of the natural antiox-idants in particular tocopherol The interrelationship withthe status of endogenous antioxidantsprooxidants should befollowed
DHPs primarily suppress the initiation stages of LPprocessThey do not entirely stop the LP propagation Actingsynergistically with tocopherol diludine may prevent patho-logical excess of ROS production within the lipid moiety ofthe cellular membranes and LDL However due to its lowsolubility and fast metabolism its concentration in the cellsis low For that reason it cannot cause antioxidative stresseven if used for an extended period of time Thus diludine(diethone) could be only a mild antioxidant it has potentialfor restoring the pool of natural antioxidants (as synergist of120572-tocopherol and polyphenols) in the cells
Moreover DHPs CA used for cardioprotection andvasodilatation as commercial drugs in low concentrationsare fast metabolized via CYP3A4 and for that reason theirapplication does not induce cellular AO stress [53 160]However Godfraind and Salomone [257] have postulated noevidence that allows recommending dietary supplementationwith antioxidants for the primary or secondary prevention ofcardiovascular disease
So far there are no reports on antioxidative stress causedby some DHPs diludine and its analogues Diludine andits analogues therefore could act as adaptogens supportinghormetic effects of mild oxidative stress These compoundsmay act as potential multisided modulators of Yin-Yang
cycles of redox and cell functions (the electroplasmic cycle)(Wagner et al [258])
4 Conclusions
14-Dihydropyridines (14-DHPs) have broad spectrum ofOS modulating activities DHPs have reducing and lipidperoxidation inhibitor properties act as reductants in simplechemical systems and stabilize various biological systems(LDL mitochondria microsomes cells and tissues) againstOS Examples and peculiarities and mechanisms of antiox-idant activity (AOA) and antiradical activity (ARA) as wellas stress-protective effect of DHPs including commercialcalcium antagonists (CA) were highlighted These activitiesdepend on various structural parameters related to DHPs(presence and character of substituents) lipophilicity anddepth of the incorporation in the biologicalmembranesTheyalso depend on the experimental model system for exploringthe lipid peroxidation or oxidative stress Stress-protectiveeffect of some metabolites of CA (nifedipine) is reviewedAlthough some DHPs including CA have prooxidant prop-erties (on epididymal sperm cells) they can generally beconsidered as potent antioxidants Therefore comparisonof the AOA and ARA of different DHPs (mutually andwith other AOs) was described in detail According to thedata presented the DHPs might be considered as bellwetheramong synthetic compounds targeting OS and as a kind ofpharmacological measure for respective field of organic andmedicinal chemistry
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
Authors from Latvian IOS acknowledge ESF 201300021DP1112013APIAVIAA011 and National Research Pro-gramme PUBLIC HEALTHBiomedicine of the Republicof Latvia for financial support administration of the Insti-tute for technical support and Rufus Smits PhD for con-sultations in English The support of Cooperation in Euro-pean System of Science and Technology (COST) Domain ofChemistry Molecular Sciences and Technologies (CMST)was of highest importance for preparation of this paper
[2] D J Triggle ldquo14-Dihydropyridines as calcium channel ligandsand privileged structuresrdquoCellular andMolecular Neurobiologyvol 23 no 3 pp 293ndash303 2003
[3] T Godfraind ldquoAntioxidant effects and the therapeutic modeof action of calcium channel blockers in hypertension andatherosclerosisrdquo Philosophical Transactions of the Royal SocietyB Biological Sciences vol 360 no 1464 pp 2259ndash2272 2005
[4] E Cadenas ldquoMitochondrial free radical production and cellsignalingrdquoMolecular Aspects of Medicine vol 25 no 1-2 pp 17ndash26 2004
[5] E Cadenas ldquoFree radicals oxidative stress and diseasesrdquo inLecture PSC 616 p 38 Missouri University of Science andTechnology Rolla Mo USA httpwwwcarnicominstituteorgarticlesenrique cadenaspdf
[6] K Rahman ldquoStudies on free radicals antioxidants and co-fac-torsrdquo Clinical Interventions in Aging vol 2 no 2 pp 219ndash2362007
[7] V Bocci and G Valacchi ldquoFree radicals and antioxidants howto reestablish redox homeostasis in chronic diseasesrdquo CurrentMedicinal Chemistry vol 20 no 27 pp 3397ndash3415 2013
[8] M Valko C J Rhodes J Moncol M Izakovic and M MazurldquoFree radicals metals and antioxidants in oxidative stress-induced cancerrdquo Chemico-Biological Interactions vol 160 no 1pp 1ndash40 2006
[9] G Bartosz ldquoReactive oxygen species destroyers or messen-gersrdquo Biochemical Pharmacology vol 77 no 8 pp 1303ndash13152009
[10] R Visconti and D Grieco ldquoNew insights on oxidative stress incancerrdquo Current Opinion in Drug Discovery and Developmentvol 12 no 2 pp 240ndash245 2009
[11] R N Kujundzic N Zarkovic and K G Troselj ldquoPyridinenucleotides in regulation of cell death and survival by redoxand non-redox reactionsrdquo Critical Reviews in Eukaryotic GeneExpression vol 24 no 4 pp 287ndash309 2014
[12] B Halliwell and J M C Gutteridge ldquoThe definition and mea-surement of antioxidants in biological systemsrdquo Free RadicalBiology and Medicine vol 18 no 1 pp 125ndash126 1995
[13] V D Kancheva and O T Kasaikina ldquoBio-antioxidantsmdashachemical base of their antioxidant activity and beneficial effect
on human healthrdquo Current Medicinal Chemistry vol 20 no 37pp 4784ndash4805 2013
[14] H V Panglossi Ed Frontiers in Antioxidants Research NovaScience Publishers New York NY USA 2006
[15] E B Burlakova E M Molochkina and G A NikiforovldquoHybrid antioxidantsrdquo Oxidation Communications vol 31 no4 pp 739ndash757 2008 httpmembraneustceducnpaperpdfHybrid20Antioxidantspdf
[16] A Bast and G R M M Haenen ldquoTen misconceptions aboutantioxidantsrdquo Trends in Pharmacological Sciences vol 34 no 8pp 430ndash436 2013
[17] E B Burlakova A V 0lesenko E M Molochkina N PPalmina and N G Khrapova Bioantioxidants for RadiationDamage and Malignant Growth Nauka Moscow Russia 1975(Russian)
[18] J Fang T Seki and H Maeda ldquoTherapeutic strategies by mod-ulating oxygen stress in cancer and inflammationrdquo AdvancedDrug Delivery Reviews vol 61 no 4 pp 290ndash302 2009
[19] M Valko D Leibfritz J Moncol M T D Cronin M Mazurand J Telser ldquoFree radicals and antioxidants in normal physi-ological functions and human diseaserdquo International Journal ofBiochemistry and Cell Biology vol 39 no 1 pp 44ndash84 2007
[20] M Jimenez-Del-Rio and C Velez-Pardo ldquoThe bad the goodand the ugly about oxidative stressrdquo Oxidative Medicine andCellular Longevity vol 2012 Article ID 163913 13 pages 2012
[21] C D Kamat S Gadal M Mhatre K S Williamson Q N Pyeand K Hensley ldquoAntioxidants in central nervous system dis-eases preclinical promise and translational challengesrdquo Journalof Alzheimerrsquos Disease vol 15 no 3 pp 473ndash493 2008
[22] A Pompella H Sies R Wacker et al ldquoThe use of totalantioxidant capacity as surrogate marker for food quality andits effect on health is to be discouragedrdquo Nutrition vol 30 no7-8 pp 791ndash793 2014
[23] Z Ye and H Song ldquoAntioxidant vitamins intake and the risk ofcoronary heart disease meta-analysis of cohort studiesrdquo Euro-pean Journal of Cardiovascular Prevention and Rehabilitationvol 15 no 1 pp 26ndash34 2008
[24] P Knekt J Ritz M A Pereira et al ldquoAntioxidant vitamins andcoronary heart disease risk a pooled analysis of 9 cohortsrdquoTheAmerican Journal of Clinical Nutrition vol 80 no 6 pp 1508ndash1520 2004
[25] A C Carr and M C M Vissers ldquoSynthetic or food-derivedvitamin Cmdashare they equally bioavailablerdquo Nutrients vol 5 no11 pp 4284ndash4304 2013
[26] R Tabrizchi ldquoEdaravoneMitsubishi-TokyordquoCurrentOpinion inInvestigational Drugs vol 1 no 3 pp 347ndash354 2000
[27] K Kikuchi S Tancharoen N Takeshige et al ldquoThe efficacy ofedaravone (radicut) a free radical scavenger for cardiovasculardiseaserdquo International Journal of Molecular Sciences vol 14 no7 pp 13909ndash13930 2013
[28] D Mauzerall and F H Westheimer ldquo1-Benzyldihydronicoti-namidemdasha model for reduced DPNrdquo Journal of the AmericanChemical Society vol 77 no 8 pp 2261ndash2264 1955 ChemicalAbstracts vol 50 Article ID 2588i 1956
[29] F Bossert and W Vater ldquo14-Dihydropyridinesmdasha basis fordeveloping new drugsrdquo Medicinal Research Reviews vol 9 no3 pp 291ndash324 1989
[30] G Swarnalatha G Prasanthi N Sirisha and CMadhusudhanaChetty ldquo14-Dihydropyridines a multtifunctional moleculemdash areviewrdquo International Journal of ChemTech Research vol 3 no1 pp 75ndash89 2011
28 Oxidative Medicine and Cellular Longevity
[31] M Cataldi and F Bruno ldquo14-Dihydropyridines the multiplepersonalities of a blockbuster drug familyrdquo Translational Medi-cine UniSa vol 4 no 2 pp 12ndash26 2012 httpwwwncbinlmnihgovpmcarticlesPMC3728803
[32] R Vitolina A Krauze G Duburs and A Velena ldquoAspects ofthe amlodipine pleiotropy in biochemistry pharmacology andclinicsrdquo International Journal of Pharmaceutical Sciences andResearch vol 3 no 5 pp 1215ndash1232 2012
[33] D Grover S N Mokale and M T Shete ldquoDihydropyridinea novel pharmacophorerdquo International Journal of Pharmaceu-tical Erudition vol 1 no 2 pp 16ndash29 2011 httppharmaeru-ditionorgContentPaper20111-RV-320Final2016-29pdf
[34] A M Vijesh A M Isloor S K Peethambar K N ShivanandaT Arulmoli and N A Isloor ldquoHantzsch reaction synthesis andcharacterization of somenew 14-dihydropyridine derivatives aspotent antimicrobial and antioxidant agentsrdquo European Journalof Medicinal Chemistry vol 46 no 11 pp 5591ndash5597 2011
[35] P Mehta and P Verma ldquoAntimicrobial activity of some deriva-tives of 14-dihydropyridinesrdquo Journal of Chemistry vol 2013Article ID 865128 4 pages 2013
[36] P Olejnıkova L Svorc D Olsovska et al ldquoAntimicrobialactivity of novel C2-substituted 14-dihydropyridine analoguesrdquoScientia Pharmaceutica vol 82 no 2 pp 221ndash232 2014
[37] S Sepehri H Perez Sanchez and A Fassihi ldquoHantzsch-typedihydropyridines and biginelli-type tetra-hydropyrimidinesa review of their chemotherapeutic activitiesrdquo Journal of Phar-macy amp Pharmaceutical Sciences vol 18 no 1 pp 1ndash52 2015httpsejournalslibraryualbertacaindexphpJPPSarticleview2383617863
[38] S A Khedkar and P B Auti ldquo14-Dihydropyridines a classof pharmacologically important moleculesrdquo Mini-Reviews inMedicinal Chemistry vol 14 no 3 pp 282ndash290 2014
[39] G D Tirzit and G Ya Duburs ldquo14-dihydropyridines as inhi-bitors of free-radical reactionsrdquo Chemistry of Heterocyclic Com-pounds vol 8 no 1 pp 126ndash127 1972 Translated from KhimiyaGeterotsiklicheskikh Soedinenii no1 pp 133ndash134 1972 (Rus-sian)
[40] I Bogeski R Kappl C Kummerow R Gulaboski M Hothand B A Niemeyer ldquoRedox regulation of calcium ion channelschemical and physiological aspectsrdquoCell Calcium vol 50 no 5pp 407ndash423 2011
[41] S A Giller G Y Dubur Y R Uldrikis et al ldquoDiludine [Themethod to obtain 35-dicarbonylderivatives of 26-dimethyl-14-dihydropyridines]rdquo Authors certificate of USSR no 3004651971 [Byull Izobret no13 p 95 1971] and following patentsPatent of England no 1294650 1973 Patent of France no2055458 1971 Patent of Japan no 702883 1973 Patent ofHolland no 149787 1976 Patent of Italy no 969022 1974 Patentof FRG no 2036403 1978 US Patent no 3883673 1975 USPatent no 3948924 1976
[42] S A Giller G Y Dubur Y R Uldrikis et al ldquoImprovementsin or relating to the stabilization of carotenerdquo GB Patent no1294650 1972
[43] S A Giller G Y Dubur Y R Uldrikis et al ldquoStabilization ofcarotenerdquo US Patent no 3883673 1975 Chemical Abstracts vol83 Article ID 95193 1975
[44] Yu A Zilber G Ya Dubur K K Kumsar and A Kh VelenaldquoThe effect of antioxidants on the peroxidation of bimole-cular phospholipid membranesrdquo Latvijas PSR ZA Vestis Izves-tia Akademii Nauk Latviyskoy SSR vol 6 pp 80ndash82 1971(Russian) translated from the original Russian Doc Accesion
No AD0771751 distributed by NTIS US Department of Com-merce httpwwwdticmildtictrfulltextu2771751pdf
[45] G Ya Dubur Yu A Zilbers A Kh Velena A O Kumerovaand G D Tirzitis ldquoMultistage study of regulation of peroxida-tion processes in biological membranes by antioxidants of 14-dihydropyridine grouprdquo Izvestiya Akademii Nauk LatviyskoySSR vol 336 no 7 pp 65ndash68 1975 (Russian)
[46] R P Mason and M W Trumbore ldquoDifferential membraneinteractions of calcium channel blockers Implications forantioxidant activityrdquo Biochemical Pharmacology vol 51 no 5pp 653ndash660 1996
[47] R P Mason M F Walter M W Trumbore E G Olmstead Jrand P E Mason ldquoMembrane antioxidant effects of the chargeddihydropyridine calcium antagonist amlodipinerdquo Journal ofMolecular and Cellular Cardiology vol 31 no 1 pp 275ndash2811999
[48] R PMason I T MakMW Trumbore and P EMason ldquoAnti-oxidant properties of calcium antagonists related to membranebiophysical interactionsrdquo American Journal of Cardiology vol84 no 4 pp 16ndash22 1999
[49] R PMasonMW Trumbore and P EMason ldquoMembrane bio-physical interaction of amlodipine and antioxidant propertiesrdquoDrugs vol 59 no 2 pp 9ndash16 2000 (French)
[50] R P Mason P Marche and T H Hintze ldquoNovel vascularbiology of third-generation L-type calcium channel antagonistsAncillary actions of amlodipinerdquo Arteriosclerosis Thrombosisand Vascular Biology vol 23 no 12 pp 2155ndash2163 2003
[51] A Augustyniak G Bartosz A Cipak et al ldquoNatural andsynthetic antioxidants an updated overviewrdquo Free RadicalResearch vol 44 no 10 pp 1216ndash1262 2010
[52] T Grune N Zarkovic and K Kostelidou ldquoLipid peroxidationresearch in Europe and the COST B35 action lsquoLipid Peroxida-tion Associated Disordersrsquordquo Free Radical Research vol 44 no10 pp 1095ndash1097 2010
[53] E Carosati P Ioan M Micucci et al ldquo14-Dihydropyridinescaffold in medicinal chemistry the story so far and perspec-tives (part 2) action in other targets and antitargetsrdquo CurrentMedicinal Chemistry vol 19 no 25 pp 4306ndash4323 2012
[54] U Eisner and J Kuthan ldquoThe chemistry of dihydropyridinesrdquoChemical Reviews vol 72 no 1 pp 1ndash42 1972 httpwwwsci-encemadnessorgtalkfilesphppid=138742ampaid=6475
[55] J Kuthan and A Kurfurst ldquoDevelopment in dihydropyri-dine chemistryrdquo Industrial amp Engineering Chemistry ProductResearch and Development vol 21 no 2 pp 191ndash261 1982
[56] A Sausins and G Duburs ldquoSynthesis of 14-dihydropyridinesby cyclocondensation reactionsrdquo Heterocycles vol 27 no 1 pp269ndash289 1988
[57] A E Sausins and G Y Duburs ldquoSynthesis of 14-dihydro-pyridines in cyclocondensation reactions (review)rdquo Chemistryof Heterocyclic Compounds vol 28 no 4 pp 363ndash391 1992Translated from Khimiya Geterotsiklicheskikh Soedinenii no 4pp 435ndash467 1992 (Russian)
[58] S Kazda ldquoTwenty years of dihydropyridinesrdquo in Dihydropy-ridines Progress in Pharmacology and Therapy W-D Busse BGarthoff and F Seuter Eds pp 1ndash12 Springer Verlag BerlinGermany 1993
[59] J-P Wan and Y Liu ldquoRecent advances in new multicomponentsynthesis of structurally diversified 14-dihydropyridinesrdquo RSCAdvances vol 2 no 26 pp 9763ndash9777 2012
[61] Reaxys Database[62] J Tuttle ldquoStructure mechanism and reactivity of hantzsch
estersrdquo in MacMillan Lab Group Meeting (082504) p 332004 httpwwwprincetoneduchemistrymacmillangroup-meetingsJBT20Hantzschpdf
[63] A Saini S Kumar and J S Sandhu ldquoHantzsch reaction recentadvances in Hantzsch 14-dihydropyridinesrdquo Journal of Sci-entific amp Industrial Research vol 67 pp 95ndash111 2008
[64] L LW Cheung S A Styler and A P Dicks ldquoRapid and conve-nient synthesis of the 14-dihydropyridine privileged structurerdquoJournal of Chemical Education vol 87 no 6 pp 628ndash630 2010
[65] A Kumar R A Maurya S Sharma M Kumar and G BhatialdquoSynthesis and biological evaluation of N-aryl-14-dihydro-pyridines as novel antidyslipidemic and antioxidant agentsrdquoEuropean Journal of Medicinal Chemistry vol 45 no 2 pp 501ndash509 2010
[66] R S Kumar A Idhayadhulla A J Abdul Nasser and J SelvinldquoSynthesis and anticoagulant activity of a new series of 14-dihydropyridine derivativesrdquo European Journal of MedicinalChemistry vol 46 no 2 pp 804ndash810 2011
[67] H A Stefani C B Oliveira R B Almeida et al ldquoDihydro-pyrimidin-(2H)-ones obtained by ultrasound irradiation anew class of potential antioxidant agentsrdquo European Journal ofMedicinal Chemistry vol 41 no 4 pp 513ndash518 2006
[68] H Sun C Shang L Jin and J Zhang ldquoSynthesis and antiox-idant activity of a series of novel 3-chalcone-substituted 14-dihydropyridine derivativesrdquoHeterocyclic Communications vol18 no 5-6 pp 239ndash243 2012
[69] D B Tikhonov and B S Zhorov ldquoStructural model for dihy-dropyridine binding to L-type calcium channelsrdquo The Journalof Biological Chemistry vol 284 no 28 pp 19006ndash19017 2009
[70] G Y Dubur and Y R Uldrikis ldquoThe oxidation of 14-dihydro-pyridinesrdquo Chemistry of Heterocyclic Compounds vol 6 no 1pp 80ndash84 1970 Translated from Khimiya GeterotsiklicheskikhSoedinenii no 1 pp 83ndash88 1970 (Russian)
[71] G Ya Duburs A O Kumerova and Ya R Uldrikis ldquoEnzymicoxidation of hydrogenated pyridines with peroxidase-hydrogenperoxide systemrdquoLatvijas PSRZAVestis vol 73 no 7 pp 73ndash771970 (Russian) Chemical Abstracts vol 73 Article ID 94913g1970
[72] K Xie Y-C Liu Y Cui J-GWang Y Fu andT CWMak ldquoN-methyl-(R)-3-(tert-butyl)-sulfinyl-14-dihydropyridine a novelNADHmodel compoundrdquoMolecules vol 12 no 3 pp 415ndash4222007
[73] S Tamagaki T Mimura and W Tagaki ldquoMetal-ion-facilitatedoxidations of dihydropyridines with molecular oxygen andhydrogen peroxiderdquo Journal of the Chemical Society PerkinTransactions 2 no 10 pp 1645ndash1650 1990
[74] D Tirzite G Tirzitis andD Antipova ldquoReductive ability of 14-dihydropyridine derivatives in relation to ions of trivalent ironrdquoChemistry of Heterocyclic Compounds vol 35 no 5 pp 592ndash594 1999
[76] J Ogle J Stradins and L Baumane ldquoFormation and decay offree cation-radicals in the course of electro-oxidation of 12- and14-dihydropyridines (Hantzsch esters)rdquo Electrochimica Actavol 39 no 1 pp 73ndash79 1994
[77] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for the
synthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts C Wittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Berlin Germany 2010
[78] WDu and Zh Yu ldquoBiomimetic in situ regeneration of cofactorsNAD(P)+ and NAD(P)H models hantzsch esters and dihy-drophenanthridinerdquo Synlett vol 23 no 9 pp 1300ndash1304 2012
[79] H K Chenault and G M Whitesides ldquoRegeneration ofnicotinamide cofactors for use in organic synthesisrdquo AppliedBiochemistry and Biotechnology vol 14 no 2 pp 147ndash197 1987
[80] Y R Uldrikis A A Zidermane E A Biseniex I E Preisa GY Dubur and G D Tirzit ldquoEsters of 26-dimethyl-14-dihydro-pyridine-35-dicarboxylic acid and method of obtainingthereofrdquo WO 8000345 A1 1978 httpworldwideespacenetcompublicationDetailsbiblioDB=EPODOCampII=1ampND=3ampadjacent=trueamplocale=en EPampFT=Dampdate=19800306ampCC=WOampNR=8000345A1ampKC=A1
[81] Y Sambongi H Nitta K Ichihashi M Futai and I Ueda ldquoAnovel water-soluble Hantzsch 14-dihydropyridine compoundthat functions in biological processes through NADH regener-ationrdquo Journal of Organic Chemistry vol 67 no 10 pp 3499ndash3501 2002
[82] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for thesynthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts ChWittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Verlag Berlin Germany 2010
[83] T Okamura T Kikuchi A Nagamine et al ldquoAn approach formeasuring in vivo cerebral redox states using the oxidative con-version of dihydropyridine to pyridinium ion and themetabolictrapping principlerdquo Free Radical Biology and Medicine vol 38no 9 pp 1197ndash1205 2005
[84] K A Schellenberg and F H Westheimer ldquoA free-radicaloxidation of a dihydropyridine1ardquo The Journal of OrganicChemistry vol 30 no 6 pp 1859ndash1862 1965
[85] K A Schellenberg ldquoReaction of hydroxyl radical with thymi-dine Scavenging by a dihydropyridinerdquo Federation Proceedingsvol 38 no 3 I p 1433 1979
[86] E S Huyser J A K Harmony and F L McMillian ldquoPeroxideoxidations of dihydropyridine derivativesrdquo Journal of the Amer-ican Chemical Society vol 94 no 9 pp 3176ndash3180 1972
[87] A Sakamoto S T Ohnishi and R Ogawa ldquoInhibition of lipidperoxidation by some dihydropyridine derivativesrdquo Journal ofAnesthesia vol 7 no 2 pp 193ndash197 1993
[88] R Hardeland ldquoReview Neuroprotection by radical avoidancesearch for suitable agentsrdquo Molecules vol 14 no 12 pp 5054ndash5102 2009
[89] G Ya Dubur A Kh Velena V M Gukasov and Yu AVladimirov ldquoRegulation of peroxidation of mitochondrialmembrane lipids initiated by Fe2+ ions by antoxidants of the14-dihydropyridine series in experiments in vitrordquo Biomed-itsinskaya Khimiya vol 22 no 5 pp 665ndash673 1976 (Russian)Chemical Abstracts vol 88 Article ID 2640 1977
[90] G RMMHaenenM J T J Arts A Bast andMD ColemanldquoStructure and activity in assessing antioxidant activity in vitroand in vivo a critical appraisal illustrated with the flavonoidsrdquoEnvironmental Toxicology and Pharmacology vol 21 no 2 pp191ndash198 2006
[91] G Tirzitis and G Bartosz ldquoDetermination of antiradical andantioxidant activity basic principles and new insightsrdquo ActaBiochimica Polonica vol 57 no 2 pp 139ndash142 2010
30 Oxidative Medicine and Cellular Longevity
[92] G R Buettner and R P Mason ldquoSpin-trapping methods fordetecting superoxide and hydroxyl free radicals in vitro and invivordquo inCritical Reviews of Oxidative Stress and Aging Advancesin Basic Science Diagnostics and Intervention R G Cutler andH Rodriguez Eds vol 1 chapter 2 pp 27ndash38World ScientificLondon UK 2003
[93] M M Tarpey and I Fridovich ldquoMethods of detection ofvascular reactive species Nitric oxide superoxide hydrogenperoxide and peroxynitriterdquo Circulation Research vol 89 no3 pp 224ndash236 2001
[94] E Y Kazush E I Sagun G D Tirzit and G Y DaburldquoQuenching of singlet oxygen by electron donating derivativesof 14-dihydropyridinerdquo Chemistry of Heterocyclic Compoundsvol 30 no 5 pp 562ndash563 1994
[95] G Tirzitis E Kazush and G Duburs ldquoReaction of 14-dihydropyridine derivatives with peroxynitrite anionrdquo Chem-istry of Heterocyclic Compounds vol 34 no 3 pp 321ndash3231998 (Russian) Translated from Khimiya GeterotsiklicheskikhSoedinenii no 3 pp 355ndash357 1998
[96] L J Nunez-Vergara C Lopez-Alarcon P A Navarrete-EncinaA M Atria C Camargo and J A Squella ldquoElectrochemicaland EPR characterization of 14-dihydropyridines Reactivitytowards alkyl radicalsrdquo Free Radical Research vol 37 no 1 pp109ndash120 2003
[97] D Tirzite A Krauze A Zubareva G Tirzitis and G DubursldquoSynthesis and antiradical activity of 5-acetyl-2-alkylthio-4-aryl-6-methyl-14-dihydropyridine-3-carboxylic acid nitrilesrdquoChemistry of Heterocyclic Compounds vol 38 no 7 pp 795ndash800 2002
[98] H Ohkawa N Ohishi and K Yagi ldquoAssay for lipid peroxidesin animal tissues by thiobarbituric acid reactionrdquo AnalyticalBiochemistry vol 95 no 2 pp 351ndash358 1979
[99] N Zarkovic ldquo4-Hydroxynonenal as a bioactive marker ofpathophysiological processesrdquo Molecular Aspects of Medicinevol 24 no 4-5 pp 281ndash291 2003
[100] M Parola G Bellomo G Robino G Barrera and M UDianzani ldquo4-Hydroxynonenal as a biological signal molecularbasis and pathophysiological implicationsrdquo Antioxidants andRedox Signaling vol 1 no 3 pp 255ndash284 1999
[101] T Lovakovic M Poljak-Blazi G Duburs et al ldquoGrowthmodulation of human cells in vitro by mild oxidative stressand 14-dihydropyridine derivative antioxidantsrdquo CollegiumAntropologicum vol 35 no 1 pp 137ndash141 2011
[102] R van den Berg G R M M Haenen H van den Bergand A Bast ldquoApplicability of an improved Trolox equivalentantioxidant capacity (TEAC) assay for evaluation of antioxidantcapacity measurements of mixturesrdquo Food Chemistry vol 66no 4 pp 511ndash517 1999
[103] C Lopez-Alarcon P Navarrete C Camargo J A Squella andL J Nunez-Vergara ldquoReactivity of 14-dihydropyridines towardalkyl alkylperoxyl radicals and ABTS radical cationrdquo ChemicalResearch in Toxicology vol 16 no 2 pp 208ndash215 2003
[104] V Valenzuela P Santander C Camargo J A Squella C Lopez-Alarcon and L J Nunez-Vergara ldquo14-Dihydropyridines reac-tivity of nitrosoaryl and nitroaryl derivatives with alkylperoxylradicals andABTS radical cationrdquo Free Radical Research vol 38no 7 pp 715ndash727 2004
[105] L G Tsetlin N A Chebotareva B I Kurganov A K VelenaG Y Dubur and V Z Lankin ldquoStudy of 14-dihydropyridinesas lipoxygenase inhibitors with the use of hydrated reversedmicellesrdquo Pharmaceutical Chemistry Journal vol 22 no 6 pp425ndash428 1988 (Russian)
[106] J Panek Z Reblova L Kocirkova et al ldquoAntioxidant activityof dihydropyridine derivativesrdquo Czech Journal of Food Sciencesvol 18 pp 144ndash145 2000
[107] G Tirzitis I Kirule and G Duburs ldquoAntioxidationsaktivitatder 35-dicarbonylderivate des 26-demethyl-14-dihydropyri-dinsrdquo Fett Wissenschaft TechnologieFat Science Technology vol90 no 10 pp 411ndash413 1988
[108] M Plotniece G Tirzitis Y Uldrikis et al ldquoSynthesis of 14-dihydropyridine derivatives having an oxy- alkoxy- or dimeth-ylaminophenyl substituent in the 4 position their antioxidantactivity and their binding to phospholipid membranesrdquo Chem-istry of Heterocyclic Compounds vol 32 no 10 pp 1166ndash11721996 Translated from Khimiya Geterotsiklicheskikh Soedineniino 10(352) pp 1358ndash1365 1996 (Russian)
[109] D Y Rubene V S Sharov V I Olenev G D Tirzit G Y Duburand Y A Vladimirov ldquoUse of chemiluminescent method forthe evaluation of antioxidant activity of some derivatives of 14-dihydropyridinerdquo Russian Journal of Physical Chemistry A vol55 no 2 pp 511ndash512 1981 (Russian)
[110] M C R Symons and JM C Gutteridge Free Radicals and IronChemistry Biology and Medicine Oxford Science PublicationsOxford University Press Oxford UK 1998
[111] M Repetto J Semprine and A Boveris ldquoLipid peroxidationchemical mechanism biological implications and analyticaldeterminationrdquo in Lipid Peroxidation A Catala Ed Section ILipid Peroxidation Chemical Mechanisms Antioxidants Bio-logical Implications of Biochemistry Genetics and MolecularBiology chapter 1 pp 3ndash30 InTech Rijeka Croatia 2012
[112] A Velena J Zilbers and G Duburs ldquoDerivatives of 14-dihydropyridines asmodulators of ascorbate-induced lipid per-oxidation and high-amplitude swelling ofmitochondria causedby ascorbate sodium linoleate and sodiumpyrophosphaterdquoCellBiochemistry and Function vol 17 no 4 pp 237ndash252 1999
[113] M V Bilenko L N Shelenkova G Y Dubur and A K VelenaldquoUse of antioxidants to prevent renal damage during acuteischemia and reperfusionrdquo Bulletin of Experimental Biology andMedicine vol 96 no 3 pp 1195ndash1198 1983 Translated fromByulletenrsquo Eksperimentalrsquonoi Biologii i Meditsiny vol 96 no 9pp 8ndash11 1983 (Russian)
[114] R Toniolo F Tubaro F Ursini and G Bontempelli ldquoAn elec-troanalytical investigation on the redox properties of calciumantagonist dihydropyridinesrdquo Electroanalysis vol 15 no 10 pp855ndash861 2003
[115] L Kourimska J Pokorny and G Tirzitis ldquoThe antioxidant aci-tivity of 26-dimethyl-35-diethoxycarbonyl-14-dihydropyri-dine in edible oilsrdquo Nahrung vol 37 no 1 pp 91ndash93 1993
[116] C Lopez-Alarcon H Speisky J A Squella C Olea-Azar CCamargo and L J Nunez-Vergara ldquoReactivity of 14-dihydro-pyridines toward SIN-1-derived peroxynitriterdquo PharmaceuticalResearch vol 21 no 10 pp 1750ndash1757 2004
[117] R A Olek W Ziolkowski J J Kaczor L Greci J Popinigisand J Antosiewicz ldquoAntioxidant activity of NADH and its ana-loguemdashan in vitro studyrdquo Journal of Biochemistry andMolecularBiology vol 37 no 4 pp 416ndash421 2004
[118] E Niki N Noguchi and N Gotoh ldquoInhibition of oxidativemodification of low density lipoprotein by antioxidantsrdquo Jour-nal of Nutritional Science andVitaminology vol 39 supplementpp S1ndashS8 1993
[119] N Rojstaczer and D J Triggle ldquoStructure-function relation-ships of calcium antagonists effect on oxidative modificationof low density lipoproteinrdquo Biochemical Pharmacology vol 51no 2 pp 141ndash150 1996
Oxidative Medicine and Cellular Longevity 31
[120] A Sevanian L Shen and FUrsini ldquoInhibition of LDLoxidationand oxidized LDL-induced cytotoxicity by dihydropyridinecalcium antagonistsrdquo Pharmaceutical Research vol 17 no 8 pp999ndash1006 2000
[121] A Negre-Salvayre and R Salvayre ldquoProtection by Ca2+ channelblockers (nifedipine diltiazem and verapamil) against the tox-icity of oxidized low density lipoprotein to cultured lymphoidcellsrdquo British Journal of Pharmacology vol 107 no 3 pp 738ndash744 1992
[122] A Negre-Salvayre G FitoussiM Troly and R Salvayre ldquoCom-parative cytoprotective effect of dihydropyridine calcium chan-nel blockers against the toxicity of oxidized low density lipopro-tein for cultured lymphoid cellsrdquo Biochemical Pharmacologyvol 44 no 12 pp 2379ndash2386 1992
[123] L Cominacini A F Pasini U Garbin et al ldquoAntioxidant activ-ity of different dihydropyridinesrdquo Biochemical and BiophysicalResearch Communications vol 302 no 4 pp 679ndash684 2003
[124] L Cominacini U Garbin A Fratta Pasini et al ldquoOxidized low-density lipoprotein increases the production of intracellularreactive oxygen species in endothelial cells inhibitory effect oflacidipinerdquo Journal of Hypertension vol 16 no 12 part 2 pp1913ndash1919 1998
[125] H M Lander ldquoAn essential role for free radicals and derivedspecies in signal transductionrdquo The FASEB Journal vol 11 no2 pp 118ndash124 1997
[126] M L L Martinez E Rizzi M M Castro et al ldquoLercanidipinedecreases vascular matrix metalloproteinase-2 activity andprotects against vascular dysfunction in diabetic ratsrdquo EuropeanJournal of Pharmacology vol 599 no 1ndash3 pp 110ndash116 2008
[127] P Lesnik C Dachet L Petit et al ldquoImpact of a combinationof a calcium antagonist and a 120573-blocker on cell- and copper-mediated oxidation of LDL and on the accumulation and effluxof cholesterol in human macrophages and murine J774 cellsrdquoArteriosclerosis Thrombosis and Vascular Biology vol 17 no 5pp 979ndash988 1997
[128] G Sobal E J Menzel and H Sinzinger ldquoCalcium antagonistsas inhibitors of in vitro low density lipoprotein oxidation andglycationrdquoBiochemical Pharmacology vol 61 no 3 pp 373ndash3792001
[129] E Lupo R Locher B Weisser and W Vetter ldquoIn vitro antiox-idant activity of calcium antagonists against LDL oxidationcompared with 120572-tocopherolrdquo Biochemical and BiophysicalResearch Communications vol 203 no 3 pp 1803ndash1808 1994
[130] J Zou Y Li H-Q Fan and J-G Wang ldquoEffects of dihydropy-ridine calcium channel blockers on oxidized low-density lipo-protein induced proliferation and oxidative stress of vascularsmooth muscle cellsrdquo BMC Research Notes vol 5 article 1682012
[131] C Napoli S Salomone T Godfraind et al ldquo14-Dihydro-pyridine calcium channel blockers inhibit plasma and LDL oxi-dation and formation of oxidation-specific epitopes in the arte-rial wall and prolong survival in stroke-prone spontaneouslyhypertensive ratsrdquo Stroke vol 30 no 9 pp 1907ndash1915 1999
[132] G Zernig I Graziadei T Moshammer C Zech N Reider andH Glossmann ldquoMitochondrial Ca2+ antagonist binding sitesare associated with an inner mitochondrial membrane anionchannelrdquo Molecular Pharmacology vol 38 no 3 pp 362ndash3691990
[133] F E Hunter Jr A Scott P E Hochstein et al ldquoStudies of themechanism of ascorbate-induced swelling and lysis of isolatedliver mitochondriardquo The Journal of Biological Chemistry vol239 pp 604ndash613 1964
[134] D R Janero B Burghardt and R Lopez ldquoProtection of cardiacmembrane phospholipid against oxidative injury by calciumantagonistsrdquoBiochemical Pharmacology vol 37 no 21 pp 4197ndash4203 1988
[135] A Karadag B Ozcelik and S S Saner ldquoReview of methods todetermine antioxidant capacitiesrdquo FoodAnalyticalMethods vol2 no 1 pp 41ndash60 2009
[136] Y I Gubskiı N V Litvinova and E V Shnurko-TabakovaldquoAntioxidant and antiradical activity of various classes of antiox-idantsrdquo Ukrainskiı Biokhimicheskiı Zhurnal vol 66 no 4 pp114ndash116 1994 (Russian)
[137] M Takei M Hiramatsu and A Mori ldquoInhibitory effects ofcalcium antagonists onmitochondrial swelling induced by lipidperoxidation or arachidonic acid in the rat brain in vitrordquoNeurochemical Research vol 19 no 9 pp 1199ndash1206 1994
[138] M Takei M Hiramatsu R Edamatsu and A Mori ldquoFreeradical scavenging by calcium antagonistsrdquo Neurosciences vol20 no 2 pp 75ndash82 1994
[139] Ya P Stradin G Ya Dubur Yu A Beilis Ya R Uldrikis andA F Korotkova ldquoVoltammetry of 14-dihydropyridine deriva-tives I Potentials of electrochemical oxidation of 35-diacyl-and 35-di(alkoxycarbonyl)-14-dihydropyridines in acetoni-trilerdquo Chemistry of Heterocyclic Compounds no 1 pp 84ndash871972 (Russian)
[140] E V Ivanov T V Ponomarjova G N Merkusev et al ldquoEinneuer Haut-Radioprotektor Diethon (experimentelle Unter-suchung)rdquo Radiobiologia Radiotherapia vol 31 no 1 pp 69ndash78 1990
[141] E V Ivanov T V Ponomareva G N Merkushev et al ldquoRadia-tion modulating properties of derivates of 14-dihydropyridineand 12345678910-decahydroacridine-18 dionerdquo Radiat-sionnaia Biologiia Radioecologiia vol 44 no 5 pp 550ndash5592004 (Russian)
[142] R O Vitolinia D A Berzinia A K Velena I A Vutsina A AKimenis and G Y Duburs ldquoThe protective effects of the cal-cium antagonist foridon in acute myocardial ischaemiardquo Kardi-ologiya vol 27 no 3 pp 90ndash93 1987 (Russian)
[143] A H Velena G Ya Duburs R O Vitolina et al ldquoEffect ofryodipine on electromechanical parameters of heart and vesselscAMP phosphodiesterase activity and swelling-contractioncycle of mitochondriardquo Arzneimittelforschung vol 35 no 6 pp907ndash914 1985
[144] L I Utno Z E Lipsberga A A Silova M I Girgensone EA Bisenieks and G I Ia ldquoCardioprotective properties of a 14-dihydropyridine derivative glutapyrone in deep hypothermiardquoBiulletenrsquo Eksperimentalrsquonoı Biologii i Meditsiny vol 108 no 11pp 558ndash561 1989 (Russian)
[145] M A S FernandesM S Santos J A F Vicente et al ldquoEffects of14-dihydropyridine derivatives (cerebrocrast gammapyroneglutapyrone and diethone) onmitochondrial bioenergetics andoxidative stress a comparative studyrdquoMitochondrion vol 3 no1 pp 47ndash59 2003
[146] M A S Fernandes M S Santos A J M Moreno et al ldquoEffectsof 5-acetyl(carbamoyl)-6-methylsulfanyl-14-dihydropyridine-5-carbonitriles on rat liver mitochondrial functionrdquo Toxicologyin Vitro vol 23 no 7 pp 1333ndash1341 2009
[147] L Klimaviciusa A Kalda A Kaasik et al ldquoNeuroprotectiveactivity of 14-dihydropyridine derivatives structure determi-nantsrdquo Proceedings of the Latvian Academy of Sciences BNatural Exact and Applied Sciences vol 61 no 1-2 pp 33ndash372007
32 Oxidative Medicine and Cellular Longevity
[148] L Klimaviciusa M A S Fernandes N Lencberga et alldquoTargeting the mitochondria by novel adamantane-containing14-dihydropyridine compoundsrdquo in Bioenergetics K B ClarkEd pp 257ndash272 InTech 2012
[149] V Klusa L Klimaviciusa G Duburs J Poikans and AZharkovsky ldquoAnti-neurotoxic effects of tauropyrone a taurineanaloguerdquo Advances in Experimental Medicine and Biology vol583 pp 499ndash508 2006
[150] N Sampson P Berger and Ch Zenzmaier ldquoRedox signalingas a therapeutic target to inhibit myofibroblast activation indegenerative fibrotic diseaserdquo BioMed Research Internationalvol 2014 Article ID 131737 14 pages 2014
[151] T L Leto and M Geiszt ldquoRole of Nox family NADPH oxidasesin host defenserdquoAntioxidantsampRedox Signaling vol 8 no 9-10pp 1549ndash1561 2006
[152] K K Griendling D Sorescu and M Ushio-Fukai ldquoNAD(P)Hoxidase role in cardiovascular biology and diseaserdquo CirculationResearch vol 86 no 5 pp 494ndash501 2000
[153] H Chen Y S Song and P H Chan ldquoInhibition of NADPHoxi-dase is neuroprotective after ischemia-reperfusionrdquo Journal ofCerebral Blood Flow and Metabolism vol 29 no 7 pp 1262ndash1272 2009
[154] P Hochstein and L Ernster ldquoADP-activated lipid peroxidationcoupled to the TPNH oxidase system of microsomesrdquo Biochem-ical and Biophysical Research Communications vol 12 no 5 pp388ndash394 1963
[155] I I Gubskiı AGGoriushkoNV Litvinova et al ldquoAntioxidantproperties and membranotropic effect of certain derivatives of14-dihydropyridinerdquo Ukrainskiı Biokhimicheskiı Zhurnal vol71 no 4 pp 35ndash39 1999 (Russian)
[156] F Engineer and R Sridhar ldquoInhibition of rat heart andliver microsomal lipid peroxidation by nifedipinerdquo BiochemicalPharmacology vol 38 no 8 pp 1279ndash1285 1989
[157] T Goncalves A P Carvalho and C R Oliveira ldquoAntioxidanteffect of calcium antagonists on microsomai membranes iso-lated from different brain areasrdquo European Journal of Pharma-cology vol 204 no 3 pp 315ndash322 1991
[158] M E Letelier P Izquierdo L Godoy A M Lepe and MFaundez ldquoLiver microsomal biotransformation of nitro-aryldrugs mechanism for potential oxidative stress inductionrdquoJournal of Applied Toxicology vol 24 no 6 pp 519ndash525 2004
[159] M E Letelier P Entrala C Lopez-Alarcon et al ldquoNitroaryl-14-dihydropyridines as antioxidants against rat liver microsomesoxidation induced by ironascorbate Nitrofurantoin and naph-thalenerdquo Toxicology in Vitro vol 21 no 8 pp 1610ndash1618 2007
[160] F P Guengerich W R Brian M Iwasaki M-A Sari CBaarnhielm and P Berntsson ldquoOxidation of dihydropyridinecalcium channel blockers and analogues by human liver cyto-chrome P-450 IIIA4rdquo Journal of Medicinal Chemistry vol 34no 6 pp 1838ndash1844 1991
[161] S H Park S-W RhaW-Y Shin et al ldquoAS-160 Calcium channelblockers of dihydropyridine class reduce the antiplatelet effectof Clopidogrel what is clinical impactrdquo The American Journalof Cardiology vol 107 no 8 supplement p 47A 2011
[162] C Asma and D M Reda ldquoEvaluation of dihydropyridinecalcium antagonist effects on the stress bioindicator orga-nism Saccharomyces cerevisiaerdquo Annals of Biological Researchvol 4 no 10 pp 40ndash46 2013 httpscholarsresearchlibrarycomABR-vol4-iss10ABR-2013-4-10-40-46pdf
[163] G Gaviraghi A M Pastorino E Ratti and D G TristldquoCalcium channel blockers with antioxidant activityrdquo in Free
Radicals Lipoprotein Oxidation andAtherosclerosis G BellomoG Finardi E Maggi and E Rice-Evans Eds pp 431ndash456Richelieu Press London UK 1995
[164] G Gaviraghi AM Pastorino E Ratti and D G Trist ldquoAntiox-idant dihydropyridines a new and comprehensive therapy forfree radical-induced cardiovascular diseasesrdquo in Free Radicalsin Biology and Environment F Minisci Ed vol 27 of NATOASI Series pp 193ndash221 Springer Dordrecht The Netherlands1997
[165] P D Henry ldquoAntiperoxidative actions of calcium antagonistsand atherogenesisrdquo Journal of Cardiovascular Pharmacologyvol 18 supplement 1 pp S6ndashS10 1991
[166] F Kouoh B Gressier T Dine et al ldquoAntioxidant effects andanti-elastase activity of the calcium antagonist nicardipine onactivated human and rabbit neutrophilsmdasha potential antiath-erosclerotic property of calcium antagonistsrdquo CardiovascularDrugs andTherapy vol 16 no 6 pp 515ndash520 2002
[167] S Parthasarathy D Litvinov K Selvarajan and M GarelnabildquoLipid peroxidation and decompositionmdashconflicting roles inplaque vulnerability and stabilityrdquo Biochimica et BiophysicaActa vol 1781 no 5 pp 221ndash231 2008
[168] D-Q Liu Z-Q Pang D-H Zhao and B-H Sheng ldquoEffects offuryl-dihydropyridines I on lipid peroxides of ischemic myo-cardium and ATPases activity of erythrocyte membranes inratsrdquo Acta Pharmacologica Sinica vol 12 no 3 pp 253ndash2561991
[169] V Lukic-Panin T Kamiya H Zhang et al ldquoPrevention of neu-ronal damage by calcium channel blockers with antioxidativeeffects after transient focal ischemia in ratsrdquo Brain Research vol1176 no 1 pp 143ndash150 2007
[170] Y Allanore D Borderie H Lemarechal O G Ekindjian andA Kahan ldquoAcute and sustained effects of dihydropyridine-typecalcium channel antagonists on oxidative stress in systemicsclerosisrdquo American Journal of Medicine vol 116 no 9 pp 595ndash600 2004
[171] I Casetta V Govoni and E Granieri ldquoOxidative stress antioxi-dants and neurodegenerative diseasesrdquo Current PharmaceuticalDesign vol 11 no 16 pp 2033ndash2052 2005
[172] M J T J Arts Assessing antioxidant activity [PhD the-sis] Maastricht University Maastricht The Netherlands 2007httparnounimaasnlshowcgifid=8676
[173] G Dıaz-Araya L Godoy L Naranjo A Squella M E Letelierand L J Nunez-Vergara ldquoAntioxidant effects of 14-dihydro-pyridine and nitroso aryl derivatives on the Fe+3ascorbate-stimulated lipid peroxidation in rat brain slicesrdquo General Phar-macology The Vascular System vol 31 no 3 pp 385ndash391 1998
[174] Y Fukuhara K Tsuchiya Y Horinouchi et al ldquoProtectiveeffect of photodegradation product of nifedipine against tumornecrosis factor 120572-induced oxidative stress in human glomerularendothelial cellsrdquo Journal of Medical Investigation vol 58 no1-2 pp 118ndash126 2011
[175] W Stengel M Jainz and K Andreas ldquoDifferent potencies ofdihydropyridine derivatives in blocking T-type but not L-typeCa2+ channels in neuroblastoma-glioma hybrid cellsrdquo EuropeanJournal of Pharmacology vol 342 no 2-3 pp 339ndash345 1998
[176] O M Panasenko D J Tirzite G D Tirzitis and G J DubursldquoEffect of some 14-dihydropyridine derivatives on structuralorganization of erythrocyte membranesrdquo Biologicheskie Mem-brany (Biochemistry (Moscow) Series A Membrane and CellBiology) vol 1 pp 919ndash925 1984 (Russian)
[177] L G Herbette Y M H Vant Erve and D G Rhodes ldquoInter-action of 14 dihydropyridine calcium channel antagonists with
Oxidative Medicine and Cellular Longevity 33
biological membranes lipid bilayer partitioning could occurbefore drug binding to receptorsrdquo Journal of Molecular andCellular Cardiology vol 21 no 2 pp 187ndash201 1989
[178] L G Herbette P E Mason G Gaviraghi T N Tulenko andR P Mason ldquoThe molecular basis for lacidipinersquos unique phar-macokinetics optimal hydrophobicity results in membraneinteractions that may facilitate the treatment of atherosclerosisrdquoJournal of Cardiovascular Pharmacology vol 23 supplement 5pp S16ndashS25 1994
[179] G V Belevitch G Y Dubur G E Dobretsov N K Kurek andM M Spirin ldquoCalcium antagonists riodipine nifedipine andverapamil binding to model and biological membranes fluore-scence analysisrdquo Biologicheskie Membrany (Biochemistry(Moscow) Series A Membrane and Cell Biology) vol 5 pp768ndash776 1988 (Russian)
[180] R P Mason G E Gonye D W Chester and L G HerbetteldquoPartitioning and location of Bay K 8644 14-dihydropyridinecalcium channel agonist in model and biological membranesrdquoBiophysical Journal vol 55 no 4 pp 769ndash778 1989
[181] M Cindric A Cipak J Serly et al ldquoReversal of multidrugresistance inmurine lymphoma cells by amphiphilic dihydropy-ridine antioxidant derivativerdquo Anticancer Research vol 30 no10 pp 4063ndash4070 2010
[182] F Shekari H Sadeghpour K Javidnia et al ldquoCytotoxic andmultidrug resistance reversal activities of novel 14-dihydro-pyridines against human cancer cellsrdquo European Journal ofPharmacology vol 746 no 1 pp 233ndash244 2015
[183] X-F Zhou Q Shao R A Coburn and M E Morris ldquoQuanti-tative structure-activity relationship and quantitative structure-pharmacokinetics relationship of 14-dihydropyridines andpyridines as multidrug resistance modulatorsrdquo PharmaceuticalResearch vol 22 no 12 pp 1989ndash1996 2005
[184] R Berkels T Breitenbach H Bartels et al ldquoDifferent antioxida-tive potencies of dihydropyridine calcium channel modulatorsin various modelsrdquo Vascular Pharmacology vol 42 no 4 pp145ndash152 2005
[185] S Borovic G Tirzitis D Tirzite et al ldquoBioactive 14-dihydro-isonicotinic acid derivatives prevent oxidative damage of livercellsrdquo European Journal of Pharmacology vol 537 no 1ndash3 pp12ndash19 2006
[186] D Ya Rubene G D Tirzitis and G Ya Duburs ldquoInteractionof some 14-dihydropyridine derivatives with Fentonrsquos reagentrdquoLatvijas PSRZinatnuAkademijas Vestis Kimijas Serija Proceed-ings of the Latvian SSR Academy of Sciences Chemistry Seriespp 212ndash216 1982 (Russian)
[187] K Ondrias V Misık D Gergel and A Stasko ldquoLipid per-oxidation of phosphatidylcholine liposomes depressed by thecalcium channel blockers nifedipine and verapamil and bythe antiarrhythmic-antihypoxic drug stobadinerdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1003 no 3pp 238ndash245 1989
[188] I T Mak and W B Weglicki ldquoComparative antioxidant acti-vities of propranolol nifedipine verapamil and diltiazemagainst sarcolemmal membrane lipid peroxidationrdquoCirculationResearch vol 66 no 5 pp 1449ndash1452 1990
[189] I T Mak P Boehme and W B Weglicki ldquoProtective effects ofcalcium channel blockers against free radical-impaired endo-thelial cell proliferationrdquo Biochemical Pharmacology vol 50 no9 pp 1531ndash1534 1995
[190] S Ray S Mondal and N Dana ldquoEvaluation of protective roleof nifedipine on lipid peroxidation using reduced glutathione as
model markerrdquo Oxidants and Antioxidants in Medical Sciencevol 1 no 2 pp 97ndash100 2012
[191] M Yamato T Shiba T Ide Y Honda K-I Yamada andH Tsutsui ldquoNifedipine treatment reduces brain damage aftertransient focal ischemia possibly through its antioxidativeeffectsrdquoHypertension Research vol 34 no 7 pp 840ndash845 2011
[192] V Chander and K Chopra ldquoNifedipine attenuates changes innitric oxide levels renal oxidative stress and nephrotoxicityinduced by cyclosporinerdquo Renal Failure vol 27 no 4 pp 441ndash450 2005
[193] K M Gaafa M M Badawy and A A Hamza ldquoThe protectiveeffects of ascorbic acid cimetidine and nifedipine on diethyl-dithiocarbamate-induced hepatic toxicity in albino ratsrdquo Drugand Chemical Toxicology vol 34 no 4 pp 405ndash419 2011
[194] H Sugawara K Tobise and S Onodera ldquoAbsence of antiox-idant effects of nifedipine and diltiazem on myocardial mem-brane lipid peroxidation in contrast with those of nisoldipineand propranololrdquo Biochemical Pharmacology vol 47 no 5 pp887ndash892 1994
[195] I E Kirule D Y Rubene E A Bisenieks G D Tirzit and GY Dubur ldquo4-Nitrophenyl-14-dihydropyridinesmdasha new groupof inhibitors of peroxide oxidationrdquo Chemistry of HeterocyclicCompounds vol 18 no 3 p 316 1982
[196] G D Tirzit I E Kirule L K Baumane R A Gavar Y PStradynrsquo andG YDubur ldquoMechanism of the antioxidant actionof 26-dimethyl-35-dimethoxy-carbonyl-4-(2-nitrophenyl)14-dihydropyridinerdquoChemistry ofHeterocyclic Compounds vol 20no 8 pp 915ndash918 1984
[197] C Yanez C Lopez-Alarcon C Camargo V Valenzuela J ASquella and L J Nunez-Vergara ldquoStructural effects on thereactivity 14-dihydropyridines with alkylperoxyl radicals andABTS radical cationrdquo Bioorganic and Medicinal Chemistry vol12 no 9 pp 2459ndash2468 2004
[198] VMisik A J Stasko D Gergel and K Ondrias ldquoSpin-trappingand antioxidant properties of illuminated and nonilluminatednifedipine and nimodipine in heart homogenate and modelsystemrdquo Molecular Pharmacology vol 40 no 3 pp 435ndash4391991
[199] K Ondrias V Misık A Stasko D Gergelrsquo and M HromadovaldquoComparison of antioxidant properties of nifedipine and illu-minated nifedipine with nitroso spin traps in low densitylipoproteins and phosphatidylcholine liposomesrdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1211 no 1pp 114ndash119 1994
[200] A Stasko V Brezova S Biskupic K Ondrias and V MisıkldquoReactive radical intermediates formed from illuminated nife-dipinerdquoFree Radical Biology andMedicine vol 17 no 6 pp 545ndash556 1994
[201] K Ishizawa Y Izawa-Ishizawa N Yamano et al ldquoNitrosoni-fedipine ameliorates the progression of type 2 diabetic nephro-pathy by exerting antioxidative effectsrdquo PLoS ONE vol 9 no 1Article ID e86335 2014
[202] H Fujii and L J Berliner ldquoIn vivo EPR evidence for free radicaladducts of nifedipinerdquoMagnetic Resonance in Medicine vol 42no 4 pp 691ndash694 1999
[203] S Bollo S Finger J C Sturm L J Nunez-Vergara and JA Squella ldquoCyclic voltammetry and scanning electrochemicalmicroscopy studies of the heterogeneous electron transferreaction of some nitrosoaromatic compoundsrdquo ElectrochimicaActa vol 52 no 15 pp 4892ndash4898 2007
34 Oxidative Medicine and Cellular Longevity
[204] F Ursini ldquoTissue protection by lacidipine insight from redoxbehaviorrdquo Journal of Cardiovascular Pharmacology vol 30supplement 2 pp S28ndashS30 1997
[205] P G Cristofori F A Crivellente I Faustinelli et al ldquoInvolve-ment of the nitric oxide system in the anti-atheroscleroticpotential of lacidipine in the apoE-deficient mouse a mor-phological functional and electrochemical studyrdquo ToxicologicPathology vol 32 no 4 pp 493ndash499 2004
[206] X-P Zhang E L Kit S Mital S Chahwala and T HHintze ldquoParadoxical release of nitric oxide by an L-type calciumchannel antagonist the R+ enantiomer of amlodipinerdquo Journalof Cardiovascular Pharmacology vol 39 no 2 pp 208ndash2142002
[207] F Franzoni G Santoro F Regoli et al ldquoAn in vitro study of theperoxyl and hydroxyl radical scavenging capacity of the calciumantagonist amlodipinerdquo Biomedicine and Pharmacotherapy vol58 no 8 pp 423ndash426 2004
[208] S V Gatsura ldquoOxygen-dependent mechanisms underlying theantiischemic effect of verapamil and amlodipinerdquo Bulletin ofExperimental Biology and Medicine vol 137 no 1 pp 40ndash422004
[209] Y Hirooka Y Kimura M Nozoe Y Sagara K Ito and KSunagawa ldquoAmlodipine-induced reduction of oxidative stressin the brain is associated with sympatho-inhibitory effects instroke-prone spontaneously hypertensive ratsrdquo HypertensionResearch vol 29 no 1 pp 49ndash56 2006
[210] B Tomlinson and I F F Benzie ldquoAntioxidant effect of lercani-dipine (note)rdquo Hypertension vol 42 no 4 pp e10ndashe11 2003
[211] A A Faraqui ldquoNeurochemical aspects of 4-hydroxynonenalrdquoin Lipid Mediators and Their Metabolism in the Brain A AFaraqui Ed chapter 6 pp 159ndash191 Springer New York NYUSA 2011
[212] V S NascimentoM S DrsquoAlva A AOliveira et al ldquoAntioxidanteffect of nimodipine in young rats after pilocarpine-inducedseizuresrdquo Pharmacology Biochemistry and Behavior vol 82 no1 pp 11ndash16 2005
[213] O Ismailoglu P Atilla S Palaoglu et al ldquoThe therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjuryrdquo Turkish Neurosurgery vol 22 no 6 pp 740ndash746 2012
[214] M Matsubara and K Hasegawa ldquoBenidipine a dihydropy-ridine-calcium channel blocker prevents lysophosphatidyl-choline-induced injury and reactive oxygen species productionin human aortic endothelial cellsrdquo Atherosclerosis vol 178 no1 pp 57ndash66 2005
[215] M Matsubara K Yao and K Hasegawa ldquoBenidipine adihydropyridine-calcium channel blocker inhibits lysophos-phatidylcholine-induced endothelial injury via stimulation ofnitric oxide releaserdquo Pharmacological Research vol 53 no 1 pp35ndash43 2006
[216] MMatsubara and K Hasegawa ldquoEffects of benidipine a dihyd-ropyridine-Ca2+ channel blocker on expression of cytokine-induced adhesion molecules and chemoattractants in humanaortic endothelial cellsrdquo European Journal of Pharmacology vol498 no 1ndash3 pp 303ndash314 2004
[217] M Matsubara O Akizuki J-I Ikeda K Saeki K Yao and KSasaki ldquoBenidipine an anti-hypertensive drug inhibits reactiveoxygen species production in polymorphonuclear leukocytesand oxidative stress in salt-loaded stroke-prone spontaneouslyhypertensive ratsrdquo European Journal of Pharmacology vol 580no 1-2 pp 201ndash213 2008
[218] A C Rosenkranz H Lob T Breitenbach R Berkels and RRoesen ldquoEndothelial antioxidant actions of dihydropyridines
and angiotensin converting enzyme inhibitorsrdquo European Jour-nal of Pharmacology vol 529 no 1ndash3 pp 55ndash62 2006
[219] V Kain S Kumar and S L Sitasawad ldquoAzelnidipine preventscardiac dysfunction in streptozotocin-diabetic rats by reducingintracellular calcium accumulation oxidative stress and apop-tosisrdquo Cardiovascular Diabetology vol 10 article 97 2011
[220] K Nakamura S Yamagishi and H Inoue ldquoUnique atheropro-tective property of azelnidipine a dihydropyridine-based cal-cium antagonistrdquoMedical Hypotheses vol 65 no 1 pp 155ndash1572005
[221] TMatsui S Yamagishi K Nakamura S Kikuchi andH InoueldquoAzelnidipine a dihydropyridine-based calcium antagonistinhibits angiotensin II-induced oxidative stress generation anddownregulation of pigment epithelium-derived factor mRNAlevels in microvascular endothelial cellsrdquo Drugs under Experi-mental and Clinical Research vol 31 no 5-6 pp 215ndash219 2005
[222] C Ohmura H Watada T Shimizu et al ldquoCalcium channelblocker azelnidipine reduces lipid hydroperoxides in patientswith type 2 diabetes independent of blood pressurerdquo EndocrineJournal vol 54 no 5 pp 805ndash811 2007
[223] H Daikuhara F Kikuchi and T Ishida ldquoThe combination ofOLmesartan and a CAlcium channel blocker (azelnidipine) orcandesartan and a calcium channel blocker (amlodipine) intype 2 diabetic hypertensive patients theOLCA studyrdquoDiabetesand Vascular Disease Research vol 9 no 4 pp 280ndash286 2012
[224] MAbe NMaruyama KOkada SMatsumoto KMatsumotoand M Soma ldquoAdditive antioxidative effects of azelnidipine onangiotensin receptor blocker olmesartan treatment for type 2diabetic patients with albuminuriardquoHypertension Research vol34 no 8 pp 935ndash941 2011
[225] K Mizushige ldquoAntioxidative activities of thiazolidinedionesand dihydropyridine-type calcium antagonistsrdquo IRYOmdashJapa-nese Journal of National Medical Services vol 59 no 11 pp 581ndash592 2005
[226] S Manabe T Okura T Fukuoka and J Higaki ldquoAntioxidativeeffects of azelnidipine on mesangial cell proliferation inducedby highly concentrated insulinrdquo European Journal of Pharma-cology vol 567 no 3 pp 252ndash257 2007
[227] Y Koyama Y Takeishi H Takahashi et al ldquoAzelnidipine inhi-bits H
2O2-induced cell death in neonatal rat cardiomyocytesrdquo
CardiovascularDrugs andTherapy vol 21 no 1 pp 69ndash72 2007[228] K Shinomiya K Mizushige M Fukunaga et al ldquoAntioxidant
effect of a new calcium antagonist azelnipidine in culturedhuman arterial endothelial cellsrdquo Journal of International Med-ical Research vol 32 no 2 pp 170ndash175 2004
[229] T Ohyama K Sato K Kishimoto et al ldquoAzelnidipine is acalcium blocker that attenuates liver fibrosis and may increaseantioxidant defencerdquo British Journal of Pharmacology vol 165no 4 pp 1173ndash1187 2012
[230] L A Calo F Zaghetto E Pagnin P A Davis A Sempliciniand A C Pessina ldquoEffect of manidipine on gene expressionand protein level of oxidative stress-related proteins p22phoxand HO-1 Relevance for antihypertensive and anti-remodelingeffectsrdquo Journal of Cardiovascular Pharmacology vol 43 no 4pp 531ndash538 2004
[231] R Ghyasi G Sepehri M Mohammadi R Badalzadeh and AGhyasi ldquoEffect of mebudipine on oxidative stress and lipid per-oxidation in myocardial ischemic-reperfusion injury in maleratrdquo Journal of Research in Medical Sciences vol 17 no 12 pp1150ndash1155 2012
Oxidative Medicine and Cellular Longevity 35
[232] DCAndersson J Fauconnier T Yamada et al ldquoMitochondrialproduction of reactive oxygen species contributes to the 120573-adrenergic stimulation of mouse cardiomycytesrdquoThe Journal ofPhysiology vol 589 no 7 pp 1791ndash1801 2011
[233] A F Ceylan-Isik N Ari M Stefek et al ldquoEffects of a long-term treatment with an antioxidant pyridoindole on vascularresponsiveness in diabetes-induced aging ratsrdquo Current AgingScience vol 4 no 2 pp 150ndash157 2011
[234] S Saponara G Sgaragli and F Fusi ldquoQuercetin antagonismof Bay K 8644 effects on rat tail artery L-type Ca2+ channelsrdquoEuropean Journal of Pharmacology vol 598 no 1ndash3 pp 75ndash802008
[235] D A Sica ldquoInteraction of grapefruit juice and calcium channelblockersrdquo American Journal of Hypertension vol 19 no 7 pp768ndash773 2006
[236] P Mulder G Litwinienko S Lin P D MacLean L R CBarclay and K U Ingold ldquoThe L-type calcium channel block-ers Hantzsch 14-dihydropyridines are not peroxyl radical-trapping chain-breaking antioxidantsrdquo Chemical Research inToxicology vol 19 no 1 pp 79ndash85 2006
[237] L J Nunez-Vergara R Salazar C Camargo et al ldquoOxidation ofC4-hydroxyphenyl 14-dihydropyridines in dimethylsulfoxideand its reactivity towards alkylperoxyl radicals in aqueousmediumrdquo Bioorganic and Medicinal Chemistry vol 15 no 12pp 4318ndash4326 2007
[238] M E Ortiz L J Nunez-Vergara and J A Squella ldquoRelativereactivity of dihydropyridine derivatives to electrogeneratedsuperoxide ion in DMSO solutions a voltammetric approachrdquoPharmaceutical Research vol 20 no 2 pp 292ndash296 2003
[239] M E Ortiz L J Nunez-Vergara C Camargo and J A SquellaldquoOxidation of Hantzsch 14-dihydropyridines of pharmacolog-ical significance by electrogenerated superoxiderdquo Pharmaceuti-cal Research vol 21 no 3 pp 428ndash435 2004
[240] R S Raghuvanshi and K N Singh ldquoSuperoxide induced oxida-tive aromatization of Hantzsch 14-dihydropyridinesrdquo IndianJournal of Chemistry Section B Organic and Medicinal Chem-istry vol 47 no 11 pp 1735ndash1738 2008
[241] I Kruk A Kladna K Lichszteld et al ldquoAntioxidant activityof 4-flavonil-14-dihydropyridine derivativesrdquo Biopolymers vol62 no 3 pp 163ndash167 2001
[242] G D Tirzit I M Byteva K I Salokhiddinov G P Gurinovichand G Y Dubur ldquo14-Dihydropyridine derivatives as deactiva-tors of singlet oxygenrdquo Chemistry of Heterocyclic Compoundsvol 17 no 7 pp 682ndash684 1981
[243] G D Tirzit E Y Kazush and G Y Dubur ldquoInfluence of14-dihydropyridine derivatives on the generation of hydroxylradicalsrdquo Chemistry of Heterocyclic Compounds vol 28 no 4pp 435ndash437 1992
[244] N A Pizarro-Urzua and L J Nunez-Vergara ldquoNifedipine andnitrendipine reactivity toward singlet oxygenrdquo Journal of Photo-chemistry and Photobiology A Chemistry vol 175 no 2-3 pp129ndash137 2005
[245] L-F Wang H-Y Zhang L Konga Z-W Chena and J-G ShildquoDFT calculations indicate that 14-dihydropyridine is a promis-ing lead antioxidantrdquo Helvetica Chimica Acta vol 87 no 6 pp1515ndash1521 2004
[246] P Mulder H-G Korth and K U Ingold ldquoWhy quantum-thermochemical calculations must be used with caution toindicate lsquoa promising lead antioxidantrsquordquoHelvetica Chimica Actavol 88 no 2 pp 370ndash374 2005
[247] K Yao Y Ina K Nagashima K Ohmori and T Ohno ldquoAntiox-idant effects of calcium antagonists in rat brain homogenatesrdquo
Biological and Pharmaceutical Bulletin vol 23 no 6 pp 766ndash769 2000
[248] T Matsui S-I Yamagishi K Nakamura and H Inoue ldquoBayw 9798 a dihydropyridine structurally related to nifedipinewith no calcium channel-blocking properties inhibits tumournecrosis factor-120572-induced vascular cell adhesion molecule-1expression in endothelial cells by suppressing reactive oxygenspecies generationrdquo Journal of International Medical Researchvol 35 no 6 pp 886ndash891 2007
[249] K AMitrega B VargheseM Porc and T F Krzeminski ldquoAnti-arrhythmic and hemodynamic effects of oxy nifedipine oxynimodipine oxy nitrendipine and oxy nisoldipinerdquo Pharmaco-logical Research vol 66 no 4 pp 300ndash308 2012
[250] V Herbert ldquoSymposium prooxidant effects of antioxidantvitamins Introductionrdquo The Journal of Nutrition vol 126 no4 supplement pp 1197Sndash1200S 1996 httpjnnutritionorgcontent1264 Suppl1197Sfullpdf
[251] B Halliwell ldquoAre polyphenols antioxidants or pro-oxidantsWhat do we learn from cell culture and in vivo studiesrdquoArchives of Biochemistry and Biophysics vol 476 no 2 pp 107ndash112 2008
[252] C Winterbourn Pro-Oxidants or Antioxidants ChristchurchSchool of Medicine Depatment of Pathology Free RadicalSchool SFRBMUniversity of Otago San Francisco Calif USA2009 httpwwwsfrbmorgfrsWinterbournpdf
[253] A Morakinyo B Iranloye and O Adegoke ldquoCalcium antag-onists modulate oxidative stress and acrosomal reaction in ratspermatozoardquo Archives of Medical Science vol 7 no 4 pp 613ndash618 2011
[254] The Alpha-Tocopherol Beta Carotene Cancer Prevention StudyGroup ldquoThe effect of vitamin E and beta carotene on theincidence of lung cancer and other cancers in male smokersrdquoTheNew England Journal of Medicine vol 330 no 15 pp 1029ndash1035 1994
[255] B Poljsak ldquoStrategies for reducing or preventing the generationof oxidative stressrdquo Oxidative Medicine and Cellular Longevityvol 2011 Article ID 194586 15 pages 2011
[256] B Poljsak and I Milisav ldquoThe neglected significance of lsquoanti-oxidative stressrsquordquoOxidativeMedicine and Cellular Longevity vol2012 Article ID 480895 12 pages 2012
[257] T Godfraind and S Salomone ldquoAmbiguities in dietary antiox-idant supplementation compared to calcium channel blockerstherapyrdquo Frontiers in Pharmacology vol 6 article 10 2015
[258] H Wagner H Norr and H Winterhoff ldquoDrugs with adap-togenic effects for strengthening the powers of resistancerdquoZeitschrift fur Phytotherapie vol 13 no 2 pp 42ndash54 1992
26 Oxidative Medicine and Cellular Longevity
oxygen and nitrogen free radical chain reactions radiopro-tecting or radiosensitizing antagonizing or synergizing Ca2+in electromechanical coupling as well as in the membranestabilization or labilization
39 Could DHPs Be Involved in Antioxidative Stress Beforebeing applied in vivo the optimal dose and optimal timeintervals forDHPs applicationmust be knownNamely whileROS have been traditionally considered as toxic byproductsof aerobic metabolism we know nowadays that ROS may actas essential signaling molecules needed for the control ofmany different physiological processes Whether the role ofROS will be damaging protective or signaling depends onthe delicate equilibrium between time- and location-specificROS production and scavenging Accordingly the imbalanceof the increased AO potential so-called antioxidative stresscould be dangerous similar to chronic OS in particular incase of extended exposure Inappropriate interventions inthe oxidative homeostasis by excessive antioxidants especiallyin case of chronic exposure to antioxidants might havevery negative effects as was published in the ATBC studyshowing an increased cancer incidence in smokers treatedby excessive beta-carotene [254] Therefore overconsump-tion of any natural or synthetic AO including DHPs asdietary supplements or drugs must be avoided in order tosuppress oxidative damage and must not disrupt the well-integrated antioxidant defense network (Poljsak [255] andPoljsak and Milisav [256]) This is especially important whenadministrating lipid-soluble antioxidants that can be storedin biomembranes thus not only attenuating or preventing LPbut also affecting physiological effects of the natural antiox-idants in particular tocopherol The interrelationship withthe status of endogenous antioxidantsprooxidants should befollowed
DHPs primarily suppress the initiation stages of LPprocessThey do not entirely stop the LP propagation Actingsynergistically with tocopherol diludine may prevent patho-logical excess of ROS production within the lipid moiety ofthe cellular membranes and LDL However due to its lowsolubility and fast metabolism its concentration in the cellsis low For that reason it cannot cause antioxidative stresseven if used for an extended period of time Thus diludine(diethone) could be only a mild antioxidant it has potentialfor restoring the pool of natural antioxidants (as synergist of120572-tocopherol and polyphenols) in the cells
Moreover DHPs CA used for cardioprotection andvasodilatation as commercial drugs in low concentrationsare fast metabolized via CYP3A4 and for that reason theirapplication does not induce cellular AO stress [53 160]However Godfraind and Salomone [257] have postulated noevidence that allows recommending dietary supplementationwith antioxidants for the primary or secondary prevention ofcardiovascular disease
So far there are no reports on antioxidative stress causedby some DHPs diludine and its analogues Diludine andits analogues therefore could act as adaptogens supportinghormetic effects of mild oxidative stress These compoundsmay act as potential multisided modulators of Yin-Yang
cycles of redox and cell functions (the electroplasmic cycle)(Wagner et al [258])
4 Conclusions
14-Dihydropyridines (14-DHPs) have broad spectrum ofOS modulating activities DHPs have reducing and lipidperoxidation inhibitor properties act as reductants in simplechemical systems and stabilize various biological systems(LDL mitochondria microsomes cells and tissues) againstOS Examples and peculiarities and mechanisms of antiox-idant activity (AOA) and antiradical activity (ARA) as wellas stress-protective effect of DHPs including commercialcalcium antagonists (CA) were highlighted These activitiesdepend on various structural parameters related to DHPs(presence and character of substituents) lipophilicity anddepth of the incorporation in the biologicalmembranesTheyalso depend on the experimental model system for exploringthe lipid peroxidation or oxidative stress Stress-protectiveeffect of some metabolites of CA (nifedipine) is reviewedAlthough some DHPs including CA have prooxidant prop-erties (on epididymal sperm cells) they can generally beconsidered as potent antioxidants Therefore comparisonof the AOA and ARA of different DHPs (mutually andwith other AOs) was described in detail According to thedata presented the DHPs might be considered as bellwetheramong synthetic compounds targeting OS and as a kind ofpharmacological measure for respective field of organic andmedicinal chemistry
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
Authors from Latvian IOS acknowledge ESF 201300021DP1112013APIAVIAA011 and National Research Pro-gramme PUBLIC HEALTHBiomedicine of the Republicof Latvia for financial support administration of the Insti-tute for technical support and Rufus Smits PhD for con-sultations in English The support of Cooperation in Euro-pean System of Science and Technology (COST) Domain ofChemistry Molecular Sciences and Technologies (CMST)was of highest importance for preparation of this paper
[2] D J Triggle ldquo14-Dihydropyridines as calcium channel ligandsand privileged structuresrdquoCellular andMolecular Neurobiologyvol 23 no 3 pp 293ndash303 2003
[3] T Godfraind ldquoAntioxidant effects and the therapeutic modeof action of calcium channel blockers in hypertension andatherosclerosisrdquo Philosophical Transactions of the Royal SocietyB Biological Sciences vol 360 no 1464 pp 2259ndash2272 2005
[4] E Cadenas ldquoMitochondrial free radical production and cellsignalingrdquoMolecular Aspects of Medicine vol 25 no 1-2 pp 17ndash26 2004
[5] E Cadenas ldquoFree radicals oxidative stress and diseasesrdquo inLecture PSC 616 p 38 Missouri University of Science andTechnology Rolla Mo USA httpwwwcarnicominstituteorgarticlesenrique cadenaspdf
[6] K Rahman ldquoStudies on free radicals antioxidants and co-fac-torsrdquo Clinical Interventions in Aging vol 2 no 2 pp 219ndash2362007
[7] V Bocci and G Valacchi ldquoFree radicals and antioxidants howto reestablish redox homeostasis in chronic diseasesrdquo CurrentMedicinal Chemistry vol 20 no 27 pp 3397ndash3415 2013
[8] M Valko C J Rhodes J Moncol M Izakovic and M MazurldquoFree radicals metals and antioxidants in oxidative stress-induced cancerrdquo Chemico-Biological Interactions vol 160 no 1pp 1ndash40 2006
[9] G Bartosz ldquoReactive oxygen species destroyers or messen-gersrdquo Biochemical Pharmacology vol 77 no 8 pp 1303ndash13152009
[10] R Visconti and D Grieco ldquoNew insights on oxidative stress incancerrdquo Current Opinion in Drug Discovery and Developmentvol 12 no 2 pp 240ndash245 2009
[11] R N Kujundzic N Zarkovic and K G Troselj ldquoPyridinenucleotides in regulation of cell death and survival by redoxand non-redox reactionsrdquo Critical Reviews in Eukaryotic GeneExpression vol 24 no 4 pp 287ndash309 2014
[12] B Halliwell and J M C Gutteridge ldquoThe definition and mea-surement of antioxidants in biological systemsrdquo Free RadicalBiology and Medicine vol 18 no 1 pp 125ndash126 1995
[13] V D Kancheva and O T Kasaikina ldquoBio-antioxidantsmdashachemical base of their antioxidant activity and beneficial effect
on human healthrdquo Current Medicinal Chemistry vol 20 no 37pp 4784ndash4805 2013
[14] H V Panglossi Ed Frontiers in Antioxidants Research NovaScience Publishers New York NY USA 2006
[15] E B Burlakova E M Molochkina and G A NikiforovldquoHybrid antioxidantsrdquo Oxidation Communications vol 31 no4 pp 739ndash757 2008 httpmembraneustceducnpaperpdfHybrid20Antioxidantspdf
[16] A Bast and G R M M Haenen ldquoTen misconceptions aboutantioxidantsrdquo Trends in Pharmacological Sciences vol 34 no 8pp 430ndash436 2013
[17] E B Burlakova A V 0lesenko E M Molochkina N PPalmina and N G Khrapova Bioantioxidants for RadiationDamage and Malignant Growth Nauka Moscow Russia 1975(Russian)
[18] J Fang T Seki and H Maeda ldquoTherapeutic strategies by mod-ulating oxygen stress in cancer and inflammationrdquo AdvancedDrug Delivery Reviews vol 61 no 4 pp 290ndash302 2009
[19] M Valko D Leibfritz J Moncol M T D Cronin M Mazurand J Telser ldquoFree radicals and antioxidants in normal physi-ological functions and human diseaserdquo International Journal ofBiochemistry and Cell Biology vol 39 no 1 pp 44ndash84 2007
[20] M Jimenez-Del-Rio and C Velez-Pardo ldquoThe bad the goodand the ugly about oxidative stressrdquo Oxidative Medicine andCellular Longevity vol 2012 Article ID 163913 13 pages 2012
[21] C D Kamat S Gadal M Mhatre K S Williamson Q N Pyeand K Hensley ldquoAntioxidants in central nervous system dis-eases preclinical promise and translational challengesrdquo Journalof Alzheimerrsquos Disease vol 15 no 3 pp 473ndash493 2008
[22] A Pompella H Sies R Wacker et al ldquoThe use of totalantioxidant capacity as surrogate marker for food quality andits effect on health is to be discouragedrdquo Nutrition vol 30 no7-8 pp 791ndash793 2014
[23] Z Ye and H Song ldquoAntioxidant vitamins intake and the risk ofcoronary heart disease meta-analysis of cohort studiesrdquo Euro-pean Journal of Cardiovascular Prevention and Rehabilitationvol 15 no 1 pp 26ndash34 2008
[24] P Knekt J Ritz M A Pereira et al ldquoAntioxidant vitamins andcoronary heart disease risk a pooled analysis of 9 cohortsrdquoTheAmerican Journal of Clinical Nutrition vol 80 no 6 pp 1508ndash1520 2004
[25] A C Carr and M C M Vissers ldquoSynthetic or food-derivedvitamin Cmdashare they equally bioavailablerdquo Nutrients vol 5 no11 pp 4284ndash4304 2013
[26] R Tabrizchi ldquoEdaravoneMitsubishi-TokyordquoCurrentOpinion inInvestigational Drugs vol 1 no 3 pp 347ndash354 2000
[27] K Kikuchi S Tancharoen N Takeshige et al ldquoThe efficacy ofedaravone (radicut) a free radical scavenger for cardiovasculardiseaserdquo International Journal of Molecular Sciences vol 14 no7 pp 13909ndash13930 2013
[28] D Mauzerall and F H Westheimer ldquo1-Benzyldihydronicoti-namidemdasha model for reduced DPNrdquo Journal of the AmericanChemical Society vol 77 no 8 pp 2261ndash2264 1955 ChemicalAbstracts vol 50 Article ID 2588i 1956
[29] F Bossert and W Vater ldquo14-Dihydropyridinesmdasha basis fordeveloping new drugsrdquo Medicinal Research Reviews vol 9 no3 pp 291ndash324 1989
[30] G Swarnalatha G Prasanthi N Sirisha and CMadhusudhanaChetty ldquo14-Dihydropyridines a multtifunctional moleculemdash areviewrdquo International Journal of ChemTech Research vol 3 no1 pp 75ndash89 2011
28 Oxidative Medicine and Cellular Longevity
[31] M Cataldi and F Bruno ldquo14-Dihydropyridines the multiplepersonalities of a blockbuster drug familyrdquo Translational Medi-cine UniSa vol 4 no 2 pp 12ndash26 2012 httpwwwncbinlmnihgovpmcarticlesPMC3728803
[32] R Vitolina A Krauze G Duburs and A Velena ldquoAspects ofthe amlodipine pleiotropy in biochemistry pharmacology andclinicsrdquo International Journal of Pharmaceutical Sciences andResearch vol 3 no 5 pp 1215ndash1232 2012
[33] D Grover S N Mokale and M T Shete ldquoDihydropyridinea novel pharmacophorerdquo International Journal of Pharmaceu-tical Erudition vol 1 no 2 pp 16ndash29 2011 httppharmaeru-ditionorgContentPaper20111-RV-320Final2016-29pdf
[34] A M Vijesh A M Isloor S K Peethambar K N ShivanandaT Arulmoli and N A Isloor ldquoHantzsch reaction synthesis andcharacterization of somenew 14-dihydropyridine derivatives aspotent antimicrobial and antioxidant agentsrdquo European Journalof Medicinal Chemistry vol 46 no 11 pp 5591ndash5597 2011
[35] P Mehta and P Verma ldquoAntimicrobial activity of some deriva-tives of 14-dihydropyridinesrdquo Journal of Chemistry vol 2013Article ID 865128 4 pages 2013
[36] P Olejnıkova L Svorc D Olsovska et al ldquoAntimicrobialactivity of novel C2-substituted 14-dihydropyridine analoguesrdquoScientia Pharmaceutica vol 82 no 2 pp 221ndash232 2014
[37] S Sepehri H Perez Sanchez and A Fassihi ldquoHantzsch-typedihydropyridines and biginelli-type tetra-hydropyrimidinesa review of their chemotherapeutic activitiesrdquo Journal of Phar-macy amp Pharmaceutical Sciences vol 18 no 1 pp 1ndash52 2015httpsejournalslibraryualbertacaindexphpJPPSarticleview2383617863
[38] S A Khedkar and P B Auti ldquo14-Dihydropyridines a classof pharmacologically important moleculesrdquo Mini-Reviews inMedicinal Chemistry vol 14 no 3 pp 282ndash290 2014
[39] G D Tirzit and G Ya Duburs ldquo14-dihydropyridines as inhi-bitors of free-radical reactionsrdquo Chemistry of Heterocyclic Com-pounds vol 8 no 1 pp 126ndash127 1972 Translated from KhimiyaGeterotsiklicheskikh Soedinenii no1 pp 133ndash134 1972 (Rus-sian)
[40] I Bogeski R Kappl C Kummerow R Gulaboski M Hothand B A Niemeyer ldquoRedox regulation of calcium ion channelschemical and physiological aspectsrdquoCell Calcium vol 50 no 5pp 407ndash423 2011
[41] S A Giller G Y Dubur Y R Uldrikis et al ldquoDiludine [Themethod to obtain 35-dicarbonylderivatives of 26-dimethyl-14-dihydropyridines]rdquo Authors certificate of USSR no 3004651971 [Byull Izobret no13 p 95 1971] and following patentsPatent of England no 1294650 1973 Patent of France no2055458 1971 Patent of Japan no 702883 1973 Patent ofHolland no 149787 1976 Patent of Italy no 969022 1974 Patentof FRG no 2036403 1978 US Patent no 3883673 1975 USPatent no 3948924 1976
[42] S A Giller G Y Dubur Y R Uldrikis et al ldquoImprovementsin or relating to the stabilization of carotenerdquo GB Patent no1294650 1972
[43] S A Giller G Y Dubur Y R Uldrikis et al ldquoStabilization ofcarotenerdquo US Patent no 3883673 1975 Chemical Abstracts vol83 Article ID 95193 1975
[44] Yu A Zilber G Ya Dubur K K Kumsar and A Kh VelenaldquoThe effect of antioxidants on the peroxidation of bimole-cular phospholipid membranesrdquo Latvijas PSR ZA Vestis Izves-tia Akademii Nauk Latviyskoy SSR vol 6 pp 80ndash82 1971(Russian) translated from the original Russian Doc Accesion
No AD0771751 distributed by NTIS US Department of Com-merce httpwwwdticmildtictrfulltextu2771751pdf
[45] G Ya Dubur Yu A Zilbers A Kh Velena A O Kumerovaand G D Tirzitis ldquoMultistage study of regulation of peroxida-tion processes in biological membranes by antioxidants of 14-dihydropyridine grouprdquo Izvestiya Akademii Nauk LatviyskoySSR vol 336 no 7 pp 65ndash68 1975 (Russian)
[46] R P Mason and M W Trumbore ldquoDifferential membraneinteractions of calcium channel blockers Implications forantioxidant activityrdquo Biochemical Pharmacology vol 51 no 5pp 653ndash660 1996
[47] R P Mason M F Walter M W Trumbore E G Olmstead Jrand P E Mason ldquoMembrane antioxidant effects of the chargeddihydropyridine calcium antagonist amlodipinerdquo Journal ofMolecular and Cellular Cardiology vol 31 no 1 pp 275ndash2811999
[48] R PMason I T MakMW Trumbore and P EMason ldquoAnti-oxidant properties of calcium antagonists related to membranebiophysical interactionsrdquo American Journal of Cardiology vol84 no 4 pp 16ndash22 1999
[49] R PMasonMW Trumbore and P EMason ldquoMembrane bio-physical interaction of amlodipine and antioxidant propertiesrdquoDrugs vol 59 no 2 pp 9ndash16 2000 (French)
[50] R P Mason P Marche and T H Hintze ldquoNovel vascularbiology of third-generation L-type calcium channel antagonistsAncillary actions of amlodipinerdquo Arteriosclerosis Thrombosisand Vascular Biology vol 23 no 12 pp 2155ndash2163 2003
[51] A Augustyniak G Bartosz A Cipak et al ldquoNatural andsynthetic antioxidants an updated overviewrdquo Free RadicalResearch vol 44 no 10 pp 1216ndash1262 2010
[52] T Grune N Zarkovic and K Kostelidou ldquoLipid peroxidationresearch in Europe and the COST B35 action lsquoLipid Peroxida-tion Associated Disordersrsquordquo Free Radical Research vol 44 no10 pp 1095ndash1097 2010
[53] E Carosati P Ioan M Micucci et al ldquo14-Dihydropyridinescaffold in medicinal chemistry the story so far and perspec-tives (part 2) action in other targets and antitargetsrdquo CurrentMedicinal Chemistry vol 19 no 25 pp 4306ndash4323 2012
[54] U Eisner and J Kuthan ldquoThe chemistry of dihydropyridinesrdquoChemical Reviews vol 72 no 1 pp 1ndash42 1972 httpwwwsci-encemadnessorgtalkfilesphppid=138742ampaid=6475
[55] J Kuthan and A Kurfurst ldquoDevelopment in dihydropyri-dine chemistryrdquo Industrial amp Engineering Chemistry ProductResearch and Development vol 21 no 2 pp 191ndash261 1982
[56] A Sausins and G Duburs ldquoSynthesis of 14-dihydropyridinesby cyclocondensation reactionsrdquo Heterocycles vol 27 no 1 pp269ndash289 1988
[57] A E Sausins and G Y Duburs ldquoSynthesis of 14-dihydro-pyridines in cyclocondensation reactions (review)rdquo Chemistryof Heterocyclic Compounds vol 28 no 4 pp 363ndash391 1992Translated from Khimiya Geterotsiklicheskikh Soedinenii no 4pp 435ndash467 1992 (Russian)
[58] S Kazda ldquoTwenty years of dihydropyridinesrdquo in Dihydropy-ridines Progress in Pharmacology and Therapy W-D Busse BGarthoff and F Seuter Eds pp 1ndash12 Springer Verlag BerlinGermany 1993
[59] J-P Wan and Y Liu ldquoRecent advances in new multicomponentsynthesis of structurally diversified 14-dihydropyridinesrdquo RSCAdvances vol 2 no 26 pp 9763ndash9777 2012
[61] Reaxys Database[62] J Tuttle ldquoStructure mechanism and reactivity of hantzsch
estersrdquo in MacMillan Lab Group Meeting (082504) p 332004 httpwwwprincetoneduchemistrymacmillangroup-meetingsJBT20Hantzschpdf
[63] A Saini S Kumar and J S Sandhu ldquoHantzsch reaction recentadvances in Hantzsch 14-dihydropyridinesrdquo Journal of Sci-entific amp Industrial Research vol 67 pp 95ndash111 2008
[64] L LW Cheung S A Styler and A P Dicks ldquoRapid and conve-nient synthesis of the 14-dihydropyridine privileged structurerdquoJournal of Chemical Education vol 87 no 6 pp 628ndash630 2010
[65] A Kumar R A Maurya S Sharma M Kumar and G BhatialdquoSynthesis and biological evaluation of N-aryl-14-dihydro-pyridines as novel antidyslipidemic and antioxidant agentsrdquoEuropean Journal of Medicinal Chemistry vol 45 no 2 pp 501ndash509 2010
[66] R S Kumar A Idhayadhulla A J Abdul Nasser and J SelvinldquoSynthesis and anticoagulant activity of a new series of 14-dihydropyridine derivativesrdquo European Journal of MedicinalChemistry vol 46 no 2 pp 804ndash810 2011
[67] H A Stefani C B Oliveira R B Almeida et al ldquoDihydro-pyrimidin-(2H)-ones obtained by ultrasound irradiation anew class of potential antioxidant agentsrdquo European Journal ofMedicinal Chemistry vol 41 no 4 pp 513ndash518 2006
[68] H Sun C Shang L Jin and J Zhang ldquoSynthesis and antiox-idant activity of a series of novel 3-chalcone-substituted 14-dihydropyridine derivativesrdquoHeterocyclic Communications vol18 no 5-6 pp 239ndash243 2012
[69] D B Tikhonov and B S Zhorov ldquoStructural model for dihy-dropyridine binding to L-type calcium channelsrdquo The Journalof Biological Chemistry vol 284 no 28 pp 19006ndash19017 2009
[70] G Y Dubur and Y R Uldrikis ldquoThe oxidation of 14-dihydro-pyridinesrdquo Chemistry of Heterocyclic Compounds vol 6 no 1pp 80ndash84 1970 Translated from Khimiya GeterotsiklicheskikhSoedinenii no 1 pp 83ndash88 1970 (Russian)
[71] G Ya Duburs A O Kumerova and Ya R Uldrikis ldquoEnzymicoxidation of hydrogenated pyridines with peroxidase-hydrogenperoxide systemrdquoLatvijas PSRZAVestis vol 73 no 7 pp 73ndash771970 (Russian) Chemical Abstracts vol 73 Article ID 94913g1970
[72] K Xie Y-C Liu Y Cui J-GWang Y Fu andT CWMak ldquoN-methyl-(R)-3-(tert-butyl)-sulfinyl-14-dihydropyridine a novelNADHmodel compoundrdquoMolecules vol 12 no 3 pp 415ndash4222007
[73] S Tamagaki T Mimura and W Tagaki ldquoMetal-ion-facilitatedoxidations of dihydropyridines with molecular oxygen andhydrogen peroxiderdquo Journal of the Chemical Society PerkinTransactions 2 no 10 pp 1645ndash1650 1990
[74] D Tirzite G Tirzitis andD Antipova ldquoReductive ability of 14-dihydropyridine derivatives in relation to ions of trivalent ironrdquoChemistry of Heterocyclic Compounds vol 35 no 5 pp 592ndash594 1999
[76] J Ogle J Stradins and L Baumane ldquoFormation and decay offree cation-radicals in the course of electro-oxidation of 12- and14-dihydropyridines (Hantzsch esters)rdquo Electrochimica Actavol 39 no 1 pp 73ndash79 1994
[77] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for the
synthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts C Wittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Berlin Germany 2010
[78] WDu and Zh Yu ldquoBiomimetic in situ regeneration of cofactorsNAD(P)+ and NAD(P)H models hantzsch esters and dihy-drophenanthridinerdquo Synlett vol 23 no 9 pp 1300ndash1304 2012
[79] H K Chenault and G M Whitesides ldquoRegeneration ofnicotinamide cofactors for use in organic synthesisrdquo AppliedBiochemistry and Biotechnology vol 14 no 2 pp 147ndash197 1987
[80] Y R Uldrikis A A Zidermane E A Biseniex I E Preisa GY Dubur and G D Tirzit ldquoEsters of 26-dimethyl-14-dihydro-pyridine-35-dicarboxylic acid and method of obtainingthereofrdquo WO 8000345 A1 1978 httpworldwideespacenetcompublicationDetailsbiblioDB=EPODOCampII=1ampND=3ampadjacent=trueamplocale=en EPampFT=Dampdate=19800306ampCC=WOampNR=8000345A1ampKC=A1
[81] Y Sambongi H Nitta K Ichihashi M Futai and I Ueda ldquoAnovel water-soluble Hantzsch 14-dihydropyridine compoundthat functions in biological processes through NADH regener-ationrdquo Journal of Organic Chemistry vol 67 no 10 pp 3499ndash3501 2002
[82] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for thesynthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts ChWittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Verlag Berlin Germany 2010
[83] T Okamura T Kikuchi A Nagamine et al ldquoAn approach formeasuring in vivo cerebral redox states using the oxidative con-version of dihydropyridine to pyridinium ion and themetabolictrapping principlerdquo Free Radical Biology and Medicine vol 38no 9 pp 1197ndash1205 2005
[84] K A Schellenberg and F H Westheimer ldquoA free-radicaloxidation of a dihydropyridine1ardquo The Journal of OrganicChemistry vol 30 no 6 pp 1859ndash1862 1965
[85] K A Schellenberg ldquoReaction of hydroxyl radical with thymi-dine Scavenging by a dihydropyridinerdquo Federation Proceedingsvol 38 no 3 I p 1433 1979
[86] E S Huyser J A K Harmony and F L McMillian ldquoPeroxideoxidations of dihydropyridine derivativesrdquo Journal of the Amer-ican Chemical Society vol 94 no 9 pp 3176ndash3180 1972
[87] A Sakamoto S T Ohnishi and R Ogawa ldquoInhibition of lipidperoxidation by some dihydropyridine derivativesrdquo Journal ofAnesthesia vol 7 no 2 pp 193ndash197 1993
[88] R Hardeland ldquoReview Neuroprotection by radical avoidancesearch for suitable agentsrdquo Molecules vol 14 no 12 pp 5054ndash5102 2009
[89] G Ya Dubur A Kh Velena V M Gukasov and Yu AVladimirov ldquoRegulation of peroxidation of mitochondrialmembrane lipids initiated by Fe2+ ions by antoxidants of the14-dihydropyridine series in experiments in vitrordquo Biomed-itsinskaya Khimiya vol 22 no 5 pp 665ndash673 1976 (Russian)Chemical Abstracts vol 88 Article ID 2640 1977
[90] G RMMHaenenM J T J Arts A Bast andMD ColemanldquoStructure and activity in assessing antioxidant activity in vitroand in vivo a critical appraisal illustrated with the flavonoidsrdquoEnvironmental Toxicology and Pharmacology vol 21 no 2 pp191ndash198 2006
[91] G Tirzitis and G Bartosz ldquoDetermination of antiradical andantioxidant activity basic principles and new insightsrdquo ActaBiochimica Polonica vol 57 no 2 pp 139ndash142 2010
30 Oxidative Medicine and Cellular Longevity
[92] G R Buettner and R P Mason ldquoSpin-trapping methods fordetecting superoxide and hydroxyl free radicals in vitro and invivordquo inCritical Reviews of Oxidative Stress and Aging Advancesin Basic Science Diagnostics and Intervention R G Cutler andH Rodriguez Eds vol 1 chapter 2 pp 27ndash38World ScientificLondon UK 2003
[93] M M Tarpey and I Fridovich ldquoMethods of detection ofvascular reactive species Nitric oxide superoxide hydrogenperoxide and peroxynitriterdquo Circulation Research vol 89 no3 pp 224ndash236 2001
[94] E Y Kazush E I Sagun G D Tirzit and G Y DaburldquoQuenching of singlet oxygen by electron donating derivativesof 14-dihydropyridinerdquo Chemistry of Heterocyclic Compoundsvol 30 no 5 pp 562ndash563 1994
[95] G Tirzitis E Kazush and G Duburs ldquoReaction of 14-dihydropyridine derivatives with peroxynitrite anionrdquo Chem-istry of Heterocyclic Compounds vol 34 no 3 pp 321ndash3231998 (Russian) Translated from Khimiya GeterotsiklicheskikhSoedinenii no 3 pp 355ndash357 1998
[96] L J Nunez-Vergara C Lopez-Alarcon P A Navarrete-EncinaA M Atria C Camargo and J A Squella ldquoElectrochemicaland EPR characterization of 14-dihydropyridines Reactivitytowards alkyl radicalsrdquo Free Radical Research vol 37 no 1 pp109ndash120 2003
[97] D Tirzite A Krauze A Zubareva G Tirzitis and G DubursldquoSynthesis and antiradical activity of 5-acetyl-2-alkylthio-4-aryl-6-methyl-14-dihydropyridine-3-carboxylic acid nitrilesrdquoChemistry of Heterocyclic Compounds vol 38 no 7 pp 795ndash800 2002
[98] H Ohkawa N Ohishi and K Yagi ldquoAssay for lipid peroxidesin animal tissues by thiobarbituric acid reactionrdquo AnalyticalBiochemistry vol 95 no 2 pp 351ndash358 1979
[99] N Zarkovic ldquo4-Hydroxynonenal as a bioactive marker ofpathophysiological processesrdquo Molecular Aspects of Medicinevol 24 no 4-5 pp 281ndash291 2003
[100] M Parola G Bellomo G Robino G Barrera and M UDianzani ldquo4-Hydroxynonenal as a biological signal molecularbasis and pathophysiological implicationsrdquo Antioxidants andRedox Signaling vol 1 no 3 pp 255ndash284 1999
[101] T Lovakovic M Poljak-Blazi G Duburs et al ldquoGrowthmodulation of human cells in vitro by mild oxidative stressand 14-dihydropyridine derivative antioxidantsrdquo CollegiumAntropologicum vol 35 no 1 pp 137ndash141 2011
[102] R van den Berg G R M M Haenen H van den Bergand A Bast ldquoApplicability of an improved Trolox equivalentantioxidant capacity (TEAC) assay for evaluation of antioxidantcapacity measurements of mixturesrdquo Food Chemistry vol 66no 4 pp 511ndash517 1999
[103] C Lopez-Alarcon P Navarrete C Camargo J A Squella andL J Nunez-Vergara ldquoReactivity of 14-dihydropyridines towardalkyl alkylperoxyl radicals and ABTS radical cationrdquo ChemicalResearch in Toxicology vol 16 no 2 pp 208ndash215 2003
[104] V Valenzuela P Santander C Camargo J A Squella C Lopez-Alarcon and L J Nunez-Vergara ldquo14-Dihydropyridines reac-tivity of nitrosoaryl and nitroaryl derivatives with alkylperoxylradicals andABTS radical cationrdquo Free Radical Research vol 38no 7 pp 715ndash727 2004
[105] L G Tsetlin N A Chebotareva B I Kurganov A K VelenaG Y Dubur and V Z Lankin ldquoStudy of 14-dihydropyridinesas lipoxygenase inhibitors with the use of hydrated reversedmicellesrdquo Pharmaceutical Chemistry Journal vol 22 no 6 pp425ndash428 1988 (Russian)
[106] J Panek Z Reblova L Kocirkova et al ldquoAntioxidant activityof dihydropyridine derivativesrdquo Czech Journal of Food Sciencesvol 18 pp 144ndash145 2000
[107] G Tirzitis I Kirule and G Duburs ldquoAntioxidationsaktivitatder 35-dicarbonylderivate des 26-demethyl-14-dihydropyri-dinsrdquo Fett Wissenschaft TechnologieFat Science Technology vol90 no 10 pp 411ndash413 1988
[108] M Plotniece G Tirzitis Y Uldrikis et al ldquoSynthesis of 14-dihydropyridine derivatives having an oxy- alkoxy- or dimeth-ylaminophenyl substituent in the 4 position their antioxidantactivity and their binding to phospholipid membranesrdquo Chem-istry of Heterocyclic Compounds vol 32 no 10 pp 1166ndash11721996 Translated from Khimiya Geterotsiklicheskikh Soedineniino 10(352) pp 1358ndash1365 1996 (Russian)
[109] D Y Rubene V S Sharov V I Olenev G D Tirzit G Y Duburand Y A Vladimirov ldquoUse of chemiluminescent method forthe evaluation of antioxidant activity of some derivatives of 14-dihydropyridinerdquo Russian Journal of Physical Chemistry A vol55 no 2 pp 511ndash512 1981 (Russian)
[110] M C R Symons and JM C Gutteridge Free Radicals and IronChemistry Biology and Medicine Oxford Science PublicationsOxford University Press Oxford UK 1998
[111] M Repetto J Semprine and A Boveris ldquoLipid peroxidationchemical mechanism biological implications and analyticaldeterminationrdquo in Lipid Peroxidation A Catala Ed Section ILipid Peroxidation Chemical Mechanisms Antioxidants Bio-logical Implications of Biochemistry Genetics and MolecularBiology chapter 1 pp 3ndash30 InTech Rijeka Croatia 2012
[112] A Velena J Zilbers and G Duburs ldquoDerivatives of 14-dihydropyridines asmodulators of ascorbate-induced lipid per-oxidation and high-amplitude swelling ofmitochondria causedby ascorbate sodium linoleate and sodiumpyrophosphaterdquoCellBiochemistry and Function vol 17 no 4 pp 237ndash252 1999
[113] M V Bilenko L N Shelenkova G Y Dubur and A K VelenaldquoUse of antioxidants to prevent renal damage during acuteischemia and reperfusionrdquo Bulletin of Experimental Biology andMedicine vol 96 no 3 pp 1195ndash1198 1983 Translated fromByulletenrsquo Eksperimentalrsquonoi Biologii i Meditsiny vol 96 no 9pp 8ndash11 1983 (Russian)
[114] R Toniolo F Tubaro F Ursini and G Bontempelli ldquoAn elec-troanalytical investigation on the redox properties of calciumantagonist dihydropyridinesrdquo Electroanalysis vol 15 no 10 pp855ndash861 2003
[115] L Kourimska J Pokorny and G Tirzitis ldquoThe antioxidant aci-tivity of 26-dimethyl-35-diethoxycarbonyl-14-dihydropyri-dine in edible oilsrdquo Nahrung vol 37 no 1 pp 91ndash93 1993
[116] C Lopez-Alarcon H Speisky J A Squella C Olea-Azar CCamargo and L J Nunez-Vergara ldquoReactivity of 14-dihydro-pyridines toward SIN-1-derived peroxynitriterdquo PharmaceuticalResearch vol 21 no 10 pp 1750ndash1757 2004
[117] R A Olek W Ziolkowski J J Kaczor L Greci J Popinigisand J Antosiewicz ldquoAntioxidant activity of NADH and its ana-loguemdashan in vitro studyrdquo Journal of Biochemistry andMolecularBiology vol 37 no 4 pp 416ndash421 2004
[118] E Niki N Noguchi and N Gotoh ldquoInhibition of oxidativemodification of low density lipoprotein by antioxidantsrdquo Jour-nal of Nutritional Science andVitaminology vol 39 supplementpp S1ndashS8 1993
[119] N Rojstaczer and D J Triggle ldquoStructure-function relation-ships of calcium antagonists effect on oxidative modificationof low density lipoproteinrdquo Biochemical Pharmacology vol 51no 2 pp 141ndash150 1996
Oxidative Medicine and Cellular Longevity 31
[120] A Sevanian L Shen and FUrsini ldquoInhibition of LDLoxidationand oxidized LDL-induced cytotoxicity by dihydropyridinecalcium antagonistsrdquo Pharmaceutical Research vol 17 no 8 pp999ndash1006 2000
[121] A Negre-Salvayre and R Salvayre ldquoProtection by Ca2+ channelblockers (nifedipine diltiazem and verapamil) against the tox-icity of oxidized low density lipoprotein to cultured lymphoidcellsrdquo British Journal of Pharmacology vol 107 no 3 pp 738ndash744 1992
[122] A Negre-Salvayre G FitoussiM Troly and R Salvayre ldquoCom-parative cytoprotective effect of dihydropyridine calcium chan-nel blockers against the toxicity of oxidized low density lipopro-tein for cultured lymphoid cellsrdquo Biochemical Pharmacologyvol 44 no 12 pp 2379ndash2386 1992
[123] L Cominacini A F Pasini U Garbin et al ldquoAntioxidant activ-ity of different dihydropyridinesrdquo Biochemical and BiophysicalResearch Communications vol 302 no 4 pp 679ndash684 2003
[124] L Cominacini U Garbin A Fratta Pasini et al ldquoOxidized low-density lipoprotein increases the production of intracellularreactive oxygen species in endothelial cells inhibitory effect oflacidipinerdquo Journal of Hypertension vol 16 no 12 part 2 pp1913ndash1919 1998
[125] H M Lander ldquoAn essential role for free radicals and derivedspecies in signal transductionrdquo The FASEB Journal vol 11 no2 pp 118ndash124 1997
[126] M L L Martinez E Rizzi M M Castro et al ldquoLercanidipinedecreases vascular matrix metalloproteinase-2 activity andprotects against vascular dysfunction in diabetic ratsrdquo EuropeanJournal of Pharmacology vol 599 no 1ndash3 pp 110ndash116 2008
[127] P Lesnik C Dachet L Petit et al ldquoImpact of a combinationof a calcium antagonist and a 120573-blocker on cell- and copper-mediated oxidation of LDL and on the accumulation and effluxof cholesterol in human macrophages and murine J774 cellsrdquoArteriosclerosis Thrombosis and Vascular Biology vol 17 no 5pp 979ndash988 1997
[128] G Sobal E J Menzel and H Sinzinger ldquoCalcium antagonistsas inhibitors of in vitro low density lipoprotein oxidation andglycationrdquoBiochemical Pharmacology vol 61 no 3 pp 373ndash3792001
[129] E Lupo R Locher B Weisser and W Vetter ldquoIn vitro antiox-idant activity of calcium antagonists against LDL oxidationcompared with 120572-tocopherolrdquo Biochemical and BiophysicalResearch Communications vol 203 no 3 pp 1803ndash1808 1994
[130] J Zou Y Li H-Q Fan and J-G Wang ldquoEffects of dihydropy-ridine calcium channel blockers on oxidized low-density lipo-protein induced proliferation and oxidative stress of vascularsmooth muscle cellsrdquo BMC Research Notes vol 5 article 1682012
[131] C Napoli S Salomone T Godfraind et al ldquo14-Dihydro-pyridine calcium channel blockers inhibit plasma and LDL oxi-dation and formation of oxidation-specific epitopes in the arte-rial wall and prolong survival in stroke-prone spontaneouslyhypertensive ratsrdquo Stroke vol 30 no 9 pp 1907ndash1915 1999
[132] G Zernig I Graziadei T Moshammer C Zech N Reider andH Glossmann ldquoMitochondrial Ca2+ antagonist binding sitesare associated with an inner mitochondrial membrane anionchannelrdquo Molecular Pharmacology vol 38 no 3 pp 362ndash3691990
[133] F E Hunter Jr A Scott P E Hochstein et al ldquoStudies of themechanism of ascorbate-induced swelling and lysis of isolatedliver mitochondriardquo The Journal of Biological Chemistry vol239 pp 604ndash613 1964
[134] D R Janero B Burghardt and R Lopez ldquoProtection of cardiacmembrane phospholipid against oxidative injury by calciumantagonistsrdquoBiochemical Pharmacology vol 37 no 21 pp 4197ndash4203 1988
[135] A Karadag B Ozcelik and S S Saner ldquoReview of methods todetermine antioxidant capacitiesrdquo FoodAnalyticalMethods vol2 no 1 pp 41ndash60 2009
[136] Y I Gubskiı N V Litvinova and E V Shnurko-TabakovaldquoAntioxidant and antiradical activity of various classes of antiox-idantsrdquo Ukrainskiı Biokhimicheskiı Zhurnal vol 66 no 4 pp114ndash116 1994 (Russian)
[137] M Takei M Hiramatsu and A Mori ldquoInhibitory effects ofcalcium antagonists onmitochondrial swelling induced by lipidperoxidation or arachidonic acid in the rat brain in vitrordquoNeurochemical Research vol 19 no 9 pp 1199ndash1206 1994
[138] M Takei M Hiramatsu R Edamatsu and A Mori ldquoFreeradical scavenging by calcium antagonistsrdquo Neurosciences vol20 no 2 pp 75ndash82 1994
[139] Ya P Stradin G Ya Dubur Yu A Beilis Ya R Uldrikis andA F Korotkova ldquoVoltammetry of 14-dihydropyridine deriva-tives I Potentials of electrochemical oxidation of 35-diacyl-and 35-di(alkoxycarbonyl)-14-dihydropyridines in acetoni-trilerdquo Chemistry of Heterocyclic Compounds no 1 pp 84ndash871972 (Russian)
[140] E V Ivanov T V Ponomarjova G N Merkusev et al ldquoEinneuer Haut-Radioprotektor Diethon (experimentelle Unter-suchung)rdquo Radiobiologia Radiotherapia vol 31 no 1 pp 69ndash78 1990
[141] E V Ivanov T V Ponomareva G N Merkushev et al ldquoRadia-tion modulating properties of derivates of 14-dihydropyridineand 12345678910-decahydroacridine-18 dionerdquo Radiat-sionnaia Biologiia Radioecologiia vol 44 no 5 pp 550ndash5592004 (Russian)
[142] R O Vitolinia D A Berzinia A K Velena I A Vutsina A AKimenis and G Y Duburs ldquoThe protective effects of the cal-cium antagonist foridon in acute myocardial ischaemiardquo Kardi-ologiya vol 27 no 3 pp 90ndash93 1987 (Russian)
[143] A H Velena G Ya Duburs R O Vitolina et al ldquoEffect ofryodipine on electromechanical parameters of heart and vesselscAMP phosphodiesterase activity and swelling-contractioncycle of mitochondriardquo Arzneimittelforschung vol 35 no 6 pp907ndash914 1985
[144] L I Utno Z E Lipsberga A A Silova M I Girgensone EA Bisenieks and G I Ia ldquoCardioprotective properties of a 14-dihydropyridine derivative glutapyrone in deep hypothermiardquoBiulletenrsquo Eksperimentalrsquonoı Biologii i Meditsiny vol 108 no 11pp 558ndash561 1989 (Russian)
[145] M A S FernandesM S Santos J A F Vicente et al ldquoEffects of14-dihydropyridine derivatives (cerebrocrast gammapyroneglutapyrone and diethone) onmitochondrial bioenergetics andoxidative stress a comparative studyrdquoMitochondrion vol 3 no1 pp 47ndash59 2003
[146] M A S Fernandes M S Santos A J M Moreno et al ldquoEffectsof 5-acetyl(carbamoyl)-6-methylsulfanyl-14-dihydropyridine-5-carbonitriles on rat liver mitochondrial functionrdquo Toxicologyin Vitro vol 23 no 7 pp 1333ndash1341 2009
[147] L Klimaviciusa A Kalda A Kaasik et al ldquoNeuroprotectiveactivity of 14-dihydropyridine derivatives structure determi-nantsrdquo Proceedings of the Latvian Academy of Sciences BNatural Exact and Applied Sciences vol 61 no 1-2 pp 33ndash372007
32 Oxidative Medicine and Cellular Longevity
[148] L Klimaviciusa M A S Fernandes N Lencberga et alldquoTargeting the mitochondria by novel adamantane-containing14-dihydropyridine compoundsrdquo in Bioenergetics K B ClarkEd pp 257ndash272 InTech 2012
[149] V Klusa L Klimaviciusa G Duburs J Poikans and AZharkovsky ldquoAnti-neurotoxic effects of tauropyrone a taurineanaloguerdquo Advances in Experimental Medicine and Biology vol583 pp 499ndash508 2006
[150] N Sampson P Berger and Ch Zenzmaier ldquoRedox signalingas a therapeutic target to inhibit myofibroblast activation indegenerative fibrotic diseaserdquo BioMed Research Internationalvol 2014 Article ID 131737 14 pages 2014
[151] T L Leto and M Geiszt ldquoRole of Nox family NADPH oxidasesin host defenserdquoAntioxidantsampRedox Signaling vol 8 no 9-10pp 1549ndash1561 2006
[152] K K Griendling D Sorescu and M Ushio-Fukai ldquoNAD(P)Hoxidase role in cardiovascular biology and diseaserdquo CirculationResearch vol 86 no 5 pp 494ndash501 2000
[153] H Chen Y S Song and P H Chan ldquoInhibition of NADPHoxi-dase is neuroprotective after ischemia-reperfusionrdquo Journal ofCerebral Blood Flow and Metabolism vol 29 no 7 pp 1262ndash1272 2009
[154] P Hochstein and L Ernster ldquoADP-activated lipid peroxidationcoupled to the TPNH oxidase system of microsomesrdquo Biochem-ical and Biophysical Research Communications vol 12 no 5 pp388ndash394 1963
[155] I I Gubskiı AGGoriushkoNV Litvinova et al ldquoAntioxidantproperties and membranotropic effect of certain derivatives of14-dihydropyridinerdquo Ukrainskiı Biokhimicheskiı Zhurnal vol71 no 4 pp 35ndash39 1999 (Russian)
[156] F Engineer and R Sridhar ldquoInhibition of rat heart andliver microsomal lipid peroxidation by nifedipinerdquo BiochemicalPharmacology vol 38 no 8 pp 1279ndash1285 1989
[157] T Goncalves A P Carvalho and C R Oliveira ldquoAntioxidanteffect of calcium antagonists on microsomai membranes iso-lated from different brain areasrdquo European Journal of Pharma-cology vol 204 no 3 pp 315ndash322 1991
[158] M E Letelier P Izquierdo L Godoy A M Lepe and MFaundez ldquoLiver microsomal biotransformation of nitro-aryldrugs mechanism for potential oxidative stress inductionrdquoJournal of Applied Toxicology vol 24 no 6 pp 519ndash525 2004
[159] M E Letelier P Entrala C Lopez-Alarcon et al ldquoNitroaryl-14-dihydropyridines as antioxidants against rat liver microsomesoxidation induced by ironascorbate Nitrofurantoin and naph-thalenerdquo Toxicology in Vitro vol 21 no 8 pp 1610ndash1618 2007
[160] F P Guengerich W R Brian M Iwasaki M-A Sari CBaarnhielm and P Berntsson ldquoOxidation of dihydropyridinecalcium channel blockers and analogues by human liver cyto-chrome P-450 IIIA4rdquo Journal of Medicinal Chemistry vol 34no 6 pp 1838ndash1844 1991
[161] S H Park S-W RhaW-Y Shin et al ldquoAS-160 Calcium channelblockers of dihydropyridine class reduce the antiplatelet effectof Clopidogrel what is clinical impactrdquo The American Journalof Cardiology vol 107 no 8 supplement p 47A 2011
[162] C Asma and D M Reda ldquoEvaluation of dihydropyridinecalcium antagonist effects on the stress bioindicator orga-nism Saccharomyces cerevisiaerdquo Annals of Biological Researchvol 4 no 10 pp 40ndash46 2013 httpscholarsresearchlibrarycomABR-vol4-iss10ABR-2013-4-10-40-46pdf
[163] G Gaviraghi A M Pastorino E Ratti and D G TristldquoCalcium channel blockers with antioxidant activityrdquo in Free
Radicals Lipoprotein Oxidation andAtherosclerosis G BellomoG Finardi E Maggi and E Rice-Evans Eds pp 431ndash456Richelieu Press London UK 1995
[164] G Gaviraghi AM Pastorino E Ratti and D G Trist ldquoAntiox-idant dihydropyridines a new and comprehensive therapy forfree radical-induced cardiovascular diseasesrdquo in Free Radicalsin Biology and Environment F Minisci Ed vol 27 of NATOASI Series pp 193ndash221 Springer Dordrecht The Netherlands1997
[165] P D Henry ldquoAntiperoxidative actions of calcium antagonistsand atherogenesisrdquo Journal of Cardiovascular Pharmacologyvol 18 supplement 1 pp S6ndashS10 1991
[166] F Kouoh B Gressier T Dine et al ldquoAntioxidant effects andanti-elastase activity of the calcium antagonist nicardipine onactivated human and rabbit neutrophilsmdasha potential antiath-erosclerotic property of calcium antagonistsrdquo CardiovascularDrugs andTherapy vol 16 no 6 pp 515ndash520 2002
[167] S Parthasarathy D Litvinov K Selvarajan and M GarelnabildquoLipid peroxidation and decompositionmdashconflicting roles inplaque vulnerability and stabilityrdquo Biochimica et BiophysicaActa vol 1781 no 5 pp 221ndash231 2008
[168] D-Q Liu Z-Q Pang D-H Zhao and B-H Sheng ldquoEffects offuryl-dihydropyridines I on lipid peroxides of ischemic myo-cardium and ATPases activity of erythrocyte membranes inratsrdquo Acta Pharmacologica Sinica vol 12 no 3 pp 253ndash2561991
[169] V Lukic-Panin T Kamiya H Zhang et al ldquoPrevention of neu-ronal damage by calcium channel blockers with antioxidativeeffects after transient focal ischemia in ratsrdquo Brain Research vol1176 no 1 pp 143ndash150 2007
[170] Y Allanore D Borderie H Lemarechal O G Ekindjian andA Kahan ldquoAcute and sustained effects of dihydropyridine-typecalcium channel antagonists on oxidative stress in systemicsclerosisrdquo American Journal of Medicine vol 116 no 9 pp 595ndash600 2004
[171] I Casetta V Govoni and E Granieri ldquoOxidative stress antioxi-dants and neurodegenerative diseasesrdquo Current PharmaceuticalDesign vol 11 no 16 pp 2033ndash2052 2005
[172] M J T J Arts Assessing antioxidant activity [PhD the-sis] Maastricht University Maastricht The Netherlands 2007httparnounimaasnlshowcgifid=8676
[173] G Dıaz-Araya L Godoy L Naranjo A Squella M E Letelierand L J Nunez-Vergara ldquoAntioxidant effects of 14-dihydro-pyridine and nitroso aryl derivatives on the Fe+3ascorbate-stimulated lipid peroxidation in rat brain slicesrdquo General Phar-macology The Vascular System vol 31 no 3 pp 385ndash391 1998
[174] Y Fukuhara K Tsuchiya Y Horinouchi et al ldquoProtectiveeffect of photodegradation product of nifedipine against tumornecrosis factor 120572-induced oxidative stress in human glomerularendothelial cellsrdquo Journal of Medical Investigation vol 58 no1-2 pp 118ndash126 2011
[175] W Stengel M Jainz and K Andreas ldquoDifferent potencies ofdihydropyridine derivatives in blocking T-type but not L-typeCa2+ channels in neuroblastoma-glioma hybrid cellsrdquo EuropeanJournal of Pharmacology vol 342 no 2-3 pp 339ndash345 1998
[176] O M Panasenko D J Tirzite G D Tirzitis and G J DubursldquoEffect of some 14-dihydropyridine derivatives on structuralorganization of erythrocyte membranesrdquo Biologicheskie Mem-brany (Biochemistry (Moscow) Series A Membrane and CellBiology) vol 1 pp 919ndash925 1984 (Russian)
[177] L G Herbette Y M H Vant Erve and D G Rhodes ldquoInter-action of 14 dihydropyridine calcium channel antagonists with
Oxidative Medicine and Cellular Longevity 33
biological membranes lipid bilayer partitioning could occurbefore drug binding to receptorsrdquo Journal of Molecular andCellular Cardiology vol 21 no 2 pp 187ndash201 1989
[178] L G Herbette P E Mason G Gaviraghi T N Tulenko andR P Mason ldquoThe molecular basis for lacidipinersquos unique phar-macokinetics optimal hydrophobicity results in membraneinteractions that may facilitate the treatment of atherosclerosisrdquoJournal of Cardiovascular Pharmacology vol 23 supplement 5pp S16ndashS25 1994
[179] G V Belevitch G Y Dubur G E Dobretsov N K Kurek andM M Spirin ldquoCalcium antagonists riodipine nifedipine andverapamil binding to model and biological membranes fluore-scence analysisrdquo Biologicheskie Membrany (Biochemistry(Moscow) Series A Membrane and Cell Biology) vol 5 pp768ndash776 1988 (Russian)
[180] R P Mason G E Gonye D W Chester and L G HerbetteldquoPartitioning and location of Bay K 8644 14-dihydropyridinecalcium channel agonist in model and biological membranesrdquoBiophysical Journal vol 55 no 4 pp 769ndash778 1989
[181] M Cindric A Cipak J Serly et al ldquoReversal of multidrugresistance inmurine lymphoma cells by amphiphilic dihydropy-ridine antioxidant derivativerdquo Anticancer Research vol 30 no10 pp 4063ndash4070 2010
[182] F Shekari H Sadeghpour K Javidnia et al ldquoCytotoxic andmultidrug resistance reversal activities of novel 14-dihydro-pyridines against human cancer cellsrdquo European Journal ofPharmacology vol 746 no 1 pp 233ndash244 2015
[183] X-F Zhou Q Shao R A Coburn and M E Morris ldquoQuanti-tative structure-activity relationship and quantitative structure-pharmacokinetics relationship of 14-dihydropyridines andpyridines as multidrug resistance modulatorsrdquo PharmaceuticalResearch vol 22 no 12 pp 1989ndash1996 2005
[184] R Berkels T Breitenbach H Bartels et al ldquoDifferent antioxida-tive potencies of dihydropyridine calcium channel modulatorsin various modelsrdquo Vascular Pharmacology vol 42 no 4 pp145ndash152 2005
[185] S Borovic G Tirzitis D Tirzite et al ldquoBioactive 14-dihydro-isonicotinic acid derivatives prevent oxidative damage of livercellsrdquo European Journal of Pharmacology vol 537 no 1ndash3 pp12ndash19 2006
[186] D Ya Rubene G D Tirzitis and G Ya Duburs ldquoInteractionof some 14-dihydropyridine derivatives with Fentonrsquos reagentrdquoLatvijas PSRZinatnuAkademijas Vestis Kimijas Serija Proceed-ings of the Latvian SSR Academy of Sciences Chemistry Seriespp 212ndash216 1982 (Russian)
[187] K Ondrias V Misık D Gergel and A Stasko ldquoLipid per-oxidation of phosphatidylcholine liposomes depressed by thecalcium channel blockers nifedipine and verapamil and bythe antiarrhythmic-antihypoxic drug stobadinerdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1003 no 3pp 238ndash245 1989
[188] I T Mak and W B Weglicki ldquoComparative antioxidant acti-vities of propranolol nifedipine verapamil and diltiazemagainst sarcolemmal membrane lipid peroxidationrdquoCirculationResearch vol 66 no 5 pp 1449ndash1452 1990
[189] I T Mak P Boehme and W B Weglicki ldquoProtective effects ofcalcium channel blockers against free radical-impaired endo-thelial cell proliferationrdquo Biochemical Pharmacology vol 50 no9 pp 1531ndash1534 1995
[190] S Ray S Mondal and N Dana ldquoEvaluation of protective roleof nifedipine on lipid peroxidation using reduced glutathione as
model markerrdquo Oxidants and Antioxidants in Medical Sciencevol 1 no 2 pp 97ndash100 2012
[191] M Yamato T Shiba T Ide Y Honda K-I Yamada andH Tsutsui ldquoNifedipine treatment reduces brain damage aftertransient focal ischemia possibly through its antioxidativeeffectsrdquoHypertension Research vol 34 no 7 pp 840ndash845 2011
[192] V Chander and K Chopra ldquoNifedipine attenuates changes innitric oxide levels renal oxidative stress and nephrotoxicityinduced by cyclosporinerdquo Renal Failure vol 27 no 4 pp 441ndash450 2005
[193] K M Gaafa M M Badawy and A A Hamza ldquoThe protectiveeffects of ascorbic acid cimetidine and nifedipine on diethyl-dithiocarbamate-induced hepatic toxicity in albino ratsrdquo Drugand Chemical Toxicology vol 34 no 4 pp 405ndash419 2011
[194] H Sugawara K Tobise and S Onodera ldquoAbsence of antiox-idant effects of nifedipine and diltiazem on myocardial mem-brane lipid peroxidation in contrast with those of nisoldipineand propranololrdquo Biochemical Pharmacology vol 47 no 5 pp887ndash892 1994
[195] I E Kirule D Y Rubene E A Bisenieks G D Tirzit and GY Dubur ldquo4-Nitrophenyl-14-dihydropyridinesmdasha new groupof inhibitors of peroxide oxidationrdquo Chemistry of HeterocyclicCompounds vol 18 no 3 p 316 1982
[196] G D Tirzit I E Kirule L K Baumane R A Gavar Y PStradynrsquo andG YDubur ldquoMechanism of the antioxidant actionof 26-dimethyl-35-dimethoxy-carbonyl-4-(2-nitrophenyl)14-dihydropyridinerdquoChemistry ofHeterocyclic Compounds vol 20no 8 pp 915ndash918 1984
[197] C Yanez C Lopez-Alarcon C Camargo V Valenzuela J ASquella and L J Nunez-Vergara ldquoStructural effects on thereactivity 14-dihydropyridines with alkylperoxyl radicals andABTS radical cationrdquo Bioorganic and Medicinal Chemistry vol12 no 9 pp 2459ndash2468 2004
[198] VMisik A J Stasko D Gergel and K Ondrias ldquoSpin-trappingand antioxidant properties of illuminated and nonilluminatednifedipine and nimodipine in heart homogenate and modelsystemrdquo Molecular Pharmacology vol 40 no 3 pp 435ndash4391991
[199] K Ondrias V Misık A Stasko D Gergelrsquo and M HromadovaldquoComparison of antioxidant properties of nifedipine and illu-minated nifedipine with nitroso spin traps in low densitylipoproteins and phosphatidylcholine liposomesrdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1211 no 1pp 114ndash119 1994
[200] A Stasko V Brezova S Biskupic K Ondrias and V MisıkldquoReactive radical intermediates formed from illuminated nife-dipinerdquoFree Radical Biology andMedicine vol 17 no 6 pp 545ndash556 1994
[201] K Ishizawa Y Izawa-Ishizawa N Yamano et al ldquoNitrosoni-fedipine ameliorates the progression of type 2 diabetic nephro-pathy by exerting antioxidative effectsrdquo PLoS ONE vol 9 no 1Article ID e86335 2014
[202] H Fujii and L J Berliner ldquoIn vivo EPR evidence for free radicaladducts of nifedipinerdquoMagnetic Resonance in Medicine vol 42no 4 pp 691ndash694 1999
[203] S Bollo S Finger J C Sturm L J Nunez-Vergara and JA Squella ldquoCyclic voltammetry and scanning electrochemicalmicroscopy studies of the heterogeneous electron transferreaction of some nitrosoaromatic compoundsrdquo ElectrochimicaActa vol 52 no 15 pp 4892ndash4898 2007
34 Oxidative Medicine and Cellular Longevity
[204] F Ursini ldquoTissue protection by lacidipine insight from redoxbehaviorrdquo Journal of Cardiovascular Pharmacology vol 30supplement 2 pp S28ndashS30 1997
[205] P G Cristofori F A Crivellente I Faustinelli et al ldquoInvolve-ment of the nitric oxide system in the anti-atheroscleroticpotential of lacidipine in the apoE-deficient mouse a mor-phological functional and electrochemical studyrdquo ToxicologicPathology vol 32 no 4 pp 493ndash499 2004
[206] X-P Zhang E L Kit S Mital S Chahwala and T HHintze ldquoParadoxical release of nitric oxide by an L-type calciumchannel antagonist the R+ enantiomer of amlodipinerdquo Journalof Cardiovascular Pharmacology vol 39 no 2 pp 208ndash2142002
[207] F Franzoni G Santoro F Regoli et al ldquoAn in vitro study of theperoxyl and hydroxyl radical scavenging capacity of the calciumantagonist amlodipinerdquo Biomedicine and Pharmacotherapy vol58 no 8 pp 423ndash426 2004
[208] S V Gatsura ldquoOxygen-dependent mechanisms underlying theantiischemic effect of verapamil and amlodipinerdquo Bulletin ofExperimental Biology and Medicine vol 137 no 1 pp 40ndash422004
[209] Y Hirooka Y Kimura M Nozoe Y Sagara K Ito and KSunagawa ldquoAmlodipine-induced reduction of oxidative stressin the brain is associated with sympatho-inhibitory effects instroke-prone spontaneously hypertensive ratsrdquo HypertensionResearch vol 29 no 1 pp 49ndash56 2006
[210] B Tomlinson and I F F Benzie ldquoAntioxidant effect of lercani-dipine (note)rdquo Hypertension vol 42 no 4 pp e10ndashe11 2003
[211] A A Faraqui ldquoNeurochemical aspects of 4-hydroxynonenalrdquoin Lipid Mediators and Their Metabolism in the Brain A AFaraqui Ed chapter 6 pp 159ndash191 Springer New York NYUSA 2011
[212] V S NascimentoM S DrsquoAlva A AOliveira et al ldquoAntioxidanteffect of nimodipine in young rats after pilocarpine-inducedseizuresrdquo Pharmacology Biochemistry and Behavior vol 82 no1 pp 11ndash16 2005
[213] O Ismailoglu P Atilla S Palaoglu et al ldquoThe therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjuryrdquo Turkish Neurosurgery vol 22 no 6 pp 740ndash746 2012
[214] M Matsubara and K Hasegawa ldquoBenidipine a dihydropy-ridine-calcium channel blocker prevents lysophosphatidyl-choline-induced injury and reactive oxygen species productionin human aortic endothelial cellsrdquo Atherosclerosis vol 178 no1 pp 57ndash66 2005
[215] M Matsubara K Yao and K Hasegawa ldquoBenidipine adihydropyridine-calcium channel blocker inhibits lysophos-phatidylcholine-induced endothelial injury via stimulation ofnitric oxide releaserdquo Pharmacological Research vol 53 no 1 pp35ndash43 2006
[216] MMatsubara and K Hasegawa ldquoEffects of benidipine a dihyd-ropyridine-Ca2+ channel blocker on expression of cytokine-induced adhesion molecules and chemoattractants in humanaortic endothelial cellsrdquo European Journal of Pharmacology vol498 no 1ndash3 pp 303ndash314 2004
[217] M Matsubara O Akizuki J-I Ikeda K Saeki K Yao and KSasaki ldquoBenidipine an anti-hypertensive drug inhibits reactiveoxygen species production in polymorphonuclear leukocytesand oxidative stress in salt-loaded stroke-prone spontaneouslyhypertensive ratsrdquo European Journal of Pharmacology vol 580no 1-2 pp 201ndash213 2008
[218] A C Rosenkranz H Lob T Breitenbach R Berkels and RRoesen ldquoEndothelial antioxidant actions of dihydropyridines
and angiotensin converting enzyme inhibitorsrdquo European Jour-nal of Pharmacology vol 529 no 1ndash3 pp 55ndash62 2006
[219] V Kain S Kumar and S L Sitasawad ldquoAzelnidipine preventscardiac dysfunction in streptozotocin-diabetic rats by reducingintracellular calcium accumulation oxidative stress and apop-tosisrdquo Cardiovascular Diabetology vol 10 article 97 2011
[220] K Nakamura S Yamagishi and H Inoue ldquoUnique atheropro-tective property of azelnidipine a dihydropyridine-based cal-cium antagonistrdquoMedical Hypotheses vol 65 no 1 pp 155ndash1572005
[221] TMatsui S Yamagishi K Nakamura S Kikuchi andH InoueldquoAzelnidipine a dihydropyridine-based calcium antagonistinhibits angiotensin II-induced oxidative stress generation anddownregulation of pigment epithelium-derived factor mRNAlevels in microvascular endothelial cellsrdquo Drugs under Experi-mental and Clinical Research vol 31 no 5-6 pp 215ndash219 2005
[222] C Ohmura H Watada T Shimizu et al ldquoCalcium channelblocker azelnidipine reduces lipid hydroperoxides in patientswith type 2 diabetes independent of blood pressurerdquo EndocrineJournal vol 54 no 5 pp 805ndash811 2007
[223] H Daikuhara F Kikuchi and T Ishida ldquoThe combination ofOLmesartan and a CAlcium channel blocker (azelnidipine) orcandesartan and a calcium channel blocker (amlodipine) intype 2 diabetic hypertensive patients theOLCA studyrdquoDiabetesand Vascular Disease Research vol 9 no 4 pp 280ndash286 2012
[224] MAbe NMaruyama KOkada SMatsumoto KMatsumotoand M Soma ldquoAdditive antioxidative effects of azelnidipine onangiotensin receptor blocker olmesartan treatment for type 2diabetic patients with albuminuriardquoHypertension Research vol34 no 8 pp 935ndash941 2011
[225] K Mizushige ldquoAntioxidative activities of thiazolidinedionesand dihydropyridine-type calcium antagonistsrdquo IRYOmdashJapa-nese Journal of National Medical Services vol 59 no 11 pp 581ndash592 2005
[226] S Manabe T Okura T Fukuoka and J Higaki ldquoAntioxidativeeffects of azelnidipine on mesangial cell proliferation inducedby highly concentrated insulinrdquo European Journal of Pharma-cology vol 567 no 3 pp 252ndash257 2007
[227] Y Koyama Y Takeishi H Takahashi et al ldquoAzelnidipine inhi-bits H
2O2-induced cell death in neonatal rat cardiomyocytesrdquo
CardiovascularDrugs andTherapy vol 21 no 1 pp 69ndash72 2007[228] K Shinomiya K Mizushige M Fukunaga et al ldquoAntioxidant
effect of a new calcium antagonist azelnipidine in culturedhuman arterial endothelial cellsrdquo Journal of International Med-ical Research vol 32 no 2 pp 170ndash175 2004
[229] T Ohyama K Sato K Kishimoto et al ldquoAzelnidipine is acalcium blocker that attenuates liver fibrosis and may increaseantioxidant defencerdquo British Journal of Pharmacology vol 165no 4 pp 1173ndash1187 2012
[230] L A Calo F Zaghetto E Pagnin P A Davis A Sempliciniand A C Pessina ldquoEffect of manidipine on gene expressionand protein level of oxidative stress-related proteins p22phoxand HO-1 Relevance for antihypertensive and anti-remodelingeffectsrdquo Journal of Cardiovascular Pharmacology vol 43 no 4pp 531ndash538 2004
[231] R Ghyasi G Sepehri M Mohammadi R Badalzadeh and AGhyasi ldquoEffect of mebudipine on oxidative stress and lipid per-oxidation in myocardial ischemic-reperfusion injury in maleratrdquo Journal of Research in Medical Sciences vol 17 no 12 pp1150ndash1155 2012
Oxidative Medicine and Cellular Longevity 35
[232] DCAndersson J Fauconnier T Yamada et al ldquoMitochondrialproduction of reactive oxygen species contributes to the 120573-adrenergic stimulation of mouse cardiomycytesrdquoThe Journal ofPhysiology vol 589 no 7 pp 1791ndash1801 2011
[233] A F Ceylan-Isik N Ari M Stefek et al ldquoEffects of a long-term treatment with an antioxidant pyridoindole on vascularresponsiveness in diabetes-induced aging ratsrdquo Current AgingScience vol 4 no 2 pp 150ndash157 2011
[234] S Saponara G Sgaragli and F Fusi ldquoQuercetin antagonismof Bay K 8644 effects on rat tail artery L-type Ca2+ channelsrdquoEuropean Journal of Pharmacology vol 598 no 1ndash3 pp 75ndash802008
[235] D A Sica ldquoInteraction of grapefruit juice and calcium channelblockersrdquo American Journal of Hypertension vol 19 no 7 pp768ndash773 2006
[236] P Mulder G Litwinienko S Lin P D MacLean L R CBarclay and K U Ingold ldquoThe L-type calcium channel block-ers Hantzsch 14-dihydropyridines are not peroxyl radical-trapping chain-breaking antioxidantsrdquo Chemical Research inToxicology vol 19 no 1 pp 79ndash85 2006
[237] L J Nunez-Vergara R Salazar C Camargo et al ldquoOxidation ofC4-hydroxyphenyl 14-dihydropyridines in dimethylsulfoxideand its reactivity towards alkylperoxyl radicals in aqueousmediumrdquo Bioorganic and Medicinal Chemistry vol 15 no 12pp 4318ndash4326 2007
[238] M E Ortiz L J Nunez-Vergara and J A Squella ldquoRelativereactivity of dihydropyridine derivatives to electrogeneratedsuperoxide ion in DMSO solutions a voltammetric approachrdquoPharmaceutical Research vol 20 no 2 pp 292ndash296 2003
[239] M E Ortiz L J Nunez-Vergara C Camargo and J A SquellaldquoOxidation of Hantzsch 14-dihydropyridines of pharmacolog-ical significance by electrogenerated superoxiderdquo Pharmaceuti-cal Research vol 21 no 3 pp 428ndash435 2004
[240] R S Raghuvanshi and K N Singh ldquoSuperoxide induced oxida-tive aromatization of Hantzsch 14-dihydropyridinesrdquo IndianJournal of Chemistry Section B Organic and Medicinal Chem-istry vol 47 no 11 pp 1735ndash1738 2008
[241] I Kruk A Kladna K Lichszteld et al ldquoAntioxidant activityof 4-flavonil-14-dihydropyridine derivativesrdquo Biopolymers vol62 no 3 pp 163ndash167 2001
[242] G D Tirzit I M Byteva K I Salokhiddinov G P Gurinovichand G Y Dubur ldquo14-Dihydropyridine derivatives as deactiva-tors of singlet oxygenrdquo Chemistry of Heterocyclic Compoundsvol 17 no 7 pp 682ndash684 1981
[243] G D Tirzit E Y Kazush and G Y Dubur ldquoInfluence of14-dihydropyridine derivatives on the generation of hydroxylradicalsrdquo Chemistry of Heterocyclic Compounds vol 28 no 4pp 435ndash437 1992
[244] N A Pizarro-Urzua and L J Nunez-Vergara ldquoNifedipine andnitrendipine reactivity toward singlet oxygenrdquo Journal of Photo-chemistry and Photobiology A Chemistry vol 175 no 2-3 pp129ndash137 2005
[245] L-F Wang H-Y Zhang L Konga Z-W Chena and J-G ShildquoDFT calculations indicate that 14-dihydropyridine is a promis-ing lead antioxidantrdquo Helvetica Chimica Acta vol 87 no 6 pp1515ndash1521 2004
[246] P Mulder H-G Korth and K U Ingold ldquoWhy quantum-thermochemical calculations must be used with caution toindicate lsquoa promising lead antioxidantrsquordquoHelvetica Chimica Actavol 88 no 2 pp 370ndash374 2005
[247] K Yao Y Ina K Nagashima K Ohmori and T Ohno ldquoAntiox-idant effects of calcium antagonists in rat brain homogenatesrdquo
Biological and Pharmaceutical Bulletin vol 23 no 6 pp 766ndash769 2000
[248] T Matsui S-I Yamagishi K Nakamura and H Inoue ldquoBayw 9798 a dihydropyridine structurally related to nifedipinewith no calcium channel-blocking properties inhibits tumournecrosis factor-120572-induced vascular cell adhesion molecule-1expression in endothelial cells by suppressing reactive oxygenspecies generationrdquo Journal of International Medical Researchvol 35 no 6 pp 886ndash891 2007
[249] K AMitrega B VargheseM Porc and T F Krzeminski ldquoAnti-arrhythmic and hemodynamic effects of oxy nifedipine oxynimodipine oxy nitrendipine and oxy nisoldipinerdquo Pharmaco-logical Research vol 66 no 4 pp 300ndash308 2012
[250] V Herbert ldquoSymposium prooxidant effects of antioxidantvitamins Introductionrdquo The Journal of Nutrition vol 126 no4 supplement pp 1197Sndash1200S 1996 httpjnnutritionorgcontent1264 Suppl1197Sfullpdf
[251] B Halliwell ldquoAre polyphenols antioxidants or pro-oxidantsWhat do we learn from cell culture and in vivo studiesrdquoArchives of Biochemistry and Biophysics vol 476 no 2 pp 107ndash112 2008
[252] C Winterbourn Pro-Oxidants or Antioxidants ChristchurchSchool of Medicine Depatment of Pathology Free RadicalSchool SFRBMUniversity of Otago San Francisco Calif USA2009 httpwwwsfrbmorgfrsWinterbournpdf
[253] A Morakinyo B Iranloye and O Adegoke ldquoCalcium antag-onists modulate oxidative stress and acrosomal reaction in ratspermatozoardquo Archives of Medical Science vol 7 no 4 pp 613ndash618 2011
[254] The Alpha-Tocopherol Beta Carotene Cancer Prevention StudyGroup ldquoThe effect of vitamin E and beta carotene on theincidence of lung cancer and other cancers in male smokersrdquoTheNew England Journal of Medicine vol 330 no 15 pp 1029ndash1035 1994
[255] B Poljsak ldquoStrategies for reducing or preventing the generationof oxidative stressrdquo Oxidative Medicine and Cellular Longevityvol 2011 Article ID 194586 15 pages 2011
[256] B Poljsak and I Milisav ldquoThe neglected significance of lsquoanti-oxidative stressrsquordquoOxidativeMedicine and Cellular Longevity vol2012 Article ID 480895 12 pages 2012
[257] T Godfraind and S Salomone ldquoAmbiguities in dietary antiox-idant supplementation compared to calcium channel blockerstherapyrdquo Frontiers in Pharmacology vol 6 article 10 2015
[258] H Wagner H Norr and H Winterhoff ldquoDrugs with adap-togenic effects for strengthening the powers of resistancerdquoZeitschrift fur Phytotherapie vol 13 no 2 pp 42ndash54 1992
Oxidative Medicine and Cellular Longevity 27
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
Authors from Latvian IOS acknowledge ESF 201300021DP1112013APIAVIAA011 and National Research Pro-gramme PUBLIC HEALTHBiomedicine of the Republicof Latvia for financial support administration of the Insti-tute for technical support and Rufus Smits PhD for con-sultations in English The support of Cooperation in Euro-pean System of Science and Technology (COST) Domain ofChemistry Molecular Sciences and Technologies (CMST)was of highest importance for preparation of this paper
[2] D J Triggle ldquo14-Dihydropyridines as calcium channel ligandsand privileged structuresrdquoCellular andMolecular Neurobiologyvol 23 no 3 pp 293ndash303 2003
[3] T Godfraind ldquoAntioxidant effects and the therapeutic modeof action of calcium channel blockers in hypertension andatherosclerosisrdquo Philosophical Transactions of the Royal SocietyB Biological Sciences vol 360 no 1464 pp 2259ndash2272 2005
[4] E Cadenas ldquoMitochondrial free radical production and cellsignalingrdquoMolecular Aspects of Medicine vol 25 no 1-2 pp 17ndash26 2004
[5] E Cadenas ldquoFree radicals oxidative stress and diseasesrdquo inLecture PSC 616 p 38 Missouri University of Science andTechnology Rolla Mo USA httpwwwcarnicominstituteorgarticlesenrique cadenaspdf
[6] K Rahman ldquoStudies on free radicals antioxidants and co-fac-torsrdquo Clinical Interventions in Aging vol 2 no 2 pp 219ndash2362007
[7] V Bocci and G Valacchi ldquoFree radicals and antioxidants howto reestablish redox homeostasis in chronic diseasesrdquo CurrentMedicinal Chemistry vol 20 no 27 pp 3397ndash3415 2013
[8] M Valko C J Rhodes J Moncol M Izakovic and M MazurldquoFree radicals metals and antioxidants in oxidative stress-induced cancerrdquo Chemico-Biological Interactions vol 160 no 1pp 1ndash40 2006
[9] G Bartosz ldquoReactive oxygen species destroyers or messen-gersrdquo Biochemical Pharmacology vol 77 no 8 pp 1303ndash13152009
[10] R Visconti and D Grieco ldquoNew insights on oxidative stress incancerrdquo Current Opinion in Drug Discovery and Developmentvol 12 no 2 pp 240ndash245 2009
[11] R N Kujundzic N Zarkovic and K G Troselj ldquoPyridinenucleotides in regulation of cell death and survival by redoxand non-redox reactionsrdquo Critical Reviews in Eukaryotic GeneExpression vol 24 no 4 pp 287ndash309 2014
[12] B Halliwell and J M C Gutteridge ldquoThe definition and mea-surement of antioxidants in biological systemsrdquo Free RadicalBiology and Medicine vol 18 no 1 pp 125ndash126 1995
[13] V D Kancheva and O T Kasaikina ldquoBio-antioxidantsmdashachemical base of their antioxidant activity and beneficial effect
on human healthrdquo Current Medicinal Chemistry vol 20 no 37pp 4784ndash4805 2013
[14] H V Panglossi Ed Frontiers in Antioxidants Research NovaScience Publishers New York NY USA 2006
[15] E B Burlakova E M Molochkina and G A NikiforovldquoHybrid antioxidantsrdquo Oxidation Communications vol 31 no4 pp 739ndash757 2008 httpmembraneustceducnpaperpdfHybrid20Antioxidantspdf
[16] A Bast and G R M M Haenen ldquoTen misconceptions aboutantioxidantsrdquo Trends in Pharmacological Sciences vol 34 no 8pp 430ndash436 2013
[17] E B Burlakova A V 0lesenko E M Molochkina N PPalmina and N G Khrapova Bioantioxidants for RadiationDamage and Malignant Growth Nauka Moscow Russia 1975(Russian)
[18] J Fang T Seki and H Maeda ldquoTherapeutic strategies by mod-ulating oxygen stress in cancer and inflammationrdquo AdvancedDrug Delivery Reviews vol 61 no 4 pp 290ndash302 2009
[19] M Valko D Leibfritz J Moncol M T D Cronin M Mazurand J Telser ldquoFree radicals and antioxidants in normal physi-ological functions and human diseaserdquo International Journal ofBiochemistry and Cell Biology vol 39 no 1 pp 44ndash84 2007
[20] M Jimenez-Del-Rio and C Velez-Pardo ldquoThe bad the goodand the ugly about oxidative stressrdquo Oxidative Medicine andCellular Longevity vol 2012 Article ID 163913 13 pages 2012
[21] C D Kamat S Gadal M Mhatre K S Williamson Q N Pyeand K Hensley ldquoAntioxidants in central nervous system dis-eases preclinical promise and translational challengesrdquo Journalof Alzheimerrsquos Disease vol 15 no 3 pp 473ndash493 2008
[22] A Pompella H Sies R Wacker et al ldquoThe use of totalantioxidant capacity as surrogate marker for food quality andits effect on health is to be discouragedrdquo Nutrition vol 30 no7-8 pp 791ndash793 2014
[23] Z Ye and H Song ldquoAntioxidant vitamins intake and the risk ofcoronary heart disease meta-analysis of cohort studiesrdquo Euro-pean Journal of Cardiovascular Prevention and Rehabilitationvol 15 no 1 pp 26ndash34 2008
[24] P Knekt J Ritz M A Pereira et al ldquoAntioxidant vitamins andcoronary heart disease risk a pooled analysis of 9 cohortsrdquoTheAmerican Journal of Clinical Nutrition vol 80 no 6 pp 1508ndash1520 2004
[25] A C Carr and M C M Vissers ldquoSynthetic or food-derivedvitamin Cmdashare they equally bioavailablerdquo Nutrients vol 5 no11 pp 4284ndash4304 2013
[26] R Tabrizchi ldquoEdaravoneMitsubishi-TokyordquoCurrentOpinion inInvestigational Drugs vol 1 no 3 pp 347ndash354 2000
[27] K Kikuchi S Tancharoen N Takeshige et al ldquoThe efficacy ofedaravone (radicut) a free radical scavenger for cardiovasculardiseaserdquo International Journal of Molecular Sciences vol 14 no7 pp 13909ndash13930 2013
[28] D Mauzerall and F H Westheimer ldquo1-Benzyldihydronicoti-namidemdasha model for reduced DPNrdquo Journal of the AmericanChemical Society vol 77 no 8 pp 2261ndash2264 1955 ChemicalAbstracts vol 50 Article ID 2588i 1956
[29] F Bossert and W Vater ldquo14-Dihydropyridinesmdasha basis fordeveloping new drugsrdquo Medicinal Research Reviews vol 9 no3 pp 291ndash324 1989
[30] G Swarnalatha G Prasanthi N Sirisha and CMadhusudhanaChetty ldquo14-Dihydropyridines a multtifunctional moleculemdash areviewrdquo International Journal of ChemTech Research vol 3 no1 pp 75ndash89 2011
28 Oxidative Medicine and Cellular Longevity
[31] M Cataldi and F Bruno ldquo14-Dihydropyridines the multiplepersonalities of a blockbuster drug familyrdquo Translational Medi-cine UniSa vol 4 no 2 pp 12ndash26 2012 httpwwwncbinlmnihgovpmcarticlesPMC3728803
[32] R Vitolina A Krauze G Duburs and A Velena ldquoAspects ofthe amlodipine pleiotropy in biochemistry pharmacology andclinicsrdquo International Journal of Pharmaceutical Sciences andResearch vol 3 no 5 pp 1215ndash1232 2012
[33] D Grover S N Mokale and M T Shete ldquoDihydropyridinea novel pharmacophorerdquo International Journal of Pharmaceu-tical Erudition vol 1 no 2 pp 16ndash29 2011 httppharmaeru-ditionorgContentPaper20111-RV-320Final2016-29pdf
[34] A M Vijesh A M Isloor S K Peethambar K N ShivanandaT Arulmoli and N A Isloor ldquoHantzsch reaction synthesis andcharacterization of somenew 14-dihydropyridine derivatives aspotent antimicrobial and antioxidant agentsrdquo European Journalof Medicinal Chemistry vol 46 no 11 pp 5591ndash5597 2011
[35] P Mehta and P Verma ldquoAntimicrobial activity of some deriva-tives of 14-dihydropyridinesrdquo Journal of Chemistry vol 2013Article ID 865128 4 pages 2013
[36] P Olejnıkova L Svorc D Olsovska et al ldquoAntimicrobialactivity of novel C2-substituted 14-dihydropyridine analoguesrdquoScientia Pharmaceutica vol 82 no 2 pp 221ndash232 2014
[37] S Sepehri H Perez Sanchez and A Fassihi ldquoHantzsch-typedihydropyridines and biginelli-type tetra-hydropyrimidinesa review of their chemotherapeutic activitiesrdquo Journal of Phar-macy amp Pharmaceutical Sciences vol 18 no 1 pp 1ndash52 2015httpsejournalslibraryualbertacaindexphpJPPSarticleview2383617863
[38] S A Khedkar and P B Auti ldquo14-Dihydropyridines a classof pharmacologically important moleculesrdquo Mini-Reviews inMedicinal Chemistry vol 14 no 3 pp 282ndash290 2014
[39] G D Tirzit and G Ya Duburs ldquo14-dihydropyridines as inhi-bitors of free-radical reactionsrdquo Chemistry of Heterocyclic Com-pounds vol 8 no 1 pp 126ndash127 1972 Translated from KhimiyaGeterotsiklicheskikh Soedinenii no1 pp 133ndash134 1972 (Rus-sian)
[40] I Bogeski R Kappl C Kummerow R Gulaboski M Hothand B A Niemeyer ldquoRedox regulation of calcium ion channelschemical and physiological aspectsrdquoCell Calcium vol 50 no 5pp 407ndash423 2011
[41] S A Giller G Y Dubur Y R Uldrikis et al ldquoDiludine [Themethod to obtain 35-dicarbonylderivatives of 26-dimethyl-14-dihydropyridines]rdquo Authors certificate of USSR no 3004651971 [Byull Izobret no13 p 95 1971] and following patentsPatent of England no 1294650 1973 Patent of France no2055458 1971 Patent of Japan no 702883 1973 Patent ofHolland no 149787 1976 Patent of Italy no 969022 1974 Patentof FRG no 2036403 1978 US Patent no 3883673 1975 USPatent no 3948924 1976
[42] S A Giller G Y Dubur Y R Uldrikis et al ldquoImprovementsin or relating to the stabilization of carotenerdquo GB Patent no1294650 1972
[43] S A Giller G Y Dubur Y R Uldrikis et al ldquoStabilization ofcarotenerdquo US Patent no 3883673 1975 Chemical Abstracts vol83 Article ID 95193 1975
[44] Yu A Zilber G Ya Dubur K K Kumsar and A Kh VelenaldquoThe effect of antioxidants on the peroxidation of bimole-cular phospholipid membranesrdquo Latvijas PSR ZA Vestis Izves-tia Akademii Nauk Latviyskoy SSR vol 6 pp 80ndash82 1971(Russian) translated from the original Russian Doc Accesion
No AD0771751 distributed by NTIS US Department of Com-merce httpwwwdticmildtictrfulltextu2771751pdf
[45] G Ya Dubur Yu A Zilbers A Kh Velena A O Kumerovaand G D Tirzitis ldquoMultistage study of regulation of peroxida-tion processes in biological membranes by antioxidants of 14-dihydropyridine grouprdquo Izvestiya Akademii Nauk LatviyskoySSR vol 336 no 7 pp 65ndash68 1975 (Russian)
[46] R P Mason and M W Trumbore ldquoDifferential membraneinteractions of calcium channel blockers Implications forantioxidant activityrdquo Biochemical Pharmacology vol 51 no 5pp 653ndash660 1996
[47] R P Mason M F Walter M W Trumbore E G Olmstead Jrand P E Mason ldquoMembrane antioxidant effects of the chargeddihydropyridine calcium antagonist amlodipinerdquo Journal ofMolecular and Cellular Cardiology vol 31 no 1 pp 275ndash2811999
[48] R PMason I T MakMW Trumbore and P EMason ldquoAnti-oxidant properties of calcium antagonists related to membranebiophysical interactionsrdquo American Journal of Cardiology vol84 no 4 pp 16ndash22 1999
[49] R PMasonMW Trumbore and P EMason ldquoMembrane bio-physical interaction of amlodipine and antioxidant propertiesrdquoDrugs vol 59 no 2 pp 9ndash16 2000 (French)
[50] R P Mason P Marche and T H Hintze ldquoNovel vascularbiology of third-generation L-type calcium channel antagonistsAncillary actions of amlodipinerdquo Arteriosclerosis Thrombosisand Vascular Biology vol 23 no 12 pp 2155ndash2163 2003
[51] A Augustyniak G Bartosz A Cipak et al ldquoNatural andsynthetic antioxidants an updated overviewrdquo Free RadicalResearch vol 44 no 10 pp 1216ndash1262 2010
[52] T Grune N Zarkovic and K Kostelidou ldquoLipid peroxidationresearch in Europe and the COST B35 action lsquoLipid Peroxida-tion Associated Disordersrsquordquo Free Radical Research vol 44 no10 pp 1095ndash1097 2010
[53] E Carosati P Ioan M Micucci et al ldquo14-Dihydropyridinescaffold in medicinal chemistry the story so far and perspec-tives (part 2) action in other targets and antitargetsrdquo CurrentMedicinal Chemistry vol 19 no 25 pp 4306ndash4323 2012
[54] U Eisner and J Kuthan ldquoThe chemistry of dihydropyridinesrdquoChemical Reviews vol 72 no 1 pp 1ndash42 1972 httpwwwsci-encemadnessorgtalkfilesphppid=138742ampaid=6475
[55] J Kuthan and A Kurfurst ldquoDevelopment in dihydropyri-dine chemistryrdquo Industrial amp Engineering Chemistry ProductResearch and Development vol 21 no 2 pp 191ndash261 1982
[56] A Sausins and G Duburs ldquoSynthesis of 14-dihydropyridinesby cyclocondensation reactionsrdquo Heterocycles vol 27 no 1 pp269ndash289 1988
[57] A E Sausins and G Y Duburs ldquoSynthesis of 14-dihydro-pyridines in cyclocondensation reactions (review)rdquo Chemistryof Heterocyclic Compounds vol 28 no 4 pp 363ndash391 1992Translated from Khimiya Geterotsiklicheskikh Soedinenii no 4pp 435ndash467 1992 (Russian)
[58] S Kazda ldquoTwenty years of dihydropyridinesrdquo in Dihydropy-ridines Progress in Pharmacology and Therapy W-D Busse BGarthoff and F Seuter Eds pp 1ndash12 Springer Verlag BerlinGermany 1993
[59] J-P Wan and Y Liu ldquoRecent advances in new multicomponentsynthesis of structurally diversified 14-dihydropyridinesrdquo RSCAdvances vol 2 no 26 pp 9763ndash9777 2012
[61] Reaxys Database[62] J Tuttle ldquoStructure mechanism and reactivity of hantzsch
estersrdquo in MacMillan Lab Group Meeting (082504) p 332004 httpwwwprincetoneduchemistrymacmillangroup-meetingsJBT20Hantzschpdf
[63] A Saini S Kumar and J S Sandhu ldquoHantzsch reaction recentadvances in Hantzsch 14-dihydropyridinesrdquo Journal of Sci-entific amp Industrial Research vol 67 pp 95ndash111 2008
[64] L LW Cheung S A Styler and A P Dicks ldquoRapid and conve-nient synthesis of the 14-dihydropyridine privileged structurerdquoJournal of Chemical Education vol 87 no 6 pp 628ndash630 2010
[65] A Kumar R A Maurya S Sharma M Kumar and G BhatialdquoSynthesis and biological evaluation of N-aryl-14-dihydro-pyridines as novel antidyslipidemic and antioxidant agentsrdquoEuropean Journal of Medicinal Chemistry vol 45 no 2 pp 501ndash509 2010
[66] R S Kumar A Idhayadhulla A J Abdul Nasser and J SelvinldquoSynthesis and anticoagulant activity of a new series of 14-dihydropyridine derivativesrdquo European Journal of MedicinalChemistry vol 46 no 2 pp 804ndash810 2011
[67] H A Stefani C B Oliveira R B Almeida et al ldquoDihydro-pyrimidin-(2H)-ones obtained by ultrasound irradiation anew class of potential antioxidant agentsrdquo European Journal ofMedicinal Chemistry vol 41 no 4 pp 513ndash518 2006
[68] H Sun C Shang L Jin and J Zhang ldquoSynthesis and antiox-idant activity of a series of novel 3-chalcone-substituted 14-dihydropyridine derivativesrdquoHeterocyclic Communications vol18 no 5-6 pp 239ndash243 2012
[69] D B Tikhonov and B S Zhorov ldquoStructural model for dihy-dropyridine binding to L-type calcium channelsrdquo The Journalof Biological Chemistry vol 284 no 28 pp 19006ndash19017 2009
[70] G Y Dubur and Y R Uldrikis ldquoThe oxidation of 14-dihydro-pyridinesrdquo Chemistry of Heterocyclic Compounds vol 6 no 1pp 80ndash84 1970 Translated from Khimiya GeterotsiklicheskikhSoedinenii no 1 pp 83ndash88 1970 (Russian)
[71] G Ya Duburs A O Kumerova and Ya R Uldrikis ldquoEnzymicoxidation of hydrogenated pyridines with peroxidase-hydrogenperoxide systemrdquoLatvijas PSRZAVestis vol 73 no 7 pp 73ndash771970 (Russian) Chemical Abstracts vol 73 Article ID 94913g1970
[72] K Xie Y-C Liu Y Cui J-GWang Y Fu andT CWMak ldquoN-methyl-(R)-3-(tert-butyl)-sulfinyl-14-dihydropyridine a novelNADHmodel compoundrdquoMolecules vol 12 no 3 pp 415ndash4222007
[73] S Tamagaki T Mimura and W Tagaki ldquoMetal-ion-facilitatedoxidations of dihydropyridines with molecular oxygen andhydrogen peroxiderdquo Journal of the Chemical Society PerkinTransactions 2 no 10 pp 1645ndash1650 1990
[74] D Tirzite G Tirzitis andD Antipova ldquoReductive ability of 14-dihydropyridine derivatives in relation to ions of trivalent ironrdquoChemistry of Heterocyclic Compounds vol 35 no 5 pp 592ndash594 1999
[76] J Ogle J Stradins and L Baumane ldquoFormation and decay offree cation-radicals in the course of electro-oxidation of 12- and14-dihydropyridines (Hantzsch esters)rdquo Electrochimica Actavol 39 no 1 pp 73ndash79 1994
[77] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for the
synthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts C Wittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Berlin Germany 2010
[78] WDu and Zh Yu ldquoBiomimetic in situ regeneration of cofactorsNAD(P)+ and NAD(P)H models hantzsch esters and dihy-drophenanthridinerdquo Synlett vol 23 no 9 pp 1300ndash1304 2012
[79] H K Chenault and G M Whitesides ldquoRegeneration ofnicotinamide cofactors for use in organic synthesisrdquo AppliedBiochemistry and Biotechnology vol 14 no 2 pp 147ndash197 1987
[80] Y R Uldrikis A A Zidermane E A Biseniex I E Preisa GY Dubur and G D Tirzit ldquoEsters of 26-dimethyl-14-dihydro-pyridine-35-dicarboxylic acid and method of obtainingthereofrdquo WO 8000345 A1 1978 httpworldwideespacenetcompublicationDetailsbiblioDB=EPODOCampII=1ampND=3ampadjacent=trueamplocale=en EPampFT=Dampdate=19800306ampCC=WOampNR=8000345A1ampKC=A1
[81] Y Sambongi H Nitta K Ichihashi M Futai and I Ueda ldquoAnovel water-soluble Hantzsch 14-dihydropyridine compoundthat functions in biological processes through NADH regener-ationrdquo Journal of Organic Chemistry vol 67 no 10 pp 3499ndash3501 2002
[82] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for thesynthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts ChWittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Verlag Berlin Germany 2010
[83] T Okamura T Kikuchi A Nagamine et al ldquoAn approach formeasuring in vivo cerebral redox states using the oxidative con-version of dihydropyridine to pyridinium ion and themetabolictrapping principlerdquo Free Radical Biology and Medicine vol 38no 9 pp 1197ndash1205 2005
[84] K A Schellenberg and F H Westheimer ldquoA free-radicaloxidation of a dihydropyridine1ardquo The Journal of OrganicChemistry vol 30 no 6 pp 1859ndash1862 1965
[85] K A Schellenberg ldquoReaction of hydroxyl radical with thymi-dine Scavenging by a dihydropyridinerdquo Federation Proceedingsvol 38 no 3 I p 1433 1979
[86] E S Huyser J A K Harmony and F L McMillian ldquoPeroxideoxidations of dihydropyridine derivativesrdquo Journal of the Amer-ican Chemical Society vol 94 no 9 pp 3176ndash3180 1972
[87] A Sakamoto S T Ohnishi and R Ogawa ldquoInhibition of lipidperoxidation by some dihydropyridine derivativesrdquo Journal ofAnesthesia vol 7 no 2 pp 193ndash197 1993
[88] R Hardeland ldquoReview Neuroprotection by radical avoidancesearch for suitable agentsrdquo Molecules vol 14 no 12 pp 5054ndash5102 2009
[89] G Ya Dubur A Kh Velena V M Gukasov and Yu AVladimirov ldquoRegulation of peroxidation of mitochondrialmembrane lipids initiated by Fe2+ ions by antoxidants of the14-dihydropyridine series in experiments in vitrordquo Biomed-itsinskaya Khimiya vol 22 no 5 pp 665ndash673 1976 (Russian)Chemical Abstracts vol 88 Article ID 2640 1977
[90] G RMMHaenenM J T J Arts A Bast andMD ColemanldquoStructure and activity in assessing antioxidant activity in vitroand in vivo a critical appraisal illustrated with the flavonoidsrdquoEnvironmental Toxicology and Pharmacology vol 21 no 2 pp191ndash198 2006
[91] G Tirzitis and G Bartosz ldquoDetermination of antiradical andantioxidant activity basic principles and new insightsrdquo ActaBiochimica Polonica vol 57 no 2 pp 139ndash142 2010
30 Oxidative Medicine and Cellular Longevity
[92] G R Buettner and R P Mason ldquoSpin-trapping methods fordetecting superoxide and hydroxyl free radicals in vitro and invivordquo inCritical Reviews of Oxidative Stress and Aging Advancesin Basic Science Diagnostics and Intervention R G Cutler andH Rodriguez Eds vol 1 chapter 2 pp 27ndash38World ScientificLondon UK 2003
[93] M M Tarpey and I Fridovich ldquoMethods of detection ofvascular reactive species Nitric oxide superoxide hydrogenperoxide and peroxynitriterdquo Circulation Research vol 89 no3 pp 224ndash236 2001
[94] E Y Kazush E I Sagun G D Tirzit and G Y DaburldquoQuenching of singlet oxygen by electron donating derivativesof 14-dihydropyridinerdquo Chemistry of Heterocyclic Compoundsvol 30 no 5 pp 562ndash563 1994
[95] G Tirzitis E Kazush and G Duburs ldquoReaction of 14-dihydropyridine derivatives with peroxynitrite anionrdquo Chem-istry of Heterocyclic Compounds vol 34 no 3 pp 321ndash3231998 (Russian) Translated from Khimiya GeterotsiklicheskikhSoedinenii no 3 pp 355ndash357 1998
[96] L J Nunez-Vergara C Lopez-Alarcon P A Navarrete-EncinaA M Atria C Camargo and J A Squella ldquoElectrochemicaland EPR characterization of 14-dihydropyridines Reactivitytowards alkyl radicalsrdquo Free Radical Research vol 37 no 1 pp109ndash120 2003
[97] D Tirzite A Krauze A Zubareva G Tirzitis and G DubursldquoSynthesis and antiradical activity of 5-acetyl-2-alkylthio-4-aryl-6-methyl-14-dihydropyridine-3-carboxylic acid nitrilesrdquoChemistry of Heterocyclic Compounds vol 38 no 7 pp 795ndash800 2002
[98] H Ohkawa N Ohishi and K Yagi ldquoAssay for lipid peroxidesin animal tissues by thiobarbituric acid reactionrdquo AnalyticalBiochemistry vol 95 no 2 pp 351ndash358 1979
[99] N Zarkovic ldquo4-Hydroxynonenal as a bioactive marker ofpathophysiological processesrdquo Molecular Aspects of Medicinevol 24 no 4-5 pp 281ndash291 2003
[100] M Parola G Bellomo G Robino G Barrera and M UDianzani ldquo4-Hydroxynonenal as a biological signal molecularbasis and pathophysiological implicationsrdquo Antioxidants andRedox Signaling vol 1 no 3 pp 255ndash284 1999
[101] T Lovakovic M Poljak-Blazi G Duburs et al ldquoGrowthmodulation of human cells in vitro by mild oxidative stressand 14-dihydropyridine derivative antioxidantsrdquo CollegiumAntropologicum vol 35 no 1 pp 137ndash141 2011
[102] R van den Berg G R M M Haenen H van den Bergand A Bast ldquoApplicability of an improved Trolox equivalentantioxidant capacity (TEAC) assay for evaluation of antioxidantcapacity measurements of mixturesrdquo Food Chemistry vol 66no 4 pp 511ndash517 1999
[103] C Lopez-Alarcon P Navarrete C Camargo J A Squella andL J Nunez-Vergara ldquoReactivity of 14-dihydropyridines towardalkyl alkylperoxyl radicals and ABTS radical cationrdquo ChemicalResearch in Toxicology vol 16 no 2 pp 208ndash215 2003
[104] V Valenzuela P Santander C Camargo J A Squella C Lopez-Alarcon and L J Nunez-Vergara ldquo14-Dihydropyridines reac-tivity of nitrosoaryl and nitroaryl derivatives with alkylperoxylradicals andABTS radical cationrdquo Free Radical Research vol 38no 7 pp 715ndash727 2004
[105] L G Tsetlin N A Chebotareva B I Kurganov A K VelenaG Y Dubur and V Z Lankin ldquoStudy of 14-dihydropyridinesas lipoxygenase inhibitors with the use of hydrated reversedmicellesrdquo Pharmaceutical Chemistry Journal vol 22 no 6 pp425ndash428 1988 (Russian)
[106] J Panek Z Reblova L Kocirkova et al ldquoAntioxidant activityof dihydropyridine derivativesrdquo Czech Journal of Food Sciencesvol 18 pp 144ndash145 2000
[107] G Tirzitis I Kirule and G Duburs ldquoAntioxidationsaktivitatder 35-dicarbonylderivate des 26-demethyl-14-dihydropyri-dinsrdquo Fett Wissenschaft TechnologieFat Science Technology vol90 no 10 pp 411ndash413 1988
[108] M Plotniece G Tirzitis Y Uldrikis et al ldquoSynthesis of 14-dihydropyridine derivatives having an oxy- alkoxy- or dimeth-ylaminophenyl substituent in the 4 position their antioxidantactivity and their binding to phospholipid membranesrdquo Chem-istry of Heterocyclic Compounds vol 32 no 10 pp 1166ndash11721996 Translated from Khimiya Geterotsiklicheskikh Soedineniino 10(352) pp 1358ndash1365 1996 (Russian)
[109] D Y Rubene V S Sharov V I Olenev G D Tirzit G Y Duburand Y A Vladimirov ldquoUse of chemiluminescent method forthe evaluation of antioxidant activity of some derivatives of 14-dihydropyridinerdquo Russian Journal of Physical Chemistry A vol55 no 2 pp 511ndash512 1981 (Russian)
[110] M C R Symons and JM C Gutteridge Free Radicals and IronChemistry Biology and Medicine Oxford Science PublicationsOxford University Press Oxford UK 1998
[111] M Repetto J Semprine and A Boveris ldquoLipid peroxidationchemical mechanism biological implications and analyticaldeterminationrdquo in Lipid Peroxidation A Catala Ed Section ILipid Peroxidation Chemical Mechanisms Antioxidants Bio-logical Implications of Biochemistry Genetics and MolecularBiology chapter 1 pp 3ndash30 InTech Rijeka Croatia 2012
[112] A Velena J Zilbers and G Duburs ldquoDerivatives of 14-dihydropyridines asmodulators of ascorbate-induced lipid per-oxidation and high-amplitude swelling ofmitochondria causedby ascorbate sodium linoleate and sodiumpyrophosphaterdquoCellBiochemistry and Function vol 17 no 4 pp 237ndash252 1999
[113] M V Bilenko L N Shelenkova G Y Dubur and A K VelenaldquoUse of antioxidants to prevent renal damage during acuteischemia and reperfusionrdquo Bulletin of Experimental Biology andMedicine vol 96 no 3 pp 1195ndash1198 1983 Translated fromByulletenrsquo Eksperimentalrsquonoi Biologii i Meditsiny vol 96 no 9pp 8ndash11 1983 (Russian)
[114] R Toniolo F Tubaro F Ursini and G Bontempelli ldquoAn elec-troanalytical investigation on the redox properties of calciumantagonist dihydropyridinesrdquo Electroanalysis vol 15 no 10 pp855ndash861 2003
[115] L Kourimska J Pokorny and G Tirzitis ldquoThe antioxidant aci-tivity of 26-dimethyl-35-diethoxycarbonyl-14-dihydropyri-dine in edible oilsrdquo Nahrung vol 37 no 1 pp 91ndash93 1993
[116] C Lopez-Alarcon H Speisky J A Squella C Olea-Azar CCamargo and L J Nunez-Vergara ldquoReactivity of 14-dihydro-pyridines toward SIN-1-derived peroxynitriterdquo PharmaceuticalResearch vol 21 no 10 pp 1750ndash1757 2004
[117] R A Olek W Ziolkowski J J Kaczor L Greci J Popinigisand J Antosiewicz ldquoAntioxidant activity of NADH and its ana-loguemdashan in vitro studyrdquo Journal of Biochemistry andMolecularBiology vol 37 no 4 pp 416ndash421 2004
[118] E Niki N Noguchi and N Gotoh ldquoInhibition of oxidativemodification of low density lipoprotein by antioxidantsrdquo Jour-nal of Nutritional Science andVitaminology vol 39 supplementpp S1ndashS8 1993
[119] N Rojstaczer and D J Triggle ldquoStructure-function relation-ships of calcium antagonists effect on oxidative modificationof low density lipoproteinrdquo Biochemical Pharmacology vol 51no 2 pp 141ndash150 1996
Oxidative Medicine and Cellular Longevity 31
[120] A Sevanian L Shen and FUrsini ldquoInhibition of LDLoxidationand oxidized LDL-induced cytotoxicity by dihydropyridinecalcium antagonistsrdquo Pharmaceutical Research vol 17 no 8 pp999ndash1006 2000
[121] A Negre-Salvayre and R Salvayre ldquoProtection by Ca2+ channelblockers (nifedipine diltiazem and verapamil) against the tox-icity of oxidized low density lipoprotein to cultured lymphoidcellsrdquo British Journal of Pharmacology vol 107 no 3 pp 738ndash744 1992
[122] A Negre-Salvayre G FitoussiM Troly and R Salvayre ldquoCom-parative cytoprotective effect of dihydropyridine calcium chan-nel blockers against the toxicity of oxidized low density lipopro-tein for cultured lymphoid cellsrdquo Biochemical Pharmacologyvol 44 no 12 pp 2379ndash2386 1992
[123] L Cominacini A F Pasini U Garbin et al ldquoAntioxidant activ-ity of different dihydropyridinesrdquo Biochemical and BiophysicalResearch Communications vol 302 no 4 pp 679ndash684 2003
[124] L Cominacini U Garbin A Fratta Pasini et al ldquoOxidized low-density lipoprotein increases the production of intracellularreactive oxygen species in endothelial cells inhibitory effect oflacidipinerdquo Journal of Hypertension vol 16 no 12 part 2 pp1913ndash1919 1998
[125] H M Lander ldquoAn essential role for free radicals and derivedspecies in signal transductionrdquo The FASEB Journal vol 11 no2 pp 118ndash124 1997
[126] M L L Martinez E Rizzi M M Castro et al ldquoLercanidipinedecreases vascular matrix metalloproteinase-2 activity andprotects against vascular dysfunction in diabetic ratsrdquo EuropeanJournal of Pharmacology vol 599 no 1ndash3 pp 110ndash116 2008
[127] P Lesnik C Dachet L Petit et al ldquoImpact of a combinationof a calcium antagonist and a 120573-blocker on cell- and copper-mediated oxidation of LDL and on the accumulation and effluxof cholesterol in human macrophages and murine J774 cellsrdquoArteriosclerosis Thrombosis and Vascular Biology vol 17 no 5pp 979ndash988 1997
[128] G Sobal E J Menzel and H Sinzinger ldquoCalcium antagonistsas inhibitors of in vitro low density lipoprotein oxidation andglycationrdquoBiochemical Pharmacology vol 61 no 3 pp 373ndash3792001
[129] E Lupo R Locher B Weisser and W Vetter ldquoIn vitro antiox-idant activity of calcium antagonists against LDL oxidationcompared with 120572-tocopherolrdquo Biochemical and BiophysicalResearch Communications vol 203 no 3 pp 1803ndash1808 1994
[130] J Zou Y Li H-Q Fan and J-G Wang ldquoEffects of dihydropy-ridine calcium channel blockers on oxidized low-density lipo-protein induced proliferation and oxidative stress of vascularsmooth muscle cellsrdquo BMC Research Notes vol 5 article 1682012
[131] C Napoli S Salomone T Godfraind et al ldquo14-Dihydro-pyridine calcium channel blockers inhibit plasma and LDL oxi-dation and formation of oxidation-specific epitopes in the arte-rial wall and prolong survival in stroke-prone spontaneouslyhypertensive ratsrdquo Stroke vol 30 no 9 pp 1907ndash1915 1999
[132] G Zernig I Graziadei T Moshammer C Zech N Reider andH Glossmann ldquoMitochondrial Ca2+ antagonist binding sitesare associated with an inner mitochondrial membrane anionchannelrdquo Molecular Pharmacology vol 38 no 3 pp 362ndash3691990
[133] F E Hunter Jr A Scott P E Hochstein et al ldquoStudies of themechanism of ascorbate-induced swelling and lysis of isolatedliver mitochondriardquo The Journal of Biological Chemistry vol239 pp 604ndash613 1964
[134] D R Janero B Burghardt and R Lopez ldquoProtection of cardiacmembrane phospholipid against oxidative injury by calciumantagonistsrdquoBiochemical Pharmacology vol 37 no 21 pp 4197ndash4203 1988
[135] A Karadag B Ozcelik and S S Saner ldquoReview of methods todetermine antioxidant capacitiesrdquo FoodAnalyticalMethods vol2 no 1 pp 41ndash60 2009
[136] Y I Gubskiı N V Litvinova and E V Shnurko-TabakovaldquoAntioxidant and antiradical activity of various classes of antiox-idantsrdquo Ukrainskiı Biokhimicheskiı Zhurnal vol 66 no 4 pp114ndash116 1994 (Russian)
[137] M Takei M Hiramatsu and A Mori ldquoInhibitory effects ofcalcium antagonists onmitochondrial swelling induced by lipidperoxidation or arachidonic acid in the rat brain in vitrordquoNeurochemical Research vol 19 no 9 pp 1199ndash1206 1994
[138] M Takei M Hiramatsu R Edamatsu and A Mori ldquoFreeradical scavenging by calcium antagonistsrdquo Neurosciences vol20 no 2 pp 75ndash82 1994
[139] Ya P Stradin G Ya Dubur Yu A Beilis Ya R Uldrikis andA F Korotkova ldquoVoltammetry of 14-dihydropyridine deriva-tives I Potentials of electrochemical oxidation of 35-diacyl-and 35-di(alkoxycarbonyl)-14-dihydropyridines in acetoni-trilerdquo Chemistry of Heterocyclic Compounds no 1 pp 84ndash871972 (Russian)
[140] E V Ivanov T V Ponomarjova G N Merkusev et al ldquoEinneuer Haut-Radioprotektor Diethon (experimentelle Unter-suchung)rdquo Radiobiologia Radiotherapia vol 31 no 1 pp 69ndash78 1990
[141] E V Ivanov T V Ponomareva G N Merkushev et al ldquoRadia-tion modulating properties of derivates of 14-dihydropyridineand 12345678910-decahydroacridine-18 dionerdquo Radiat-sionnaia Biologiia Radioecologiia vol 44 no 5 pp 550ndash5592004 (Russian)
[142] R O Vitolinia D A Berzinia A K Velena I A Vutsina A AKimenis and G Y Duburs ldquoThe protective effects of the cal-cium antagonist foridon in acute myocardial ischaemiardquo Kardi-ologiya vol 27 no 3 pp 90ndash93 1987 (Russian)
[143] A H Velena G Ya Duburs R O Vitolina et al ldquoEffect ofryodipine on electromechanical parameters of heart and vesselscAMP phosphodiesterase activity and swelling-contractioncycle of mitochondriardquo Arzneimittelforschung vol 35 no 6 pp907ndash914 1985
[144] L I Utno Z E Lipsberga A A Silova M I Girgensone EA Bisenieks and G I Ia ldquoCardioprotective properties of a 14-dihydropyridine derivative glutapyrone in deep hypothermiardquoBiulletenrsquo Eksperimentalrsquonoı Biologii i Meditsiny vol 108 no 11pp 558ndash561 1989 (Russian)
[145] M A S FernandesM S Santos J A F Vicente et al ldquoEffects of14-dihydropyridine derivatives (cerebrocrast gammapyroneglutapyrone and diethone) onmitochondrial bioenergetics andoxidative stress a comparative studyrdquoMitochondrion vol 3 no1 pp 47ndash59 2003
[146] M A S Fernandes M S Santos A J M Moreno et al ldquoEffectsof 5-acetyl(carbamoyl)-6-methylsulfanyl-14-dihydropyridine-5-carbonitriles on rat liver mitochondrial functionrdquo Toxicologyin Vitro vol 23 no 7 pp 1333ndash1341 2009
[147] L Klimaviciusa A Kalda A Kaasik et al ldquoNeuroprotectiveactivity of 14-dihydropyridine derivatives structure determi-nantsrdquo Proceedings of the Latvian Academy of Sciences BNatural Exact and Applied Sciences vol 61 no 1-2 pp 33ndash372007
32 Oxidative Medicine and Cellular Longevity
[148] L Klimaviciusa M A S Fernandes N Lencberga et alldquoTargeting the mitochondria by novel adamantane-containing14-dihydropyridine compoundsrdquo in Bioenergetics K B ClarkEd pp 257ndash272 InTech 2012
[149] V Klusa L Klimaviciusa G Duburs J Poikans and AZharkovsky ldquoAnti-neurotoxic effects of tauropyrone a taurineanaloguerdquo Advances in Experimental Medicine and Biology vol583 pp 499ndash508 2006
[150] N Sampson P Berger and Ch Zenzmaier ldquoRedox signalingas a therapeutic target to inhibit myofibroblast activation indegenerative fibrotic diseaserdquo BioMed Research Internationalvol 2014 Article ID 131737 14 pages 2014
[151] T L Leto and M Geiszt ldquoRole of Nox family NADPH oxidasesin host defenserdquoAntioxidantsampRedox Signaling vol 8 no 9-10pp 1549ndash1561 2006
[152] K K Griendling D Sorescu and M Ushio-Fukai ldquoNAD(P)Hoxidase role in cardiovascular biology and diseaserdquo CirculationResearch vol 86 no 5 pp 494ndash501 2000
[153] H Chen Y S Song and P H Chan ldquoInhibition of NADPHoxi-dase is neuroprotective after ischemia-reperfusionrdquo Journal ofCerebral Blood Flow and Metabolism vol 29 no 7 pp 1262ndash1272 2009
[154] P Hochstein and L Ernster ldquoADP-activated lipid peroxidationcoupled to the TPNH oxidase system of microsomesrdquo Biochem-ical and Biophysical Research Communications vol 12 no 5 pp388ndash394 1963
[155] I I Gubskiı AGGoriushkoNV Litvinova et al ldquoAntioxidantproperties and membranotropic effect of certain derivatives of14-dihydropyridinerdquo Ukrainskiı Biokhimicheskiı Zhurnal vol71 no 4 pp 35ndash39 1999 (Russian)
[156] F Engineer and R Sridhar ldquoInhibition of rat heart andliver microsomal lipid peroxidation by nifedipinerdquo BiochemicalPharmacology vol 38 no 8 pp 1279ndash1285 1989
[157] T Goncalves A P Carvalho and C R Oliveira ldquoAntioxidanteffect of calcium antagonists on microsomai membranes iso-lated from different brain areasrdquo European Journal of Pharma-cology vol 204 no 3 pp 315ndash322 1991
[158] M E Letelier P Izquierdo L Godoy A M Lepe and MFaundez ldquoLiver microsomal biotransformation of nitro-aryldrugs mechanism for potential oxidative stress inductionrdquoJournal of Applied Toxicology vol 24 no 6 pp 519ndash525 2004
[159] M E Letelier P Entrala C Lopez-Alarcon et al ldquoNitroaryl-14-dihydropyridines as antioxidants against rat liver microsomesoxidation induced by ironascorbate Nitrofurantoin and naph-thalenerdquo Toxicology in Vitro vol 21 no 8 pp 1610ndash1618 2007
[160] F P Guengerich W R Brian M Iwasaki M-A Sari CBaarnhielm and P Berntsson ldquoOxidation of dihydropyridinecalcium channel blockers and analogues by human liver cyto-chrome P-450 IIIA4rdquo Journal of Medicinal Chemistry vol 34no 6 pp 1838ndash1844 1991
[161] S H Park S-W RhaW-Y Shin et al ldquoAS-160 Calcium channelblockers of dihydropyridine class reduce the antiplatelet effectof Clopidogrel what is clinical impactrdquo The American Journalof Cardiology vol 107 no 8 supplement p 47A 2011
[162] C Asma and D M Reda ldquoEvaluation of dihydropyridinecalcium antagonist effects on the stress bioindicator orga-nism Saccharomyces cerevisiaerdquo Annals of Biological Researchvol 4 no 10 pp 40ndash46 2013 httpscholarsresearchlibrarycomABR-vol4-iss10ABR-2013-4-10-40-46pdf
[163] G Gaviraghi A M Pastorino E Ratti and D G TristldquoCalcium channel blockers with antioxidant activityrdquo in Free
Radicals Lipoprotein Oxidation andAtherosclerosis G BellomoG Finardi E Maggi and E Rice-Evans Eds pp 431ndash456Richelieu Press London UK 1995
[164] G Gaviraghi AM Pastorino E Ratti and D G Trist ldquoAntiox-idant dihydropyridines a new and comprehensive therapy forfree radical-induced cardiovascular diseasesrdquo in Free Radicalsin Biology and Environment F Minisci Ed vol 27 of NATOASI Series pp 193ndash221 Springer Dordrecht The Netherlands1997
[165] P D Henry ldquoAntiperoxidative actions of calcium antagonistsand atherogenesisrdquo Journal of Cardiovascular Pharmacologyvol 18 supplement 1 pp S6ndashS10 1991
[166] F Kouoh B Gressier T Dine et al ldquoAntioxidant effects andanti-elastase activity of the calcium antagonist nicardipine onactivated human and rabbit neutrophilsmdasha potential antiath-erosclerotic property of calcium antagonistsrdquo CardiovascularDrugs andTherapy vol 16 no 6 pp 515ndash520 2002
[167] S Parthasarathy D Litvinov K Selvarajan and M GarelnabildquoLipid peroxidation and decompositionmdashconflicting roles inplaque vulnerability and stabilityrdquo Biochimica et BiophysicaActa vol 1781 no 5 pp 221ndash231 2008
[168] D-Q Liu Z-Q Pang D-H Zhao and B-H Sheng ldquoEffects offuryl-dihydropyridines I on lipid peroxides of ischemic myo-cardium and ATPases activity of erythrocyte membranes inratsrdquo Acta Pharmacologica Sinica vol 12 no 3 pp 253ndash2561991
[169] V Lukic-Panin T Kamiya H Zhang et al ldquoPrevention of neu-ronal damage by calcium channel blockers with antioxidativeeffects after transient focal ischemia in ratsrdquo Brain Research vol1176 no 1 pp 143ndash150 2007
[170] Y Allanore D Borderie H Lemarechal O G Ekindjian andA Kahan ldquoAcute and sustained effects of dihydropyridine-typecalcium channel antagonists on oxidative stress in systemicsclerosisrdquo American Journal of Medicine vol 116 no 9 pp 595ndash600 2004
[171] I Casetta V Govoni and E Granieri ldquoOxidative stress antioxi-dants and neurodegenerative diseasesrdquo Current PharmaceuticalDesign vol 11 no 16 pp 2033ndash2052 2005
[172] M J T J Arts Assessing antioxidant activity [PhD the-sis] Maastricht University Maastricht The Netherlands 2007httparnounimaasnlshowcgifid=8676
[173] G Dıaz-Araya L Godoy L Naranjo A Squella M E Letelierand L J Nunez-Vergara ldquoAntioxidant effects of 14-dihydro-pyridine and nitroso aryl derivatives on the Fe+3ascorbate-stimulated lipid peroxidation in rat brain slicesrdquo General Phar-macology The Vascular System vol 31 no 3 pp 385ndash391 1998
[174] Y Fukuhara K Tsuchiya Y Horinouchi et al ldquoProtectiveeffect of photodegradation product of nifedipine against tumornecrosis factor 120572-induced oxidative stress in human glomerularendothelial cellsrdquo Journal of Medical Investigation vol 58 no1-2 pp 118ndash126 2011
[175] W Stengel M Jainz and K Andreas ldquoDifferent potencies ofdihydropyridine derivatives in blocking T-type but not L-typeCa2+ channels in neuroblastoma-glioma hybrid cellsrdquo EuropeanJournal of Pharmacology vol 342 no 2-3 pp 339ndash345 1998
[176] O M Panasenko D J Tirzite G D Tirzitis and G J DubursldquoEffect of some 14-dihydropyridine derivatives on structuralorganization of erythrocyte membranesrdquo Biologicheskie Mem-brany (Biochemistry (Moscow) Series A Membrane and CellBiology) vol 1 pp 919ndash925 1984 (Russian)
[177] L G Herbette Y M H Vant Erve and D G Rhodes ldquoInter-action of 14 dihydropyridine calcium channel antagonists with
Oxidative Medicine and Cellular Longevity 33
biological membranes lipid bilayer partitioning could occurbefore drug binding to receptorsrdquo Journal of Molecular andCellular Cardiology vol 21 no 2 pp 187ndash201 1989
[178] L G Herbette P E Mason G Gaviraghi T N Tulenko andR P Mason ldquoThe molecular basis for lacidipinersquos unique phar-macokinetics optimal hydrophobicity results in membraneinteractions that may facilitate the treatment of atherosclerosisrdquoJournal of Cardiovascular Pharmacology vol 23 supplement 5pp S16ndashS25 1994
[179] G V Belevitch G Y Dubur G E Dobretsov N K Kurek andM M Spirin ldquoCalcium antagonists riodipine nifedipine andverapamil binding to model and biological membranes fluore-scence analysisrdquo Biologicheskie Membrany (Biochemistry(Moscow) Series A Membrane and Cell Biology) vol 5 pp768ndash776 1988 (Russian)
[180] R P Mason G E Gonye D W Chester and L G HerbetteldquoPartitioning and location of Bay K 8644 14-dihydropyridinecalcium channel agonist in model and biological membranesrdquoBiophysical Journal vol 55 no 4 pp 769ndash778 1989
[181] M Cindric A Cipak J Serly et al ldquoReversal of multidrugresistance inmurine lymphoma cells by amphiphilic dihydropy-ridine antioxidant derivativerdquo Anticancer Research vol 30 no10 pp 4063ndash4070 2010
[182] F Shekari H Sadeghpour K Javidnia et al ldquoCytotoxic andmultidrug resistance reversal activities of novel 14-dihydro-pyridines against human cancer cellsrdquo European Journal ofPharmacology vol 746 no 1 pp 233ndash244 2015
[183] X-F Zhou Q Shao R A Coburn and M E Morris ldquoQuanti-tative structure-activity relationship and quantitative structure-pharmacokinetics relationship of 14-dihydropyridines andpyridines as multidrug resistance modulatorsrdquo PharmaceuticalResearch vol 22 no 12 pp 1989ndash1996 2005
[184] R Berkels T Breitenbach H Bartels et al ldquoDifferent antioxida-tive potencies of dihydropyridine calcium channel modulatorsin various modelsrdquo Vascular Pharmacology vol 42 no 4 pp145ndash152 2005
[185] S Borovic G Tirzitis D Tirzite et al ldquoBioactive 14-dihydro-isonicotinic acid derivatives prevent oxidative damage of livercellsrdquo European Journal of Pharmacology vol 537 no 1ndash3 pp12ndash19 2006
[186] D Ya Rubene G D Tirzitis and G Ya Duburs ldquoInteractionof some 14-dihydropyridine derivatives with Fentonrsquos reagentrdquoLatvijas PSRZinatnuAkademijas Vestis Kimijas Serija Proceed-ings of the Latvian SSR Academy of Sciences Chemistry Seriespp 212ndash216 1982 (Russian)
[187] K Ondrias V Misık D Gergel and A Stasko ldquoLipid per-oxidation of phosphatidylcholine liposomes depressed by thecalcium channel blockers nifedipine and verapamil and bythe antiarrhythmic-antihypoxic drug stobadinerdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1003 no 3pp 238ndash245 1989
[188] I T Mak and W B Weglicki ldquoComparative antioxidant acti-vities of propranolol nifedipine verapamil and diltiazemagainst sarcolemmal membrane lipid peroxidationrdquoCirculationResearch vol 66 no 5 pp 1449ndash1452 1990
[189] I T Mak P Boehme and W B Weglicki ldquoProtective effects ofcalcium channel blockers against free radical-impaired endo-thelial cell proliferationrdquo Biochemical Pharmacology vol 50 no9 pp 1531ndash1534 1995
[190] S Ray S Mondal and N Dana ldquoEvaluation of protective roleof nifedipine on lipid peroxidation using reduced glutathione as
model markerrdquo Oxidants and Antioxidants in Medical Sciencevol 1 no 2 pp 97ndash100 2012
[191] M Yamato T Shiba T Ide Y Honda K-I Yamada andH Tsutsui ldquoNifedipine treatment reduces brain damage aftertransient focal ischemia possibly through its antioxidativeeffectsrdquoHypertension Research vol 34 no 7 pp 840ndash845 2011
[192] V Chander and K Chopra ldquoNifedipine attenuates changes innitric oxide levels renal oxidative stress and nephrotoxicityinduced by cyclosporinerdquo Renal Failure vol 27 no 4 pp 441ndash450 2005
[193] K M Gaafa M M Badawy and A A Hamza ldquoThe protectiveeffects of ascorbic acid cimetidine and nifedipine on diethyl-dithiocarbamate-induced hepatic toxicity in albino ratsrdquo Drugand Chemical Toxicology vol 34 no 4 pp 405ndash419 2011
[194] H Sugawara K Tobise and S Onodera ldquoAbsence of antiox-idant effects of nifedipine and diltiazem on myocardial mem-brane lipid peroxidation in contrast with those of nisoldipineand propranololrdquo Biochemical Pharmacology vol 47 no 5 pp887ndash892 1994
[195] I E Kirule D Y Rubene E A Bisenieks G D Tirzit and GY Dubur ldquo4-Nitrophenyl-14-dihydropyridinesmdasha new groupof inhibitors of peroxide oxidationrdquo Chemistry of HeterocyclicCompounds vol 18 no 3 p 316 1982
[196] G D Tirzit I E Kirule L K Baumane R A Gavar Y PStradynrsquo andG YDubur ldquoMechanism of the antioxidant actionof 26-dimethyl-35-dimethoxy-carbonyl-4-(2-nitrophenyl)14-dihydropyridinerdquoChemistry ofHeterocyclic Compounds vol 20no 8 pp 915ndash918 1984
[197] C Yanez C Lopez-Alarcon C Camargo V Valenzuela J ASquella and L J Nunez-Vergara ldquoStructural effects on thereactivity 14-dihydropyridines with alkylperoxyl radicals andABTS radical cationrdquo Bioorganic and Medicinal Chemistry vol12 no 9 pp 2459ndash2468 2004
[198] VMisik A J Stasko D Gergel and K Ondrias ldquoSpin-trappingand antioxidant properties of illuminated and nonilluminatednifedipine and nimodipine in heart homogenate and modelsystemrdquo Molecular Pharmacology vol 40 no 3 pp 435ndash4391991
[199] K Ondrias V Misık A Stasko D Gergelrsquo and M HromadovaldquoComparison of antioxidant properties of nifedipine and illu-minated nifedipine with nitroso spin traps in low densitylipoproteins and phosphatidylcholine liposomesrdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1211 no 1pp 114ndash119 1994
[200] A Stasko V Brezova S Biskupic K Ondrias and V MisıkldquoReactive radical intermediates formed from illuminated nife-dipinerdquoFree Radical Biology andMedicine vol 17 no 6 pp 545ndash556 1994
[201] K Ishizawa Y Izawa-Ishizawa N Yamano et al ldquoNitrosoni-fedipine ameliorates the progression of type 2 diabetic nephro-pathy by exerting antioxidative effectsrdquo PLoS ONE vol 9 no 1Article ID e86335 2014
[202] H Fujii and L J Berliner ldquoIn vivo EPR evidence for free radicaladducts of nifedipinerdquoMagnetic Resonance in Medicine vol 42no 4 pp 691ndash694 1999
[203] S Bollo S Finger J C Sturm L J Nunez-Vergara and JA Squella ldquoCyclic voltammetry and scanning electrochemicalmicroscopy studies of the heterogeneous electron transferreaction of some nitrosoaromatic compoundsrdquo ElectrochimicaActa vol 52 no 15 pp 4892ndash4898 2007
34 Oxidative Medicine and Cellular Longevity
[204] F Ursini ldquoTissue protection by lacidipine insight from redoxbehaviorrdquo Journal of Cardiovascular Pharmacology vol 30supplement 2 pp S28ndashS30 1997
[205] P G Cristofori F A Crivellente I Faustinelli et al ldquoInvolve-ment of the nitric oxide system in the anti-atheroscleroticpotential of lacidipine in the apoE-deficient mouse a mor-phological functional and electrochemical studyrdquo ToxicologicPathology vol 32 no 4 pp 493ndash499 2004
[206] X-P Zhang E L Kit S Mital S Chahwala and T HHintze ldquoParadoxical release of nitric oxide by an L-type calciumchannel antagonist the R+ enantiomer of amlodipinerdquo Journalof Cardiovascular Pharmacology vol 39 no 2 pp 208ndash2142002
[207] F Franzoni G Santoro F Regoli et al ldquoAn in vitro study of theperoxyl and hydroxyl radical scavenging capacity of the calciumantagonist amlodipinerdquo Biomedicine and Pharmacotherapy vol58 no 8 pp 423ndash426 2004
[208] S V Gatsura ldquoOxygen-dependent mechanisms underlying theantiischemic effect of verapamil and amlodipinerdquo Bulletin ofExperimental Biology and Medicine vol 137 no 1 pp 40ndash422004
[209] Y Hirooka Y Kimura M Nozoe Y Sagara K Ito and KSunagawa ldquoAmlodipine-induced reduction of oxidative stressin the brain is associated with sympatho-inhibitory effects instroke-prone spontaneously hypertensive ratsrdquo HypertensionResearch vol 29 no 1 pp 49ndash56 2006
[210] B Tomlinson and I F F Benzie ldquoAntioxidant effect of lercani-dipine (note)rdquo Hypertension vol 42 no 4 pp e10ndashe11 2003
[211] A A Faraqui ldquoNeurochemical aspects of 4-hydroxynonenalrdquoin Lipid Mediators and Their Metabolism in the Brain A AFaraqui Ed chapter 6 pp 159ndash191 Springer New York NYUSA 2011
[212] V S NascimentoM S DrsquoAlva A AOliveira et al ldquoAntioxidanteffect of nimodipine in young rats after pilocarpine-inducedseizuresrdquo Pharmacology Biochemistry and Behavior vol 82 no1 pp 11ndash16 2005
[213] O Ismailoglu P Atilla S Palaoglu et al ldquoThe therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjuryrdquo Turkish Neurosurgery vol 22 no 6 pp 740ndash746 2012
[214] M Matsubara and K Hasegawa ldquoBenidipine a dihydropy-ridine-calcium channel blocker prevents lysophosphatidyl-choline-induced injury and reactive oxygen species productionin human aortic endothelial cellsrdquo Atherosclerosis vol 178 no1 pp 57ndash66 2005
[215] M Matsubara K Yao and K Hasegawa ldquoBenidipine adihydropyridine-calcium channel blocker inhibits lysophos-phatidylcholine-induced endothelial injury via stimulation ofnitric oxide releaserdquo Pharmacological Research vol 53 no 1 pp35ndash43 2006
[216] MMatsubara and K Hasegawa ldquoEffects of benidipine a dihyd-ropyridine-Ca2+ channel blocker on expression of cytokine-induced adhesion molecules and chemoattractants in humanaortic endothelial cellsrdquo European Journal of Pharmacology vol498 no 1ndash3 pp 303ndash314 2004
[217] M Matsubara O Akizuki J-I Ikeda K Saeki K Yao and KSasaki ldquoBenidipine an anti-hypertensive drug inhibits reactiveoxygen species production in polymorphonuclear leukocytesand oxidative stress in salt-loaded stroke-prone spontaneouslyhypertensive ratsrdquo European Journal of Pharmacology vol 580no 1-2 pp 201ndash213 2008
[218] A C Rosenkranz H Lob T Breitenbach R Berkels and RRoesen ldquoEndothelial antioxidant actions of dihydropyridines
and angiotensin converting enzyme inhibitorsrdquo European Jour-nal of Pharmacology vol 529 no 1ndash3 pp 55ndash62 2006
[219] V Kain S Kumar and S L Sitasawad ldquoAzelnidipine preventscardiac dysfunction in streptozotocin-diabetic rats by reducingintracellular calcium accumulation oxidative stress and apop-tosisrdquo Cardiovascular Diabetology vol 10 article 97 2011
[220] K Nakamura S Yamagishi and H Inoue ldquoUnique atheropro-tective property of azelnidipine a dihydropyridine-based cal-cium antagonistrdquoMedical Hypotheses vol 65 no 1 pp 155ndash1572005
[221] TMatsui S Yamagishi K Nakamura S Kikuchi andH InoueldquoAzelnidipine a dihydropyridine-based calcium antagonistinhibits angiotensin II-induced oxidative stress generation anddownregulation of pigment epithelium-derived factor mRNAlevels in microvascular endothelial cellsrdquo Drugs under Experi-mental and Clinical Research vol 31 no 5-6 pp 215ndash219 2005
[222] C Ohmura H Watada T Shimizu et al ldquoCalcium channelblocker azelnidipine reduces lipid hydroperoxides in patientswith type 2 diabetes independent of blood pressurerdquo EndocrineJournal vol 54 no 5 pp 805ndash811 2007
[223] H Daikuhara F Kikuchi and T Ishida ldquoThe combination ofOLmesartan and a CAlcium channel blocker (azelnidipine) orcandesartan and a calcium channel blocker (amlodipine) intype 2 diabetic hypertensive patients theOLCA studyrdquoDiabetesand Vascular Disease Research vol 9 no 4 pp 280ndash286 2012
[224] MAbe NMaruyama KOkada SMatsumoto KMatsumotoand M Soma ldquoAdditive antioxidative effects of azelnidipine onangiotensin receptor blocker olmesartan treatment for type 2diabetic patients with albuminuriardquoHypertension Research vol34 no 8 pp 935ndash941 2011
[225] K Mizushige ldquoAntioxidative activities of thiazolidinedionesand dihydropyridine-type calcium antagonistsrdquo IRYOmdashJapa-nese Journal of National Medical Services vol 59 no 11 pp 581ndash592 2005
[226] S Manabe T Okura T Fukuoka and J Higaki ldquoAntioxidativeeffects of azelnidipine on mesangial cell proliferation inducedby highly concentrated insulinrdquo European Journal of Pharma-cology vol 567 no 3 pp 252ndash257 2007
[227] Y Koyama Y Takeishi H Takahashi et al ldquoAzelnidipine inhi-bits H
2O2-induced cell death in neonatal rat cardiomyocytesrdquo
CardiovascularDrugs andTherapy vol 21 no 1 pp 69ndash72 2007[228] K Shinomiya K Mizushige M Fukunaga et al ldquoAntioxidant
effect of a new calcium antagonist azelnipidine in culturedhuman arterial endothelial cellsrdquo Journal of International Med-ical Research vol 32 no 2 pp 170ndash175 2004
[229] T Ohyama K Sato K Kishimoto et al ldquoAzelnidipine is acalcium blocker that attenuates liver fibrosis and may increaseantioxidant defencerdquo British Journal of Pharmacology vol 165no 4 pp 1173ndash1187 2012
[230] L A Calo F Zaghetto E Pagnin P A Davis A Sempliciniand A C Pessina ldquoEffect of manidipine on gene expressionand protein level of oxidative stress-related proteins p22phoxand HO-1 Relevance for antihypertensive and anti-remodelingeffectsrdquo Journal of Cardiovascular Pharmacology vol 43 no 4pp 531ndash538 2004
[231] R Ghyasi G Sepehri M Mohammadi R Badalzadeh and AGhyasi ldquoEffect of mebudipine on oxidative stress and lipid per-oxidation in myocardial ischemic-reperfusion injury in maleratrdquo Journal of Research in Medical Sciences vol 17 no 12 pp1150ndash1155 2012
Oxidative Medicine and Cellular Longevity 35
[232] DCAndersson J Fauconnier T Yamada et al ldquoMitochondrialproduction of reactive oxygen species contributes to the 120573-adrenergic stimulation of mouse cardiomycytesrdquoThe Journal ofPhysiology vol 589 no 7 pp 1791ndash1801 2011
[233] A F Ceylan-Isik N Ari M Stefek et al ldquoEffects of a long-term treatment with an antioxidant pyridoindole on vascularresponsiveness in diabetes-induced aging ratsrdquo Current AgingScience vol 4 no 2 pp 150ndash157 2011
[234] S Saponara G Sgaragli and F Fusi ldquoQuercetin antagonismof Bay K 8644 effects on rat tail artery L-type Ca2+ channelsrdquoEuropean Journal of Pharmacology vol 598 no 1ndash3 pp 75ndash802008
[235] D A Sica ldquoInteraction of grapefruit juice and calcium channelblockersrdquo American Journal of Hypertension vol 19 no 7 pp768ndash773 2006
[236] P Mulder G Litwinienko S Lin P D MacLean L R CBarclay and K U Ingold ldquoThe L-type calcium channel block-ers Hantzsch 14-dihydropyridines are not peroxyl radical-trapping chain-breaking antioxidantsrdquo Chemical Research inToxicology vol 19 no 1 pp 79ndash85 2006
[237] L J Nunez-Vergara R Salazar C Camargo et al ldquoOxidation ofC4-hydroxyphenyl 14-dihydropyridines in dimethylsulfoxideand its reactivity towards alkylperoxyl radicals in aqueousmediumrdquo Bioorganic and Medicinal Chemistry vol 15 no 12pp 4318ndash4326 2007
[238] M E Ortiz L J Nunez-Vergara and J A Squella ldquoRelativereactivity of dihydropyridine derivatives to electrogeneratedsuperoxide ion in DMSO solutions a voltammetric approachrdquoPharmaceutical Research vol 20 no 2 pp 292ndash296 2003
[239] M E Ortiz L J Nunez-Vergara C Camargo and J A SquellaldquoOxidation of Hantzsch 14-dihydropyridines of pharmacolog-ical significance by electrogenerated superoxiderdquo Pharmaceuti-cal Research vol 21 no 3 pp 428ndash435 2004
[240] R S Raghuvanshi and K N Singh ldquoSuperoxide induced oxida-tive aromatization of Hantzsch 14-dihydropyridinesrdquo IndianJournal of Chemistry Section B Organic and Medicinal Chem-istry vol 47 no 11 pp 1735ndash1738 2008
[241] I Kruk A Kladna K Lichszteld et al ldquoAntioxidant activityof 4-flavonil-14-dihydropyridine derivativesrdquo Biopolymers vol62 no 3 pp 163ndash167 2001
[242] G D Tirzit I M Byteva K I Salokhiddinov G P Gurinovichand G Y Dubur ldquo14-Dihydropyridine derivatives as deactiva-tors of singlet oxygenrdquo Chemistry of Heterocyclic Compoundsvol 17 no 7 pp 682ndash684 1981
[243] G D Tirzit E Y Kazush and G Y Dubur ldquoInfluence of14-dihydropyridine derivatives on the generation of hydroxylradicalsrdquo Chemistry of Heterocyclic Compounds vol 28 no 4pp 435ndash437 1992
[244] N A Pizarro-Urzua and L J Nunez-Vergara ldquoNifedipine andnitrendipine reactivity toward singlet oxygenrdquo Journal of Photo-chemistry and Photobiology A Chemistry vol 175 no 2-3 pp129ndash137 2005
[245] L-F Wang H-Y Zhang L Konga Z-W Chena and J-G ShildquoDFT calculations indicate that 14-dihydropyridine is a promis-ing lead antioxidantrdquo Helvetica Chimica Acta vol 87 no 6 pp1515ndash1521 2004
[246] P Mulder H-G Korth and K U Ingold ldquoWhy quantum-thermochemical calculations must be used with caution toindicate lsquoa promising lead antioxidantrsquordquoHelvetica Chimica Actavol 88 no 2 pp 370ndash374 2005
[247] K Yao Y Ina K Nagashima K Ohmori and T Ohno ldquoAntiox-idant effects of calcium antagonists in rat brain homogenatesrdquo
Biological and Pharmaceutical Bulletin vol 23 no 6 pp 766ndash769 2000
[248] T Matsui S-I Yamagishi K Nakamura and H Inoue ldquoBayw 9798 a dihydropyridine structurally related to nifedipinewith no calcium channel-blocking properties inhibits tumournecrosis factor-120572-induced vascular cell adhesion molecule-1expression in endothelial cells by suppressing reactive oxygenspecies generationrdquo Journal of International Medical Researchvol 35 no 6 pp 886ndash891 2007
[249] K AMitrega B VargheseM Porc and T F Krzeminski ldquoAnti-arrhythmic and hemodynamic effects of oxy nifedipine oxynimodipine oxy nitrendipine and oxy nisoldipinerdquo Pharmaco-logical Research vol 66 no 4 pp 300ndash308 2012
[250] V Herbert ldquoSymposium prooxidant effects of antioxidantvitamins Introductionrdquo The Journal of Nutrition vol 126 no4 supplement pp 1197Sndash1200S 1996 httpjnnutritionorgcontent1264 Suppl1197Sfullpdf
[251] B Halliwell ldquoAre polyphenols antioxidants or pro-oxidantsWhat do we learn from cell culture and in vivo studiesrdquoArchives of Biochemistry and Biophysics vol 476 no 2 pp 107ndash112 2008
[252] C Winterbourn Pro-Oxidants or Antioxidants ChristchurchSchool of Medicine Depatment of Pathology Free RadicalSchool SFRBMUniversity of Otago San Francisco Calif USA2009 httpwwwsfrbmorgfrsWinterbournpdf
[253] A Morakinyo B Iranloye and O Adegoke ldquoCalcium antag-onists modulate oxidative stress and acrosomal reaction in ratspermatozoardquo Archives of Medical Science vol 7 no 4 pp 613ndash618 2011
[254] The Alpha-Tocopherol Beta Carotene Cancer Prevention StudyGroup ldquoThe effect of vitamin E and beta carotene on theincidence of lung cancer and other cancers in male smokersrdquoTheNew England Journal of Medicine vol 330 no 15 pp 1029ndash1035 1994
[255] B Poljsak ldquoStrategies for reducing or preventing the generationof oxidative stressrdquo Oxidative Medicine and Cellular Longevityvol 2011 Article ID 194586 15 pages 2011
[256] B Poljsak and I Milisav ldquoThe neglected significance of lsquoanti-oxidative stressrsquordquoOxidativeMedicine and Cellular Longevity vol2012 Article ID 480895 12 pages 2012
[257] T Godfraind and S Salomone ldquoAmbiguities in dietary antiox-idant supplementation compared to calcium channel blockerstherapyrdquo Frontiers in Pharmacology vol 6 article 10 2015
[258] H Wagner H Norr and H Winterhoff ldquoDrugs with adap-togenic effects for strengthening the powers of resistancerdquoZeitschrift fur Phytotherapie vol 13 no 2 pp 42ndash54 1992
28 Oxidative Medicine and Cellular Longevity
[31] M Cataldi and F Bruno ldquo14-Dihydropyridines the multiplepersonalities of a blockbuster drug familyrdquo Translational Medi-cine UniSa vol 4 no 2 pp 12ndash26 2012 httpwwwncbinlmnihgovpmcarticlesPMC3728803
[32] R Vitolina A Krauze G Duburs and A Velena ldquoAspects ofthe amlodipine pleiotropy in biochemistry pharmacology andclinicsrdquo International Journal of Pharmaceutical Sciences andResearch vol 3 no 5 pp 1215ndash1232 2012
[33] D Grover S N Mokale and M T Shete ldquoDihydropyridinea novel pharmacophorerdquo International Journal of Pharmaceu-tical Erudition vol 1 no 2 pp 16ndash29 2011 httppharmaeru-ditionorgContentPaper20111-RV-320Final2016-29pdf
[34] A M Vijesh A M Isloor S K Peethambar K N ShivanandaT Arulmoli and N A Isloor ldquoHantzsch reaction synthesis andcharacterization of somenew 14-dihydropyridine derivatives aspotent antimicrobial and antioxidant agentsrdquo European Journalof Medicinal Chemistry vol 46 no 11 pp 5591ndash5597 2011
[35] P Mehta and P Verma ldquoAntimicrobial activity of some deriva-tives of 14-dihydropyridinesrdquo Journal of Chemistry vol 2013Article ID 865128 4 pages 2013
[36] P Olejnıkova L Svorc D Olsovska et al ldquoAntimicrobialactivity of novel C2-substituted 14-dihydropyridine analoguesrdquoScientia Pharmaceutica vol 82 no 2 pp 221ndash232 2014
[37] S Sepehri H Perez Sanchez and A Fassihi ldquoHantzsch-typedihydropyridines and biginelli-type tetra-hydropyrimidinesa review of their chemotherapeutic activitiesrdquo Journal of Phar-macy amp Pharmaceutical Sciences vol 18 no 1 pp 1ndash52 2015httpsejournalslibraryualbertacaindexphpJPPSarticleview2383617863
[38] S A Khedkar and P B Auti ldquo14-Dihydropyridines a classof pharmacologically important moleculesrdquo Mini-Reviews inMedicinal Chemistry vol 14 no 3 pp 282ndash290 2014
[39] G D Tirzit and G Ya Duburs ldquo14-dihydropyridines as inhi-bitors of free-radical reactionsrdquo Chemistry of Heterocyclic Com-pounds vol 8 no 1 pp 126ndash127 1972 Translated from KhimiyaGeterotsiklicheskikh Soedinenii no1 pp 133ndash134 1972 (Rus-sian)
[40] I Bogeski R Kappl C Kummerow R Gulaboski M Hothand B A Niemeyer ldquoRedox regulation of calcium ion channelschemical and physiological aspectsrdquoCell Calcium vol 50 no 5pp 407ndash423 2011
[41] S A Giller G Y Dubur Y R Uldrikis et al ldquoDiludine [Themethod to obtain 35-dicarbonylderivatives of 26-dimethyl-14-dihydropyridines]rdquo Authors certificate of USSR no 3004651971 [Byull Izobret no13 p 95 1971] and following patentsPatent of England no 1294650 1973 Patent of France no2055458 1971 Patent of Japan no 702883 1973 Patent ofHolland no 149787 1976 Patent of Italy no 969022 1974 Patentof FRG no 2036403 1978 US Patent no 3883673 1975 USPatent no 3948924 1976
[42] S A Giller G Y Dubur Y R Uldrikis et al ldquoImprovementsin or relating to the stabilization of carotenerdquo GB Patent no1294650 1972
[43] S A Giller G Y Dubur Y R Uldrikis et al ldquoStabilization ofcarotenerdquo US Patent no 3883673 1975 Chemical Abstracts vol83 Article ID 95193 1975
[44] Yu A Zilber G Ya Dubur K K Kumsar and A Kh VelenaldquoThe effect of antioxidants on the peroxidation of bimole-cular phospholipid membranesrdquo Latvijas PSR ZA Vestis Izves-tia Akademii Nauk Latviyskoy SSR vol 6 pp 80ndash82 1971(Russian) translated from the original Russian Doc Accesion
No AD0771751 distributed by NTIS US Department of Com-merce httpwwwdticmildtictrfulltextu2771751pdf
[45] G Ya Dubur Yu A Zilbers A Kh Velena A O Kumerovaand G D Tirzitis ldquoMultistage study of regulation of peroxida-tion processes in biological membranes by antioxidants of 14-dihydropyridine grouprdquo Izvestiya Akademii Nauk LatviyskoySSR vol 336 no 7 pp 65ndash68 1975 (Russian)
[46] R P Mason and M W Trumbore ldquoDifferential membraneinteractions of calcium channel blockers Implications forantioxidant activityrdquo Biochemical Pharmacology vol 51 no 5pp 653ndash660 1996
[47] R P Mason M F Walter M W Trumbore E G Olmstead Jrand P E Mason ldquoMembrane antioxidant effects of the chargeddihydropyridine calcium antagonist amlodipinerdquo Journal ofMolecular and Cellular Cardiology vol 31 no 1 pp 275ndash2811999
[48] R PMason I T MakMW Trumbore and P EMason ldquoAnti-oxidant properties of calcium antagonists related to membranebiophysical interactionsrdquo American Journal of Cardiology vol84 no 4 pp 16ndash22 1999
[49] R PMasonMW Trumbore and P EMason ldquoMembrane bio-physical interaction of amlodipine and antioxidant propertiesrdquoDrugs vol 59 no 2 pp 9ndash16 2000 (French)
[50] R P Mason P Marche and T H Hintze ldquoNovel vascularbiology of third-generation L-type calcium channel antagonistsAncillary actions of amlodipinerdquo Arteriosclerosis Thrombosisand Vascular Biology vol 23 no 12 pp 2155ndash2163 2003
[51] A Augustyniak G Bartosz A Cipak et al ldquoNatural andsynthetic antioxidants an updated overviewrdquo Free RadicalResearch vol 44 no 10 pp 1216ndash1262 2010
[52] T Grune N Zarkovic and K Kostelidou ldquoLipid peroxidationresearch in Europe and the COST B35 action lsquoLipid Peroxida-tion Associated Disordersrsquordquo Free Radical Research vol 44 no10 pp 1095ndash1097 2010
[53] E Carosati P Ioan M Micucci et al ldquo14-Dihydropyridinescaffold in medicinal chemistry the story so far and perspec-tives (part 2) action in other targets and antitargetsrdquo CurrentMedicinal Chemistry vol 19 no 25 pp 4306ndash4323 2012
[54] U Eisner and J Kuthan ldquoThe chemistry of dihydropyridinesrdquoChemical Reviews vol 72 no 1 pp 1ndash42 1972 httpwwwsci-encemadnessorgtalkfilesphppid=138742ampaid=6475
[55] J Kuthan and A Kurfurst ldquoDevelopment in dihydropyri-dine chemistryrdquo Industrial amp Engineering Chemistry ProductResearch and Development vol 21 no 2 pp 191ndash261 1982
[56] A Sausins and G Duburs ldquoSynthesis of 14-dihydropyridinesby cyclocondensation reactionsrdquo Heterocycles vol 27 no 1 pp269ndash289 1988
[57] A E Sausins and G Y Duburs ldquoSynthesis of 14-dihydro-pyridines in cyclocondensation reactions (review)rdquo Chemistryof Heterocyclic Compounds vol 28 no 4 pp 363ndash391 1992Translated from Khimiya Geterotsiklicheskikh Soedinenii no 4pp 435ndash467 1992 (Russian)
[58] S Kazda ldquoTwenty years of dihydropyridinesrdquo in Dihydropy-ridines Progress in Pharmacology and Therapy W-D Busse BGarthoff and F Seuter Eds pp 1ndash12 Springer Verlag BerlinGermany 1993
[59] J-P Wan and Y Liu ldquoRecent advances in new multicomponentsynthesis of structurally diversified 14-dihydropyridinesrdquo RSCAdvances vol 2 no 26 pp 9763ndash9777 2012
[61] Reaxys Database[62] J Tuttle ldquoStructure mechanism and reactivity of hantzsch
estersrdquo in MacMillan Lab Group Meeting (082504) p 332004 httpwwwprincetoneduchemistrymacmillangroup-meetingsJBT20Hantzschpdf
[63] A Saini S Kumar and J S Sandhu ldquoHantzsch reaction recentadvances in Hantzsch 14-dihydropyridinesrdquo Journal of Sci-entific amp Industrial Research vol 67 pp 95ndash111 2008
[64] L LW Cheung S A Styler and A P Dicks ldquoRapid and conve-nient synthesis of the 14-dihydropyridine privileged structurerdquoJournal of Chemical Education vol 87 no 6 pp 628ndash630 2010
[65] A Kumar R A Maurya S Sharma M Kumar and G BhatialdquoSynthesis and biological evaluation of N-aryl-14-dihydro-pyridines as novel antidyslipidemic and antioxidant agentsrdquoEuropean Journal of Medicinal Chemistry vol 45 no 2 pp 501ndash509 2010
[66] R S Kumar A Idhayadhulla A J Abdul Nasser and J SelvinldquoSynthesis and anticoagulant activity of a new series of 14-dihydropyridine derivativesrdquo European Journal of MedicinalChemistry vol 46 no 2 pp 804ndash810 2011
[67] H A Stefani C B Oliveira R B Almeida et al ldquoDihydro-pyrimidin-(2H)-ones obtained by ultrasound irradiation anew class of potential antioxidant agentsrdquo European Journal ofMedicinal Chemistry vol 41 no 4 pp 513ndash518 2006
[68] H Sun C Shang L Jin and J Zhang ldquoSynthesis and antiox-idant activity of a series of novel 3-chalcone-substituted 14-dihydropyridine derivativesrdquoHeterocyclic Communications vol18 no 5-6 pp 239ndash243 2012
[69] D B Tikhonov and B S Zhorov ldquoStructural model for dihy-dropyridine binding to L-type calcium channelsrdquo The Journalof Biological Chemistry vol 284 no 28 pp 19006ndash19017 2009
[70] G Y Dubur and Y R Uldrikis ldquoThe oxidation of 14-dihydro-pyridinesrdquo Chemistry of Heterocyclic Compounds vol 6 no 1pp 80ndash84 1970 Translated from Khimiya GeterotsiklicheskikhSoedinenii no 1 pp 83ndash88 1970 (Russian)
[71] G Ya Duburs A O Kumerova and Ya R Uldrikis ldquoEnzymicoxidation of hydrogenated pyridines with peroxidase-hydrogenperoxide systemrdquoLatvijas PSRZAVestis vol 73 no 7 pp 73ndash771970 (Russian) Chemical Abstracts vol 73 Article ID 94913g1970
[72] K Xie Y-C Liu Y Cui J-GWang Y Fu andT CWMak ldquoN-methyl-(R)-3-(tert-butyl)-sulfinyl-14-dihydropyridine a novelNADHmodel compoundrdquoMolecules vol 12 no 3 pp 415ndash4222007
[73] S Tamagaki T Mimura and W Tagaki ldquoMetal-ion-facilitatedoxidations of dihydropyridines with molecular oxygen andhydrogen peroxiderdquo Journal of the Chemical Society PerkinTransactions 2 no 10 pp 1645ndash1650 1990
[74] D Tirzite G Tirzitis andD Antipova ldquoReductive ability of 14-dihydropyridine derivatives in relation to ions of trivalent ironrdquoChemistry of Heterocyclic Compounds vol 35 no 5 pp 592ndash594 1999
[76] J Ogle J Stradins and L Baumane ldquoFormation and decay offree cation-radicals in the course of electro-oxidation of 12- and14-dihydropyridines (Hantzsch esters)rdquo Electrochimica Actavol 39 no 1 pp 73ndash79 1994
[77] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for the
synthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts C Wittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Berlin Germany 2010
[78] WDu and Zh Yu ldquoBiomimetic in situ regeneration of cofactorsNAD(P)+ and NAD(P)H models hantzsch esters and dihy-drophenanthridinerdquo Synlett vol 23 no 9 pp 1300ndash1304 2012
[79] H K Chenault and G M Whitesides ldquoRegeneration ofnicotinamide cofactors for use in organic synthesisrdquo AppliedBiochemistry and Biotechnology vol 14 no 2 pp 147ndash197 1987
[80] Y R Uldrikis A A Zidermane E A Biseniex I E Preisa GY Dubur and G D Tirzit ldquoEsters of 26-dimethyl-14-dihydro-pyridine-35-dicarboxylic acid and method of obtainingthereofrdquo WO 8000345 A1 1978 httpworldwideespacenetcompublicationDetailsbiblioDB=EPODOCampII=1ampND=3ampadjacent=trueamplocale=en EPampFT=Dampdate=19800306ampCC=WOampNR=8000345A1ampKC=A1
[81] Y Sambongi H Nitta K Ichihashi M Futai and I Ueda ldquoAnovel water-soluble Hantzsch 14-dihydropyridine compoundthat functions in biological processes through NADH regener-ationrdquo Journal of Organic Chemistry vol 67 no 10 pp 3499ndash3501 2002
[82] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for thesynthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts ChWittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Verlag Berlin Germany 2010
[83] T Okamura T Kikuchi A Nagamine et al ldquoAn approach formeasuring in vivo cerebral redox states using the oxidative con-version of dihydropyridine to pyridinium ion and themetabolictrapping principlerdquo Free Radical Biology and Medicine vol 38no 9 pp 1197ndash1205 2005
[84] K A Schellenberg and F H Westheimer ldquoA free-radicaloxidation of a dihydropyridine1ardquo The Journal of OrganicChemistry vol 30 no 6 pp 1859ndash1862 1965
[85] K A Schellenberg ldquoReaction of hydroxyl radical with thymi-dine Scavenging by a dihydropyridinerdquo Federation Proceedingsvol 38 no 3 I p 1433 1979
[86] E S Huyser J A K Harmony and F L McMillian ldquoPeroxideoxidations of dihydropyridine derivativesrdquo Journal of the Amer-ican Chemical Society vol 94 no 9 pp 3176ndash3180 1972
[87] A Sakamoto S T Ohnishi and R Ogawa ldquoInhibition of lipidperoxidation by some dihydropyridine derivativesrdquo Journal ofAnesthesia vol 7 no 2 pp 193ndash197 1993
[88] R Hardeland ldquoReview Neuroprotection by radical avoidancesearch for suitable agentsrdquo Molecules vol 14 no 12 pp 5054ndash5102 2009
[89] G Ya Dubur A Kh Velena V M Gukasov and Yu AVladimirov ldquoRegulation of peroxidation of mitochondrialmembrane lipids initiated by Fe2+ ions by antoxidants of the14-dihydropyridine series in experiments in vitrordquo Biomed-itsinskaya Khimiya vol 22 no 5 pp 665ndash673 1976 (Russian)Chemical Abstracts vol 88 Article ID 2640 1977
[90] G RMMHaenenM J T J Arts A Bast andMD ColemanldquoStructure and activity in assessing antioxidant activity in vitroand in vivo a critical appraisal illustrated with the flavonoidsrdquoEnvironmental Toxicology and Pharmacology vol 21 no 2 pp191ndash198 2006
[91] G Tirzitis and G Bartosz ldquoDetermination of antiradical andantioxidant activity basic principles and new insightsrdquo ActaBiochimica Polonica vol 57 no 2 pp 139ndash142 2010
30 Oxidative Medicine and Cellular Longevity
[92] G R Buettner and R P Mason ldquoSpin-trapping methods fordetecting superoxide and hydroxyl free radicals in vitro and invivordquo inCritical Reviews of Oxidative Stress and Aging Advancesin Basic Science Diagnostics and Intervention R G Cutler andH Rodriguez Eds vol 1 chapter 2 pp 27ndash38World ScientificLondon UK 2003
[93] M M Tarpey and I Fridovich ldquoMethods of detection ofvascular reactive species Nitric oxide superoxide hydrogenperoxide and peroxynitriterdquo Circulation Research vol 89 no3 pp 224ndash236 2001
[94] E Y Kazush E I Sagun G D Tirzit and G Y DaburldquoQuenching of singlet oxygen by electron donating derivativesof 14-dihydropyridinerdquo Chemistry of Heterocyclic Compoundsvol 30 no 5 pp 562ndash563 1994
[95] G Tirzitis E Kazush and G Duburs ldquoReaction of 14-dihydropyridine derivatives with peroxynitrite anionrdquo Chem-istry of Heterocyclic Compounds vol 34 no 3 pp 321ndash3231998 (Russian) Translated from Khimiya GeterotsiklicheskikhSoedinenii no 3 pp 355ndash357 1998
[96] L J Nunez-Vergara C Lopez-Alarcon P A Navarrete-EncinaA M Atria C Camargo and J A Squella ldquoElectrochemicaland EPR characterization of 14-dihydropyridines Reactivitytowards alkyl radicalsrdquo Free Radical Research vol 37 no 1 pp109ndash120 2003
[97] D Tirzite A Krauze A Zubareva G Tirzitis and G DubursldquoSynthesis and antiradical activity of 5-acetyl-2-alkylthio-4-aryl-6-methyl-14-dihydropyridine-3-carboxylic acid nitrilesrdquoChemistry of Heterocyclic Compounds vol 38 no 7 pp 795ndash800 2002
[98] H Ohkawa N Ohishi and K Yagi ldquoAssay for lipid peroxidesin animal tissues by thiobarbituric acid reactionrdquo AnalyticalBiochemistry vol 95 no 2 pp 351ndash358 1979
[99] N Zarkovic ldquo4-Hydroxynonenal as a bioactive marker ofpathophysiological processesrdquo Molecular Aspects of Medicinevol 24 no 4-5 pp 281ndash291 2003
[100] M Parola G Bellomo G Robino G Barrera and M UDianzani ldquo4-Hydroxynonenal as a biological signal molecularbasis and pathophysiological implicationsrdquo Antioxidants andRedox Signaling vol 1 no 3 pp 255ndash284 1999
[101] T Lovakovic M Poljak-Blazi G Duburs et al ldquoGrowthmodulation of human cells in vitro by mild oxidative stressand 14-dihydropyridine derivative antioxidantsrdquo CollegiumAntropologicum vol 35 no 1 pp 137ndash141 2011
[102] R van den Berg G R M M Haenen H van den Bergand A Bast ldquoApplicability of an improved Trolox equivalentantioxidant capacity (TEAC) assay for evaluation of antioxidantcapacity measurements of mixturesrdquo Food Chemistry vol 66no 4 pp 511ndash517 1999
[103] C Lopez-Alarcon P Navarrete C Camargo J A Squella andL J Nunez-Vergara ldquoReactivity of 14-dihydropyridines towardalkyl alkylperoxyl radicals and ABTS radical cationrdquo ChemicalResearch in Toxicology vol 16 no 2 pp 208ndash215 2003
[104] V Valenzuela P Santander C Camargo J A Squella C Lopez-Alarcon and L J Nunez-Vergara ldquo14-Dihydropyridines reac-tivity of nitrosoaryl and nitroaryl derivatives with alkylperoxylradicals andABTS radical cationrdquo Free Radical Research vol 38no 7 pp 715ndash727 2004
[105] L G Tsetlin N A Chebotareva B I Kurganov A K VelenaG Y Dubur and V Z Lankin ldquoStudy of 14-dihydropyridinesas lipoxygenase inhibitors with the use of hydrated reversedmicellesrdquo Pharmaceutical Chemistry Journal vol 22 no 6 pp425ndash428 1988 (Russian)
[106] J Panek Z Reblova L Kocirkova et al ldquoAntioxidant activityof dihydropyridine derivativesrdquo Czech Journal of Food Sciencesvol 18 pp 144ndash145 2000
[107] G Tirzitis I Kirule and G Duburs ldquoAntioxidationsaktivitatder 35-dicarbonylderivate des 26-demethyl-14-dihydropyri-dinsrdquo Fett Wissenschaft TechnologieFat Science Technology vol90 no 10 pp 411ndash413 1988
[108] M Plotniece G Tirzitis Y Uldrikis et al ldquoSynthesis of 14-dihydropyridine derivatives having an oxy- alkoxy- or dimeth-ylaminophenyl substituent in the 4 position their antioxidantactivity and their binding to phospholipid membranesrdquo Chem-istry of Heterocyclic Compounds vol 32 no 10 pp 1166ndash11721996 Translated from Khimiya Geterotsiklicheskikh Soedineniino 10(352) pp 1358ndash1365 1996 (Russian)
[109] D Y Rubene V S Sharov V I Olenev G D Tirzit G Y Duburand Y A Vladimirov ldquoUse of chemiluminescent method forthe evaluation of antioxidant activity of some derivatives of 14-dihydropyridinerdquo Russian Journal of Physical Chemistry A vol55 no 2 pp 511ndash512 1981 (Russian)
[110] M C R Symons and JM C Gutteridge Free Radicals and IronChemistry Biology and Medicine Oxford Science PublicationsOxford University Press Oxford UK 1998
[111] M Repetto J Semprine and A Boveris ldquoLipid peroxidationchemical mechanism biological implications and analyticaldeterminationrdquo in Lipid Peroxidation A Catala Ed Section ILipid Peroxidation Chemical Mechanisms Antioxidants Bio-logical Implications of Biochemistry Genetics and MolecularBiology chapter 1 pp 3ndash30 InTech Rijeka Croatia 2012
[112] A Velena J Zilbers and G Duburs ldquoDerivatives of 14-dihydropyridines asmodulators of ascorbate-induced lipid per-oxidation and high-amplitude swelling ofmitochondria causedby ascorbate sodium linoleate and sodiumpyrophosphaterdquoCellBiochemistry and Function vol 17 no 4 pp 237ndash252 1999
[113] M V Bilenko L N Shelenkova G Y Dubur and A K VelenaldquoUse of antioxidants to prevent renal damage during acuteischemia and reperfusionrdquo Bulletin of Experimental Biology andMedicine vol 96 no 3 pp 1195ndash1198 1983 Translated fromByulletenrsquo Eksperimentalrsquonoi Biologii i Meditsiny vol 96 no 9pp 8ndash11 1983 (Russian)
[114] R Toniolo F Tubaro F Ursini and G Bontempelli ldquoAn elec-troanalytical investigation on the redox properties of calciumantagonist dihydropyridinesrdquo Electroanalysis vol 15 no 10 pp855ndash861 2003
[115] L Kourimska J Pokorny and G Tirzitis ldquoThe antioxidant aci-tivity of 26-dimethyl-35-diethoxycarbonyl-14-dihydropyri-dine in edible oilsrdquo Nahrung vol 37 no 1 pp 91ndash93 1993
[116] C Lopez-Alarcon H Speisky J A Squella C Olea-Azar CCamargo and L J Nunez-Vergara ldquoReactivity of 14-dihydro-pyridines toward SIN-1-derived peroxynitriterdquo PharmaceuticalResearch vol 21 no 10 pp 1750ndash1757 2004
[117] R A Olek W Ziolkowski J J Kaczor L Greci J Popinigisand J Antosiewicz ldquoAntioxidant activity of NADH and its ana-loguemdashan in vitro studyrdquo Journal of Biochemistry andMolecularBiology vol 37 no 4 pp 416ndash421 2004
[118] E Niki N Noguchi and N Gotoh ldquoInhibition of oxidativemodification of low density lipoprotein by antioxidantsrdquo Jour-nal of Nutritional Science andVitaminology vol 39 supplementpp S1ndashS8 1993
[119] N Rojstaczer and D J Triggle ldquoStructure-function relation-ships of calcium antagonists effect on oxidative modificationof low density lipoproteinrdquo Biochemical Pharmacology vol 51no 2 pp 141ndash150 1996
Oxidative Medicine and Cellular Longevity 31
[120] A Sevanian L Shen and FUrsini ldquoInhibition of LDLoxidationand oxidized LDL-induced cytotoxicity by dihydropyridinecalcium antagonistsrdquo Pharmaceutical Research vol 17 no 8 pp999ndash1006 2000
[121] A Negre-Salvayre and R Salvayre ldquoProtection by Ca2+ channelblockers (nifedipine diltiazem and verapamil) against the tox-icity of oxidized low density lipoprotein to cultured lymphoidcellsrdquo British Journal of Pharmacology vol 107 no 3 pp 738ndash744 1992
[122] A Negre-Salvayre G FitoussiM Troly and R Salvayre ldquoCom-parative cytoprotective effect of dihydropyridine calcium chan-nel blockers against the toxicity of oxidized low density lipopro-tein for cultured lymphoid cellsrdquo Biochemical Pharmacologyvol 44 no 12 pp 2379ndash2386 1992
[123] L Cominacini A F Pasini U Garbin et al ldquoAntioxidant activ-ity of different dihydropyridinesrdquo Biochemical and BiophysicalResearch Communications vol 302 no 4 pp 679ndash684 2003
[124] L Cominacini U Garbin A Fratta Pasini et al ldquoOxidized low-density lipoprotein increases the production of intracellularreactive oxygen species in endothelial cells inhibitory effect oflacidipinerdquo Journal of Hypertension vol 16 no 12 part 2 pp1913ndash1919 1998
[125] H M Lander ldquoAn essential role for free radicals and derivedspecies in signal transductionrdquo The FASEB Journal vol 11 no2 pp 118ndash124 1997
[126] M L L Martinez E Rizzi M M Castro et al ldquoLercanidipinedecreases vascular matrix metalloproteinase-2 activity andprotects against vascular dysfunction in diabetic ratsrdquo EuropeanJournal of Pharmacology vol 599 no 1ndash3 pp 110ndash116 2008
[127] P Lesnik C Dachet L Petit et al ldquoImpact of a combinationof a calcium antagonist and a 120573-blocker on cell- and copper-mediated oxidation of LDL and on the accumulation and effluxof cholesterol in human macrophages and murine J774 cellsrdquoArteriosclerosis Thrombosis and Vascular Biology vol 17 no 5pp 979ndash988 1997
[128] G Sobal E J Menzel and H Sinzinger ldquoCalcium antagonistsas inhibitors of in vitro low density lipoprotein oxidation andglycationrdquoBiochemical Pharmacology vol 61 no 3 pp 373ndash3792001
[129] E Lupo R Locher B Weisser and W Vetter ldquoIn vitro antiox-idant activity of calcium antagonists against LDL oxidationcompared with 120572-tocopherolrdquo Biochemical and BiophysicalResearch Communications vol 203 no 3 pp 1803ndash1808 1994
[130] J Zou Y Li H-Q Fan and J-G Wang ldquoEffects of dihydropy-ridine calcium channel blockers on oxidized low-density lipo-protein induced proliferation and oxidative stress of vascularsmooth muscle cellsrdquo BMC Research Notes vol 5 article 1682012
[131] C Napoli S Salomone T Godfraind et al ldquo14-Dihydro-pyridine calcium channel blockers inhibit plasma and LDL oxi-dation and formation of oxidation-specific epitopes in the arte-rial wall and prolong survival in stroke-prone spontaneouslyhypertensive ratsrdquo Stroke vol 30 no 9 pp 1907ndash1915 1999
[132] G Zernig I Graziadei T Moshammer C Zech N Reider andH Glossmann ldquoMitochondrial Ca2+ antagonist binding sitesare associated with an inner mitochondrial membrane anionchannelrdquo Molecular Pharmacology vol 38 no 3 pp 362ndash3691990
[133] F E Hunter Jr A Scott P E Hochstein et al ldquoStudies of themechanism of ascorbate-induced swelling and lysis of isolatedliver mitochondriardquo The Journal of Biological Chemistry vol239 pp 604ndash613 1964
[134] D R Janero B Burghardt and R Lopez ldquoProtection of cardiacmembrane phospholipid against oxidative injury by calciumantagonistsrdquoBiochemical Pharmacology vol 37 no 21 pp 4197ndash4203 1988
[135] A Karadag B Ozcelik and S S Saner ldquoReview of methods todetermine antioxidant capacitiesrdquo FoodAnalyticalMethods vol2 no 1 pp 41ndash60 2009
[136] Y I Gubskiı N V Litvinova and E V Shnurko-TabakovaldquoAntioxidant and antiradical activity of various classes of antiox-idantsrdquo Ukrainskiı Biokhimicheskiı Zhurnal vol 66 no 4 pp114ndash116 1994 (Russian)
[137] M Takei M Hiramatsu and A Mori ldquoInhibitory effects ofcalcium antagonists onmitochondrial swelling induced by lipidperoxidation or arachidonic acid in the rat brain in vitrordquoNeurochemical Research vol 19 no 9 pp 1199ndash1206 1994
[138] M Takei M Hiramatsu R Edamatsu and A Mori ldquoFreeradical scavenging by calcium antagonistsrdquo Neurosciences vol20 no 2 pp 75ndash82 1994
[139] Ya P Stradin G Ya Dubur Yu A Beilis Ya R Uldrikis andA F Korotkova ldquoVoltammetry of 14-dihydropyridine deriva-tives I Potentials of electrochemical oxidation of 35-diacyl-and 35-di(alkoxycarbonyl)-14-dihydropyridines in acetoni-trilerdquo Chemistry of Heterocyclic Compounds no 1 pp 84ndash871972 (Russian)
[140] E V Ivanov T V Ponomarjova G N Merkusev et al ldquoEinneuer Haut-Radioprotektor Diethon (experimentelle Unter-suchung)rdquo Radiobiologia Radiotherapia vol 31 no 1 pp 69ndash78 1990
[141] E V Ivanov T V Ponomareva G N Merkushev et al ldquoRadia-tion modulating properties of derivates of 14-dihydropyridineand 12345678910-decahydroacridine-18 dionerdquo Radiat-sionnaia Biologiia Radioecologiia vol 44 no 5 pp 550ndash5592004 (Russian)
[142] R O Vitolinia D A Berzinia A K Velena I A Vutsina A AKimenis and G Y Duburs ldquoThe protective effects of the cal-cium antagonist foridon in acute myocardial ischaemiardquo Kardi-ologiya vol 27 no 3 pp 90ndash93 1987 (Russian)
[143] A H Velena G Ya Duburs R O Vitolina et al ldquoEffect ofryodipine on electromechanical parameters of heart and vesselscAMP phosphodiesterase activity and swelling-contractioncycle of mitochondriardquo Arzneimittelforschung vol 35 no 6 pp907ndash914 1985
[144] L I Utno Z E Lipsberga A A Silova M I Girgensone EA Bisenieks and G I Ia ldquoCardioprotective properties of a 14-dihydropyridine derivative glutapyrone in deep hypothermiardquoBiulletenrsquo Eksperimentalrsquonoı Biologii i Meditsiny vol 108 no 11pp 558ndash561 1989 (Russian)
[145] M A S FernandesM S Santos J A F Vicente et al ldquoEffects of14-dihydropyridine derivatives (cerebrocrast gammapyroneglutapyrone and diethone) onmitochondrial bioenergetics andoxidative stress a comparative studyrdquoMitochondrion vol 3 no1 pp 47ndash59 2003
[146] M A S Fernandes M S Santos A J M Moreno et al ldquoEffectsof 5-acetyl(carbamoyl)-6-methylsulfanyl-14-dihydropyridine-5-carbonitriles on rat liver mitochondrial functionrdquo Toxicologyin Vitro vol 23 no 7 pp 1333ndash1341 2009
[147] L Klimaviciusa A Kalda A Kaasik et al ldquoNeuroprotectiveactivity of 14-dihydropyridine derivatives structure determi-nantsrdquo Proceedings of the Latvian Academy of Sciences BNatural Exact and Applied Sciences vol 61 no 1-2 pp 33ndash372007
32 Oxidative Medicine and Cellular Longevity
[148] L Klimaviciusa M A S Fernandes N Lencberga et alldquoTargeting the mitochondria by novel adamantane-containing14-dihydropyridine compoundsrdquo in Bioenergetics K B ClarkEd pp 257ndash272 InTech 2012
[149] V Klusa L Klimaviciusa G Duburs J Poikans and AZharkovsky ldquoAnti-neurotoxic effects of tauropyrone a taurineanaloguerdquo Advances in Experimental Medicine and Biology vol583 pp 499ndash508 2006
[150] N Sampson P Berger and Ch Zenzmaier ldquoRedox signalingas a therapeutic target to inhibit myofibroblast activation indegenerative fibrotic diseaserdquo BioMed Research Internationalvol 2014 Article ID 131737 14 pages 2014
[151] T L Leto and M Geiszt ldquoRole of Nox family NADPH oxidasesin host defenserdquoAntioxidantsampRedox Signaling vol 8 no 9-10pp 1549ndash1561 2006
[152] K K Griendling D Sorescu and M Ushio-Fukai ldquoNAD(P)Hoxidase role in cardiovascular biology and diseaserdquo CirculationResearch vol 86 no 5 pp 494ndash501 2000
[153] H Chen Y S Song and P H Chan ldquoInhibition of NADPHoxi-dase is neuroprotective after ischemia-reperfusionrdquo Journal ofCerebral Blood Flow and Metabolism vol 29 no 7 pp 1262ndash1272 2009
[154] P Hochstein and L Ernster ldquoADP-activated lipid peroxidationcoupled to the TPNH oxidase system of microsomesrdquo Biochem-ical and Biophysical Research Communications vol 12 no 5 pp388ndash394 1963
[155] I I Gubskiı AGGoriushkoNV Litvinova et al ldquoAntioxidantproperties and membranotropic effect of certain derivatives of14-dihydropyridinerdquo Ukrainskiı Biokhimicheskiı Zhurnal vol71 no 4 pp 35ndash39 1999 (Russian)
[156] F Engineer and R Sridhar ldquoInhibition of rat heart andliver microsomal lipid peroxidation by nifedipinerdquo BiochemicalPharmacology vol 38 no 8 pp 1279ndash1285 1989
[157] T Goncalves A P Carvalho and C R Oliveira ldquoAntioxidanteffect of calcium antagonists on microsomai membranes iso-lated from different brain areasrdquo European Journal of Pharma-cology vol 204 no 3 pp 315ndash322 1991
[158] M E Letelier P Izquierdo L Godoy A M Lepe and MFaundez ldquoLiver microsomal biotransformation of nitro-aryldrugs mechanism for potential oxidative stress inductionrdquoJournal of Applied Toxicology vol 24 no 6 pp 519ndash525 2004
[159] M E Letelier P Entrala C Lopez-Alarcon et al ldquoNitroaryl-14-dihydropyridines as antioxidants against rat liver microsomesoxidation induced by ironascorbate Nitrofurantoin and naph-thalenerdquo Toxicology in Vitro vol 21 no 8 pp 1610ndash1618 2007
[160] F P Guengerich W R Brian M Iwasaki M-A Sari CBaarnhielm and P Berntsson ldquoOxidation of dihydropyridinecalcium channel blockers and analogues by human liver cyto-chrome P-450 IIIA4rdquo Journal of Medicinal Chemistry vol 34no 6 pp 1838ndash1844 1991
[161] S H Park S-W RhaW-Y Shin et al ldquoAS-160 Calcium channelblockers of dihydropyridine class reduce the antiplatelet effectof Clopidogrel what is clinical impactrdquo The American Journalof Cardiology vol 107 no 8 supplement p 47A 2011
[162] C Asma and D M Reda ldquoEvaluation of dihydropyridinecalcium antagonist effects on the stress bioindicator orga-nism Saccharomyces cerevisiaerdquo Annals of Biological Researchvol 4 no 10 pp 40ndash46 2013 httpscholarsresearchlibrarycomABR-vol4-iss10ABR-2013-4-10-40-46pdf
[163] G Gaviraghi A M Pastorino E Ratti and D G TristldquoCalcium channel blockers with antioxidant activityrdquo in Free
Radicals Lipoprotein Oxidation andAtherosclerosis G BellomoG Finardi E Maggi and E Rice-Evans Eds pp 431ndash456Richelieu Press London UK 1995
[164] G Gaviraghi AM Pastorino E Ratti and D G Trist ldquoAntiox-idant dihydropyridines a new and comprehensive therapy forfree radical-induced cardiovascular diseasesrdquo in Free Radicalsin Biology and Environment F Minisci Ed vol 27 of NATOASI Series pp 193ndash221 Springer Dordrecht The Netherlands1997
[165] P D Henry ldquoAntiperoxidative actions of calcium antagonistsand atherogenesisrdquo Journal of Cardiovascular Pharmacologyvol 18 supplement 1 pp S6ndashS10 1991
[166] F Kouoh B Gressier T Dine et al ldquoAntioxidant effects andanti-elastase activity of the calcium antagonist nicardipine onactivated human and rabbit neutrophilsmdasha potential antiath-erosclerotic property of calcium antagonistsrdquo CardiovascularDrugs andTherapy vol 16 no 6 pp 515ndash520 2002
[167] S Parthasarathy D Litvinov K Selvarajan and M GarelnabildquoLipid peroxidation and decompositionmdashconflicting roles inplaque vulnerability and stabilityrdquo Biochimica et BiophysicaActa vol 1781 no 5 pp 221ndash231 2008
[168] D-Q Liu Z-Q Pang D-H Zhao and B-H Sheng ldquoEffects offuryl-dihydropyridines I on lipid peroxides of ischemic myo-cardium and ATPases activity of erythrocyte membranes inratsrdquo Acta Pharmacologica Sinica vol 12 no 3 pp 253ndash2561991
[169] V Lukic-Panin T Kamiya H Zhang et al ldquoPrevention of neu-ronal damage by calcium channel blockers with antioxidativeeffects after transient focal ischemia in ratsrdquo Brain Research vol1176 no 1 pp 143ndash150 2007
[170] Y Allanore D Borderie H Lemarechal O G Ekindjian andA Kahan ldquoAcute and sustained effects of dihydropyridine-typecalcium channel antagonists on oxidative stress in systemicsclerosisrdquo American Journal of Medicine vol 116 no 9 pp 595ndash600 2004
[171] I Casetta V Govoni and E Granieri ldquoOxidative stress antioxi-dants and neurodegenerative diseasesrdquo Current PharmaceuticalDesign vol 11 no 16 pp 2033ndash2052 2005
[172] M J T J Arts Assessing antioxidant activity [PhD the-sis] Maastricht University Maastricht The Netherlands 2007httparnounimaasnlshowcgifid=8676
[173] G Dıaz-Araya L Godoy L Naranjo A Squella M E Letelierand L J Nunez-Vergara ldquoAntioxidant effects of 14-dihydro-pyridine and nitroso aryl derivatives on the Fe+3ascorbate-stimulated lipid peroxidation in rat brain slicesrdquo General Phar-macology The Vascular System vol 31 no 3 pp 385ndash391 1998
[174] Y Fukuhara K Tsuchiya Y Horinouchi et al ldquoProtectiveeffect of photodegradation product of nifedipine against tumornecrosis factor 120572-induced oxidative stress in human glomerularendothelial cellsrdquo Journal of Medical Investigation vol 58 no1-2 pp 118ndash126 2011
[175] W Stengel M Jainz and K Andreas ldquoDifferent potencies ofdihydropyridine derivatives in blocking T-type but not L-typeCa2+ channels in neuroblastoma-glioma hybrid cellsrdquo EuropeanJournal of Pharmacology vol 342 no 2-3 pp 339ndash345 1998
[176] O M Panasenko D J Tirzite G D Tirzitis and G J DubursldquoEffect of some 14-dihydropyridine derivatives on structuralorganization of erythrocyte membranesrdquo Biologicheskie Mem-brany (Biochemistry (Moscow) Series A Membrane and CellBiology) vol 1 pp 919ndash925 1984 (Russian)
[177] L G Herbette Y M H Vant Erve and D G Rhodes ldquoInter-action of 14 dihydropyridine calcium channel antagonists with
Oxidative Medicine and Cellular Longevity 33
biological membranes lipid bilayer partitioning could occurbefore drug binding to receptorsrdquo Journal of Molecular andCellular Cardiology vol 21 no 2 pp 187ndash201 1989
[178] L G Herbette P E Mason G Gaviraghi T N Tulenko andR P Mason ldquoThe molecular basis for lacidipinersquos unique phar-macokinetics optimal hydrophobicity results in membraneinteractions that may facilitate the treatment of atherosclerosisrdquoJournal of Cardiovascular Pharmacology vol 23 supplement 5pp S16ndashS25 1994
[179] G V Belevitch G Y Dubur G E Dobretsov N K Kurek andM M Spirin ldquoCalcium antagonists riodipine nifedipine andverapamil binding to model and biological membranes fluore-scence analysisrdquo Biologicheskie Membrany (Biochemistry(Moscow) Series A Membrane and Cell Biology) vol 5 pp768ndash776 1988 (Russian)
[180] R P Mason G E Gonye D W Chester and L G HerbetteldquoPartitioning and location of Bay K 8644 14-dihydropyridinecalcium channel agonist in model and biological membranesrdquoBiophysical Journal vol 55 no 4 pp 769ndash778 1989
[181] M Cindric A Cipak J Serly et al ldquoReversal of multidrugresistance inmurine lymphoma cells by amphiphilic dihydropy-ridine antioxidant derivativerdquo Anticancer Research vol 30 no10 pp 4063ndash4070 2010
[182] F Shekari H Sadeghpour K Javidnia et al ldquoCytotoxic andmultidrug resistance reversal activities of novel 14-dihydro-pyridines against human cancer cellsrdquo European Journal ofPharmacology vol 746 no 1 pp 233ndash244 2015
[183] X-F Zhou Q Shao R A Coburn and M E Morris ldquoQuanti-tative structure-activity relationship and quantitative structure-pharmacokinetics relationship of 14-dihydropyridines andpyridines as multidrug resistance modulatorsrdquo PharmaceuticalResearch vol 22 no 12 pp 1989ndash1996 2005
[184] R Berkels T Breitenbach H Bartels et al ldquoDifferent antioxida-tive potencies of dihydropyridine calcium channel modulatorsin various modelsrdquo Vascular Pharmacology vol 42 no 4 pp145ndash152 2005
[185] S Borovic G Tirzitis D Tirzite et al ldquoBioactive 14-dihydro-isonicotinic acid derivatives prevent oxidative damage of livercellsrdquo European Journal of Pharmacology vol 537 no 1ndash3 pp12ndash19 2006
[186] D Ya Rubene G D Tirzitis and G Ya Duburs ldquoInteractionof some 14-dihydropyridine derivatives with Fentonrsquos reagentrdquoLatvijas PSRZinatnuAkademijas Vestis Kimijas Serija Proceed-ings of the Latvian SSR Academy of Sciences Chemistry Seriespp 212ndash216 1982 (Russian)
[187] K Ondrias V Misık D Gergel and A Stasko ldquoLipid per-oxidation of phosphatidylcholine liposomes depressed by thecalcium channel blockers nifedipine and verapamil and bythe antiarrhythmic-antihypoxic drug stobadinerdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1003 no 3pp 238ndash245 1989
[188] I T Mak and W B Weglicki ldquoComparative antioxidant acti-vities of propranolol nifedipine verapamil and diltiazemagainst sarcolemmal membrane lipid peroxidationrdquoCirculationResearch vol 66 no 5 pp 1449ndash1452 1990
[189] I T Mak P Boehme and W B Weglicki ldquoProtective effects ofcalcium channel blockers against free radical-impaired endo-thelial cell proliferationrdquo Biochemical Pharmacology vol 50 no9 pp 1531ndash1534 1995
[190] S Ray S Mondal and N Dana ldquoEvaluation of protective roleof nifedipine on lipid peroxidation using reduced glutathione as
model markerrdquo Oxidants and Antioxidants in Medical Sciencevol 1 no 2 pp 97ndash100 2012
[191] M Yamato T Shiba T Ide Y Honda K-I Yamada andH Tsutsui ldquoNifedipine treatment reduces brain damage aftertransient focal ischemia possibly through its antioxidativeeffectsrdquoHypertension Research vol 34 no 7 pp 840ndash845 2011
[192] V Chander and K Chopra ldquoNifedipine attenuates changes innitric oxide levels renal oxidative stress and nephrotoxicityinduced by cyclosporinerdquo Renal Failure vol 27 no 4 pp 441ndash450 2005
[193] K M Gaafa M M Badawy and A A Hamza ldquoThe protectiveeffects of ascorbic acid cimetidine and nifedipine on diethyl-dithiocarbamate-induced hepatic toxicity in albino ratsrdquo Drugand Chemical Toxicology vol 34 no 4 pp 405ndash419 2011
[194] H Sugawara K Tobise and S Onodera ldquoAbsence of antiox-idant effects of nifedipine and diltiazem on myocardial mem-brane lipid peroxidation in contrast with those of nisoldipineand propranololrdquo Biochemical Pharmacology vol 47 no 5 pp887ndash892 1994
[195] I E Kirule D Y Rubene E A Bisenieks G D Tirzit and GY Dubur ldquo4-Nitrophenyl-14-dihydropyridinesmdasha new groupof inhibitors of peroxide oxidationrdquo Chemistry of HeterocyclicCompounds vol 18 no 3 p 316 1982
[196] G D Tirzit I E Kirule L K Baumane R A Gavar Y PStradynrsquo andG YDubur ldquoMechanism of the antioxidant actionof 26-dimethyl-35-dimethoxy-carbonyl-4-(2-nitrophenyl)14-dihydropyridinerdquoChemistry ofHeterocyclic Compounds vol 20no 8 pp 915ndash918 1984
[197] C Yanez C Lopez-Alarcon C Camargo V Valenzuela J ASquella and L J Nunez-Vergara ldquoStructural effects on thereactivity 14-dihydropyridines with alkylperoxyl radicals andABTS radical cationrdquo Bioorganic and Medicinal Chemistry vol12 no 9 pp 2459ndash2468 2004
[198] VMisik A J Stasko D Gergel and K Ondrias ldquoSpin-trappingand antioxidant properties of illuminated and nonilluminatednifedipine and nimodipine in heart homogenate and modelsystemrdquo Molecular Pharmacology vol 40 no 3 pp 435ndash4391991
[199] K Ondrias V Misık A Stasko D Gergelrsquo and M HromadovaldquoComparison of antioxidant properties of nifedipine and illu-minated nifedipine with nitroso spin traps in low densitylipoproteins and phosphatidylcholine liposomesrdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1211 no 1pp 114ndash119 1994
[200] A Stasko V Brezova S Biskupic K Ondrias and V MisıkldquoReactive radical intermediates formed from illuminated nife-dipinerdquoFree Radical Biology andMedicine vol 17 no 6 pp 545ndash556 1994
[201] K Ishizawa Y Izawa-Ishizawa N Yamano et al ldquoNitrosoni-fedipine ameliorates the progression of type 2 diabetic nephro-pathy by exerting antioxidative effectsrdquo PLoS ONE vol 9 no 1Article ID e86335 2014
[202] H Fujii and L J Berliner ldquoIn vivo EPR evidence for free radicaladducts of nifedipinerdquoMagnetic Resonance in Medicine vol 42no 4 pp 691ndash694 1999
[203] S Bollo S Finger J C Sturm L J Nunez-Vergara and JA Squella ldquoCyclic voltammetry and scanning electrochemicalmicroscopy studies of the heterogeneous electron transferreaction of some nitrosoaromatic compoundsrdquo ElectrochimicaActa vol 52 no 15 pp 4892ndash4898 2007
34 Oxidative Medicine and Cellular Longevity
[204] F Ursini ldquoTissue protection by lacidipine insight from redoxbehaviorrdquo Journal of Cardiovascular Pharmacology vol 30supplement 2 pp S28ndashS30 1997
[205] P G Cristofori F A Crivellente I Faustinelli et al ldquoInvolve-ment of the nitric oxide system in the anti-atheroscleroticpotential of lacidipine in the apoE-deficient mouse a mor-phological functional and electrochemical studyrdquo ToxicologicPathology vol 32 no 4 pp 493ndash499 2004
[206] X-P Zhang E L Kit S Mital S Chahwala and T HHintze ldquoParadoxical release of nitric oxide by an L-type calciumchannel antagonist the R+ enantiomer of amlodipinerdquo Journalof Cardiovascular Pharmacology vol 39 no 2 pp 208ndash2142002
[207] F Franzoni G Santoro F Regoli et al ldquoAn in vitro study of theperoxyl and hydroxyl radical scavenging capacity of the calciumantagonist amlodipinerdquo Biomedicine and Pharmacotherapy vol58 no 8 pp 423ndash426 2004
[208] S V Gatsura ldquoOxygen-dependent mechanisms underlying theantiischemic effect of verapamil and amlodipinerdquo Bulletin ofExperimental Biology and Medicine vol 137 no 1 pp 40ndash422004
[209] Y Hirooka Y Kimura M Nozoe Y Sagara K Ito and KSunagawa ldquoAmlodipine-induced reduction of oxidative stressin the brain is associated with sympatho-inhibitory effects instroke-prone spontaneously hypertensive ratsrdquo HypertensionResearch vol 29 no 1 pp 49ndash56 2006
[210] B Tomlinson and I F F Benzie ldquoAntioxidant effect of lercani-dipine (note)rdquo Hypertension vol 42 no 4 pp e10ndashe11 2003
[211] A A Faraqui ldquoNeurochemical aspects of 4-hydroxynonenalrdquoin Lipid Mediators and Their Metabolism in the Brain A AFaraqui Ed chapter 6 pp 159ndash191 Springer New York NYUSA 2011
[212] V S NascimentoM S DrsquoAlva A AOliveira et al ldquoAntioxidanteffect of nimodipine in young rats after pilocarpine-inducedseizuresrdquo Pharmacology Biochemistry and Behavior vol 82 no1 pp 11ndash16 2005
[213] O Ismailoglu P Atilla S Palaoglu et al ldquoThe therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjuryrdquo Turkish Neurosurgery vol 22 no 6 pp 740ndash746 2012
[214] M Matsubara and K Hasegawa ldquoBenidipine a dihydropy-ridine-calcium channel blocker prevents lysophosphatidyl-choline-induced injury and reactive oxygen species productionin human aortic endothelial cellsrdquo Atherosclerosis vol 178 no1 pp 57ndash66 2005
[215] M Matsubara K Yao and K Hasegawa ldquoBenidipine adihydropyridine-calcium channel blocker inhibits lysophos-phatidylcholine-induced endothelial injury via stimulation ofnitric oxide releaserdquo Pharmacological Research vol 53 no 1 pp35ndash43 2006
[216] MMatsubara and K Hasegawa ldquoEffects of benidipine a dihyd-ropyridine-Ca2+ channel blocker on expression of cytokine-induced adhesion molecules and chemoattractants in humanaortic endothelial cellsrdquo European Journal of Pharmacology vol498 no 1ndash3 pp 303ndash314 2004
[217] M Matsubara O Akizuki J-I Ikeda K Saeki K Yao and KSasaki ldquoBenidipine an anti-hypertensive drug inhibits reactiveoxygen species production in polymorphonuclear leukocytesand oxidative stress in salt-loaded stroke-prone spontaneouslyhypertensive ratsrdquo European Journal of Pharmacology vol 580no 1-2 pp 201ndash213 2008
[218] A C Rosenkranz H Lob T Breitenbach R Berkels and RRoesen ldquoEndothelial antioxidant actions of dihydropyridines
and angiotensin converting enzyme inhibitorsrdquo European Jour-nal of Pharmacology vol 529 no 1ndash3 pp 55ndash62 2006
[219] V Kain S Kumar and S L Sitasawad ldquoAzelnidipine preventscardiac dysfunction in streptozotocin-diabetic rats by reducingintracellular calcium accumulation oxidative stress and apop-tosisrdquo Cardiovascular Diabetology vol 10 article 97 2011
[220] K Nakamura S Yamagishi and H Inoue ldquoUnique atheropro-tective property of azelnidipine a dihydropyridine-based cal-cium antagonistrdquoMedical Hypotheses vol 65 no 1 pp 155ndash1572005
[221] TMatsui S Yamagishi K Nakamura S Kikuchi andH InoueldquoAzelnidipine a dihydropyridine-based calcium antagonistinhibits angiotensin II-induced oxidative stress generation anddownregulation of pigment epithelium-derived factor mRNAlevels in microvascular endothelial cellsrdquo Drugs under Experi-mental and Clinical Research vol 31 no 5-6 pp 215ndash219 2005
[222] C Ohmura H Watada T Shimizu et al ldquoCalcium channelblocker azelnidipine reduces lipid hydroperoxides in patientswith type 2 diabetes independent of blood pressurerdquo EndocrineJournal vol 54 no 5 pp 805ndash811 2007
[223] H Daikuhara F Kikuchi and T Ishida ldquoThe combination ofOLmesartan and a CAlcium channel blocker (azelnidipine) orcandesartan and a calcium channel blocker (amlodipine) intype 2 diabetic hypertensive patients theOLCA studyrdquoDiabetesand Vascular Disease Research vol 9 no 4 pp 280ndash286 2012
[224] MAbe NMaruyama KOkada SMatsumoto KMatsumotoand M Soma ldquoAdditive antioxidative effects of azelnidipine onangiotensin receptor blocker olmesartan treatment for type 2diabetic patients with albuminuriardquoHypertension Research vol34 no 8 pp 935ndash941 2011
[225] K Mizushige ldquoAntioxidative activities of thiazolidinedionesand dihydropyridine-type calcium antagonistsrdquo IRYOmdashJapa-nese Journal of National Medical Services vol 59 no 11 pp 581ndash592 2005
[226] S Manabe T Okura T Fukuoka and J Higaki ldquoAntioxidativeeffects of azelnidipine on mesangial cell proliferation inducedby highly concentrated insulinrdquo European Journal of Pharma-cology vol 567 no 3 pp 252ndash257 2007
[227] Y Koyama Y Takeishi H Takahashi et al ldquoAzelnidipine inhi-bits H
2O2-induced cell death in neonatal rat cardiomyocytesrdquo
CardiovascularDrugs andTherapy vol 21 no 1 pp 69ndash72 2007[228] K Shinomiya K Mizushige M Fukunaga et al ldquoAntioxidant
effect of a new calcium antagonist azelnipidine in culturedhuman arterial endothelial cellsrdquo Journal of International Med-ical Research vol 32 no 2 pp 170ndash175 2004
[229] T Ohyama K Sato K Kishimoto et al ldquoAzelnidipine is acalcium blocker that attenuates liver fibrosis and may increaseantioxidant defencerdquo British Journal of Pharmacology vol 165no 4 pp 1173ndash1187 2012
[230] L A Calo F Zaghetto E Pagnin P A Davis A Sempliciniand A C Pessina ldquoEffect of manidipine on gene expressionand protein level of oxidative stress-related proteins p22phoxand HO-1 Relevance for antihypertensive and anti-remodelingeffectsrdquo Journal of Cardiovascular Pharmacology vol 43 no 4pp 531ndash538 2004
[231] R Ghyasi G Sepehri M Mohammadi R Badalzadeh and AGhyasi ldquoEffect of mebudipine on oxidative stress and lipid per-oxidation in myocardial ischemic-reperfusion injury in maleratrdquo Journal of Research in Medical Sciences vol 17 no 12 pp1150ndash1155 2012
Oxidative Medicine and Cellular Longevity 35
[232] DCAndersson J Fauconnier T Yamada et al ldquoMitochondrialproduction of reactive oxygen species contributes to the 120573-adrenergic stimulation of mouse cardiomycytesrdquoThe Journal ofPhysiology vol 589 no 7 pp 1791ndash1801 2011
[233] A F Ceylan-Isik N Ari M Stefek et al ldquoEffects of a long-term treatment with an antioxidant pyridoindole on vascularresponsiveness in diabetes-induced aging ratsrdquo Current AgingScience vol 4 no 2 pp 150ndash157 2011
[234] S Saponara G Sgaragli and F Fusi ldquoQuercetin antagonismof Bay K 8644 effects on rat tail artery L-type Ca2+ channelsrdquoEuropean Journal of Pharmacology vol 598 no 1ndash3 pp 75ndash802008
[235] D A Sica ldquoInteraction of grapefruit juice and calcium channelblockersrdquo American Journal of Hypertension vol 19 no 7 pp768ndash773 2006
[236] P Mulder G Litwinienko S Lin P D MacLean L R CBarclay and K U Ingold ldquoThe L-type calcium channel block-ers Hantzsch 14-dihydropyridines are not peroxyl radical-trapping chain-breaking antioxidantsrdquo Chemical Research inToxicology vol 19 no 1 pp 79ndash85 2006
[237] L J Nunez-Vergara R Salazar C Camargo et al ldquoOxidation ofC4-hydroxyphenyl 14-dihydropyridines in dimethylsulfoxideand its reactivity towards alkylperoxyl radicals in aqueousmediumrdquo Bioorganic and Medicinal Chemistry vol 15 no 12pp 4318ndash4326 2007
[238] M E Ortiz L J Nunez-Vergara and J A Squella ldquoRelativereactivity of dihydropyridine derivatives to electrogeneratedsuperoxide ion in DMSO solutions a voltammetric approachrdquoPharmaceutical Research vol 20 no 2 pp 292ndash296 2003
[239] M E Ortiz L J Nunez-Vergara C Camargo and J A SquellaldquoOxidation of Hantzsch 14-dihydropyridines of pharmacolog-ical significance by electrogenerated superoxiderdquo Pharmaceuti-cal Research vol 21 no 3 pp 428ndash435 2004
[240] R S Raghuvanshi and K N Singh ldquoSuperoxide induced oxida-tive aromatization of Hantzsch 14-dihydropyridinesrdquo IndianJournal of Chemistry Section B Organic and Medicinal Chem-istry vol 47 no 11 pp 1735ndash1738 2008
[241] I Kruk A Kladna K Lichszteld et al ldquoAntioxidant activityof 4-flavonil-14-dihydropyridine derivativesrdquo Biopolymers vol62 no 3 pp 163ndash167 2001
[242] G D Tirzit I M Byteva K I Salokhiddinov G P Gurinovichand G Y Dubur ldquo14-Dihydropyridine derivatives as deactiva-tors of singlet oxygenrdquo Chemistry of Heterocyclic Compoundsvol 17 no 7 pp 682ndash684 1981
[243] G D Tirzit E Y Kazush and G Y Dubur ldquoInfluence of14-dihydropyridine derivatives on the generation of hydroxylradicalsrdquo Chemistry of Heterocyclic Compounds vol 28 no 4pp 435ndash437 1992
[244] N A Pizarro-Urzua and L J Nunez-Vergara ldquoNifedipine andnitrendipine reactivity toward singlet oxygenrdquo Journal of Photo-chemistry and Photobiology A Chemistry vol 175 no 2-3 pp129ndash137 2005
[245] L-F Wang H-Y Zhang L Konga Z-W Chena and J-G ShildquoDFT calculations indicate that 14-dihydropyridine is a promis-ing lead antioxidantrdquo Helvetica Chimica Acta vol 87 no 6 pp1515ndash1521 2004
[246] P Mulder H-G Korth and K U Ingold ldquoWhy quantum-thermochemical calculations must be used with caution toindicate lsquoa promising lead antioxidantrsquordquoHelvetica Chimica Actavol 88 no 2 pp 370ndash374 2005
[247] K Yao Y Ina K Nagashima K Ohmori and T Ohno ldquoAntiox-idant effects of calcium antagonists in rat brain homogenatesrdquo
Biological and Pharmaceutical Bulletin vol 23 no 6 pp 766ndash769 2000
[248] T Matsui S-I Yamagishi K Nakamura and H Inoue ldquoBayw 9798 a dihydropyridine structurally related to nifedipinewith no calcium channel-blocking properties inhibits tumournecrosis factor-120572-induced vascular cell adhesion molecule-1expression in endothelial cells by suppressing reactive oxygenspecies generationrdquo Journal of International Medical Researchvol 35 no 6 pp 886ndash891 2007
[249] K AMitrega B VargheseM Porc and T F Krzeminski ldquoAnti-arrhythmic and hemodynamic effects of oxy nifedipine oxynimodipine oxy nitrendipine and oxy nisoldipinerdquo Pharmaco-logical Research vol 66 no 4 pp 300ndash308 2012
[250] V Herbert ldquoSymposium prooxidant effects of antioxidantvitamins Introductionrdquo The Journal of Nutrition vol 126 no4 supplement pp 1197Sndash1200S 1996 httpjnnutritionorgcontent1264 Suppl1197Sfullpdf
[251] B Halliwell ldquoAre polyphenols antioxidants or pro-oxidantsWhat do we learn from cell culture and in vivo studiesrdquoArchives of Biochemistry and Biophysics vol 476 no 2 pp 107ndash112 2008
[252] C Winterbourn Pro-Oxidants or Antioxidants ChristchurchSchool of Medicine Depatment of Pathology Free RadicalSchool SFRBMUniversity of Otago San Francisco Calif USA2009 httpwwwsfrbmorgfrsWinterbournpdf
[253] A Morakinyo B Iranloye and O Adegoke ldquoCalcium antag-onists modulate oxidative stress and acrosomal reaction in ratspermatozoardquo Archives of Medical Science vol 7 no 4 pp 613ndash618 2011
[254] The Alpha-Tocopherol Beta Carotene Cancer Prevention StudyGroup ldquoThe effect of vitamin E and beta carotene on theincidence of lung cancer and other cancers in male smokersrdquoTheNew England Journal of Medicine vol 330 no 15 pp 1029ndash1035 1994
[255] B Poljsak ldquoStrategies for reducing or preventing the generationof oxidative stressrdquo Oxidative Medicine and Cellular Longevityvol 2011 Article ID 194586 15 pages 2011
[256] B Poljsak and I Milisav ldquoThe neglected significance of lsquoanti-oxidative stressrsquordquoOxidativeMedicine and Cellular Longevity vol2012 Article ID 480895 12 pages 2012
[257] T Godfraind and S Salomone ldquoAmbiguities in dietary antiox-idant supplementation compared to calcium channel blockerstherapyrdquo Frontiers in Pharmacology vol 6 article 10 2015
[258] H Wagner H Norr and H Winterhoff ldquoDrugs with adap-togenic effects for strengthening the powers of resistancerdquoZeitschrift fur Phytotherapie vol 13 no 2 pp 42ndash54 1992
Oxidative Medicine and Cellular Longevity 29
[61] Reaxys Database[62] J Tuttle ldquoStructure mechanism and reactivity of hantzsch
estersrdquo in MacMillan Lab Group Meeting (082504) p 332004 httpwwwprincetoneduchemistrymacmillangroup-meetingsJBT20Hantzschpdf
[63] A Saini S Kumar and J S Sandhu ldquoHantzsch reaction recentadvances in Hantzsch 14-dihydropyridinesrdquo Journal of Sci-entific amp Industrial Research vol 67 pp 95ndash111 2008
[64] L LW Cheung S A Styler and A P Dicks ldquoRapid and conve-nient synthesis of the 14-dihydropyridine privileged structurerdquoJournal of Chemical Education vol 87 no 6 pp 628ndash630 2010
[65] A Kumar R A Maurya S Sharma M Kumar and G BhatialdquoSynthesis and biological evaluation of N-aryl-14-dihydro-pyridines as novel antidyslipidemic and antioxidant agentsrdquoEuropean Journal of Medicinal Chemistry vol 45 no 2 pp 501ndash509 2010
[66] R S Kumar A Idhayadhulla A J Abdul Nasser and J SelvinldquoSynthesis and anticoagulant activity of a new series of 14-dihydropyridine derivativesrdquo European Journal of MedicinalChemistry vol 46 no 2 pp 804ndash810 2011
[67] H A Stefani C B Oliveira R B Almeida et al ldquoDihydro-pyrimidin-(2H)-ones obtained by ultrasound irradiation anew class of potential antioxidant agentsrdquo European Journal ofMedicinal Chemistry vol 41 no 4 pp 513ndash518 2006
[68] H Sun C Shang L Jin and J Zhang ldquoSynthesis and antiox-idant activity of a series of novel 3-chalcone-substituted 14-dihydropyridine derivativesrdquoHeterocyclic Communications vol18 no 5-6 pp 239ndash243 2012
[69] D B Tikhonov and B S Zhorov ldquoStructural model for dihy-dropyridine binding to L-type calcium channelsrdquo The Journalof Biological Chemistry vol 284 no 28 pp 19006ndash19017 2009
[70] G Y Dubur and Y R Uldrikis ldquoThe oxidation of 14-dihydro-pyridinesrdquo Chemistry of Heterocyclic Compounds vol 6 no 1pp 80ndash84 1970 Translated from Khimiya GeterotsiklicheskikhSoedinenii no 1 pp 83ndash88 1970 (Russian)
[71] G Ya Duburs A O Kumerova and Ya R Uldrikis ldquoEnzymicoxidation of hydrogenated pyridines with peroxidase-hydrogenperoxide systemrdquoLatvijas PSRZAVestis vol 73 no 7 pp 73ndash771970 (Russian) Chemical Abstracts vol 73 Article ID 94913g1970
[72] K Xie Y-C Liu Y Cui J-GWang Y Fu andT CWMak ldquoN-methyl-(R)-3-(tert-butyl)-sulfinyl-14-dihydropyridine a novelNADHmodel compoundrdquoMolecules vol 12 no 3 pp 415ndash4222007
[73] S Tamagaki T Mimura and W Tagaki ldquoMetal-ion-facilitatedoxidations of dihydropyridines with molecular oxygen andhydrogen peroxiderdquo Journal of the Chemical Society PerkinTransactions 2 no 10 pp 1645ndash1650 1990
[74] D Tirzite G Tirzitis andD Antipova ldquoReductive ability of 14-dihydropyridine derivatives in relation to ions of trivalent ironrdquoChemistry of Heterocyclic Compounds vol 35 no 5 pp 592ndash594 1999
[76] J Ogle J Stradins and L Baumane ldquoFormation and decay offree cation-radicals in the course of electro-oxidation of 12- and14-dihydropyridines (Hantzsch esters)rdquo Electrochimica Actavol 39 no 1 pp 73ndash79 1994
[77] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for the
synthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts C Wittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Berlin Germany 2010
[78] WDu and Zh Yu ldquoBiomimetic in situ regeneration of cofactorsNAD(P)+ and NAD(P)H models hantzsch esters and dihy-drophenanthridinerdquo Synlett vol 23 no 9 pp 1300ndash1304 2012
[79] H K Chenault and G M Whitesides ldquoRegeneration ofnicotinamide cofactors for use in organic synthesisrdquo AppliedBiochemistry and Biotechnology vol 14 no 2 pp 147ndash197 1987
[80] Y R Uldrikis A A Zidermane E A Biseniex I E Preisa GY Dubur and G D Tirzit ldquoEsters of 26-dimethyl-14-dihydro-pyridine-35-dicarboxylic acid and method of obtainingthereofrdquo WO 8000345 A1 1978 httpworldwideespacenetcompublicationDetailsbiblioDB=EPODOCampII=1ampND=3ampadjacent=trueamplocale=en EPampFT=Dampdate=19800306ampCC=WOampNR=8000345A1ampKC=A1
[81] Y Sambongi H Nitta K Ichihashi M Futai and I Ueda ldquoAnovel water-soluble Hantzsch 14-dihydropyridine compoundthat functions in biological processes through NADH regener-ationrdquo Journal of Organic Chemistry vol 67 no 10 pp 3499ndash3501 2002
[82] A Weckbecker H Groger and W Hummel ldquoRegeneration ofnicotinamide coenzymes principles and applications for thesynthesis of chiral compoundsrdquo in Biosystems Engineering ICreating Superior Biocatalysts ChWittmann and R Krull Edsvol 120 of Advances in Biochemical EngineeringBiotechnologypp 195ndash242 Springer Verlag Berlin Germany 2010
[83] T Okamura T Kikuchi A Nagamine et al ldquoAn approach formeasuring in vivo cerebral redox states using the oxidative con-version of dihydropyridine to pyridinium ion and themetabolictrapping principlerdquo Free Radical Biology and Medicine vol 38no 9 pp 1197ndash1205 2005
[84] K A Schellenberg and F H Westheimer ldquoA free-radicaloxidation of a dihydropyridine1ardquo The Journal of OrganicChemistry vol 30 no 6 pp 1859ndash1862 1965
[85] K A Schellenberg ldquoReaction of hydroxyl radical with thymi-dine Scavenging by a dihydropyridinerdquo Federation Proceedingsvol 38 no 3 I p 1433 1979
[86] E S Huyser J A K Harmony and F L McMillian ldquoPeroxideoxidations of dihydropyridine derivativesrdquo Journal of the Amer-ican Chemical Society vol 94 no 9 pp 3176ndash3180 1972
[87] A Sakamoto S T Ohnishi and R Ogawa ldquoInhibition of lipidperoxidation by some dihydropyridine derivativesrdquo Journal ofAnesthesia vol 7 no 2 pp 193ndash197 1993
[88] R Hardeland ldquoReview Neuroprotection by radical avoidancesearch for suitable agentsrdquo Molecules vol 14 no 12 pp 5054ndash5102 2009
[89] G Ya Dubur A Kh Velena V M Gukasov and Yu AVladimirov ldquoRegulation of peroxidation of mitochondrialmembrane lipids initiated by Fe2+ ions by antoxidants of the14-dihydropyridine series in experiments in vitrordquo Biomed-itsinskaya Khimiya vol 22 no 5 pp 665ndash673 1976 (Russian)Chemical Abstracts vol 88 Article ID 2640 1977
[90] G RMMHaenenM J T J Arts A Bast andMD ColemanldquoStructure and activity in assessing antioxidant activity in vitroand in vivo a critical appraisal illustrated with the flavonoidsrdquoEnvironmental Toxicology and Pharmacology vol 21 no 2 pp191ndash198 2006
[91] G Tirzitis and G Bartosz ldquoDetermination of antiradical andantioxidant activity basic principles and new insightsrdquo ActaBiochimica Polonica vol 57 no 2 pp 139ndash142 2010
30 Oxidative Medicine and Cellular Longevity
[92] G R Buettner and R P Mason ldquoSpin-trapping methods fordetecting superoxide and hydroxyl free radicals in vitro and invivordquo inCritical Reviews of Oxidative Stress and Aging Advancesin Basic Science Diagnostics and Intervention R G Cutler andH Rodriguez Eds vol 1 chapter 2 pp 27ndash38World ScientificLondon UK 2003
[93] M M Tarpey and I Fridovich ldquoMethods of detection ofvascular reactive species Nitric oxide superoxide hydrogenperoxide and peroxynitriterdquo Circulation Research vol 89 no3 pp 224ndash236 2001
[94] E Y Kazush E I Sagun G D Tirzit and G Y DaburldquoQuenching of singlet oxygen by electron donating derivativesof 14-dihydropyridinerdquo Chemistry of Heterocyclic Compoundsvol 30 no 5 pp 562ndash563 1994
[95] G Tirzitis E Kazush and G Duburs ldquoReaction of 14-dihydropyridine derivatives with peroxynitrite anionrdquo Chem-istry of Heterocyclic Compounds vol 34 no 3 pp 321ndash3231998 (Russian) Translated from Khimiya GeterotsiklicheskikhSoedinenii no 3 pp 355ndash357 1998
[96] L J Nunez-Vergara C Lopez-Alarcon P A Navarrete-EncinaA M Atria C Camargo and J A Squella ldquoElectrochemicaland EPR characterization of 14-dihydropyridines Reactivitytowards alkyl radicalsrdquo Free Radical Research vol 37 no 1 pp109ndash120 2003
[97] D Tirzite A Krauze A Zubareva G Tirzitis and G DubursldquoSynthesis and antiradical activity of 5-acetyl-2-alkylthio-4-aryl-6-methyl-14-dihydropyridine-3-carboxylic acid nitrilesrdquoChemistry of Heterocyclic Compounds vol 38 no 7 pp 795ndash800 2002
[98] H Ohkawa N Ohishi and K Yagi ldquoAssay for lipid peroxidesin animal tissues by thiobarbituric acid reactionrdquo AnalyticalBiochemistry vol 95 no 2 pp 351ndash358 1979
[99] N Zarkovic ldquo4-Hydroxynonenal as a bioactive marker ofpathophysiological processesrdquo Molecular Aspects of Medicinevol 24 no 4-5 pp 281ndash291 2003
[100] M Parola G Bellomo G Robino G Barrera and M UDianzani ldquo4-Hydroxynonenal as a biological signal molecularbasis and pathophysiological implicationsrdquo Antioxidants andRedox Signaling vol 1 no 3 pp 255ndash284 1999
[101] T Lovakovic M Poljak-Blazi G Duburs et al ldquoGrowthmodulation of human cells in vitro by mild oxidative stressand 14-dihydropyridine derivative antioxidantsrdquo CollegiumAntropologicum vol 35 no 1 pp 137ndash141 2011
[102] R van den Berg G R M M Haenen H van den Bergand A Bast ldquoApplicability of an improved Trolox equivalentantioxidant capacity (TEAC) assay for evaluation of antioxidantcapacity measurements of mixturesrdquo Food Chemistry vol 66no 4 pp 511ndash517 1999
[103] C Lopez-Alarcon P Navarrete C Camargo J A Squella andL J Nunez-Vergara ldquoReactivity of 14-dihydropyridines towardalkyl alkylperoxyl radicals and ABTS radical cationrdquo ChemicalResearch in Toxicology vol 16 no 2 pp 208ndash215 2003
[104] V Valenzuela P Santander C Camargo J A Squella C Lopez-Alarcon and L J Nunez-Vergara ldquo14-Dihydropyridines reac-tivity of nitrosoaryl and nitroaryl derivatives with alkylperoxylradicals andABTS radical cationrdquo Free Radical Research vol 38no 7 pp 715ndash727 2004
[105] L G Tsetlin N A Chebotareva B I Kurganov A K VelenaG Y Dubur and V Z Lankin ldquoStudy of 14-dihydropyridinesas lipoxygenase inhibitors with the use of hydrated reversedmicellesrdquo Pharmaceutical Chemistry Journal vol 22 no 6 pp425ndash428 1988 (Russian)
[106] J Panek Z Reblova L Kocirkova et al ldquoAntioxidant activityof dihydropyridine derivativesrdquo Czech Journal of Food Sciencesvol 18 pp 144ndash145 2000
[107] G Tirzitis I Kirule and G Duburs ldquoAntioxidationsaktivitatder 35-dicarbonylderivate des 26-demethyl-14-dihydropyri-dinsrdquo Fett Wissenschaft TechnologieFat Science Technology vol90 no 10 pp 411ndash413 1988
[108] M Plotniece G Tirzitis Y Uldrikis et al ldquoSynthesis of 14-dihydropyridine derivatives having an oxy- alkoxy- or dimeth-ylaminophenyl substituent in the 4 position their antioxidantactivity and their binding to phospholipid membranesrdquo Chem-istry of Heterocyclic Compounds vol 32 no 10 pp 1166ndash11721996 Translated from Khimiya Geterotsiklicheskikh Soedineniino 10(352) pp 1358ndash1365 1996 (Russian)
[109] D Y Rubene V S Sharov V I Olenev G D Tirzit G Y Duburand Y A Vladimirov ldquoUse of chemiluminescent method forthe evaluation of antioxidant activity of some derivatives of 14-dihydropyridinerdquo Russian Journal of Physical Chemistry A vol55 no 2 pp 511ndash512 1981 (Russian)
[110] M C R Symons and JM C Gutteridge Free Radicals and IronChemistry Biology and Medicine Oxford Science PublicationsOxford University Press Oxford UK 1998
[111] M Repetto J Semprine and A Boveris ldquoLipid peroxidationchemical mechanism biological implications and analyticaldeterminationrdquo in Lipid Peroxidation A Catala Ed Section ILipid Peroxidation Chemical Mechanisms Antioxidants Bio-logical Implications of Biochemistry Genetics and MolecularBiology chapter 1 pp 3ndash30 InTech Rijeka Croatia 2012
[112] A Velena J Zilbers and G Duburs ldquoDerivatives of 14-dihydropyridines asmodulators of ascorbate-induced lipid per-oxidation and high-amplitude swelling ofmitochondria causedby ascorbate sodium linoleate and sodiumpyrophosphaterdquoCellBiochemistry and Function vol 17 no 4 pp 237ndash252 1999
[113] M V Bilenko L N Shelenkova G Y Dubur and A K VelenaldquoUse of antioxidants to prevent renal damage during acuteischemia and reperfusionrdquo Bulletin of Experimental Biology andMedicine vol 96 no 3 pp 1195ndash1198 1983 Translated fromByulletenrsquo Eksperimentalrsquonoi Biologii i Meditsiny vol 96 no 9pp 8ndash11 1983 (Russian)
[114] R Toniolo F Tubaro F Ursini and G Bontempelli ldquoAn elec-troanalytical investigation on the redox properties of calciumantagonist dihydropyridinesrdquo Electroanalysis vol 15 no 10 pp855ndash861 2003
[115] L Kourimska J Pokorny and G Tirzitis ldquoThe antioxidant aci-tivity of 26-dimethyl-35-diethoxycarbonyl-14-dihydropyri-dine in edible oilsrdquo Nahrung vol 37 no 1 pp 91ndash93 1993
[116] C Lopez-Alarcon H Speisky J A Squella C Olea-Azar CCamargo and L J Nunez-Vergara ldquoReactivity of 14-dihydro-pyridines toward SIN-1-derived peroxynitriterdquo PharmaceuticalResearch vol 21 no 10 pp 1750ndash1757 2004
[117] R A Olek W Ziolkowski J J Kaczor L Greci J Popinigisand J Antosiewicz ldquoAntioxidant activity of NADH and its ana-loguemdashan in vitro studyrdquo Journal of Biochemistry andMolecularBiology vol 37 no 4 pp 416ndash421 2004
[118] E Niki N Noguchi and N Gotoh ldquoInhibition of oxidativemodification of low density lipoprotein by antioxidantsrdquo Jour-nal of Nutritional Science andVitaminology vol 39 supplementpp S1ndashS8 1993
[119] N Rojstaczer and D J Triggle ldquoStructure-function relation-ships of calcium antagonists effect on oxidative modificationof low density lipoproteinrdquo Biochemical Pharmacology vol 51no 2 pp 141ndash150 1996
Oxidative Medicine and Cellular Longevity 31
[120] A Sevanian L Shen and FUrsini ldquoInhibition of LDLoxidationand oxidized LDL-induced cytotoxicity by dihydropyridinecalcium antagonistsrdquo Pharmaceutical Research vol 17 no 8 pp999ndash1006 2000
[121] A Negre-Salvayre and R Salvayre ldquoProtection by Ca2+ channelblockers (nifedipine diltiazem and verapamil) against the tox-icity of oxidized low density lipoprotein to cultured lymphoidcellsrdquo British Journal of Pharmacology vol 107 no 3 pp 738ndash744 1992
[122] A Negre-Salvayre G FitoussiM Troly and R Salvayre ldquoCom-parative cytoprotective effect of dihydropyridine calcium chan-nel blockers against the toxicity of oxidized low density lipopro-tein for cultured lymphoid cellsrdquo Biochemical Pharmacologyvol 44 no 12 pp 2379ndash2386 1992
[123] L Cominacini A F Pasini U Garbin et al ldquoAntioxidant activ-ity of different dihydropyridinesrdquo Biochemical and BiophysicalResearch Communications vol 302 no 4 pp 679ndash684 2003
[124] L Cominacini U Garbin A Fratta Pasini et al ldquoOxidized low-density lipoprotein increases the production of intracellularreactive oxygen species in endothelial cells inhibitory effect oflacidipinerdquo Journal of Hypertension vol 16 no 12 part 2 pp1913ndash1919 1998
[125] H M Lander ldquoAn essential role for free radicals and derivedspecies in signal transductionrdquo The FASEB Journal vol 11 no2 pp 118ndash124 1997
[126] M L L Martinez E Rizzi M M Castro et al ldquoLercanidipinedecreases vascular matrix metalloproteinase-2 activity andprotects against vascular dysfunction in diabetic ratsrdquo EuropeanJournal of Pharmacology vol 599 no 1ndash3 pp 110ndash116 2008
[127] P Lesnik C Dachet L Petit et al ldquoImpact of a combinationof a calcium antagonist and a 120573-blocker on cell- and copper-mediated oxidation of LDL and on the accumulation and effluxof cholesterol in human macrophages and murine J774 cellsrdquoArteriosclerosis Thrombosis and Vascular Biology vol 17 no 5pp 979ndash988 1997
[128] G Sobal E J Menzel and H Sinzinger ldquoCalcium antagonistsas inhibitors of in vitro low density lipoprotein oxidation andglycationrdquoBiochemical Pharmacology vol 61 no 3 pp 373ndash3792001
[129] E Lupo R Locher B Weisser and W Vetter ldquoIn vitro antiox-idant activity of calcium antagonists against LDL oxidationcompared with 120572-tocopherolrdquo Biochemical and BiophysicalResearch Communications vol 203 no 3 pp 1803ndash1808 1994
[130] J Zou Y Li H-Q Fan and J-G Wang ldquoEffects of dihydropy-ridine calcium channel blockers on oxidized low-density lipo-protein induced proliferation and oxidative stress of vascularsmooth muscle cellsrdquo BMC Research Notes vol 5 article 1682012
[131] C Napoli S Salomone T Godfraind et al ldquo14-Dihydro-pyridine calcium channel blockers inhibit plasma and LDL oxi-dation and formation of oxidation-specific epitopes in the arte-rial wall and prolong survival in stroke-prone spontaneouslyhypertensive ratsrdquo Stroke vol 30 no 9 pp 1907ndash1915 1999
[132] G Zernig I Graziadei T Moshammer C Zech N Reider andH Glossmann ldquoMitochondrial Ca2+ antagonist binding sitesare associated with an inner mitochondrial membrane anionchannelrdquo Molecular Pharmacology vol 38 no 3 pp 362ndash3691990
[133] F E Hunter Jr A Scott P E Hochstein et al ldquoStudies of themechanism of ascorbate-induced swelling and lysis of isolatedliver mitochondriardquo The Journal of Biological Chemistry vol239 pp 604ndash613 1964
[134] D R Janero B Burghardt and R Lopez ldquoProtection of cardiacmembrane phospholipid against oxidative injury by calciumantagonistsrdquoBiochemical Pharmacology vol 37 no 21 pp 4197ndash4203 1988
[135] A Karadag B Ozcelik and S S Saner ldquoReview of methods todetermine antioxidant capacitiesrdquo FoodAnalyticalMethods vol2 no 1 pp 41ndash60 2009
[136] Y I Gubskiı N V Litvinova and E V Shnurko-TabakovaldquoAntioxidant and antiradical activity of various classes of antiox-idantsrdquo Ukrainskiı Biokhimicheskiı Zhurnal vol 66 no 4 pp114ndash116 1994 (Russian)
[137] M Takei M Hiramatsu and A Mori ldquoInhibitory effects ofcalcium antagonists onmitochondrial swelling induced by lipidperoxidation or arachidonic acid in the rat brain in vitrordquoNeurochemical Research vol 19 no 9 pp 1199ndash1206 1994
[138] M Takei M Hiramatsu R Edamatsu and A Mori ldquoFreeradical scavenging by calcium antagonistsrdquo Neurosciences vol20 no 2 pp 75ndash82 1994
[139] Ya P Stradin G Ya Dubur Yu A Beilis Ya R Uldrikis andA F Korotkova ldquoVoltammetry of 14-dihydropyridine deriva-tives I Potentials of electrochemical oxidation of 35-diacyl-and 35-di(alkoxycarbonyl)-14-dihydropyridines in acetoni-trilerdquo Chemistry of Heterocyclic Compounds no 1 pp 84ndash871972 (Russian)
[140] E V Ivanov T V Ponomarjova G N Merkusev et al ldquoEinneuer Haut-Radioprotektor Diethon (experimentelle Unter-suchung)rdquo Radiobiologia Radiotherapia vol 31 no 1 pp 69ndash78 1990
[141] E V Ivanov T V Ponomareva G N Merkushev et al ldquoRadia-tion modulating properties of derivates of 14-dihydropyridineand 12345678910-decahydroacridine-18 dionerdquo Radiat-sionnaia Biologiia Radioecologiia vol 44 no 5 pp 550ndash5592004 (Russian)
[142] R O Vitolinia D A Berzinia A K Velena I A Vutsina A AKimenis and G Y Duburs ldquoThe protective effects of the cal-cium antagonist foridon in acute myocardial ischaemiardquo Kardi-ologiya vol 27 no 3 pp 90ndash93 1987 (Russian)
[143] A H Velena G Ya Duburs R O Vitolina et al ldquoEffect ofryodipine on electromechanical parameters of heart and vesselscAMP phosphodiesterase activity and swelling-contractioncycle of mitochondriardquo Arzneimittelforschung vol 35 no 6 pp907ndash914 1985
[144] L I Utno Z E Lipsberga A A Silova M I Girgensone EA Bisenieks and G I Ia ldquoCardioprotective properties of a 14-dihydropyridine derivative glutapyrone in deep hypothermiardquoBiulletenrsquo Eksperimentalrsquonoı Biologii i Meditsiny vol 108 no 11pp 558ndash561 1989 (Russian)
[145] M A S FernandesM S Santos J A F Vicente et al ldquoEffects of14-dihydropyridine derivatives (cerebrocrast gammapyroneglutapyrone and diethone) onmitochondrial bioenergetics andoxidative stress a comparative studyrdquoMitochondrion vol 3 no1 pp 47ndash59 2003
[146] M A S Fernandes M S Santos A J M Moreno et al ldquoEffectsof 5-acetyl(carbamoyl)-6-methylsulfanyl-14-dihydropyridine-5-carbonitriles on rat liver mitochondrial functionrdquo Toxicologyin Vitro vol 23 no 7 pp 1333ndash1341 2009
[147] L Klimaviciusa A Kalda A Kaasik et al ldquoNeuroprotectiveactivity of 14-dihydropyridine derivatives structure determi-nantsrdquo Proceedings of the Latvian Academy of Sciences BNatural Exact and Applied Sciences vol 61 no 1-2 pp 33ndash372007
32 Oxidative Medicine and Cellular Longevity
[148] L Klimaviciusa M A S Fernandes N Lencberga et alldquoTargeting the mitochondria by novel adamantane-containing14-dihydropyridine compoundsrdquo in Bioenergetics K B ClarkEd pp 257ndash272 InTech 2012
[149] V Klusa L Klimaviciusa G Duburs J Poikans and AZharkovsky ldquoAnti-neurotoxic effects of tauropyrone a taurineanaloguerdquo Advances in Experimental Medicine and Biology vol583 pp 499ndash508 2006
[150] N Sampson P Berger and Ch Zenzmaier ldquoRedox signalingas a therapeutic target to inhibit myofibroblast activation indegenerative fibrotic diseaserdquo BioMed Research Internationalvol 2014 Article ID 131737 14 pages 2014
[151] T L Leto and M Geiszt ldquoRole of Nox family NADPH oxidasesin host defenserdquoAntioxidantsampRedox Signaling vol 8 no 9-10pp 1549ndash1561 2006
[152] K K Griendling D Sorescu and M Ushio-Fukai ldquoNAD(P)Hoxidase role in cardiovascular biology and diseaserdquo CirculationResearch vol 86 no 5 pp 494ndash501 2000
[153] H Chen Y S Song and P H Chan ldquoInhibition of NADPHoxi-dase is neuroprotective after ischemia-reperfusionrdquo Journal ofCerebral Blood Flow and Metabolism vol 29 no 7 pp 1262ndash1272 2009
[154] P Hochstein and L Ernster ldquoADP-activated lipid peroxidationcoupled to the TPNH oxidase system of microsomesrdquo Biochem-ical and Biophysical Research Communications vol 12 no 5 pp388ndash394 1963
[155] I I Gubskiı AGGoriushkoNV Litvinova et al ldquoAntioxidantproperties and membranotropic effect of certain derivatives of14-dihydropyridinerdquo Ukrainskiı Biokhimicheskiı Zhurnal vol71 no 4 pp 35ndash39 1999 (Russian)
[156] F Engineer and R Sridhar ldquoInhibition of rat heart andliver microsomal lipid peroxidation by nifedipinerdquo BiochemicalPharmacology vol 38 no 8 pp 1279ndash1285 1989
[157] T Goncalves A P Carvalho and C R Oliveira ldquoAntioxidanteffect of calcium antagonists on microsomai membranes iso-lated from different brain areasrdquo European Journal of Pharma-cology vol 204 no 3 pp 315ndash322 1991
[158] M E Letelier P Izquierdo L Godoy A M Lepe and MFaundez ldquoLiver microsomal biotransformation of nitro-aryldrugs mechanism for potential oxidative stress inductionrdquoJournal of Applied Toxicology vol 24 no 6 pp 519ndash525 2004
[159] M E Letelier P Entrala C Lopez-Alarcon et al ldquoNitroaryl-14-dihydropyridines as antioxidants against rat liver microsomesoxidation induced by ironascorbate Nitrofurantoin and naph-thalenerdquo Toxicology in Vitro vol 21 no 8 pp 1610ndash1618 2007
[160] F P Guengerich W R Brian M Iwasaki M-A Sari CBaarnhielm and P Berntsson ldquoOxidation of dihydropyridinecalcium channel blockers and analogues by human liver cyto-chrome P-450 IIIA4rdquo Journal of Medicinal Chemistry vol 34no 6 pp 1838ndash1844 1991
[161] S H Park S-W RhaW-Y Shin et al ldquoAS-160 Calcium channelblockers of dihydropyridine class reduce the antiplatelet effectof Clopidogrel what is clinical impactrdquo The American Journalof Cardiology vol 107 no 8 supplement p 47A 2011
[162] C Asma and D M Reda ldquoEvaluation of dihydropyridinecalcium antagonist effects on the stress bioindicator orga-nism Saccharomyces cerevisiaerdquo Annals of Biological Researchvol 4 no 10 pp 40ndash46 2013 httpscholarsresearchlibrarycomABR-vol4-iss10ABR-2013-4-10-40-46pdf
[163] G Gaviraghi A M Pastorino E Ratti and D G TristldquoCalcium channel blockers with antioxidant activityrdquo in Free
Radicals Lipoprotein Oxidation andAtherosclerosis G BellomoG Finardi E Maggi and E Rice-Evans Eds pp 431ndash456Richelieu Press London UK 1995
[164] G Gaviraghi AM Pastorino E Ratti and D G Trist ldquoAntiox-idant dihydropyridines a new and comprehensive therapy forfree radical-induced cardiovascular diseasesrdquo in Free Radicalsin Biology and Environment F Minisci Ed vol 27 of NATOASI Series pp 193ndash221 Springer Dordrecht The Netherlands1997
[165] P D Henry ldquoAntiperoxidative actions of calcium antagonistsand atherogenesisrdquo Journal of Cardiovascular Pharmacologyvol 18 supplement 1 pp S6ndashS10 1991
[166] F Kouoh B Gressier T Dine et al ldquoAntioxidant effects andanti-elastase activity of the calcium antagonist nicardipine onactivated human and rabbit neutrophilsmdasha potential antiath-erosclerotic property of calcium antagonistsrdquo CardiovascularDrugs andTherapy vol 16 no 6 pp 515ndash520 2002
[167] S Parthasarathy D Litvinov K Selvarajan and M GarelnabildquoLipid peroxidation and decompositionmdashconflicting roles inplaque vulnerability and stabilityrdquo Biochimica et BiophysicaActa vol 1781 no 5 pp 221ndash231 2008
[168] D-Q Liu Z-Q Pang D-H Zhao and B-H Sheng ldquoEffects offuryl-dihydropyridines I on lipid peroxides of ischemic myo-cardium and ATPases activity of erythrocyte membranes inratsrdquo Acta Pharmacologica Sinica vol 12 no 3 pp 253ndash2561991
[169] V Lukic-Panin T Kamiya H Zhang et al ldquoPrevention of neu-ronal damage by calcium channel blockers with antioxidativeeffects after transient focal ischemia in ratsrdquo Brain Research vol1176 no 1 pp 143ndash150 2007
[170] Y Allanore D Borderie H Lemarechal O G Ekindjian andA Kahan ldquoAcute and sustained effects of dihydropyridine-typecalcium channel antagonists on oxidative stress in systemicsclerosisrdquo American Journal of Medicine vol 116 no 9 pp 595ndash600 2004
[171] I Casetta V Govoni and E Granieri ldquoOxidative stress antioxi-dants and neurodegenerative diseasesrdquo Current PharmaceuticalDesign vol 11 no 16 pp 2033ndash2052 2005
[172] M J T J Arts Assessing antioxidant activity [PhD the-sis] Maastricht University Maastricht The Netherlands 2007httparnounimaasnlshowcgifid=8676
[173] G Dıaz-Araya L Godoy L Naranjo A Squella M E Letelierand L J Nunez-Vergara ldquoAntioxidant effects of 14-dihydro-pyridine and nitroso aryl derivatives on the Fe+3ascorbate-stimulated lipid peroxidation in rat brain slicesrdquo General Phar-macology The Vascular System vol 31 no 3 pp 385ndash391 1998
[174] Y Fukuhara K Tsuchiya Y Horinouchi et al ldquoProtectiveeffect of photodegradation product of nifedipine against tumornecrosis factor 120572-induced oxidative stress in human glomerularendothelial cellsrdquo Journal of Medical Investigation vol 58 no1-2 pp 118ndash126 2011
[175] W Stengel M Jainz and K Andreas ldquoDifferent potencies ofdihydropyridine derivatives in blocking T-type but not L-typeCa2+ channels in neuroblastoma-glioma hybrid cellsrdquo EuropeanJournal of Pharmacology vol 342 no 2-3 pp 339ndash345 1998
[176] O M Panasenko D J Tirzite G D Tirzitis and G J DubursldquoEffect of some 14-dihydropyridine derivatives on structuralorganization of erythrocyte membranesrdquo Biologicheskie Mem-brany (Biochemistry (Moscow) Series A Membrane and CellBiology) vol 1 pp 919ndash925 1984 (Russian)
[177] L G Herbette Y M H Vant Erve and D G Rhodes ldquoInter-action of 14 dihydropyridine calcium channel antagonists with
Oxidative Medicine and Cellular Longevity 33
biological membranes lipid bilayer partitioning could occurbefore drug binding to receptorsrdquo Journal of Molecular andCellular Cardiology vol 21 no 2 pp 187ndash201 1989
[178] L G Herbette P E Mason G Gaviraghi T N Tulenko andR P Mason ldquoThe molecular basis for lacidipinersquos unique phar-macokinetics optimal hydrophobicity results in membraneinteractions that may facilitate the treatment of atherosclerosisrdquoJournal of Cardiovascular Pharmacology vol 23 supplement 5pp S16ndashS25 1994
[179] G V Belevitch G Y Dubur G E Dobretsov N K Kurek andM M Spirin ldquoCalcium antagonists riodipine nifedipine andverapamil binding to model and biological membranes fluore-scence analysisrdquo Biologicheskie Membrany (Biochemistry(Moscow) Series A Membrane and Cell Biology) vol 5 pp768ndash776 1988 (Russian)
[180] R P Mason G E Gonye D W Chester and L G HerbetteldquoPartitioning and location of Bay K 8644 14-dihydropyridinecalcium channel agonist in model and biological membranesrdquoBiophysical Journal vol 55 no 4 pp 769ndash778 1989
[181] M Cindric A Cipak J Serly et al ldquoReversal of multidrugresistance inmurine lymphoma cells by amphiphilic dihydropy-ridine antioxidant derivativerdquo Anticancer Research vol 30 no10 pp 4063ndash4070 2010
[182] F Shekari H Sadeghpour K Javidnia et al ldquoCytotoxic andmultidrug resistance reversal activities of novel 14-dihydro-pyridines against human cancer cellsrdquo European Journal ofPharmacology vol 746 no 1 pp 233ndash244 2015
[183] X-F Zhou Q Shao R A Coburn and M E Morris ldquoQuanti-tative structure-activity relationship and quantitative structure-pharmacokinetics relationship of 14-dihydropyridines andpyridines as multidrug resistance modulatorsrdquo PharmaceuticalResearch vol 22 no 12 pp 1989ndash1996 2005
[184] R Berkels T Breitenbach H Bartels et al ldquoDifferent antioxida-tive potencies of dihydropyridine calcium channel modulatorsin various modelsrdquo Vascular Pharmacology vol 42 no 4 pp145ndash152 2005
[185] S Borovic G Tirzitis D Tirzite et al ldquoBioactive 14-dihydro-isonicotinic acid derivatives prevent oxidative damage of livercellsrdquo European Journal of Pharmacology vol 537 no 1ndash3 pp12ndash19 2006
[186] D Ya Rubene G D Tirzitis and G Ya Duburs ldquoInteractionof some 14-dihydropyridine derivatives with Fentonrsquos reagentrdquoLatvijas PSRZinatnuAkademijas Vestis Kimijas Serija Proceed-ings of the Latvian SSR Academy of Sciences Chemistry Seriespp 212ndash216 1982 (Russian)
[187] K Ondrias V Misık D Gergel and A Stasko ldquoLipid per-oxidation of phosphatidylcholine liposomes depressed by thecalcium channel blockers nifedipine and verapamil and bythe antiarrhythmic-antihypoxic drug stobadinerdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1003 no 3pp 238ndash245 1989
[188] I T Mak and W B Weglicki ldquoComparative antioxidant acti-vities of propranolol nifedipine verapamil and diltiazemagainst sarcolemmal membrane lipid peroxidationrdquoCirculationResearch vol 66 no 5 pp 1449ndash1452 1990
[189] I T Mak P Boehme and W B Weglicki ldquoProtective effects ofcalcium channel blockers against free radical-impaired endo-thelial cell proliferationrdquo Biochemical Pharmacology vol 50 no9 pp 1531ndash1534 1995
[190] S Ray S Mondal and N Dana ldquoEvaluation of protective roleof nifedipine on lipid peroxidation using reduced glutathione as
model markerrdquo Oxidants and Antioxidants in Medical Sciencevol 1 no 2 pp 97ndash100 2012
[191] M Yamato T Shiba T Ide Y Honda K-I Yamada andH Tsutsui ldquoNifedipine treatment reduces brain damage aftertransient focal ischemia possibly through its antioxidativeeffectsrdquoHypertension Research vol 34 no 7 pp 840ndash845 2011
[192] V Chander and K Chopra ldquoNifedipine attenuates changes innitric oxide levels renal oxidative stress and nephrotoxicityinduced by cyclosporinerdquo Renal Failure vol 27 no 4 pp 441ndash450 2005
[193] K M Gaafa M M Badawy and A A Hamza ldquoThe protectiveeffects of ascorbic acid cimetidine and nifedipine on diethyl-dithiocarbamate-induced hepatic toxicity in albino ratsrdquo Drugand Chemical Toxicology vol 34 no 4 pp 405ndash419 2011
[194] H Sugawara K Tobise and S Onodera ldquoAbsence of antiox-idant effects of nifedipine and diltiazem on myocardial mem-brane lipid peroxidation in contrast with those of nisoldipineand propranololrdquo Biochemical Pharmacology vol 47 no 5 pp887ndash892 1994
[195] I E Kirule D Y Rubene E A Bisenieks G D Tirzit and GY Dubur ldquo4-Nitrophenyl-14-dihydropyridinesmdasha new groupof inhibitors of peroxide oxidationrdquo Chemistry of HeterocyclicCompounds vol 18 no 3 p 316 1982
[196] G D Tirzit I E Kirule L K Baumane R A Gavar Y PStradynrsquo andG YDubur ldquoMechanism of the antioxidant actionof 26-dimethyl-35-dimethoxy-carbonyl-4-(2-nitrophenyl)14-dihydropyridinerdquoChemistry ofHeterocyclic Compounds vol 20no 8 pp 915ndash918 1984
[197] C Yanez C Lopez-Alarcon C Camargo V Valenzuela J ASquella and L J Nunez-Vergara ldquoStructural effects on thereactivity 14-dihydropyridines with alkylperoxyl radicals andABTS radical cationrdquo Bioorganic and Medicinal Chemistry vol12 no 9 pp 2459ndash2468 2004
[198] VMisik A J Stasko D Gergel and K Ondrias ldquoSpin-trappingand antioxidant properties of illuminated and nonilluminatednifedipine and nimodipine in heart homogenate and modelsystemrdquo Molecular Pharmacology vol 40 no 3 pp 435ndash4391991
[199] K Ondrias V Misık A Stasko D Gergelrsquo and M HromadovaldquoComparison of antioxidant properties of nifedipine and illu-minated nifedipine with nitroso spin traps in low densitylipoproteins and phosphatidylcholine liposomesrdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1211 no 1pp 114ndash119 1994
[200] A Stasko V Brezova S Biskupic K Ondrias and V MisıkldquoReactive radical intermediates formed from illuminated nife-dipinerdquoFree Radical Biology andMedicine vol 17 no 6 pp 545ndash556 1994
[201] K Ishizawa Y Izawa-Ishizawa N Yamano et al ldquoNitrosoni-fedipine ameliorates the progression of type 2 diabetic nephro-pathy by exerting antioxidative effectsrdquo PLoS ONE vol 9 no 1Article ID e86335 2014
[202] H Fujii and L J Berliner ldquoIn vivo EPR evidence for free radicaladducts of nifedipinerdquoMagnetic Resonance in Medicine vol 42no 4 pp 691ndash694 1999
[203] S Bollo S Finger J C Sturm L J Nunez-Vergara and JA Squella ldquoCyclic voltammetry and scanning electrochemicalmicroscopy studies of the heterogeneous electron transferreaction of some nitrosoaromatic compoundsrdquo ElectrochimicaActa vol 52 no 15 pp 4892ndash4898 2007
34 Oxidative Medicine and Cellular Longevity
[204] F Ursini ldquoTissue protection by lacidipine insight from redoxbehaviorrdquo Journal of Cardiovascular Pharmacology vol 30supplement 2 pp S28ndashS30 1997
[205] P G Cristofori F A Crivellente I Faustinelli et al ldquoInvolve-ment of the nitric oxide system in the anti-atheroscleroticpotential of lacidipine in the apoE-deficient mouse a mor-phological functional and electrochemical studyrdquo ToxicologicPathology vol 32 no 4 pp 493ndash499 2004
[206] X-P Zhang E L Kit S Mital S Chahwala and T HHintze ldquoParadoxical release of nitric oxide by an L-type calciumchannel antagonist the R+ enantiomer of amlodipinerdquo Journalof Cardiovascular Pharmacology vol 39 no 2 pp 208ndash2142002
[207] F Franzoni G Santoro F Regoli et al ldquoAn in vitro study of theperoxyl and hydroxyl radical scavenging capacity of the calciumantagonist amlodipinerdquo Biomedicine and Pharmacotherapy vol58 no 8 pp 423ndash426 2004
[208] S V Gatsura ldquoOxygen-dependent mechanisms underlying theantiischemic effect of verapamil and amlodipinerdquo Bulletin ofExperimental Biology and Medicine vol 137 no 1 pp 40ndash422004
[209] Y Hirooka Y Kimura M Nozoe Y Sagara K Ito and KSunagawa ldquoAmlodipine-induced reduction of oxidative stressin the brain is associated with sympatho-inhibitory effects instroke-prone spontaneously hypertensive ratsrdquo HypertensionResearch vol 29 no 1 pp 49ndash56 2006
[210] B Tomlinson and I F F Benzie ldquoAntioxidant effect of lercani-dipine (note)rdquo Hypertension vol 42 no 4 pp e10ndashe11 2003
[211] A A Faraqui ldquoNeurochemical aspects of 4-hydroxynonenalrdquoin Lipid Mediators and Their Metabolism in the Brain A AFaraqui Ed chapter 6 pp 159ndash191 Springer New York NYUSA 2011
[212] V S NascimentoM S DrsquoAlva A AOliveira et al ldquoAntioxidanteffect of nimodipine in young rats after pilocarpine-inducedseizuresrdquo Pharmacology Biochemistry and Behavior vol 82 no1 pp 11ndash16 2005
[213] O Ismailoglu P Atilla S Palaoglu et al ldquoThe therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjuryrdquo Turkish Neurosurgery vol 22 no 6 pp 740ndash746 2012
[214] M Matsubara and K Hasegawa ldquoBenidipine a dihydropy-ridine-calcium channel blocker prevents lysophosphatidyl-choline-induced injury and reactive oxygen species productionin human aortic endothelial cellsrdquo Atherosclerosis vol 178 no1 pp 57ndash66 2005
[215] M Matsubara K Yao and K Hasegawa ldquoBenidipine adihydropyridine-calcium channel blocker inhibits lysophos-phatidylcholine-induced endothelial injury via stimulation ofnitric oxide releaserdquo Pharmacological Research vol 53 no 1 pp35ndash43 2006
[216] MMatsubara and K Hasegawa ldquoEffects of benidipine a dihyd-ropyridine-Ca2+ channel blocker on expression of cytokine-induced adhesion molecules and chemoattractants in humanaortic endothelial cellsrdquo European Journal of Pharmacology vol498 no 1ndash3 pp 303ndash314 2004
[217] M Matsubara O Akizuki J-I Ikeda K Saeki K Yao and KSasaki ldquoBenidipine an anti-hypertensive drug inhibits reactiveoxygen species production in polymorphonuclear leukocytesand oxidative stress in salt-loaded stroke-prone spontaneouslyhypertensive ratsrdquo European Journal of Pharmacology vol 580no 1-2 pp 201ndash213 2008
[218] A C Rosenkranz H Lob T Breitenbach R Berkels and RRoesen ldquoEndothelial antioxidant actions of dihydropyridines
and angiotensin converting enzyme inhibitorsrdquo European Jour-nal of Pharmacology vol 529 no 1ndash3 pp 55ndash62 2006
[219] V Kain S Kumar and S L Sitasawad ldquoAzelnidipine preventscardiac dysfunction in streptozotocin-diabetic rats by reducingintracellular calcium accumulation oxidative stress and apop-tosisrdquo Cardiovascular Diabetology vol 10 article 97 2011
[220] K Nakamura S Yamagishi and H Inoue ldquoUnique atheropro-tective property of azelnidipine a dihydropyridine-based cal-cium antagonistrdquoMedical Hypotheses vol 65 no 1 pp 155ndash1572005
[221] TMatsui S Yamagishi K Nakamura S Kikuchi andH InoueldquoAzelnidipine a dihydropyridine-based calcium antagonistinhibits angiotensin II-induced oxidative stress generation anddownregulation of pigment epithelium-derived factor mRNAlevels in microvascular endothelial cellsrdquo Drugs under Experi-mental and Clinical Research vol 31 no 5-6 pp 215ndash219 2005
[222] C Ohmura H Watada T Shimizu et al ldquoCalcium channelblocker azelnidipine reduces lipid hydroperoxides in patientswith type 2 diabetes independent of blood pressurerdquo EndocrineJournal vol 54 no 5 pp 805ndash811 2007
[223] H Daikuhara F Kikuchi and T Ishida ldquoThe combination ofOLmesartan and a CAlcium channel blocker (azelnidipine) orcandesartan and a calcium channel blocker (amlodipine) intype 2 diabetic hypertensive patients theOLCA studyrdquoDiabetesand Vascular Disease Research vol 9 no 4 pp 280ndash286 2012
[224] MAbe NMaruyama KOkada SMatsumoto KMatsumotoand M Soma ldquoAdditive antioxidative effects of azelnidipine onangiotensin receptor blocker olmesartan treatment for type 2diabetic patients with albuminuriardquoHypertension Research vol34 no 8 pp 935ndash941 2011
[225] K Mizushige ldquoAntioxidative activities of thiazolidinedionesand dihydropyridine-type calcium antagonistsrdquo IRYOmdashJapa-nese Journal of National Medical Services vol 59 no 11 pp 581ndash592 2005
[226] S Manabe T Okura T Fukuoka and J Higaki ldquoAntioxidativeeffects of azelnidipine on mesangial cell proliferation inducedby highly concentrated insulinrdquo European Journal of Pharma-cology vol 567 no 3 pp 252ndash257 2007
[227] Y Koyama Y Takeishi H Takahashi et al ldquoAzelnidipine inhi-bits H
2O2-induced cell death in neonatal rat cardiomyocytesrdquo
CardiovascularDrugs andTherapy vol 21 no 1 pp 69ndash72 2007[228] K Shinomiya K Mizushige M Fukunaga et al ldquoAntioxidant
effect of a new calcium antagonist azelnipidine in culturedhuman arterial endothelial cellsrdquo Journal of International Med-ical Research vol 32 no 2 pp 170ndash175 2004
[229] T Ohyama K Sato K Kishimoto et al ldquoAzelnidipine is acalcium blocker that attenuates liver fibrosis and may increaseantioxidant defencerdquo British Journal of Pharmacology vol 165no 4 pp 1173ndash1187 2012
[230] L A Calo F Zaghetto E Pagnin P A Davis A Sempliciniand A C Pessina ldquoEffect of manidipine on gene expressionand protein level of oxidative stress-related proteins p22phoxand HO-1 Relevance for antihypertensive and anti-remodelingeffectsrdquo Journal of Cardiovascular Pharmacology vol 43 no 4pp 531ndash538 2004
[231] R Ghyasi G Sepehri M Mohammadi R Badalzadeh and AGhyasi ldquoEffect of mebudipine on oxidative stress and lipid per-oxidation in myocardial ischemic-reperfusion injury in maleratrdquo Journal of Research in Medical Sciences vol 17 no 12 pp1150ndash1155 2012
Oxidative Medicine and Cellular Longevity 35
[232] DCAndersson J Fauconnier T Yamada et al ldquoMitochondrialproduction of reactive oxygen species contributes to the 120573-adrenergic stimulation of mouse cardiomycytesrdquoThe Journal ofPhysiology vol 589 no 7 pp 1791ndash1801 2011
[233] A F Ceylan-Isik N Ari M Stefek et al ldquoEffects of a long-term treatment with an antioxidant pyridoindole on vascularresponsiveness in diabetes-induced aging ratsrdquo Current AgingScience vol 4 no 2 pp 150ndash157 2011
[234] S Saponara G Sgaragli and F Fusi ldquoQuercetin antagonismof Bay K 8644 effects on rat tail artery L-type Ca2+ channelsrdquoEuropean Journal of Pharmacology vol 598 no 1ndash3 pp 75ndash802008
[235] D A Sica ldquoInteraction of grapefruit juice and calcium channelblockersrdquo American Journal of Hypertension vol 19 no 7 pp768ndash773 2006
[236] P Mulder G Litwinienko S Lin P D MacLean L R CBarclay and K U Ingold ldquoThe L-type calcium channel block-ers Hantzsch 14-dihydropyridines are not peroxyl radical-trapping chain-breaking antioxidantsrdquo Chemical Research inToxicology vol 19 no 1 pp 79ndash85 2006
[237] L J Nunez-Vergara R Salazar C Camargo et al ldquoOxidation ofC4-hydroxyphenyl 14-dihydropyridines in dimethylsulfoxideand its reactivity towards alkylperoxyl radicals in aqueousmediumrdquo Bioorganic and Medicinal Chemistry vol 15 no 12pp 4318ndash4326 2007
[238] M E Ortiz L J Nunez-Vergara and J A Squella ldquoRelativereactivity of dihydropyridine derivatives to electrogeneratedsuperoxide ion in DMSO solutions a voltammetric approachrdquoPharmaceutical Research vol 20 no 2 pp 292ndash296 2003
[239] M E Ortiz L J Nunez-Vergara C Camargo and J A SquellaldquoOxidation of Hantzsch 14-dihydropyridines of pharmacolog-ical significance by electrogenerated superoxiderdquo Pharmaceuti-cal Research vol 21 no 3 pp 428ndash435 2004
[240] R S Raghuvanshi and K N Singh ldquoSuperoxide induced oxida-tive aromatization of Hantzsch 14-dihydropyridinesrdquo IndianJournal of Chemistry Section B Organic and Medicinal Chem-istry vol 47 no 11 pp 1735ndash1738 2008
[241] I Kruk A Kladna K Lichszteld et al ldquoAntioxidant activityof 4-flavonil-14-dihydropyridine derivativesrdquo Biopolymers vol62 no 3 pp 163ndash167 2001
[242] G D Tirzit I M Byteva K I Salokhiddinov G P Gurinovichand G Y Dubur ldquo14-Dihydropyridine derivatives as deactiva-tors of singlet oxygenrdquo Chemistry of Heterocyclic Compoundsvol 17 no 7 pp 682ndash684 1981
[243] G D Tirzit E Y Kazush and G Y Dubur ldquoInfluence of14-dihydropyridine derivatives on the generation of hydroxylradicalsrdquo Chemistry of Heterocyclic Compounds vol 28 no 4pp 435ndash437 1992
[244] N A Pizarro-Urzua and L J Nunez-Vergara ldquoNifedipine andnitrendipine reactivity toward singlet oxygenrdquo Journal of Photo-chemistry and Photobiology A Chemistry vol 175 no 2-3 pp129ndash137 2005
[245] L-F Wang H-Y Zhang L Konga Z-W Chena and J-G ShildquoDFT calculations indicate that 14-dihydropyridine is a promis-ing lead antioxidantrdquo Helvetica Chimica Acta vol 87 no 6 pp1515ndash1521 2004
[246] P Mulder H-G Korth and K U Ingold ldquoWhy quantum-thermochemical calculations must be used with caution toindicate lsquoa promising lead antioxidantrsquordquoHelvetica Chimica Actavol 88 no 2 pp 370ndash374 2005
[247] K Yao Y Ina K Nagashima K Ohmori and T Ohno ldquoAntiox-idant effects of calcium antagonists in rat brain homogenatesrdquo
Biological and Pharmaceutical Bulletin vol 23 no 6 pp 766ndash769 2000
[248] T Matsui S-I Yamagishi K Nakamura and H Inoue ldquoBayw 9798 a dihydropyridine structurally related to nifedipinewith no calcium channel-blocking properties inhibits tumournecrosis factor-120572-induced vascular cell adhesion molecule-1expression in endothelial cells by suppressing reactive oxygenspecies generationrdquo Journal of International Medical Researchvol 35 no 6 pp 886ndash891 2007
[249] K AMitrega B VargheseM Porc and T F Krzeminski ldquoAnti-arrhythmic and hemodynamic effects of oxy nifedipine oxynimodipine oxy nitrendipine and oxy nisoldipinerdquo Pharmaco-logical Research vol 66 no 4 pp 300ndash308 2012
[250] V Herbert ldquoSymposium prooxidant effects of antioxidantvitamins Introductionrdquo The Journal of Nutrition vol 126 no4 supplement pp 1197Sndash1200S 1996 httpjnnutritionorgcontent1264 Suppl1197Sfullpdf
[251] B Halliwell ldquoAre polyphenols antioxidants or pro-oxidantsWhat do we learn from cell culture and in vivo studiesrdquoArchives of Biochemistry and Biophysics vol 476 no 2 pp 107ndash112 2008
[252] C Winterbourn Pro-Oxidants or Antioxidants ChristchurchSchool of Medicine Depatment of Pathology Free RadicalSchool SFRBMUniversity of Otago San Francisco Calif USA2009 httpwwwsfrbmorgfrsWinterbournpdf
[253] A Morakinyo B Iranloye and O Adegoke ldquoCalcium antag-onists modulate oxidative stress and acrosomal reaction in ratspermatozoardquo Archives of Medical Science vol 7 no 4 pp 613ndash618 2011
[254] The Alpha-Tocopherol Beta Carotene Cancer Prevention StudyGroup ldquoThe effect of vitamin E and beta carotene on theincidence of lung cancer and other cancers in male smokersrdquoTheNew England Journal of Medicine vol 330 no 15 pp 1029ndash1035 1994
[255] B Poljsak ldquoStrategies for reducing or preventing the generationof oxidative stressrdquo Oxidative Medicine and Cellular Longevityvol 2011 Article ID 194586 15 pages 2011
[256] B Poljsak and I Milisav ldquoThe neglected significance of lsquoanti-oxidative stressrsquordquoOxidativeMedicine and Cellular Longevity vol2012 Article ID 480895 12 pages 2012
[257] T Godfraind and S Salomone ldquoAmbiguities in dietary antiox-idant supplementation compared to calcium channel blockerstherapyrdquo Frontiers in Pharmacology vol 6 article 10 2015
[258] H Wagner H Norr and H Winterhoff ldquoDrugs with adap-togenic effects for strengthening the powers of resistancerdquoZeitschrift fur Phytotherapie vol 13 no 2 pp 42ndash54 1992
30 Oxidative Medicine and Cellular Longevity
[92] G R Buettner and R P Mason ldquoSpin-trapping methods fordetecting superoxide and hydroxyl free radicals in vitro and invivordquo inCritical Reviews of Oxidative Stress and Aging Advancesin Basic Science Diagnostics and Intervention R G Cutler andH Rodriguez Eds vol 1 chapter 2 pp 27ndash38World ScientificLondon UK 2003
[93] M M Tarpey and I Fridovich ldquoMethods of detection ofvascular reactive species Nitric oxide superoxide hydrogenperoxide and peroxynitriterdquo Circulation Research vol 89 no3 pp 224ndash236 2001
[94] E Y Kazush E I Sagun G D Tirzit and G Y DaburldquoQuenching of singlet oxygen by electron donating derivativesof 14-dihydropyridinerdquo Chemistry of Heterocyclic Compoundsvol 30 no 5 pp 562ndash563 1994
[95] G Tirzitis E Kazush and G Duburs ldquoReaction of 14-dihydropyridine derivatives with peroxynitrite anionrdquo Chem-istry of Heterocyclic Compounds vol 34 no 3 pp 321ndash3231998 (Russian) Translated from Khimiya GeterotsiklicheskikhSoedinenii no 3 pp 355ndash357 1998
[96] L J Nunez-Vergara C Lopez-Alarcon P A Navarrete-EncinaA M Atria C Camargo and J A Squella ldquoElectrochemicaland EPR characterization of 14-dihydropyridines Reactivitytowards alkyl radicalsrdquo Free Radical Research vol 37 no 1 pp109ndash120 2003
[97] D Tirzite A Krauze A Zubareva G Tirzitis and G DubursldquoSynthesis and antiradical activity of 5-acetyl-2-alkylthio-4-aryl-6-methyl-14-dihydropyridine-3-carboxylic acid nitrilesrdquoChemistry of Heterocyclic Compounds vol 38 no 7 pp 795ndash800 2002
[98] H Ohkawa N Ohishi and K Yagi ldquoAssay for lipid peroxidesin animal tissues by thiobarbituric acid reactionrdquo AnalyticalBiochemistry vol 95 no 2 pp 351ndash358 1979
[99] N Zarkovic ldquo4-Hydroxynonenal as a bioactive marker ofpathophysiological processesrdquo Molecular Aspects of Medicinevol 24 no 4-5 pp 281ndash291 2003
[100] M Parola G Bellomo G Robino G Barrera and M UDianzani ldquo4-Hydroxynonenal as a biological signal molecularbasis and pathophysiological implicationsrdquo Antioxidants andRedox Signaling vol 1 no 3 pp 255ndash284 1999
[101] T Lovakovic M Poljak-Blazi G Duburs et al ldquoGrowthmodulation of human cells in vitro by mild oxidative stressand 14-dihydropyridine derivative antioxidantsrdquo CollegiumAntropologicum vol 35 no 1 pp 137ndash141 2011
[102] R van den Berg G R M M Haenen H van den Bergand A Bast ldquoApplicability of an improved Trolox equivalentantioxidant capacity (TEAC) assay for evaluation of antioxidantcapacity measurements of mixturesrdquo Food Chemistry vol 66no 4 pp 511ndash517 1999
[103] C Lopez-Alarcon P Navarrete C Camargo J A Squella andL J Nunez-Vergara ldquoReactivity of 14-dihydropyridines towardalkyl alkylperoxyl radicals and ABTS radical cationrdquo ChemicalResearch in Toxicology vol 16 no 2 pp 208ndash215 2003
[104] V Valenzuela P Santander C Camargo J A Squella C Lopez-Alarcon and L J Nunez-Vergara ldquo14-Dihydropyridines reac-tivity of nitrosoaryl and nitroaryl derivatives with alkylperoxylradicals andABTS radical cationrdquo Free Radical Research vol 38no 7 pp 715ndash727 2004
[105] L G Tsetlin N A Chebotareva B I Kurganov A K VelenaG Y Dubur and V Z Lankin ldquoStudy of 14-dihydropyridinesas lipoxygenase inhibitors with the use of hydrated reversedmicellesrdquo Pharmaceutical Chemistry Journal vol 22 no 6 pp425ndash428 1988 (Russian)
[106] J Panek Z Reblova L Kocirkova et al ldquoAntioxidant activityof dihydropyridine derivativesrdquo Czech Journal of Food Sciencesvol 18 pp 144ndash145 2000
[107] G Tirzitis I Kirule and G Duburs ldquoAntioxidationsaktivitatder 35-dicarbonylderivate des 26-demethyl-14-dihydropyri-dinsrdquo Fett Wissenschaft TechnologieFat Science Technology vol90 no 10 pp 411ndash413 1988
[108] M Plotniece G Tirzitis Y Uldrikis et al ldquoSynthesis of 14-dihydropyridine derivatives having an oxy- alkoxy- or dimeth-ylaminophenyl substituent in the 4 position their antioxidantactivity and their binding to phospholipid membranesrdquo Chem-istry of Heterocyclic Compounds vol 32 no 10 pp 1166ndash11721996 Translated from Khimiya Geterotsiklicheskikh Soedineniino 10(352) pp 1358ndash1365 1996 (Russian)
[109] D Y Rubene V S Sharov V I Olenev G D Tirzit G Y Duburand Y A Vladimirov ldquoUse of chemiluminescent method forthe evaluation of antioxidant activity of some derivatives of 14-dihydropyridinerdquo Russian Journal of Physical Chemistry A vol55 no 2 pp 511ndash512 1981 (Russian)
[110] M C R Symons and JM C Gutteridge Free Radicals and IronChemistry Biology and Medicine Oxford Science PublicationsOxford University Press Oxford UK 1998
[111] M Repetto J Semprine and A Boveris ldquoLipid peroxidationchemical mechanism biological implications and analyticaldeterminationrdquo in Lipid Peroxidation A Catala Ed Section ILipid Peroxidation Chemical Mechanisms Antioxidants Bio-logical Implications of Biochemistry Genetics and MolecularBiology chapter 1 pp 3ndash30 InTech Rijeka Croatia 2012
[112] A Velena J Zilbers and G Duburs ldquoDerivatives of 14-dihydropyridines asmodulators of ascorbate-induced lipid per-oxidation and high-amplitude swelling ofmitochondria causedby ascorbate sodium linoleate and sodiumpyrophosphaterdquoCellBiochemistry and Function vol 17 no 4 pp 237ndash252 1999
[113] M V Bilenko L N Shelenkova G Y Dubur and A K VelenaldquoUse of antioxidants to prevent renal damage during acuteischemia and reperfusionrdquo Bulletin of Experimental Biology andMedicine vol 96 no 3 pp 1195ndash1198 1983 Translated fromByulletenrsquo Eksperimentalrsquonoi Biologii i Meditsiny vol 96 no 9pp 8ndash11 1983 (Russian)
[114] R Toniolo F Tubaro F Ursini and G Bontempelli ldquoAn elec-troanalytical investigation on the redox properties of calciumantagonist dihydropyridinesrdquo Electroanalysis vol 15 no 10 pp855ndash861 2003
[115] L Kourimska J Pokorny and G Tirzitis ldquoThe antioxidant aci-tivity of 26-dimethyl-35-diethoxycarbonyl-14-dihydropyri-dine in edible oilsrdquo Nahrung vol 37 no 1 pp 91ndash93 1993
[116] C Lopez-Alarcon H Speisky J A Squella C Olea-Azar CCamargo and L J Nunez-Vergara ldquoReactivity of 14-dihydro-pyridines toward SIN-1-derived peroxynitriterdquo PharmaceuticalResearch vol 21 no 10 pp 1750ndash1757 2004
[117] R A Olek W Ziolkowski J J Kaczor L Greci J Popinigisand J Antosiewicz ldquoAntioxidant activity of NADH and its ana-loguemdashan in vitro studyrdquo Journal of Biochemistry andMolecularBiology vol 37 no 4 pp 416ndash421 2004
[118] E Niki N Noguchi and N Gotoh ldquoInhibition of oxidativemodification of low density lipoprotein by antioxidantsrdquo Jour-nal of Nutritional Science andVitaminology vol 39 supplementpp S1ndashS8 1993
[119] N Rojstaczer and D J Triggle ldquoStructure-function relation-ships of calcium antagonists effect on oxidative modificationof low density lipoproteinrdquo Biochemical Pharmacology vol 51no 2 pp 141ndash150 1996
Oxidative Medicine and Cellular Longevity 31
[120] A Sevanian L Shen and FUrsini ldquoInhibition of LDLoxidationand oxidized LDL-induced cytotoxicity by dihydropyridinecalcium antagonistsrdquo Pharmaceutical Research vol 17 no 8 pp999ndash1006 2000
[121] A Negre-Salvayre and R Salvayre ldquoProtection by Ca2+ channelblockers (nifedipine diltiazem and verapamil) against the tox-icity of oxidized low density lipoprotein to cultured lymphoidcellsrdquo British Journal of Pharmacology vol 107 no 3 pp 738ndash744 1992
[122] A Negre-Salvayre G FitoussiM Troly and R Salvayre ldquoCom-parative cytoprotective effect of dihydropyridine calcium chan-nel blockers against the toxicity of oxidized low density lipopro-tein for cultured lymphoid cellsrdquo Biochemical Pharmacologyvol 44 no 12 pp 2379ndash2386 1992
[123] L Cominacini A F Pasini U Garbin et al ldquoAntioxidant activ-ity of different dihydropyridinesrdquo Biochemical and BiophysicalResearch Communications vol 302 no 4 pp 679ndash684 2003
[124] L Cominacini U Garbin A Fratta Pasini et al ldquoOxidized low-density lipoprotein increases the production of intracellularreactive oxygen species in endothelial cells inhibitory effect oflacidipinerdquo Journal of Hypertension vol 16 no 12 part 2 pp1913ndash1919 1998
[125] H M Lander ldquoAn essential role for free radicals and derivedspecies in signal transductionrdquo The FASEB Journal vol 11 no2 pp 118ndash124 1997
[126] M L L Martinez E Rizzi M M Castro et al ldquoLercanidipinedecreases vascular matrix metalloproteinase-2 activity andprotects against vascular dysfunction in diabetic ratsrdquo EuropeanJournal of Pharmacology vol 599 no 1ndash3 pp 110ndash116 2008
[127] P Lesnik C Dachet L Petit et al ldquoImpact of a combinationof a calcium antagonist and a 120573-blocker on cell- and copper-mediated oxidation of LDL and on the accumulation and effluxof cholesterol in human macrophages and murine J774 cellsrdquoArteriosclerosis Thrombosis and Vascular Biology vol 17 no 5pp 979ndash988 1997
[128] G Sobal E J Menzel and H Sinzinger ldquoCalcium antagonistsas inhibitors of in vitro low density lipoprotein oxidation andglycationrdquoBiochemical Pharmacology vol 61 no 3 pp 373ndash3792001
[129] E Lupo R Locher B Weisser and W Vetter ldquoIn vitro antiox-idant activity of calcium antagonists against LDL oxidationcompared with 120572-tocopherolrdquo Biochemical and BiophysicalResearch Communications vol 203 no 3 pp 1803ndash1808 1994
[130] J Zou Y Li H-Q Fan and J-G Wang ldquoEffects of dihydropy-ridine calcium channel blockers on oxidized low-density lipo-protein induced proliferation and oxidative stress of vascularsmooth muscle cellsrdquo BMC Research Notes vol 5 article 1682012
[131] C Napoli S Salomone T Godfraind et al ldquo14-Dihydro-pyridine calcium channel blockers inhibit plasma and LDL oxi-dation and formation of oxidation-specific epitopes in the arte-rial wall and prolong survival in stroke-prone spontaneouslyhypertensive ratsrdquo Stroke vol 30 no 9 pp 1907ndash1915 1999
[132] G Zernig I Graziadei T Moshammer C Zech N Reider andH Glossmann ldquoMitochondrial Ca2+ antagonist binding sitesare associated with an inner mitochondrial membrane anionchannelrdquo Molecular Pharmacology vol 38 no 3 pp 362ndash3691990
[133] F E Hunter Jr A Scott P E Hochstein et al ldquoStudies of themechanism of ascorbate-induced swelling and lysis of isolatedliver mitochondriardquo The Journal of Biological Chemistry vol239 pp 604ndash613 1964
[134] D R Janero B Burghardt and R Lopez ldquoProtection of cardiacmembrane phospholipid against oxidative injury by calciumantagonistsrdquoBiochemical Pharmacology vol 37 no 21 pp 4197ndash4203 1988
[135] A Karadag B Ozcelik and S S Saner ldquoReview of methods todetermine antioxidant capacitiesrdquo FoodAnalyticalMethods vol2 no 1 pp 41ndash60 2009
[136] Y I Gubskiı N V Litvinova and E V Shnurko-TabakovaldquoAntioxidant and antiradical activity of various classes of antiox-idantsrdquo Ukrainskiı Biokhimicheskiı Zhurnal vol 66 no 4 pp114ndash116 1994 (Russian)
[137] M Takei M Hiramatsu and A Mori ldquoInhibitory effects ofcalcium antagonists onmitochondrial swelling induced by lipidperoxidation or arachidonic acid in the rat brain in vitrordquoNeurochemical Research vol 19 no 9 pp 1199ndash1206 1994
[138] M Takei M Hiramatsu R Edamatsu and A Mori ldquoFreeradical scavenging by calcium antagonistsrdquo Neurosciences vol20 no 2 pp 75ndash82 1994
[139] Ya P Stradin G Ya Dubur Yu A Beilis Ya R Uldrikis andA F Korotkova ldquoVoltammetry of 14-dihydropyridine deriva-tives I Potentials of electrochemical oxidation of 35-diacyl-and 35-di(alkoxycarbonyl)-14-dihydropyridines in acetoni-trilerdquo Chemistry of Heterocyclic Compounds no 1 pp 84ndash871972 (Russian)
[140] E V Ivanov T V Ponomarjova G N Merkusev et al ldquoEinneuer Haut-Radioprotektor Diethon (experimentelle Unter-suchung)rdquo Radiobiologia Radiotherapia vol 31 no 1 pp 69ndash78 1990
[141] E V Ivanov T V Ponomareva G N Merkushev et al ldquoRadia-tion modulating properties of derivates of 14-dihydropyridineand 12345678910-decahydroacridine-18 dionerdquo Radiat-sionnaia Biologiia Radioecologiia vol 44 no 5 pp 550ndash5592004 (Russian)
[142] R O Vitolinia D A Berzinia A K Velena I A Vutsina A AKimenis and G Y Duburs ldquoThe protective effects of the cal-cium antagonist foridon in acute myocardial ischaemiardquo Kardi-ologiya vol 27 no 3 pp 90ndash93 1987 (Russian)
[143] A H Velena G Ya Duburs R O Vitolina et al ldquoEffect ofryodipine on electromechanical parameters of heart and vesselscAMP phosphodiesterase activity and swelling-contractioncycle of mitochondriardquo Arzneimittelforschung vol 35 no 6 pp907ndash914 1985
[144] L I Utno Z E Lipsberga A A Silova M I Girgensone EA Bisenieks and G I Ia ldquoCardioprotective properties of a 14-dihydropyridine derivative glutapyrone in deep hypothermiardquoBiulletenrsquo Eksperimentalrsquonoı Biologii i Meditsiny vol 108 no 11pp 558ndash561 1989 (Russian)
[145] M A S FernandesM S Santos J A F Vicente et al ldquoEffects of14-dihydropyridine derivatives (cerebrocrast gammapyroneglutapyrone and diethone) onmitochondrial bioenergetics andoxidative stress a comparative studyrdquoMitochondrion vol 3 no1 pp 47ndash59 2003
[146] M A S Fernandes M S Santos A J M Moreno et al ldquoEffectsof 5-acetyl(carbamoyl)-6-methylsulfanyl-14-dihydropyridine-5-carbonitriles on rat liver mitochondrial functionrdquo Toxicologyin Vitro vol 23 no 7 pp 1333ndash1341 2009
[147] L Klimaviciusa A Kalda A Kaasik et al ldquoNeuroprotectiveactivity of 14-dihydropyridine derivatives structure determi-nantsrdquo Proceedings of the Latvian Academy of Sciences BNatural Exact and Applied Sciences vol 61 no 1-2 pp 33ndash372007
32 Oxidative Medicine and Cellular Longevity
[148] L Klimaviciusa M A S Fernandes N Lencberga et alldquoTargeting the mitochondria by novel adamantane-containing14-dihydropyridine compoundsrdquo in Bioenergetics K B ClarkEd pp 257ndash272 InTech 2012
[149] V Klusa L Klimaviciusa G Duburs J Poikans and AZharkovsky ldquoAnti-neurotoxic effects of tauropyrone a taurineanaloguerdquo Advances in Experimental Medicine and Biology vol583 pp 499ndash508 2006
[150] N Sampson P Berger and Ch Zenzmaier ldquoRedox signalingas a therapeutic target to inhibit myofibroblast activation indegenerative fibrotic diseaserdquo BioMed Research Internationalvol 2014 Article ID 131737 14 pages 2014
[151] T L Leto and M Geiszt ldquoRole of Nox family NADPH oxidasesin host defenserdquoAntioxidantsampRedox Signaling vol 8 no 9-10pp 1549ndash1561 2006
[152] K K Griendling D Sorescu and M Ushio-Fukai ldquoNAD(P)Hoxidase role in cardiovascular biology and diseaserdquo CirculationResearch vol 86 no 5 pp 494ndash501 2000
[153] H Chen Y S Song and P H Chan ldquoInhibition of NADPHoxi-dase is neuroprotective after ischemia-reperfusionrdquo Journal ofCerebral Blood Flow and Metabolism vol 29 no 7 pp 1262ndash1272 2009
[154] P Hochstein and L Ernster ldquoADP-activated lipid peroxidationcoupled to the TPNH oxidase system of microsomesrdquo Biochem-ical and Biophysical Research Communications vol 12 no 5 pp388ndash394 1963
[155] I I Gubskiı AGGoriushkoNV Litvinova et al ldquoAntioxidantproperties and membranotropic effect of certain derivatives of14-dihydropyridinerdquo Ukrainskiı Biokhimicheskiı Zhurnal vol71 no 4 pp 35ndash39 1999 (Russian)
[156] F Engineer and R Sridhar ldquoInhibition of rat heart andliver microsomal lipid peroxidation by nifedipinerdquo BiochemicalPharmacology vol 38 no 8 pp 1279ndash1285 1989
[157] T Goncalves A P Carvalho and C R Oliveira ldquoAntioxidanteffect of calcium antagonists on microsomai membranes iso-lated from different brain areasrdquo European Journal of Pharma-cology vol 204 no 3 pp 315ndash322 1991
[158] M E Letelier P Izquierdo L Godoy A M Lepe and MFaundez ldquoLiver microsomal biotransformation of nitro-aryldrugs mechanism for potential oxidative stress inductionrdquoJournal of Applied Toxicology vol 24 no 6 pp 519ndash525 2004
[159] M E Letelier P Entrala C Lopez-Alarcon et al ldquoNitroaryl-14-dihydropyridines as antioxidants against rat liver microsomesoxidation induced by ironascorbate Nitrofurantoin and naph-thalenerdquo Toxicology in Vitro vol 21 no 8 pp 1610ndash1618 2007
[160] F P Guengerich W R Brian M Iwasaki M-A Sari CBaarnhielm and P Berntsson ldquoOxidation of dihydropyridinecalcium channel blockers and analogues by human liver cyto-chrome P-450 IIIA4rdquo Journal of Medicinal Chemistry vol 34no 6 pp 1838ndash1844 1991
[161] S H Park S-W RhaW-Y Shin et al ldquoAS-160 Calcium channelblockers of dihydropyridine class reduce the antiplatelet effectof Clopidogrel what is clinical impactrdquo The American Journalof Cardiology vol 107 no 8 supplement p 47A 2011
[162] C Asma and D M Reda ldquoEvaluation of dihydropyridinecalcium antagonist effects on the stress bioindicator orga-nism Saccharomyces cerevisiaerdquo Annals of Biological Researchvol 4 no 10 pp 40ndash46 2013 httpscholarsresearchlibrarycomABR-vol4-iss10ABR-2013-4-10-40-46pdf
[163] G Gaviraghi A M Pastorino E Ratti and D G TristldquoCalcium channel blockers with antioxidant activityrdquo in Free
Radicals Lipoprotein Oxidation andAtherosclerosis G BellomoG Finardi E Maggi and E Rice-Evans Eds pp 431ndash456Richelieu Press London UK 1995
[164] G Gaviraghi AM Pastorino E Ratti and D G Trist ldquoAntiox-idant dihydropyridines a new and comprehensive therapy forfree radical-induced cardiovascular diseasesrdquo in Free Radicalsin Biology and Environment F Minisci Ed vol 27 of NATOASI Series pp 193ndash221 Springer Dordrecht The Netherlands1997
[165] P D Henry ldquoAntiperoxidative actions of calcium antagonistsand atherogenesisrdquo Journal of Cardiovascular Pharmacologyvol 18 supplement 1 pp S6ndashS10 1991
[166] F Kouoh B Gressier T Dine et al ldquoAntioxidant effects andanti-elastase activity of the calcium antagonist nicardipine onactivated human and rabbit neutrophilsmdasha potential antiath-erosclerotic property of calcium antagonistsrdquo CardiovascularDrugs andTherapy vol 16 no 6 pp 515ndash520 2002
[167] S Parthasarathy D Litvinov K Selvarajan and M GarelnabildquoLipid peroxidation and decompositionmdashconflicting roles inplaque vulnerability and stabilityrdquo Biochimica et BiophysicaActa vol 1781 no 5 pp 221ndash231 2008
[168] D-Q Liu Z-Q Pang D-H Zhao and B-H Sheng ldquoEffects offuryl-dihydropyridines I on lipid peroxides of ischemic myo-cardium and ATPases activity of erythrocyte membranes inratsrdquo Acta Pharmacologica Sinica vol 12 no 3 pp 253ndash2561991
[169] V Lukic-Panin T Kamiya H Zhang et al ldquoPrevention of neu-ronal damage by calcium channel blockers with antioxidativeeffects after transient focal ischemia in ratsrdquo Brain Research vol1176 no 1 pp 143ndash150 2007
[170] Y Allanore D Borderie H Lemarechal O G Ekindjian andA Kahan ldquoAcute and sustained effects of dihydropyridine-typecalcium channel antagonists on oxidative stress in systemicsclerosisrdquo American Journal of Medicine vol 116 no 9 pp 595ndash600 2004
[171] I Casetta V Govoni and E Granieri ldquoOxidative stress antioxi-dants and neurodegenerative diseasesrdquo Current PharmaceuticalDesign vol 11 no 16 pp 2033ndash2052 2005
[172] M J T J Arts Assessing antioxidant activity [PhD the-sis] Maastricht University Maastricht The Netherlands 2007httparnounimaasnlshowcgifid=8676
[173] G Dıaz-Araya L Godoy L Naranjo A Squella M E Letelierand L J Nunez-Vergara ldquoAntioxidant effects of 14-dihydro-pyridine and nitroso aryl derivatives on the Fe+3ascorbate-stimulated lipid peroxidation in rat brain slicesrdquo General Phar-macology The Vascular System vol 31 no 3 pp 385ndash391 1998
[174] Y Fukuhara K Tsuchiya Y Horinouchi et al ldquoProtectiveeffect of photodegradation product of nifedipine against tumornecrosis factor 120572-induced oxidative stress in human glomerularendothelial cellsrdquo Journal of Medical Investigation vol 58 no1-2 pp 118ndash126 2011
[175] W Stengel M Jainz and K Andreas ldquoDifferent potencies ofdihydropyridine derivatives in blocking T-type but not L-typeCa2+ channels in neuroblastoma-glioma hybrid cellsrdquo EuropeanJournal of Pharmacology vol 342 no 2-3 pp 339ndash345 1998
[176] O M Panasenko D J Tirzite G D Tirzitis and G J DubursldquoEffect of some 14-dihydropyridine derivatives on structuralorganization of erythrocyte membranesrdquo Biologicheskie Mem-brany (Biochemistry (Moscow) Series A Membrane and CellBiology) vol 1 pp 919ndash925 1984 (Russian)
[177] L G Herbette Y M H Vant Erve and D G Rhodes ldquoInter-action of 14 dihydropyridine calcium channel antagonists with
Oxidative Medicine and Cellular Longevity 33
biological membranes lipid bilayer partitioning could occurbefore drug binding to receptorsrdquo Journal of Molecular andCellular Cardiology vol 21 no 2 pp 187ndash201 1989
[178] L G Herbette P E Mason G Gaviraghi T N Tulenko andR P Mason ldquoThe molecular basis for lacidipinersquos unique phar-macokinetics optimal hydrophobicity results in membraneinteractions that may facilitate the treatment of atherosclerosisrdquoJournal of Cardiovascular Pharmacology vol 23 supplement 5pp S16ndashS25 1994
[179] G V Belevitch G Y Dubur G E Dobretsov N K Kurek andM M Spirin ldquoCalcium antagonists riodipine nifedipine andverapamil binding to model and biological membranes fluore-scence analysisrdquo Biologicheskie Membrany (Biochemistry(Moscow) Series A Membrane and Cell Biology) vol 5 pp768ndash776 1988 (Russian)
[180] R P Mason G E Gonye D W Chester and L G HerbetteldquoPartitioning and location of Bay K 8644 14-dihydropyridinecalcium channel agonist in model and biological membranesrdquoBiophysical Journal vol 55 no 4 pp 769ndash778 1989
[181] M Cindric A Cipak J Serly et al ldquoReversal of multidrugresistance inmurine lymphoma cells by amphiphilic dihydropy-ridine antioxidant derivativerdquo Anticancer Research vol 30 no10 pp 4063ndash4070 2010
[182] F Shekari H Sadeghpour K Javidnia et al ldquoCytotoxic andmultidrug resistance reversal activities of novel 14-dihydro-pyridines against human cancer cellsrdquo European Journal ofPharmacology vol 746 no 1 pp 233ndash244 2015
[183] X-F Zhou Q Shao R A Coburn and M E Morris ldquoQuanti-tative structure-activity relationship and quantitative structure-pharmacokinetics relationship of 14-dihydropyridines andpyridines as multidrug resistance modulatorsrdquo PharmaceuticalResearch vol 22 no 12 pp 1989ndash1996 2005
[184] R Berkels T Breitenbach H Bartels et al ldquoDifferent antioxida-tive potencies of dihydropyridine calcium channel modulatorsin various modelsrdquo Vascular Pharmacology vol 42 no 4 pp145ndash152 2005
[185] S Borovic G Tirzitis D Tirzite et al ldquoBioactive 14-dihydro-isonicotinic acid derivatives prevent oxidative damage of livercellsrdquo European Journal of Pharmacology vol 537 no 1ndash3 pp12ndash19 2006
[186] D Ya Rubene G D Tirzitis and G Ya Duburs ldquoInteractionof some 14-dihydropyridine derivatives with Fentonrsquos reagentrdquoLatvijas PSRZinatnuAkademijas Vestis Kimijas Serija Proceed-ings of the Latvian SSR Academy of Sciences Chemistry Seriespp 212ndash216 1982 (Russian)
[187] K Ondrias V Misık D Gergel and A Stasko ldquoLipid per-oxidation of phosphatidylcholine liposomes depressed by thecalcium channel blockers nifedipine and verapamil and bythe antiarrhythmic-antihypoxic drug stobadinerdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1003 no 3pp 238ndash245 1989
[188] I T Mak and W B Weglicki ldquoComparative antioxidant acti-vities of propranolol nifedipine verapamil and diltiazemagainst sarcolemmal membrane lipid peroxidationrdquoCirculationResearch vol 66 no 5 pp 1449ndash1452 1990
[189] I T Mak P Boehme and W B Weglicki ldquoProtective effects ofcalcium channel blockers against free radical-impaired endo-thelial cell proliferationrdquo Biochemical Pharmacology vol 50 no9 pp 1531ndash1534 1995
[190] S Ray S Mondal and N Dana ldquoEvaluation of protective roleof nifedipine on lipid peroxidation using reduced glutathione as
model markerrdquo Oxidants and Antioxidants in Medical Sciencevol 1 no 2 pp 97ndash100 2012
[191] M Yamato T Shiba T Ide Y Honda K-I Yamada andH Tsutsui ldquoNifedipine treatment reduces brain damage aftertransient focal ischemia possibly through its antioxidativeeffectsrdquoHypertension Research vol 34 no 7 pp 840ndash845 2011
[192] V Chander and K Chopra ldquoNifedipine attenuates changes innitric oxide levels renal oxidative stress and nephrotoxicityinduced by cyclosporinerdquo Renal Failure vol 27 no 4 pp 441ndash450 2005
[193] K M Gaafa M M Badawy and A A Hamza ldquoThe protectiveeffects of ascorbic acid cimetidine and nifedipine on diethyl-dithiocarbamate-induced hepatic toxicity in albino ratsrdquo Drugand Chemical Toxicology vol 34 no 4 pp 405ndash419 2011
[194] H Sugawara K Tobise and S Onodera ldquoAbsence of antiox-idant effects of nifedipine and diltiazem on myocardial mem-brane lipid peroxidation in contrast with those of nisoldipineand propranololrdquo Biochemical Pharmacology vol 47 no 5 pp887ndash892 1994
[195] I E Kirule D Y Rubene E A Bisenieks G D Tirzit and GY Dubur ldquo4-Nitrophenyl-14-dihydropyridinesmdasha new groupof inhibitors of peroxide oxidationrdquo Chemistry of HeterocyclicCompounds vol 18 no 3 p 316 1982
[196] G D Tirzit I E Kirule L K Baumane R A Gavar Y PStradynrsquo andG YDubur ldquoMechanism of the antioxidant actionof 26-dimethyl-35-dimethoxy-carbonyl-4-(2-nitrophenyl)14-dihydropyridinerdquoChemistry ofHeterocyclic Compounds vol 20no 8 pp 915ndash918 1984
[197] C Yanez C Lopez-Alarcon C Camargo V Valenzuela J ASquella and L J Nunez-Vergara ldquoStructural effects on thereactivity 14-dihydropyridines with alkylperoxyl radicals andABTS radical cationrdquo Bioorganic and Medicinal Chemistry vol12 no 9 pp 2459ndash2468 2004
[198] VMisik A J Stasko D Gergel and K Ondrias ldquoSpin-trappingand antioxidant properties of illuminated and nonilluminatednifedipine and nimodipine in heart homogenate and modelsystemrdquo Molecular Pharmacology vol 40 no 3 pp 435ndash4391991
[199] K Ondrias V Misık A Stasko D Gergelrsquo and M HromadovaldquoComparison of antioxidant properties of nifedipine and illu-minated nifedipine with nitroso spin traps in low densitylipoproteins and phosphatidylcholine liposomesrdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1211 no 1pp 114ndash119 1994
[200] A Stasko V Brezova S Biskupic K Ondrias and V MisıkldquoReactive radical intermediates formed from illuminated nife-dipinerdquoFree Radical Biology andMedicine vol 17 no 6 pp 545ndash556 1994
[201] K Ishizawa Y Izawa-Ishizawa N Yamano et al ldquoNitrosoni-fedipine ameliorates the progression of type 2 diabetic nephro-pathy by exerting antioxidative effectsrdquo PLoS ONE vol 9 no 1Article ID e86335 2014
[202] H Fujii and L J Berliner ldquoIn vivo EPR evidence for free radicaladducts of nifedipinerdquoMagnetic Resonance in Medicine vol 42no 4 pp 691ndash694 1999
[203] S Bollo S Finger J C Sturm L J Nunez-Vergara and JA Squella ldquoCyclic voltammetry and scanning electrochemicalmicroscopy studies of the heterogeneous electron transferreaction of some nitrosoaromatic compoundsrdquo ElectrochimicaActa vol 52 no 15 pp 4892ndash4898 2007
34 Oxidative Medicine and Cellular Longevity
[204] F Ursini ldquoTissue protection by lacidipine insight from redoxbehaviorrdquo Journal of Cardiovascular Pharmacology vol 30supplement 2 pp S28ndashS30 1997
[205] P G Cristofori F A Crivellente I Faustinelli et al ldquoInvolve-ment of the nitric oxide system in the anti-atheroscleroticpotential of lacidipine in the apoE-deficient mouse a mor-phological functional and electrochemical studyrdquo ToxicologicPathology vol 32 no 4 pp 493ndash499 2004
[206] X-P Zhang E L Kit S Mital S Chahwala and T HHintze ldquoParadoxical release of nitric oxide by an L-type calciumchannel antagonist the R+ enantiomer of amlodipinerdquo Journalof Cardiovascular Pharmacology vol 39 no 2 pp 208ndash2142002
[207] F Franzoni G Santoro F Regoli et al ldquoAn in vitro study of theperoxyl and hydroxyl radical scavenging capacity of the calciumantagonist amlodipinerdquo Biomedicine and Pharmacotherapy vol58 no 8 pp 423ndash426 2004
[208] S V Gatsura ldquoOxygen-dependent mechanisms underlying theantiischemic effect of verapamil and amlodipinerdquo Bulletin ofExperimental Biology and Medicine vol 137 no 1 pp 40ndash422004
[209] Y Hirooka Y Kimura M Nozoe Y Sagara K Ito and KSunagawa ldquoAmlodipine-induced reduction of oxidative stressin the brain is associated with sympatho-inhibitory effects instroke-prone spontaneously hypertensive ratsrdquo HypertensionResearch vol 29 no 1 pp 49ndash56 2006
[210] B Tomlinson and I F F Benzie ldquoAntioxidant effect of lercani-dipine (note)rdquo Hypertension vol 42 no 4 pp e10ndashe11 2003
[211] A A Faraqui ldquoNeurochemical aspects of 4-hydroxynonenalrdquoin Lipid Mediators and Their Metabolism in the Brain A AFaraqui Ed chapter 6 pp 159ndash191 Springer New York NYUSA 2011
[212] V S NascimentoM S DrsquoAlva A AOliveira et al ldquoAntioxidanteffect of nimodipine in young rats after pilocarpine-inducedseizuresrdquo Pharmacology Biochemistry and Behavior vol 82 no1 pp 11ndash16 2005
[213] O Ismailoglu P Atilla S Palaoglu et al ldquoThe therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjuryrdquo Turkish Neurosurgery vol 22 no 6 pp 740ndash746 2012
[214] M Matsubara and K Hasegawa ldquoBenidipine a dihydropy-ridine-calcium channel blocker prevents lysophosphatidyl-choline-induced injury and reactive oxygen species productionin human aortic endothelial cellsrdquo Atherosclerosis vol 178 no1 pp 57ndash66 2005
[215] M Matsubara K Yao and K Hasegawa ldquoBenidipine adihydropyridine-calcium channel blocker inhibits lysophos-phatidylcholine-induced endothelial injury via stimulation ofnitric oxide releaserdquo Pharmacological Research vol 53 no 1 pp35ndash43 2006
[216] MMatsubara and K Hasegawa ldquoEffects of benidipine a dihyd-ropyridine-Ca2+ channel blocker on expression of cytokine-induced adhesion molecules and chemoattractants in humanaortic endothelial cellsrdquo European Journal of Pharmacology vol498 no 1ndash3 pp 303ndash314 2004
[217] M Matsubara O Akizuki J-I Ikeda K Saeki K Yao and KSasaki ldquoBenidipine an anti-hypertensive drug inhibits reactiveoxygen species production in polymorphonuclear leukocytesand oxidative stress in salt-loaded stroke-prone spontaneouslyhypertensive ratsrdquo European Journal of Pharmacology vol 580no 1-2 pp 201ndash213 2008
[218] A C Rosenkranz H Lob T Breitenbach R Berkels and RRoesen ldquoEndothelial antioxidant actions of dihydropyridines
and angiotensin converting enzyme inhibitorsrdquo European Jour-nal of Pharmacology vol 529 no 1ndash3 pp 55ndash62 2006
[219] V Kain S Kumar and S L Sitasawad ldquoAzelnidipine preventscardiac dysfunction in streptozotocin-diabetic rats by reducingintracellular calcium accumulation oxidative stress and apop-tosisrdquo Cardiovascular Diabetology vol 10 article 97 2011
[220] K Nakamura S Yamagishi and H Inoue ldquoUnique atheropro-tective property of azelnidipine a dihydropyridine-based cal-cium antagonistrdquoMedical Hypotheses vol 65 no 1 pp 155ndash1572005
[221] TMatsui S Yamagishi K Nakamura S Kikuchi andH InoueldquoAzelnidipine a dihydropyridine-based calcium antagonistinhibits angiotensin II-induced oxidative stress generation anddownregulation of pigment epithelium-derived factor mRNAlevels in microvascular endothelial cellsrdquo Drugs under Experi-mental and Clinical Research vol 31 no 5-6 pp 215ndash219 2005
[222] C Ohmura H Watada T Shimizu et al ldquoCalcium channelblocker azelnidipine reduces lipid hydroperoxides in patientswith type 2 diabetes independent of blood pressurerdquo EndocrineJournal vol 54 no 5 pp 805ndash811 2007
[223] H Daikuhara F Kikuchi and T Ishida ldquoThe combination ofOLmesartan and a CAlcium channel blocker (azelnidipine) orcandesartan and a calcium channel blocker (amlodipine) intype 2 diabetic hypertensive patients theOLCA studyrdquoDiabetesand Vascular Disease Research vol 9 no 4 pp 280ndash286 2012
[224] MAbe NMaruyama KOkada SMatsumoto KMatsumotoand M Soma ldquoAdditive antioxidative effects of azelnidipine onangiotensin receptor blocker olmesartan treatment for type 2diabetic patients with albuminuriardquoHypertension Research vol34 no 8 pp 935ndash941 2011
[225] K Mizushige ldquoAntioxidative activities of thiazolidinedionesand dihydropyridine-type calcium antagonistsrdquo IRYOmdashJapa-nese Journal of National Medical Services vol 59 no 11 pp 581ndash592 2005
[226] S Manabe T Okura T Fukuoka and J Higaki ldquoAntioxidativeeffects of azelnidipine on mesangial cell proliferation inducedby highly concentrated insulinrdquo European Journal of Pharma-cology vol 567 no 3 pp 252ndash257 2007
[227] Y Koyama Y Takeishi H Takahashi et al ldquoAzelnidipine inhi-bits H
2O2-induced cell death in neonatal rat cardiomyocytesrdquo
CardiovascularDrugs andTherapy vol 21 no 1 pp 69ndash72 2007[228] K Shinomiya K Mizushige M Fukunaga et al ldquoAntioxidant
effect of a new calcium antagonist azelnipidine in culturedhuman arterial endothelial cellsrdquo Journal of International Med-ical Research vol 32 no 2 pp 170ndash175 2004
[229] T Ohyama K Sato K Kishimoto et al ldquoAzelnidipine is acalcium blocker that attenuates liver fibrosis and may increaseantioxidant defencerdquo British Journal of Pharmacology vol 165no 4 pp 1173ndash1187 2012
[230] L A Calo F Zaghetto E Pagnin P A Davis A Sempliciniand A C Pessina ldquoEffect of manidipine on gene expressionand protein level of oxidative stress-related proteins p22phoxand HO-1 Relevance for antihypertensive and anti-remodelingeffectsrdquo Journal of Cardiovascular Pharmacology vol 43 no 4pp 531ndash538 2004
[231] R Ghyasi G Sepehri M Mohammadi R Badalzadeh and AGhyasi ldquoEffect of mebudipine on oxidative stress and lipid per-oxidation in myocardial ischemic-reperfusion injury in maleratrdquo Journal of Research in Medical Sciences vol 17 no 12 pp1150ndash1155 2012
Oxidative Medicine and Cellular Longevity 35
[232] DCAndersson J Fauconnier T Yamada et al ldquoMitochondrialproduction of reactive oxygen species contributes to the 120573-adrenergic stimulation of mouse cardiomycytesrdquoThe Journal ofPhysiology vol 589 no 7 pp 1791ndash1801 2011
[233] A F Ceylan-Isik N Ari M Stefek et al ldquoEffects of a long-term treatment with an antioxidant pyridoindole on vascularresponsiveness in diabetes-induced aging ratsrdquo Current AgingScience vol 4 no 2 pp 150ndash157 2011
[234] S Saponara G Sgaragli and F Fusi ldquoQuercetin antagonismof Bay K 8644 effects on rat tail artery L-type Ca2+ channelsrdquoEuropean Journal of Pharmacology vol 598 no 1ndash3 pp 75ndash802008
[235] D A Sica ldquoInteraction of grapefruit juice and calcium channelblockersrdquo American Journal of Hypertension vol 19 no 7 pp768ndash773 2006
[236] P Mulder G Litwinienko S Lin P D MacLean L R CBarclay and K U Ingold ldquoThe L-type calcium channel block-ers Hantzsch 14-dihydropyridines are not peroxyl radical-trapping chain-breaking antioxidantsrdquo Chemical Research inToxicology vol 19 no 1 pp 79ndash85 2006
[237] L J Nunez-Vergara R Salazar C Camargo et al ldquoOxidation ofC4-hydroxyphenyl 14-dihydropyridines in dimethylsulfoxideand its reactivity towards alkylperoxyl radicals in aqueousmediumrdquo Bioorganic and Medicinal Chemistry vol 15 no 12pp 4318ndash4326 2007
[238] M E Ortiz L J Nunez-Vergara and J A Squella ldquoRelativereactivity of dihydropyridine derivatives to electrogeneratedsuperoxide ion in DMSO solutions a voltammetric approachrdquoPharmaceutical Research vol 20 no 2 pp 292ndash296 2003
[239] M E Ortiz L J Nunez-Vergara C Camargo and J A SquellaldquoOxidation of Hantzsch 14-dihydropyridines of pharmacolog-ical significance by electrogenerated superoxiderdquo Pharmaceuti-cal Research vol 21 no 3 pp 428ndash435 2004
[240] R S Raghuvanshi and K N Singh ldquoSuperoxide induced oxida-tive aromatization of Hantzsch 14-dihydropyridinesrdquo IndianJournal of Chemistry Section B Organic and Medicinal Chem-istry vol 47 no 11 pp 1735ndash1738 2008
[241] I Kruk A Kladna K Lichszteld et al ldquoAntioxidant activityof 4-flavonil-14-dihydropyridine derivativesrdquo Biopolymers vol62 no 3 pp 163ndash167 2001
[242] G D Tirzit I M Byteva K I Salokhiddinov G P Gurinovichand G Y Dubur ldquo14-Dihydropyridine derivatives as deactiva-tors of singlet oxygenrdquo Chemistry of Heterocyclic Compoundsvol 17 no 7 pp 682ndash684 1981
[243] G D Tirzit E Y Kazush and G Y Dubur ldquoInfluence of14-dihydropyridine derivatives on the generation of hydroxylradicalsrdquo Chemistry of Heterocyclic Compounds vol 28 no 4pp 435ndash437 1992
[244] N A Pizarro-Urzua and L J Nunez-Vergara ldquoNifedipine andnitrendipine reactivity toward singlet oxygenrdquo Journal of Photo-chemistry and Photobiology A Chemistry vol 175 no 2-3 pp129ndash137 2005
[245] L-F Wang H-Y Zhang L Konga Z-W Chena and J-G ShildquoDFT calculations indicate that 14-dihydropyridine is a promis-ing lead antioxidantrdquo Helvetica Chimica Acta vol 87 no 6 pp1515ndash1521 2004
[246] P Mulder H-G Korth and K U Ingold ldquoWhy quantum-thermochemical calculations must be used with caution toindicate lsquoa promising lead antioxidantrsquordquoHelvetica Chimica Actavol 88 no 2 pp 370ndash374 2005
[247] K Yao Y Ina K Nagashima K Ohmori and T Ohno ldquoAntiox-idant effects of calcium antagonists in rat brain homogenatesrdquo
Biological and Pharmaceutical Bulletin vol 23 no 6 pp 766ndash769 2000
[248] T Matsui S-I Yamagishi K Nakamura and H Inoue ldquoBayw 9798 a dihydropyridine structurally related to nifedipinewith no calcium channel-blocking properties inhibits tumournecrosis factor-120572-induced vascular cell adhesion molecule-1expression in endothelial cells by suppressing reactive oxygenspecies generationrdquo Journal of International Medical Researchvol 35 no 6 pp 886ndash891 2007
[249] K AMitrega B VargheseM Porc and T F Krzeminski ldquoAnti-arrhythmic and hemodynamic effects of oxy nifedipine oxynimodipine oxy nitrendipine and oxy nisoldipinerdquo Pharmaco-logical Research vol 66 no 4 pp 300ndash308 2012
[250] V Herbert ldquoSymposium prooxidant effects of antioxidantvitamins Introductionrdquo The Journal of Nutrition vol 126 no4 supplement pp 1197Sndash1200S 1996 httpjnnutritionorgcontent1264 Suppl1197Sfullpdf
[251] B Halliwell ldquoAre polyphenols antioxidants or pro-oxidantsWhat do we learn from cell culture and in vivo studiesrdquoArchives of Biochemistry and Biophysics vol 476 no 2 pp 107ndash112 2008
[252] C Winterbourn Pro-Oxidants or Antioxidants ChristchurchSchool of Medicine Depatment of Pathology Free RadicalSchool SFRBMUniversity of Otago San Francisco Calif USA2009 httpwwwsfrbmorgfrsWinterbournpdf
[253] A Morakinyo B Iranloye and O Adegoke ldquoCalcium antag-onists modulate oxidative stress and acrosomal reaction in ratspermatozoardquo Archives of Medical Science vol 7 no 4 pp 613ndash618 2011
[254] The Alpha-Tocopherol Beta Carotene Cancer Prevention StudyGroup ldquoThe effect of vitamin E and beta carotene on theincidence of lung cancer and other cancers in male smokersrdquoTheNew England Journal of Medicine vol 330 no 15 pp 1029ndash1035 1994
[255] B Poljsak ldquoStrategies for reducing or preventing the generationof oxidative stressrdquo Oxidative Medicine and Cellular Longevityvol 2011 Article ID 194586 15 pages 2011
[256] B Poljsak and I Milisav ldquoThe neglected significance of lsquoanti-oxidative stressrsquordquoOxidativeMedicine and Cellular Longevity vol2012 Article ID 480895 12 pages 2012
[257] T Godfraind and S Salomone ldquoAmbiguities in dietary antiox-idant supplementation compared to calcium channel blockerstherapyrdquo Frontiers in Pharmacology vol 6 article 10 2015
[258] H Wagner H Norr and H Winterhoff ldquoDrugs with adap-togenic effects for strengthening the powers of resistancerdquoZeitschrift fur Phytotherapie vol 13 no 2 pp 42ndash54 1992
Oxidative Medicine and Cellular Longevity 31
[120] A Sevanian L Shen and FUrsini ldquoInhibition of LDLoxidationand oxidized LDL-induced cytotoxicity by dihydropyridinecalcium antagonistsrdquo Pharmaceutical Research vol 17 no 8 pp999ndash1006 2000
[121] A Negre-Salvayre and R Salvayre ldquoProtection by Ca2+ channelblockers (nifedipine diltiazem and verapamil) against the tox-icity of oxidized low density lipoprotein to cultured lymphoidcellsrdquo British Journal of Pharmacology vol 107 no 3 pp 738ndash744 1992
[122] A Negre-Salvayre G FitoussiM Troly and R Salvayre ldquoCom-parative cytoprotective effect of dihydropyridine calcium chan-nel blockers against the toxicity of oxidized low density lipopro-tein for cultured lymphoid cellsrdquo Biochemical Pharmacologyvol 44 no 12 pp 2379ndash2386 1992
[123] L Cominacini A F Pasini U Garbin et al ldquoAntioxidant activ-ity of different dihydropyridinesrdquo Biochemical and BiophysicalResearch Communications vol 302 no 4 pp 679ndash684 2003
[124] L Cominacini U Garbin A Fratta Pasini et al ldquoOxidized low-density lipoprotein increases the production of intracellularreactive oxygen species in endothelial cells inhibitory effect oflacidipinerdquo Journal of Hypertension vol 16 no 12 part 2 pp1913ndash1919 1998
[125] H M Lander ldquoAn essential role for free radicals and derivedspecies in signal transductionrdquo The FASEB Journal vol 11 no2 pp 118ndash124 1997
[126] M L L Martinez E Rizzi M M Castro et al ldquoLercanidipinedecreases vascular matrix metalloproteinase-2 activity andprotects against vascular dysfunction in diabetic ratsrdquo EuropeanJournal of Pharmacology vol 599 no 1ndash3 pp 110ndash116 2008
[127] P Lesnik C Dachet L Petit et al ldquoImpact of a combinationof a calcium antagonist and a 120573-blocker on cell- and copper-mediated oxidation of LDL and on the accumulation and effluxof cholesterol in human macrophages and murine J774 cellsrdquoArteriosclerosis Thrombosis and Vascular Biology vol 17 no 5pp 979ndash988 1997
[128] G Sobal E J Menzel and H Sinzinger ldquoCalcium antagonistsas inhibitors of in vitro low density lipoprotein oxidation andglycationrdquoBiochemical Pharmacology vol 61 no 3 pp 373ndash3792001
[129] E Lupo R Locher B Weisser and W Vetter ldquoIn vitro antiox-idant activity of calcium antagonists against LDL oxidationcompared with 120572-tocopherolrdquo Biochemical and BiophysicalResearch Communications vol 203 no 3 pp 1803ndash1808 1994
[130] J Zou Y Li H-Q Fan and J-G Wang ldquoEffects of dihydropy-ridine calcium channel blockers on oxidized low-density lipo-protein induced proliferation and oxidative stress of vascularsmooth muscle cellsrdquo BMC Research Notes vol 5 article 1682012
[131] C Napoli S Salomone T Godfraind et al ldquo14-Dihydro-pyridine calcium channel blockers inhibit plasma and LDL oxi-dation and formation of oxidation-specific epitopes in the arte-rial wall and prolong survival in stroke-prone spontaneouslyhypertensive ratsrdquo Stroke vol 30 no 9 pp 1907ndash1915 1999
[132] G Zernig I Graziadei T Moshammer C Zech N Reider andH Glossmann ldquoMitochondrial Ca2+ antagonist binding sitesare associated with an inner mitochondrial membrane anionchannelrdquo Molecular Pharmacology vol 38 no 3 pp 362ndash3691990
[133] F E Hunter Jr A Scott P E Hochstein et al ldquoStudies of themechanism of ascorbate-induced swelling and lysis of isolatedliver mitochondriardquo The Journal of Biological Chemistry vol239 pp 604ndash613 1964
[134] D R Janero B Burghardt and R Lopez ldquoProtection of cardiacmembrane phospholipid against oxidative injury by calciumantagonistsrdquoBiochemical Pharmacology vol 37 no 21 pp 4197ndash4203 1988
[135] A Karadag B Ozcelik and S S Saner ldquoReview of methods todetermine antioxidant capacitiesrdquo FoodAnalyticalMethods vol2 no 1 pp 41ndash60 2009
[136] Y I Gubskiı N V Litvinova and E V Shnurko-TabakovaldquoAntioxidant and antiradical activity of various classes of antiox-idantsrdquo Ukrainskiı Biokhimicheskiı Zhurnal vol 66 no 4 pp114ndash116 1994 (Russian)
[137] M Takei M Hiramatsu and A Mori ldquoInhibitory effects ofcalcium antagonists onmitochondrial swelling induced by lipidperoxidation or arachidonic acid in the rat brain in vitrordquoNeurochemical Research vol 19 no 9 pp 1199ndash1206 1994
[138] M Takei M Hiramatsu R Edamatsu and A Mori ldquoFreeradical scavenging by calcium antagonistsrdquo Neurosciences vol20 no 2 pp 75ndash82 1994
[139] Ya P Stradin G Ya Dubur Yu A Beilis Ya R Uldrikis andA F Korotkova ldquoVoltammetry of 14-dihydropyridine deriva-tives I Potentials of electrochemical oxidation of 35-diacyl-and 35-di(alkoxycarbonyl)-14-dihydropyridines in acetoni-trilerdquo Chemistry of Heterocyclic Compounds no 1 pp 84ndash871972 (Russian)
[140] E V Ivanov T V Ponomarjova G N Merkusev et al ldquoEinneuer Haut-Radioprotektor Diethon (experimentelle Unter-suchung)rdquo Radiobiologia Radiotherapia vol 31 no 1 pp 69ndash78 1990
[141] E V Ivanov T V Ponomareva G N Merkushev et al ldquoRadia-tion modulating properties of derivates of 14-dihydropyridineand 12345678910-decahydroacridine-18 dionerdquo Radiat-sionnaia Biologiia Radioecologiia vol 44 no 5 pp 550ndash5592004 (Russian)
[142] R O Vitolinia D A Berzinia A K Velena I A Vutsina A AKimenis and G Y Duburs ldquoThe protective effects of the cal-cium antagonist foridon in acute myocardial ischaemiardquo Kardi-ologiya vol 27 no 3 pp 90ndash93 1987 (Russian)
[143] A H Velena G Ya Duburs R O Vitolina et al ldquoEffect ofryodipine on electromechanical parameters of heart and vesselscAMP phosphodiesterase activity and swelling-contractioncycle of mitochondriardquo Arzneimittelforschung vol 35 no 6 pp907ndash914 1985
[144] L I Utno Z E Lipsberga A A Silova M I Girgensone EA Bisenieks and G I Ia ldquoCardioprotective properties of a 14-dihydropyridine derivative glutapyrone in deep hypothermiardquoBiulletenrsquo Eksperimentalrsquonoı Biologii i Meditsiny vol 108 no 11pp 558ndash561 1989 (Russian)
[145] M A S FernandesM S Santos J A F Vicente et al ldquoEffects of14-dihydropyridine derivatives (cerebrocrast gammapyroneglutapyrone and diethone) onmitochondrial bioenergetics andoxidative stress a comparative studyrdquoMitochondrion vol 3 no1 pp 47ndash59 2003
[146] M A S Fernandes M S Santos A J M Moreno et al ldquoEffectsof 5-acetyl(carbamoyl)-6-methylsulfanyl-14-dihydropyridine-5-carbonitriles on rat liver mitochondrial functionrdquo Toxicologyin Vitro vol 23 no 7 pp 1333ndash1341 2009
[147] L Klimaviciusa A Kalda A Kaasik et al ldquoNeuroprotectiveactivity of 14-dihydropyridine derivatives structure determi-nantsrdquo Proceedings of the Latvian Academy of Sciences BNatural Exact and Applied Sciences vol 61 no 1-2 pp 33ndash372007
32 Oxidative Medicine and Cellular Longevity
[148] L Klimaviciusa M A S Fernandes N Lencberga et alldquoTargeting the mitochondria by novel adamantane-containing14-dihydropyridine compoundsrdquo in Bioenergetics K B ClarkEd pp 257ndash272 InTech 2012
[149] V Klusa L Klimaviciusa G Duburs J Poikans and AZharkovsky ldquoAnti-neurotoxic effects of tauropyrone a taurineanaloguerdquo Advances in Experimental Medicine and Biology vol583 pp 499ndash508 2006
[150] N Sampson P Berger and Ch Zenzmaier ldquoRedox signalingas a therapeutic target to inhibit myofibroblast activation indegenerative fibrotic diseaserdquo BioMed Research Internationalvol 2014 Article ID 131737 14 pages 2014
[151] T L Leto and M Geiszt ldquoRole of Nox family NADPH oxidasesin host defenserdquoAntioxidantsampRedox Signaling vol 8 no 9-10pp 1549ndash1561 2006
[152] K K Griendling D Sorescu and M Ushio-Fukai ldquoNAD(P)Hoxidase role in cardiovascular biology and diseaserdquo CirculationResearch vol 86 no 5 pp 494ndash501 2000
[153] H Chen Y S Song and P H Chan ldquoInhibition of NADPHoxi-dase is neuroprotective after ischemia-reperfusionrdquo Journal ofCerebral Blood Flow and Metabolism vol 29 no 7 pp 1262ndash1272 2009
[154] P Hochstein and L Ernster ldquoADP-activated lipid peroxidationcoupled to the TPNH oxidase system of microsomesrdquo Biochem-ical and Biophysical Research Communications vol 12 no 5 pp388ndash394 1963
[155] I I Gubskiı AGGoriushkoNV Litvinova et al ldquoAntioxidantproperties and membranotropic effect of certain derivatives of14-dihydropyridinerdquo Ukrainskiı Biokhimicheskiı Zhurnal vol71 no 4 pp 35ndash39 1999 (Russian)
[156] F Engineer and R Sridhar ldquoInhibition of rat heart andliver microsomal lipid peroxidation by nifedipinerdquo BiochemicalPharmacology vol 38 no 8 pp 1279ndash1285 1989
[157] T Goncalves A P Carvalho and C R Oliveira ldquoAntioxidanteffect of calcium antagonists on microsomai membranes iso-lated from different brain areasrdquo European Journal of Pharma-cology vol 204 no 3 pp 315ndash322 1991
[158] M E Letelier P Izquierdo L Godoy A M Lepe and MFaundez ldquoLiver microsomal biotransformation of nitro-aryldrugs mechanism for potential oxidative stress inductionrdquoJournal of Applied Toxicology vol 24 no 6 pp 519ndash525 2004
[159] M E Letelier P Entrala C Lopez-Alarcon et al ldquoNitroaryl-14-dihydropyridines as antioxidants against rat liver microsomesoxidation induced by ironascorbate Nitrofurantoin and naph-thalenerdquo Toxicology in Vitro vol 21 no 8 pp 1610ndash1618 2007
[160] F P Guengerich W R Brian M Iwasaki M-A Sari CBaarnhielm and P Berntsson ldquoOxidation of dihydropyridinecalcium channel blockers and analogues by human liver cyto-chrome P-450 IIIA4rdquo Journal of Medicinal Chemistry vol 34no 6 pp 1838ndash1844 1991
[161] S H Park S-W RhaW-Y Shin et al ldquoAS-160 Calcium channelblockers of dihydropyridine class reduce the antiplatelet effectof Clopidogrel what is clinical impactrdquo The American Journalof Cardiology vol 107 no 8 supplement p 47A 2011
[162] C Asma and D M Reda ldquoEvaluation of dihydropyridinecalcium antagonist effects on the stress bioindicator orga-nism Saccharomyces cerevisiaerdquo Annals of Biological Researchvol 4 no 10 pp 40ndash46 2013 httpscholarsresearchlibrarycomABR-vol4-iss10ABR-2013-4-10-40-46pdf
[163] G Gaviraghi A M Pastorino E Ratti and D G TristldquoCalcium channel blockers with antioxidant activityrdquo in Free
Radicals Lipoprotein Oxidation andAtherosclerosis G BellomoG Finardi E Maggi and E Rice-Evans Eds pp 431ndash456Richelieu Press London UK 1995
[164] G Gaviraghi AM Pastorino E Ratti and D G Trist ldquoAntiox-idant dihydropyridines a new and comprehensive therapy forfree radical-induced cardiovascular diseasesrdquo in Free Radicalsin Biology and Environment F Minisci Ed vol 27 of NATOASI Series pp 193ndash221 Springer Dordrecht The Netherlands1997
[165] P D Henry ldquoAntiperoxidative actions of calcium antagonistsand atherogenesisrdquo Journal of Cardiovascular Pharmacologyvol 18 supplement 1 pp S6ndashS10 1991
[166] F Kouoh B Gressier T Dine et al ldquoAntioxidant effects andanti-elastase activity of the calcium antagonist nicardipine onactivated human and rabbit neutrophilsmdasha potential antiath-erosclerotic property of calcium antagonistsrdquo CardiovascularDrugs andTherapy vol 16 no 6 pp 515ndash520 2002
[167] S Parthasarathy D Litvinov K Selvarajan and M GarelnabildquoLipid peroxidation and decompositionmdashconflicting roles inplaque vulnerability and stabilityrdquo Biochimica et BiophysicaActa vol 1781 no 5 pp 221ndash231 2008
[168] D-Q Liu Z-Q Pang D-H Zhao and B-H Sheng ldquoEffects offuryl-dihydropyridines I on lipid peroxides of ischemic myo-cardium and ATPases activity of erythrocyte membranes inratsrdquo Acta Pharmacologica Sinica vol 12 no 3 pp 253ndash2561991
[169] V Lukic-Panin T Kamiya H Zhang et al ldquoPrevention of neu-ronal damage by calcium channel blockers with antioxidativeeffects after transient focal ischemia in ratsrdquo Brain Research vol1176 no 1 pp 143ndash150 2007
[170] Y Allanore D Borderie H Lemarechal O G Ekindjian andA Kahan ldquoAcute and sustained effects of dihydropyridine-typecalcium channel antagonists on oxidative stress in systemicsclerosisrdquo American Journal of Medicine vol 116 no 9 pp 595ndash600 2004
[171] I Casetta V Govoni and E Granieri ldquoOxidative stress antioxi-dants and neurodegenerative diseasesrdquo Current PharmaceuticalDesign vol 11 no 16 pp 2033ndash2052 2005
[172] M J T J Arts Assessing antioxidant activity [PhD the-sis] Maastricht University Maastricht The Netherlands 2007httparnounimaasnlshowcgifid=8676
[173] G Dıaz-Araya L Godoy L Naranjo A Squella M E Letelierand L J Nunez-Vergara ldquoAntioxidant effects of 14-dihydro-pyridine and nitroso aryl derivatives on the Fe+3ascorbate-stimulated lipid peroxidation in rat brain slicesrdquo General Phar-macology The Vascular System vol 31 no 3 pp 385ndash391 1998
[174] Y Fukuhara K Tsuchiya Y Horinouchi et al ldquoProtectiveeffect of photodegradation product of nifedipine against tumornecrosis factor 120572-induced oxidative stress in human glomerularendothelial cellsrdquo Journal of Medical Investigation vol 58 no1-2 pp 118ndash126 2011
[175] W Stengel M Jainz and K Andreas ldquoDifferent potencies ofdihydropyridine derivatives in blocking T-type but not L-typeCa2+ channels in neuroblastoma-glioma hybrid cellsrdquo EuropeanJournal of Pharmacology vol 342 no 2-3 pp 339ndash345 1998
[176] O M Panasenko D J Tirzite G D Tirzitis and G J DubursldquoEffect of some 14-dihydropyridine derivatives on structuralorganization of erythrocyte membranesrdquo Biologicheskie Mem-brany (Biochemistry (Moscow) Series A Membrane and CellBiology) vol 1 pp 919ndash925 1984 (Russian)
[177] L G Herbette Y M H Vant Erve and D G Rhodes ldquoInter-action of 14 dihydropyridine calcium channel antagonists with
Oxidative Medicine and Cellular Longevity 33
biological membranes lipid bilayer partitioning could occurbefore drug binding to receptorsrdquo Journal of Molecular andCellular Cardiology vol 21 no 2 pp 187ndash201 1989
[178] L G Herbette P E Mason G Gaviraghi T N Tulenko andR P Mason ldquoThe molecular basis for lacidipinersquos unique phar-macokinetics optimal hydrophobicity results in membraneinteractions that may facilitate the treatment of atherosclerosisrdquoJournal of Cardiovascular Pharmacology vol 23 supplement 5pp S16ndashS25 1994
[179] G V Belevitch G Y Dubur G E Dobretsov N K Kurek andM M Spirin ldquoCalcium antagonists riodipine nifedipine andverapamil binding to model and biological membranes fluore-scence analysisrdquo Biologicheskie Membrany (Biochemistry(Moscow) Series A Membrane and Cell Biology) vol 5 pp768ndash776 1988 (Russian)
[180] R P Mason G E Gonye D W Chester and L G HerbetteldquoPartitioning and location of Bay K 8644 14-dihydropyridinecalcium channel agonist in model and biological membranesrdquoBiophysical Journal vol 55 no 4 pp 769ndash778 1989
[181] M Cindric A Cipak J Serly et al ldquoReversal of multidrugresistance inmurine lymphoma cells by amphiphilic dihydropy-ridine antioxidant derivativerdquo Anticancer Research vol 30 no10 pp 4063ndash4070 2010
[182] F Shekari H Sadeghpour K Javidnia et al ldquoCytotoxic andmultidrug resistance reversal activities of novel 14-dihydro-pyridines against human cancer cellsrdquo European Journal ofPharmacology vol 746 no 1 pp 233ndash244 2015
[183] X-F Zhou Q Shao R A Coburn and M E Morris ldquoQuanti-tative structure-activity relationship and quantitative structure-pharmacokinetics relationship of 14-dihydropyridines andpyridines as multidrug resistance modulatorsrdquo PharmaceuticalResearch vol 22 no 12 pp 1989ndash1996 2005
[184] R Berkels T Breitenbach H Bartels et al ldquoDifferent antioxida-tive potencies of dihydropyridine calcium channel modulatorsin various modelsrdquo Vascular Pharmacology vol 42 no 4 pp145ndash152 2005
[185] S Borovic G Tirzitis D Tirzite et al ldquoBioactive 14-dihydro-isonicotinic acid derivatives prevent oxidative damage of livercellsrdquo European Journal of Pharmacology vol 537 no 1ndash3 pp12ndash19 2006
[186] D Ya Rubene G D Tirzitis and G Ya Duburs ldquoInteractionof some 14-dihydropyridine derivatives with Fentonrsquos reagentrdquoLatvijas PSRZinatnuAkademijas Vestis Kimijas Serija Proceed-ings of the Latvian SSR Academy of Sciences Chemistry Seriespp 212ndash216 1982 (Russian)
[187] K Ondrias V Misık D Gergel and A Stasko ldquoLipid per-oxidation of phosphatidylcholine liposomes depressed by thecalcium channel blockers nifedipine and verapamil and bythe antiarrhythmic-antihypoxic drug stobadinerdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1003 no 3pp 238ndash245 1989
[188] I T Mak and W B Weglicki ldquoComparative antioxidant acti-vities of propranolol nifedipine verapamil and diltiazemagainst sarcolemmal membrane lipid peroxidationrdquoCirculationResearch vol 66 no 5 pp 1449ndash1452 1990
[189] I T Mak P Boehme and W B Weglicki ldquoProtective effects ofcalcium channel blockers against free radical-impaired endo-thelial cell proliferationrdquo Biochemical Pharmacology vol 50 no9 pp 1531ndash1534 1995
[190] S Ray S Mondal and N Dana ldquoEvaluation of protective roleof nifedipine on lipid peroxidation using reduced glutathione as
model markerrdquo Oxidants and Antioxidants in Medical Sciencevol 1 no 2 pp 97ndash100 2012
[191] M Yamato T Shiba T Ide Y Honda K-I Yamada andH Tsutsui ldquoNifedipine treatment reduces brain damage aftertransient focal ischemia possibly through its antioxidativeeffectsrdquoHypertension Research vol 34 no 7 pp 840ndash845 2011
[192] V Chander and K Chopra ldquoNifedipine attenuates changes innitric oxide levels renal oxidative stress and nephrotoxicityinduced by cyclosporinerdquo Renal Failure vol 27 no 4 pp 441ndash450 2005
[193] K M Gaafa M M Badawy and A A Hamza ldquoThe protectiveeffects of ascorbic acid cimetidine and nifedipine on diethyl-dithiocarbamate-induced hepatic toxicity in albino ratsrdquo Drugand Chemical Toxicology vol 34 no 4 pp 405ndash419 2011
[194] H Sugawara K Tobise and S Onodera ldquoAbsence of antiox-idant effects of nifedipine and diltiazem on myocardial mem-brane lipid peroxidation in contrast with those of nisoldipineand propranololrdquo Biochemical Pharmacology vol 47 no 5 pp887ndash892 1994
[195] I E Kirule D Y Rubene E A Bisenieks G D Tirzit and GY Dubur ldquo4-Nitrophenyl-14-dihydropyridinesmdasha new groupof inhibitors of peroxide oxidationrdquo Chemistry of HeterocyclicCompounds vol 18 no 3 p 316 1982
[196] G D Tirzit I E Kirule L K Baumane R A Gavar Y PStradynrsquo andG YDubur ldquoMechanism of the antioxidant actionof 26-dimethyl-35-dimethoxy-carbonyl-4-(2-nitrophenyl)14-dihydropyridinerdquoChemistry ofHeterocyclic Compounds vol 20no 8 pp 915ndash918 1984
[197] C Yanez C Lopez-Alarcon C Camargo V Valenzuela J ASquella and L J Nunez-Vergara ldquoStructural effects on thereactivity 14-dihydropyridines with alkylperoxyl radicals andABTS radical cationrdquo Bioorganic and Medicinal Chemistry vol12 no 9 pp 2459ndash2468 2004
[198] VMisik A J Stasko D Gergel and K Ondrias ldquoSpin-trappingand antioxidant properties of illuminated and nonilluminatednifedipine and nimodipine in heart homogenate and modelsystemrdquo Molecular Pharmacology vol 40 no 3 pp 435ndash4391991
[199] K Ondrias V Misık A Stasko D Gergelrsquo and M HromadovaldquoComparison of antioxidant properties of nifedipine and illu-minated nifedipine with nitroso spin traps in low densitylipoproteins and phosphatidylcholine liposomesrdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1211 no 1pp 114ndash119 1994
[200] A Stasko V Brezova S Biskupic K Ondrias and V MisıkldquoReactive radical intermediates formed from illuminated nife-dipinerdquoFree Radical Biology andMedicine vol 17 no 6 pp 545ndash556 1994
[201] K Ishizawa Y Izawa-Ishizawa N Yamano et al ldquoNitrosoni-fedipine ameliorates the progression of type 2 diabetic nephro-pathy by exerting antioxidative effectsrdquo PLoS ONE vol 9 no 1Article ID e86335 2014
[202] H Fujii and L J Berliner ldquoIn vivo EPR evidence for free radicaladducts of nifedipinerdquoMagnetic Resonance in Medicine vol 42no 4 pp 691ndash694 1999
[203] S Bollo S Finger J C Sturm L J Nunez-Vergara and JA Squella ldquoCyclic voltammetry and scanning electrochemicalmicroscopy studies of the heterogeneous electron transferreaction of some nitrosoaromatic compoundsrdquo ElectrochimicaActa vol 52 no 15 pp 4892ndash4898 2007
34 Oxidative Medicine and Cellular Longevity
[204] F Ursini ldquoTissue protection by lacidipine insight from redoxbehaviorrdquo Journal of Cardiovascular Pharmacology vol 30supplement 2 pp S28ndashS30 1997
[205] P G Cristofori F A Crivellente I Faustinelli et al ldquoInvolve-ment of the nitric oxide system in the anti-atheroscleroticpotential of lacidipine in the apoE-deficient mouse a mor-phological functional and electrochemical studyrdquo ToxicologicPathology vol 32 no 4 pp 493ndash499 2004
[206] X-P Zhang E L Kit S Mital S Chahwala and T HHintze ldquoParadoxical release of nitric oxide by an L-type calciumchannel antagonist the R+ enantiomer of amlodipinerdquo Journalof Cardiovascular Pharmacology vol 39 no 2 pp 208ndash2142002
[207] F Franzoni G Santoro F Regoli et al ldquoAn in vitro study of theperoxyl and hydroxyl radical scavenging capacity of the calciumantagonist amlodipinerdquo Biomedicine and Pharmacotherapy vol58 no 8 pp 423ndash426 2004
[208] S V Gatsura ldquoOxygen-dependent mechanisms underlying theantiischemic effect of verapamil and amlodipinerdquo Bulletin ofExperimental Biology and Medicine vol 137 no 1 pp 40ndash422004
[209] Y Hirooka Y Kimura M Nozoe Y Sagara K Ito and KSunagawa ldquoAmlodipine-induced reduction of oxidative stressin the brain is associated with sympatho-inhibitory effects instroke-prone spontaneously hypertensive ratsrdquo HypertensionResearch vol 29 no 1 pp 49ndash56 2006
[210] B Tomlinson and I F F Benzie ldquoAntioxidant effect of lercani-dipine (note)rdquo Hypertension vol 42 no 4 pp e10ndashe11 2003
[211] A A Faraqui ldquoNeurochemical aspects of 4-hydroxynonenalrdquoin Lipid Mediators and Their Metabolism in the Brain A AFaraqui Ed chapter 6 pp 159ndash191 Springer New York NYUSA 2011
[212] V S NascimentoM S DrsquoAlva A AOliveira et al ldquoAntioxidanteffect of nimodipine in young rats after pilocarpine-inducedseizuresrdquo Pharmacology Biochemistry and Behavior vol 82 no1 pp 11ndash16 2005
[213] O Ismailoglu P Atilla S Palaoglu et al ldquoThe therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjuryrdquo Turkish Neurosurgery vol 22 no 6 pp 740ndash746 2012
[214] M Matsubara and K Hasegawa ldquoBenidipine a dihydropy-ridine-calcium channel blocker prevents lysophosphatidyl-choline-induced injury and reactive oxygen species productionin human aortic endothelial cellsrdquo Atherosclerosis vol 178 no1 pp 57ndash66 2005
[215] M Matsubara K Yao and K Hasegawa ldquoBenidipine adihydropyridine-calcium channel blocker inhibits lysophos-phatidylcholine-induced endothelial injury via stimulation ofnitric oxide releaserdquo Pharmacological Research vol 53 no 1 pp35ndash43 2006
[216] MMatsubara and K Hasegawa ldquoEffects of benidipine a dihyd-ropyridine-Ca2+ channel blocker on expression of cytokine-induced adhesion molecules and chemoattractants in humanaortic endothelial cellsrdquo European Journal of Pharmacology vol498 no 1ndash3 pp 303ndash314 2004
[217] M Matsubara O Akizuki J-I Ikeda K Saeki K Yao and KSasaki ldquoBenidipine an anti-hypertensive drug inhibits reactiveoxygen species production in polymorphonuclear leukocytesand oxidative stress in salt-loaded stroke-prone spontaneouslyhypertensive ratsrdquo European Journal of Pharmacology vol 580no 1-2 pp 201ndash213 2008
[218] A C Rosenkranz H Lob T Breitenbach R Berkels and RRoesen ldquoEndothelial antioxidant actions of dihydropyridines
and angiotensin converting enzyme inhibitorsrdquo European Jour-nal of Pharmacology vol 529 no 1ndash3 pp 55ndash62 2006
[219] V Kain S Kumar and S L Sitasawad ldquoAzelnidipine preventscardiac dysfunction in streptozotocin-diabetic rats by reducingintracellular calcium accumulation oxidative stress and apop-tosisrdquo Cardiovascular Diabetology vol 10 article 97 2011
[220] K Nakamura S Yamagishi and H Inoue ldquoUnique atheropro-tective property of azelnidipine a dihydropyridine-based cal-cium antagonistrdquoMedical Hypotheses vol 65 no 1 pp 155ndash1572005
[221] TMatsui S Yamagishi K Nakamura S Kikuchi andH InoueldquoAzelnidipine a dihydropyridine-based calcium antagonistinhibits angiotensin II-induced oxidative stress generation anddownregulation of pigment epithelium-derived factor mRNAlevels in microvascular endothelial cellsrdquo Drugs under Experi-mental and Clinical Research vol 31 no 5-6 pp 215ndash219 2005
[222] C Ohmura H Watada T Shimizu et al ldquoCalcium channelblocker azelnidipine reduces lipid hydroperoxides in patientswith type 2 diabetes independent of blood pressurerdquo EndocrineJournal vol 54 no 5 pp 805ndash811 2007
[223] H Daikuhara F Kikuchi and T Ishida ldquoThe combination ofOLmesartan and a CAlcium channel blocker (azelnidipine) orcandesartan and a calcium channel blocker (amlodipine) intype 2 diabetic hypertensive patients theOLCA studyrdquoDiabetesand Vascular Disease Research vol 9 no 4 pp 280ndash286 2012
[224] MAbe NMaruyama KOkada SMatsumoto KMatsumotoand M Soma ldquoAdditive antioxidative effects of azelnidipine onangiotensin receptor blocker olmesartan treatment for type 2diabetic patients with albuminuriardquoHypertension Research vol34 no 8 pp 935ndash941 2011
[225] K Mizushige ldquoAntioxidative activities of thiazolidinedionesand dihydropyridine-type calcium antagonistsrdquo IRYOmdashJapa-nese Journal of National Medical Services vol 59 no 11 pp 581ndash592 2005
[226] S Manabe T Okura T Fukuoka and J Higaki ldquoAntioxidativeeffects of azelnidipine on mesangial cell proliferation inducedby highly concentrated insulinrdquo European Journal of Pharma-cology vol 567 no 3 pp 252ndash257 2007
[227] Y Koyama Y Takeishi H Takahashi et al ldquoAzelnidipine inhi-bits H
2O2-induced cell death in neonatal rat cardiomyocytesrdquo
CardiovascularDrugs andTherapy vol 21 no 1 pp 69ndash72 2007[228] K Shinomiya K Mizushige M Fukunaga et al ldquoAntioxidant
effect of a new calcium antagonist azelnipidine in culturedhuman arterial endothelial cellsrdquo Journal of International Med-ical Research vol 32 no 2 pp 170ndash175 2004
[229] T Ohyama K Sato K Kishimoto et al ldquoAzelnidipine is acalcium blocker that attenuates liver fibrosis and may increaseantioxidant defencerdquo British Journal of Pharmacology vol 165no 4 pp 1173ndash1187 2012
[230] L A Calo F Zaghetto E Pagnin P A Davis A Sempliciniand A C Pessina ldquoEffect of manidipine on gene expressionand protein level of oxidative stress-related proteins p22phoxand HO-1 Relevance for antihypertensive and anti-remodelingeffectsrdquo Journal of Cardiovascular Pharmacology vol 43 no 4pp 531ndash538 2004
[231] R Ghyasi G Sepehri M Mohammadi R Badalzadeh and AGhyasi ldquoEffect of mebudipine on oxidative stress and lipid per-oxidation in myocardial ischemic-reperfusion injury in maleratrdquo Journal of Research in Medical Sciences vol 17 no 12 pp1150ndash1155 2012
Oxidative Medicine and Cellular Longevity 35
[232] DCAndersson J Fauconnier T Yamada et al ldquoMitochondrialproduction of reactive oxygen species contributes to the 120573-adrenergic stimulation of mouse cardiomycytesrdquoThe Journal ofPhysiology vol 589 no 7 pp 1791ndash1801 2011
[233] A F Ceylan-Isik N Ari M Stefek et al ldquoEffects of a long-term treatment with an antioxidant pyridoindole on vascularresponsiveness in diabetes-induced aging ratsrdquo Current AgingScience vol 4 no 2 pp 150ndash157 2011
[234] S Saponara G Sgaragli and F Fusi ldquoQuercetin antagonismof Bay K 8644 effects on rat tail artery L-type Ca2+ channelsrdquoEuropean Journal of Pharmacology vol 598 no 1ndash3 pp 75ndash802008
[235] D A Sica ldquoInteraction of grapefruit juice and calcium channelblockersrdquo American Journal of Hypertension vol 19 no 7 pp768ndash773 2006
[236] P Mulder G Litwinienko S Lin P D MacLean L R CBarclay and K U Ingold ldquoThe L-type calcium channel block-ers Hantzsch 14-dihydropyridines are not peroxyl radical-trapping chain-breaking antioxidantsrdquo Chemical Research inToxicology vol 19 no 1 pp 79ndash85 2006
[237] L J Nunez-Vergara R Salazar C Camargo et al ldquoOxidation ofC4-hydroxyphenyl 14-dihydropyridines in dimethylsulfoxideand its reactivity towards alkylperoxyl radicals in aqueousmediumrdquo Bioorganic and Medicinal Chemistry vol 15 no 12pp 4318ndash4326 2007
[238] M E Ortiz L J Nunez-Vergara and J A Squella ldquoRelativereactivity of dihydropyridine derivatives to electrogeneratedsuperoxide ion in DMSO solutions a voltammetric approachrdquoPharmaceutical Research vol 20 no 2 pp 292ndash296 2003
[239] M E Ortiz L J Nunez-Vergara C Camargo and J A SquellaldquoOxidation of Hantzsch 14-dihydropyridines of pharmacolog-ical significance by electrogenerated superoxiderdquo Pharmaceuti-cal Research vol 21 no 3 pp 428ndash435 2004
[240] R S Raghuvanshi and K N Singh ldquoSuperoxide induced oxida-tive aromatization of Hantzsch 14-dihydropyridinesrdquo IndianJournal of Chemistry Section B Organic and Medicinal Chem-istry vol 47 no 11 pp 1735ndash1738 2008
[241] I Kruk A Kladna K Lichszteld et al ldquoAntioxidant activityof 4-flavonil-14-dihydropyridine derivativesrdquo Biopolymers vol62 no 3 pp 163ndash167 2001
[242] G D Tirzit I M Byteva K I Salokhiddinov G P Gurinovichand G Y Dubur ldquo14-Dihydropyridine derivatives as deactiva-tors of singlet oxygenrdquo Chemistry of Heterocyclic Compoundsvol 17 no 7 pp 682ndash684 1981
[243] G D Tirzit E Y Kazush and G Y Dubur ldquoInfluence of14-dihydropyridine derivatives on the generation of hydroxylradicalsrdquo Chemistry of Heterocyclic Compounds vol 28 no 4pp 435ndash437 1992
[244] N A Pizarro-Urzua and L J Nunez-Vergara ldquoNifedipine andnitrendipine reactivity toward singlet oxygenrdquo Journal of Photo-chemistry and Photobiology A Chemistry vol 175 no 2-3 pp129ndash137 2005
[245] L-F Wang H-Y Zhang L Konga Z-W Chena and J-G ShildquoDFT calculations indicate that 14-dihydropyridine is a promis-ing lead antioxidantrdquo Helvetica Chimica Acta vol 87 no 6 pp1515ndash1521 2004
[246] P Mulder H-G Korth and K U Ingold ldquoWhy quantum-thermochemical calculations must be used with caution toindicate lsquoa promising lead antioxidantrsquordquoHelvetica Chimica Actavol 88 no 2 pp 370ndash374 2005
[247] K Yao Y Ina K Nagashima K Ohmori and T Ohno ldquoAntiox-idant effects of calcium antagonists in rat brain homogenatesrdquo
Biological and Pharmaceutical Bulletin vol 23 no 6 pp 766ndash769 2000
[248] T Matsui S-I Yamagishi K Nakamura and H Inoue ldquoBayw 9798 a dihydropyridine structurally related to nifedipinewith no calcium channel-blocking properties inhibits tumournecrosis factor-120572-induced vascular cell adhesion molecule-1expression in endothelial cells by suppressing reactive oxygenspecies generationrdquo Journal of International Medical Researchvol 35 no 6 pp 886ndash891 2007
[249] K AMitrega B VargheseM Porc and T F Krzeminski ldquoAnti-arrhythmic and hemodynamic effects of oxy nifedipine oxynimodipine oxy nitrendipine and oxy nisoldipinerdquo Pharmaco-logical Research vol 66 no 4 pp 300ndash308 2012
[250] V Herbert ldquoSymposium prooxidant effects of antioxidantvitamins Introductionrdquo The Journal of Nutrition vol 126 no4 supplement pp 1197Sndash1200S 1996 httpjnnutritionorgcontent1264 Suppl1197Sfullpdf
[251] B Halliwell ldquoAre polyphenols antioxidants or pro-oxidantsWhat do we learn from cell culture and in vivo studiesrdquoArchives of Biochemistry and Biophysics vol 476 no 2 pp 107ndash112 2008
[252] C Winterbourn Pro-Oxidants or Antioxidants ChristchurchSchool of Medicine Depatment of Pathology Free RadicalSchool SFRBMUniversity of Otago San Francisco Calif USA2009 httpwwwsfrbmorgfrsWinterbournpdf
[253] A Morakinyo B Iranloye and O Adegoke ldquoCalcium antag-onists modulate oxidative stress and acrosomal reaction in ratspermatozoardquo Archives of Medical Science vol 7 no 4 pp 613ndash618 2011
[254] The Alpha-Tocopherol Beta Carotene Cancer Prevention StudyGroup ldquoThe effect of vitamin E and beta carotene on theincidence of lung cancer and other cancers in male smokersrdquoTheNew England Journal of Medicine vol 330 no 15 pp 1029ndash1035 1994
[255] B Poljsak ldquoStrategies for reducing or preventing the generationof oxidative stressrdquo Oxidative Medicine and Cellular Longevityvol 2011 Article ID 194586 15 pages 2011
[256] B Poljsak and I Milisav ldquoThe neglected significance of lsquoanti-oxidative stressrsquordquoOxidativeMedicine and Cellular Longevity vol2012 Article ID 480895 12 pages 2012
[257] T Godfraind and S Salomone ldquoAmbiguities in dietary antiox-idant supplementation compared to calcium channel blockerstherapyrdquo Frontiers in Pharmacology vol 6 article 10 2015
[258] H Wagner H Norr and H Winterhoff ldquoDrugs with adap-togenic effects for strengthening the powers of resistancerdquoZeitschrift fur Phytotherapie vol 13 no 2 pp 42ndash54 1992
32 Oxidative Medicine and Cellular Longevity
[148] L Klimaviciusa M A S Fernandes N Lencberga et alldquoTargeting the mitochondria by novel adamantane-containing14-dihydropyridine compoundsrdquo in Bioenergetics K B ClarkEd pp 257ndash272 InTech 2012
[149] V Klusa L Klimaviciusa G Duburs J Poikans and AZharkovsky ldquoAnti-neurotoxic effects of tauropyrone a taurineanaloguerdquo Advances in Experimental Medicine and Biology vol583 pp 499ndash508 2006
[150] N Sampson P Berger and Ch Zenzmaier ldquoRedox signalingas a therapeutic target to inhibit myofibroblast activation indegenerative fibrotic diseaserdquo BioMed Research Internationalvol 2014 Article ID 131737 14 pages 2014
[151] T L Leto and M Geiszt ldquoRole of Nox family NADPH oxidasesin host defenserdquoAntioxidantsampRedox Signaling vol 8 no 9-10pp 1549ndash1561 2006
[152] K K Griendling D Sorescu and M Ushio-Fukai ldquoNAD(P)Hoxidase role in cardiovascular biology and diseaserdquo CirculationResearch vol 86 no 5 pp 494ndash501 2000
[153] H Chen Y S Song and P H Chan ldquoInhibition of NADPHoxi-dase is neuroprotective after ischemia-reperfusionrdquo Journal ofCerebral Blood Flow and Metabolism vol 29 no 7 pp 1262ndash1272 2009
[154] P Hochstein and L Ernster ldquoADP-activated lipid peroxidationcoupled to the TPNH oxidase system of microsomesrdquo Biochem-ical and Biophysical Research Communications vol 12 no 5 pp388ndash394 1963
[155] I I Gubskiı AGGoriushkoNV Litvinova et al ldquoAntioxidantproperties and membranotropic effect of certain derivatives of14-dihydropyridinerdquo Ukrainskiı Biokhimicheskiı Zhurnal vol71 no 4 pp 35ndash39 1999 (Russian)
[156] F Engineer and R Sridhar ldquoInhibition of rat heart andliver microsomal lipid peroxidation by nifedipinerdquo BiochemicalPharmacology vol 38 no 8 pp 1279ndash1285 1989
[157] T Goncalves A P Carvalho and C R Oliveira ldquoAntioxidanteffect of calcium antagonists on microsomai membranes iso-lated from different brain areasrdquo European Journal of Pharma-cology vol 204 no 3 pp 315ndash322 1991
[158] M E Letelier P Izquierdo L Godoy A M Lepe and MFaundez ldquoLiver microsomal biotransformation of nitro-aryldrugs mechanism for potential oxidative stress inductionrdquoJournal of Applied Toxicology vol 24 no 6 pp 519ndash525 2004
[159] M E Letelier P Entrala C Lopez-Alarcon et al ldquoNitroaryl-14-dihydropyridines as antioxidants against rat liver microsomesoxidation induced by ironascorbate Nitrofurantoin and naph-thalenerdquo Toxicology in Vitro vol 21 no 8 pp 1610ndash1618 2007
[160] F P Guengerich W R Brian M Iwasaki M-A Sari CBaarnhielm and P Berntsson ldquoOxidation of dihydropyridinecalcium channel blockers and analogues by human liver cyto-chrome P-450 IIIA4rdquo Journal of Medicinal Chemistry vol 34no 6 pp 1838ndash1844 1991
[161] S H Park S-W RhaW-Y Shin et al ldquoAS-160 Calcium channelblockers of dihydropyridine class reduce the antiplatelet effectof Clopidogrel what is clinical impactrdquo The American Journalof Cardiology vol 107 no 8 supplement p 47A 2011
[162] C Asma and D M Reda ldquoEvaluation of dihydropyridinecalcium antagonist effects on the stress bioindicator orga-nism Saccharomyces cerevisiaerdquo Annals of Biological Researchvol 4 no 10 pp 40ndash46 2013 httpscholarsresearchlibrarycomABR-vol4-iss10ABR-2013-4-10-40-46pdf
[163] G Gaviraghi A M Pastorino E Ratti and D G TristldquoCalcium channel blockers with antioxidant activityrdquo in Free
Radicals Lipoprotein Oxidation andAtherosclerosis G BellomoG Finardi E Maggi and E Rice-Evans Eds pp 431ndash456Richelieu Press London UK 1995
[164] G Gaviraghi AM Pastorino E Ratti and D G Trist ldquoAntiox-idant dihydropyridines a new and comprehensive therapy forfree radical-induced cardiovascular diseasesrdquo in Free Radicalsin Biology and Environment F Minisci Ed vol 27 of NATOASI Series pp 193ndash221 Springer Dordrecht The Netherlands1997
[165] P D Henry ldquoAntiperoxidative actions of calcium antagonistsand atherogenesisrdquo Journal of Cardiovascular Pharmacologyvol 18 supplement 1 pp S6ndashS10 1991
[166] F Kouoh B Gressier T Dine et al ldquoAntioxidant effects andanti-elastase activity of the calcium antagonist nicardipine onactivated human and rabbit neutrophilsmdasha potential antiath-erosclerotic property of calcium antagonistsrdquo CardiovascularDrugs andTherapy vol 16 no 6 pp 515ndash520 2002
[167] S Parthasarathy D Litvinov K Selvarajan and M GarelnabildquoLipid peroxidation and decompositionmdashconflicting roles inplaque vulnerability and stabilityrdquo Biochimica et BiophysicaActa vol 1781 no 5 pp 221ndash231 2008
[168] D-Q Liu Z-Q Pang D-H Zhao and B-H Sheng ldquoEffects offuryl-dihydropyridines I on lipid peroxides of ischemic myo-cardium and ATPases activity of erythrocyte membranes inratsrdquo Acta Pharmacologica Sinica vol 12 no 3 pp 253ndash2561991
[169] V Lukic-Panin T Kamiya H Zhang et al ldquoPrevention of neu-ronal damage by calcium channel blockers with antioxidativeeffects after transient focal ischemia in ratsrdquo Brain Research vol1176 no 1 pp 143ndash150 2007
[170] Y Allanore D Borderie H Lemarechal O G Ekindjian andA Kahan ldquoAcute and sustained effects of dihydropyridine-typecalcium channel antagonists on oxidative stress in systemicsclerosisrdquo American Journal of Medicine vol 116 no 9 pp 595ndash600 2004
[171] I Casetta V Govoni and E Granieri ldquoOxidative stress antioxi-dants and neurodegenerative diseasesrdquo Current PharmaceuticalDesign vol 11 no 16 pp 2033ndash2052 2005
[172] M J T J Arts Assessing antioxidant activity [PhD the-sis] Maastricht University Maastricht The Netherlands 2007httparnounimaasnlshowcgifid=8676
[173] G Dıaz-Araya L Godoy L Naranjo A Squella M E Letelierand L J Nunez-Vergara ldquoAntioxidant effects of 14-dihydro-pyridine and nitroso aryl derivatives on the Fe+3ascorbate-stimulated lipid peroxidation in rat brain slicesrdquo General Phar-macology The Vascular System vol 31 no 3 pp 385ndash391 1998
[174] Y Fukuhara K Tsuchiya Y Horinouchi et al ldquoProtectiveeffect of photodegradation product of nifedipine against tumornecrosis factor 120572-induced oxidative stress in human glomerularendothelial cellsrdquo Journal of Medical Investigation vol 58 no1-2 pp 118ndash126 2011
[175] W Stengel M Jainz and K Andreas ldquoDifferent potencies ofdihydropyridine derivatives in blocking T-type but not L-typeCa2+ channels in neuroblastoma-glioma hybrid cellsrdquo EuropeanJournal of Pharmacology vol 342 no 2-3 pp 339ndash345 1998
[176] O M Panasenko D J Tirzite G D Tirzitis and G J DubursldquoEffect of some 14-dihydropyridine derivatives on structuralorganization of erythrocyte membranesrdquo Biologicheskie Mem-brany (Biochemistry (Moscow) Series A Membrane and CellBiology) vol 1 pp 919ndash925 1984 (Russian)
[177] L G Herbette Y M H Vant Erve and D G Rhodes ldquoInter-action of 14 dihydropyridine calcium channel antagonists with
Oxidative Medicine and Cellular Longevity 33
biological membranes lipid bilayer partitioning could occurbefore drug binding to receptorsrdquo Journal of Molecular andCellular Cardiology vol 21 no 2 pp 187ndash201 1989
[178] L G Herbette P E Mason G Gaviraghi T N Tulenko andR P Mason ldquoThe molecular basis for lacidipinersquos unique phar-macokinetics optimal hydrophobicity results in membraneinteractions that may facilitate the treatment of atherosclerosisrdquoJournal of Cardiovascular Pharmacology vol 23 supplement 5pp S16ndashS25 1994
[179] G V Belevitch G Y Dubur G E Dobretsov N K Kurek andM M Spirin ldquoCalcium antagonists riodipine nifedipine andverapamil binding to model and biological membranes fluore-scence analysisrdquo Biologicheskie Membrany (Biochemistry(Moscow) Series A Membrane and Cell Biology) vol 5 pp768ndash776 1988 (Russian)
[180] R P Mason G E Gonye D W Chester and L G HerbetteldquoPartitioning and location of Bay K 8644 14-dihydropyridinecalcium channel agonist in model and biological membranesrdquoBiophysical Journal vol 55 no 4 pp 769ndash778 1989
[181] M Cindric A Cipak J Serly et al ldquoReversal of multidrugresistance inmurine lymphoma cells by amphiphilic dihydropy-ridine antioxidant derivativerdquo Anticancer Research vol 30 no10 pp 4063ndash4070 2010
[182] F Shekari H Sadeghpour K Javidnia et al ldquoCytotoxic andmultidrug resistance reversal activities of novel 14-dihydro-pyridines against human cancer cellsrdquo European Journal ofPharmacology vol 746 no 1 pp 233ndash244 2015
[183] X-F Zhou Q Shao R A Coburn and M E Morris ldquoQuanti-tative structure-activity relationship and quantitative structure-pharmacokinetics relationship of 14-dihydropyridines andpyridines as multidrug resistance modulatorsrdquo PharmaceuticalResearch vol 22 no 12 pp 1989ndash1996 2005
[184] R Berkels T Breitenbach H Bartels et al ldquoDifferent antioxida-tive potencies of dihydropyridine calcium channel modulatorsin various modelsrdquo Vascular Pharmacology vol 42 no 4 pp145ndash152 2005
[185] S Borovic G Tirzitis D Tirzite et al ldquoBioactive 14-dihydro-isonicotinic acid derivatives prevent oxidative damage of livercellsrdquo European Journal of Pharmacology vol 537 no 1ndash3 pp12ndash19 2006
[186] D Ya Rubene G D Tirzitis and G Ya Duburs ldquoInteractionof some 14-dihydropyridine derivatives with Fentonrsquos reagentrdquoLatvijas PSRZinatnuAkademijas Vestis Kimijas Serija Proceed-ings of the Latvian SSR Academy of Sciences Chemistry Seriespp 212ndash216 1982 (Russian)
[187] K Ondrias V Misık D Gergel and A Stasko ldquoLipid per-oxidation of phosphatidylcholine liposomes depressed by thecalcium channel blockers nifedipine and verapamil and bythe antiarrhythmic-antihypoxic drug stobadinerdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1003 no 3pp 238ndash245 1989
[188] I T Mak and W B Weglicki ldquoComparative antioxidant acti-vities of propranolol nifedipine verapamil and diltiazemagainst sarcolemmal membrane lipid peroxidationrdquoCirculationResearch vol 66 no 5 pp 1449ndash1452 1990
[189] I T Mak P Boehme and W B Weglicki ldquoProtective effects ofcalcium channel blockers against free radical-impaired endo-thelial cell proliferationrdquo Biochemical Pharmacology vol 50 no9 pp 1531ndash1534 1995
[190] S Ray S Mondal and N Dana ldquoEvaluation of protective roleof nifedipine on lipid peroxidation using reduced glutathione as
model markerrdquo Oxidants and Antioxidants in Medical Sciencevol 1 no 2 pp 97ndash100 2012
[191] M Yamato T Shiba T Ide Y Honda K-I Yamada andH Tsutsui ldquoNifedipine treatment reduces brain damage aftertransient focal ischemia possibly through its antioxidativeeffectsrdquoHypertension Research vol 34 no 7 pp 840ndash845 2011
[192] V Chander and K Chopra ldquoNifedipine attenuates changes innitric oxide levels renal oxidative stress and nephrotoxicityinduced by cyclosporinerdquo Renal Failure vol 27 no 4 pp 441ndash450 2005
[193] K M Gaafa M M Badawy and A A Hamza ldquoThe protectiveeffects of ascorbic acid cimetidine and nifedipine on diethyl-dithiocarbamate-induced hepatic toxicity in albino ratsrdquo Drugand Chemical Toxicology vol 34 no 4 pp 405ndash419 2011
[194] H Sugawara K Tobise and S Onodera ldquoAbsence of antiox-idant effects of nifedipine and diltiazem on myocardial mem-brane lipid peroxidation in contrast with those of nisoldipineand propranololrdquo Biochemical Pharmacology vol 47 no 5 pp887ndash892 1994
[195] I E Kirule D Y Rubene E A Bisenieks G D Tirzit and GY Dubur ldquo4-Nitrophenyl-14-dihydropyridinesmdasha new groupof inhibitors of peroxide oxidationrdquo Chemistry of HeterocyclicCompounds vol 18 no 3 p 316 1982
[196] G D Tirzit I E Kirule L K Baumane R A Gavar Y PStradynrsquo andG YDubur ldquoMechanism of the antioxidant actionof 26-dimethyl-35-dimethoxy-carbonyl-4-(2-nitrophenyl)14-dihydropyridinerdquoChemistry ofHeterocyclic Compounds vol 20no 8 pp 915ndash918 1984
[197] C Yanez C Lopez-Alarcon C Camargo V Valenzuela J ASquella and L J Nunez-Vergara ldquoStructural effects on thereactivity 14-dihydropyridines with alkylperoxyl radicals andABTS radical cationrdquo Bioorganic and Medicinal Chemistry vol12 no 9 pp 2459ndash2468 2004
[198] VMisik A J Stasko D Gergel and K Ondrias ldquoSpin-trappingand antioxidant properties of illuminated and nonilluminatednifedipine and nimodipine in heart homogenate and modelsystemrdquo Molecular Pharmacology vol 40 no 3 pp 435ndash4391991
[199] K Ondrias V Misık A Stasko D Gergelrsquo and M HromadovaldquoComparison of antioxidant properties of nifedipine and illu-minated nifedipine with nitroso spin traps in low densitylipoproteins and phosphatidylcholine liposomesrdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1211 no 1pp 114ndash119 1994
[200] A Stasko V Brezova S Biskupic K Ondrias and V MisıkldquoReactive radical intermediates formed from illuminated nife-dipinerdquoFree Radical Biology andMedicine vol 17 no 6 pp 545ndash556 1994
[201] K Ishizawa Y Izawa-Ishizawa N Yamano et al ldquoNitrosoni-fedipine ameliorates the progression of type 2 diabetic nephro-pathy by exerting antioxidative effectsrdquo PLoS ONE vol 9 no 1Article ID e86335 2014
[202] H Fujii and L J Berliner ldquoIn vivo EPR evidence for free radicaladducts of nifedipinerdquoMagnetic Resonance in Medicine vol 42no 4 pp 691ndash694 1999
[203] S Bollo S Finger J C Sturm L J Nunez-Vergara and JA Squella ldquoCyclic voltammetry and scanning electrochemicalmicroscopy studies of the heterogeneous electron transferreaction of some nitrosoaromatic compoundsrdquo ElectrochimicaActa vol 52 no 15 pp 4892ndash4898 2007
34 Oxidative Medicine and Cellular Longevity
[204] F Ursini ldquoTissue protection by lacidipine insight from redoxbehaviorrdquo Journal of Cardiovascular Pharmacology vol 30supplement 2 pp S28ndashS30 1997
[205] P G Cristofori F A Crivellente I Faustinelli et al ldquoInvolve-ment of the nitric oxide system in the anti-atheroscleroticpotential of lacidipine in the apoE-deficient mouse a mor-phological functional and electrochemical studyrdquo ToxicologicPathology vol 32 no 4 pp 493ndash499 2004
[206] X-P Zhang E L Kit S Mital S Chahwala and T HHintze ldquoParadoxical release of nitric oxide by an L-type calciumchannel antagonist the R+ enantiomer of amlodipinerdquo Journalof Cardiovascular Pharmacology vol 39 no 2 pp 208ndash2142002
[207] F Franzoni G Santoro F Regoli et al ldquoAn in vitro study of theperoxyl and hydroxyl radical scavenging capacity of the calciumantagonist amlodipinerdquo Biomedicine and Pharmacotherapy vol58 no 8 pp 423ndash426 2004
[208] S V Gatsura ldquoOxygen-dependent mechanisms underlying theantiischemic effect of verapamil and amlodipinerdquo Bulletin ofExperimental Biology and Medicine vol 137 no 1 pp 40ndash422004
[209] Y Hirooka Y Kimura M Nozoe Y Sagara K Ito and KSunagawa ldquoAmlodipine-induced reduction of oxidative stressin the brain is associated with sympatho-inhibitory effects instroke-prone spontaneously hypertensive ratsrdquo HypertensionResearch vol 29 no 1 pp 49ndash56 2006
[210] B Tomlinson and I F F Benzie ldquoAntioxidant effect of lercani-dipine (note)rdquo Hypertension vol 42 no 4 pp e10ndashe11 2003
[211] A A Faraqui ldquoNeurochemical aspects of 4-hydroxynonenalrdquoin Lipid Mediators and Their Metabolism in the Brain A AFaraqui Ed chapter 6 pp 159ndash191 Springer New York NYUSA 2011
[212] V S NascimentoM S DrsquoAlva A AOliveira et al ldquoAntioxidanteffect of nimodipine in young rats after pilocarpine-inducedseizuresrdquo Pharmacology Biochemistry and Behavior vol 82 no1 pp 11ndash16 2005
[213] O Ismailoglu P Atilla S Palaoglu et al ldquoThe therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjuryrdquo Turkish Neurosurgery vol 22 no 6 pp 740ndash746 2012
[214] M Matsubara and K Hasegawa ldquoBenidipine a dihydropy-ridine-calcium channel blocker prevents lysophosphatidyl-choline-induced injury and reactive oxygen species productionin human aortic endothelial cellsrdquo Atherosclerosis vol 178 no1 pp 57ndash66 2005
[215] M Matsubara K Yao and K Hasegawa ldquoBenidipine adihydropyridine-calcium channel blocker inhibits lysophos-phatidylcholine-induced endothelial injury via stimulation ofnitric oxide releaserdquo Pharmacological Research vol 53 no 1 pp35ndash43 2006
[216] MMatsubara and K Hasegawa ldquoEffects of benidipine a dihyd-ropyridine-Ca2+ channel blocker on expression of cytokine-induced adhesion molecules and chemoattractants in humanaortic endothelial cellsrdquo European Journal of Pharmacology vol498 no 1ndash3 pp 303ndash314 2004
[217] M Matsubara O Akizuki J-I Ikeda K Saeki K Yao and KSasaki ldquoBenidipine an anti-hypertensive drug inhibits reactiveoxygen species production in polymorphonuclear leukocytesand oxidative stress in salt-loaded stroke-prone spontaneouslyhypertensive ratsrdquo European Journal of Pharmacology vol 580no 1-2 pp 201ndash213 2008
[218] A C Rosenkranz H Lob T Breitenbach R Berkels and RRoesen ldquoEndothelial antioxidant actions of dihydropyridines
and angiotensin converting enzyme inhibitorsrdquo European Jour-nal of Pharmacology vol 529 no 1ndash3 pp 55ndash62 2006
[219] V Kain S Kumar and S L Sitasawad ldquoAzelnidipine preventscardiac dysfunction in streptozotocin-diabetic rats by reducingintracellular calcium accumulation oxidative stress and apop-tosisrdquo Cardiovascular Diabetology vol 10 article 97 2011
[220] K Nakamura S Yamagishi and H Inoue ldquoUnique atheropro-tective property of azelnidipine a dihydropyridine-based cal-cium antagonistrdquoMedical Hypotheses vol 65 no 1 pp 155ndash1572005
[221] TMatsui S Yamagishi K Nakamura S Kikuchi andH InoueldquoAzelnidipine a dihydropyridine-based calcium antagonistinhibits angiotensin II-induced oxidative stress generation anddownregulation of pigment epithelium-derived factor mRNAlevels in microvascular endothelial cellsrdquo Drugs under Experi-mental and Clinical Research vol 31 no 5-6 pp 215ndash219 2005
[222] C Ohmura H Watada T Shimizu et al ldquoCalcium channelblocker azelnidipine reduces lipid hydroperoxides in patientswith type 2 diabetes independent of blood pressurerdquo EndocrineJournal vol 54 no 5 pp 805ndash811 2007
[223] H Daikuhara F Kikuchi and T Ishida ldquoThe combination ofOLmesartan and a CAlcium channel blocker (azelnidipine) orcandesartan and a calcium channel blocker (amlodipine) intype 2 diabetic hypertensive patients theOLCA studyrdquoDiabetesand Vascular Disease Research vol 9 no 4 pp 280ndash286 2012
[224] MAbe NMaruyama KOkada SMatsumoto KMatsumotoand M Soma ldquoAdditive antioxidative effects of azelnidipine onangiotensin receptor blocker olmesartan treatment for type 2diabetic patients with albuminuriardquoHypertension Research vol34 no 8 pp 935ndash941 2011
[225] K Mizushige ldquoAntioxidative activities of thiazolidinedionesand dihydropyridine-type calcium antagonistsrdquo IRYOmdashJapa-nese Journal of National Medical Services vol 59 no 11 pp 581ndash592 2005
[226] S Manabe T Okura T Fukuoka and J Higaki ldquoAntioxidativeeffects of azelnidipine on mesangial cell proliferation inducedby highly concentrated insulinrdquo European Journal of Pharma-cology vol 567 no 3 pp 252ndash257 2007
[227] Y Koyama Y Takeishi H Takahashi et al ldquoAzelnidipine inhi-bits H
2O2-induced cell death in neonatal rat cardiomyocytesrdquo
CardiovascularDrugs andTherapy vol 21 no 1 pp 69ndash72 2007[228] K Shinomiya K Mizushige M Fukunaga et al ldquoAntioxidant
effect of a new calcium antagonist azelnipidine in culturedhuman arterial endothelial cellsrdquo Journal of International Med-ical Research vol 32 no 2 pp 170ndash175 2004
[229] T Ohyama K Sato K Kishimoto et al ldquoAzelnidipine is acalcium blocker that attenuates liver fibrosis and may increaseantioxidant defencerdquo British Journal of Pharmacology vol 165no 4 pp 1173ndash1187 2012
[230] L A Calo F Zaghetto E Pagnin P A Davis A Sempliciniand A C Pessina ldquoEffect of manidipine on gene expressionand protein level of oxidative stress-related proteins p22phoxand HO-1 Relevance for antihypertensive and anti-remodelingeffectsrdquo Journal of Cardiovascular Pharmacology vol 43 no 4pp 531ndash538 2004
[231] R Ghyasi G Sepehri M Mohammadi R Badalzadeh and AGhyasi ldquoEffect of mebudipine on oxidative stress and lipid per-oxidation in myocardial ischemic-reperfusion injury in maleratrdquo Journal of Research in Medical Sciences vol 17 no 12 pp1150ndash1155 2012
Oxidative Medicine and Cellular Longevity 35
[232] DCAndersson J Fauconnier T Yamada et al ldquoMitochondrialproduction of reactive oxygen species contributes to the 120573-adrenergic stimulation of mouse cardiomycytesrdquoThe Journal ofPhysiology vol 589 no 7 pp 1791ndash1801 2011
[233] A F Ceylan-Isik N Ari M Stefek et al ldquoEffects of a long-term treatment with an antioxidant pyridoindole on vascularresponsiveness in diabetes-induced aging ratsrdquo Current AgingScience vol 4 no 2 pp 150ndash157 2011
[234] S Saponara G Sgaragli and F Fusi ldquoQuercetin antagonismof Bay K 8644 effects on rat tail artery L-type Ca2+ channelsrdquoEuropean Journal of Pharmacology vol 598 no 1ndash3 pp 75ndash802008
[235] D A Sica ldquoInteraction of grapefruit juice and calcium channelblockersrdquo American Journal of Hypertension vol 19 no 7 pp768ndash773 2006
[236] P Mulder G Litwinienko S Lin P D MacLean L R CBarclay and K U Ingold ldquoThe L-type calcium channel block-ers Hantzsch 14-dihydropyridines are not peroxyl radical-trapping chain-breaking antioxidantsrdquo Chemical Research inToxicology vol 19 no 1 pp 79ndash85 2006
[237] L J Nunez-Vergara R Salazar C Camargo et al ldquoOxidation ofC4-hydroxyphenyl 14-dihydropyridines in dimethylsulfoxideand its reactivity towards alkylperoxyl radicals in aqueousmediumrdquo Bioorganic and Medicinal Chemistry vol 15 no 12pp 4318ndash4326 2007
[238] M E Ortiz L J Nunez-Vergara and J A Squella ldquoRelativereactivity of dihydropyridine derivatives to electrogeneratedsuperoxide ion in DMSO solutions a voltammetric approachrdquoPharmaceutical Research vol 20 no 2 pp 292ndash296 2003
[239] M E Ortiz L J Nunez-Vergara C Camargo and J A SquellaldquoOxidation of Hantzsch 14-dihydropyridines of pharmacolog-ical significance by electrogenerated superoxiderdquo Pharmaceuti-cal Research vol 21 no 3 pp 428ndash435 2004
[240] R S Raghuvanshi and K N Singh ldquoSuperoxide induced oxida-tive aromatization of Hantzsch 14-dihydropyridinesrdquo IndianJournal of Chemistry Section B Organic and Medicinal Chem-istry vol 47 no 11 pp 1735ndash1738 2008
[241] I Kruk A Kladna K Lichszteld et al ldquoAntioxidant activityof 4-flavonil-14-dihydropyridine derivativesrdquo Biopolymers vol62 no 3 pp 163ndash167 2001
[242] G D Tirzit I M Byteva K I Salokhiddinov G P Gurinovichand G Y Dubur ldquo14-Dihydropyridine derivatives as deactiva-tors of singlet oxygenrdquo Chemistry of Heterocyclic Compoundsvol 17 no 7 pp 682ndash684 1981
[243] G D Tirzit E Y Kazush and G Y Dubur ldquoInfluence of14-dihydropyridine derivatives on the generation of hydroxylradicalsrdquo Chemistry of Heterocyclic Compounds vol 28 no 4pp 435ndash437 1992
[244] N A Pizarro-Urzua and L J Nunez-Vergara ldquoNifedipine andnitrendipine reactivity toward singlet oxygenrdquo Journal of Photo-chemistry and Photobiology A Chemistry vol 175 no 2-3 pp129ndash137 2005
[245] L-F Wang H-Y Zhang L Konga Z-W Chena and J-G ShildquoDFT calculations indicate that 14-dihydropyridine is a promis-ing lead antioxidantrdquo Helvetica Chimica Acta vol 87 no 6 pp1515ndash1521 2004
[246] P Mulder H-G Korth and K U Ingold ldquoWhy quantum-thermochemical calculations must be used with caution toindicate lsquoa promising lead antioxidantrsquordquoHelvetica Chimica Actavol 88 no 2 pp 370ndash374 2005
[247] K Yao Y Ina K Nagashima K Ohmori and T Ohno ldquoAntiox-idant effects of calcium antagonists in rat brain homogenatesrdquo
Biological and Pharmaceutical Bulletin vol 23 no 6 pp 766ndash769 2000
[248] T Matsui S-I Yamagishi K Nakamura and H Inoue ldquoBayw 9798 a dihydropyridine structurally related to nifedipinewith no calcium channel-blocking properties inhibits tumournecrosis factor-120572-induced vascular cell adhesion molecule-1expression in endothelial cells by suppressing reactive oxygenspecies generationrdquo Journal of International Medical Researchvol 35 no 6 pp 886ndash891 2007
[249] K AMitrega B VargheseM Porc and T F Krzeminski ldquoAnti-arrhythmic and hemodynamic effects of oxy nifedipine oxynimodipine oxy nitrendipine and oxy nisoldipinerdquo Pharmaco-logical Research vol 66 no 4 pp 300ndash308 2012
[250] V Herbert ldquoSymposium prooxidant effects of antioxidantvitamins Introductionrdquo The Journal of Nutrition vol 126 no4 supplement pp 1197Sndash1200S 1996 httpjnnutritionorgcontent1264 Suppl1197Sfullpdf
[251] B Halliwell ldquoAre polyphenols antioxidants or pro-oxidantsWhat do we learn from cell culture and in vivo studiesrdquoArchives of Biochemistry and Biophysics vol 476 no 2 pp 107ndash112 2008
[252] C Winterbourn Pro-Oxidants or Antioxidants ChristchurchSchool of Medicine Depatment of Pathology Free RadicalSchool SFRBMUniversity of Otago San Francisco Calif USA2009 httpwwwsfrbmorgfrsWinterbournpdf
[253] A Morakinyo B Iranloye and O Adegoke ldquoCalcium antag-onists modulate oxidative stress and acrosomal reaction in ratspermatozoardquo Archives of Medical Science vol 7 no 4 pp 613ndash618 2011
[254] The Alpha-Tocopherol Beta Carotene Cancer Prevention StudyGroup ldquoThe effect of vitamin E and beta carotene on theincidence of lung cancer and other cancers in male smokersrdquoTheNew England Journal of Medicine vol 330 no 15 pp 1029ndash1035 1994
[255] B Poljsak ldquoStrategies for reducing or preventing the generationof oxidative stressrdquo Oxidative Medicine and Cellular Longevityvol 2011 Article ID 194586 15 pages 2011
[256] B Poljsak and I Milisav ldquoThe neglected significance of lsquoanti-oxidative stressrsquordquoOxidativeMedicine and Cellular Longevity vol2012 Article ID 480895 12 pages 2012
[257] T Godfraind and S Salomone ldquoAmbiguities in dietary antiox-idant supplementation compared to calcium channel blockerstherapyrdquo Frontiers in Pharmacology vol 6 article 10 2015
[258] H Wagner H Norr and H Winterhoff ldquoDrugs with adap-togenic effects for strengthening the powers of resistancerdquoZeitschrift fur Phytotherapie vol 13 no 2 pp 42ndash54 1992
Oxidative Medicine and Cellular Longevity 33
biological membranes lipid bilayer partitioning could occurbefore drug binding to receptorsrdquo Journal of Molecular andCellular Cardiology vol 21 no 2 pp 187ndash201 1989
[178] L G Herbette P E Mason G Gaviraghi T N Tulenko andR P Mason ldquoThe molecular basis for lacidipinersquos unique phar-macokinetics optimal hydrophobicity results in membraneinteractions that may facilitate the treatment of atherosclerosisrdquoJournal of Cardiovascular Pharmacology vol 23 supplement 5pp S16ndashS25 1994
[179] G V Belevitch G Y Dubur G E Dobretsov N K Kurek andM M Spirin ldquoCalcium antagonists riodipine nifedipine andverapamil binding to model and biological membranes fluore-scence analysisrdquo Biologicheskie Membrany (Biochemistry(Moscow) Series A Membrane and Cell Biology) vol 5 pp768ndash776 1988 (Russian)
[180] R P Mason G E Gonye D W Chester and L G HerbetteldquoPartitioning and location of Bay K 8644 14-dihydropyridinecalcium channel agonist in model and biological membranesrdquoBiophysical Journal vol 55 no 4 pp 769ndash778 1989
[181] M Cindric A Cipak J Serly et al ldquoReversal of multidrugresistance inmurine lymphoma cells by amphiphilic dihydropy-ridine antioxidant derivativerdquo Anticancer Research vol 30 no10 pp 4063ndash4070 2010
[182] F Shekari H Sadeghpour K Javidnia et al ldquoCytotoxic andmultidrug resistance reversal activities of novel 14-dihydro-pyridines against human cancer cellsrdquo European Journal ofPharmacology vol 746 no 1 pp 233ndash244 2015
[183] X-F Zhou Q Shao R A Coburn and M E Morris ldquoQuanti-tative structure-activity relationship and quantitative structure-pharmacokinetics relationship of 14-dihydropyridines andpyridines as multidrug resistance modulatorsrdquo PharmaceuticalResearch vol 22 no 12 pp 1989ndash1996 2005
[184] R Berkels T Breitenbach H Bartels et al ldquoDifferent antioxida-tive potencies of dihydropyridine calcium channel modulatorsin various modelsrdquo Vascular Pharmacology vol 42 no 4 pp145ndash152 2005
[185] S Borovic G Tirzitis D Tirzite et al ldquoBioactive 14-dihydro-isonicotinic acid derivatives prevent oxidative damage of livercellsrdquo European Journal of Pharmacology vol 537 no 1ndash3 pp12ndash19 2006
[186] D Ya Rubene G D Tirzitis and G Ya Duburs ldquoInteractionof some 14-dihydropyridine derivatives with Fentonrsquos reagentrdquoLatvijas PSRZinatnuAkademijas Vestis Kimijas Serija Proceed-ings of the Latvian SSR Academy of Sciences Chemistry Seriespp 212ndash216 1982 (Russian)
[187] K Ondrias V Misık D Gergel and A Stasko ldquoLipid per-oxidation of phosphatidylcholine liposomes depressed by thecalcium channel blockers nifedipine and verapamil and bythe antiarrhythmic-antihypoxic drug stobadinerdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1003 no 3pp 238ndash245 1989
[188] I T Mak and W B Weglicki ldquoComparative antioxidant acti-vities of propranolol nifedipine verapamil and diltiazemagainst sarcolemmal membrane lipid peroxidationrdquoCirculationResearch vol 66 no 5 pp 1449ndash1452 1990
[189] I T Mak P Boehme and W B Weglicki ldquoProtective effects ofcalcium channel blockers against free radical-impaired endo-thelial cell proliferationrdquo Biochemical Pharmacology vol 50 no9 pp 1531ndash1534 1995
[190] S Ray S Mondal and N Dana ldquoEvaluation of protective roleof nifedipine on lipid peroxidation using reduced glutathione as
model markerrdquo Oxidants and Antioxidants in Medical Sciencevol 1 no 2 pp 97ndash100 2012
[191] M Yamato T Shiba T Ide Y Honda K-I Yamada andH Tsutsui ldquoNifedipine treatment reduces brain damage aftertransient focal ischemia possibly through its antioxidativeeffectsrdquoHypertension Research vol 34 no 7 pp 840ndash845 2011
[192] V Chander and K Chopra ldquoNifedipine attenuates changes innitric oxide levels renal oxidative stress and nephrotoxicityinduced by cyclosporinerdquo Renal Failure vol 27 no 4 pp 441ndash450 2005
[193] K M Gaafa M M Badawy and A A Hamza ldquoThe protectiveeffects of ascorbic acid cimetidine and nifedipine on diethyl-dithiocarbamate-induced hepatic toxicity in albino ratsrdquo Drugand Chemical Toxicology vol 34 no 4 pp 405ndash419 2011
[194] H Sugawara K Tobise and S Onodera ldquoAbsence of antiox-idant effects of nifedipine and diltiazem on myocardial mem-brane lipid peroxidation in contrast with those of nisoldipineand propranololrdquo Biochemical Pharmacology vol 47 no 5 pp887ndash892 1994
[195] I E Kirule D Y Rubene E A Bisenieks G D Tirzit and GY Dubur ldquo4-Nitrophenyl-14-dihydropyridinesmdasha new groupof inhibitors of peroxide oxidationrdquo Chemistry of HeterocyclicCompounds vol 18 no 3 p 316 1982
[196] G D Tirzit I E Kirule L K Baumane R A Gavar Y PStradynrsquo andG YDubur ldquoMechanism of the antioxidant actionof 26-dimethyl-35-dimethoxy-carbonyl-4-(2-nitrophenyl)14-dihydropyridinerdquoChemistry ofHeterocyclic Compounds vol 20no 8 pp 915ndash918 1984
[197] C Yanez C Lopez-Alarcon C Camargo V Valenzuela J ASquella and L J Nunez-Vergara ldquoStructural effects on thereactivity 14-dihydropyridines with alkylperoxyl radicals andABTS radical cationrdquo Bioorganic and Medicinal Chemistry vol12 no 9 pp 2459ndash2468 2004
[198] VMisik A J Stasko D Gergel and K Ondrias ldquoSpin-trappingand antioxidant properties of illuminated and nonilluminatednifedipine and nimodipine in heart homogenate and modelsystemrdquo Molecular Pharmacology vol 40 no 3 pp 435ndash4391991
[199] K Ondrias V Misık A Stasko D Gergelrsquo and M HromadovaldquoComparison of antioxidant properties of nifedipine and illu-minated nifedipine with nitroso spin traps in low densitylipoproteins and phosphatidylcholine liposomesrdquo Biochimica etBiophysica ActamdashLipids and Lipid Metabolism vol 1211 no 1pp 114ndash119 1994
[200] A Stasko V Brezova S Biskupic K Ondrias and V MisıkldquoReactive radical intermediates formed from illuminated nife-dipinerdquoFree Radical Biology andMedicine vol 17 no 6 pp 545ndash556 1994
[201] K Ishizawa Y Izawa-Ishizawa N Yamano et al ldquoNitrosoni-fedipine ameliorates the progression of type 2 diabetic nephro-pathy by exerting antioxidative effectsrdquo PLoS ONE vol 9 no 1Article ID e86335 2014
[202] H Fujii and L J Berliner ldquoIn vivo EPR evidence for free radicaladducts of nifedipinerdquoMagnetic Resonance in Medicine vol 42no 4 pp 691ndash694 1999
[203] S Bollo S Finger J C Sturm L J Nunez-Vergara and JA Squella ldquoCyclic voltammetry and scanning electrochemicalmicroscopy studies of the heterogeneous electron transferreaction of some nitrosoaromatic compoundsrdquo ElectrochimicaActa vol 52 no 15 pp 4892ndash4898 2007
34 Oxidative Medicine and Cellular Longevity
[204] F Ursini ldquoTissue protection by lacidipine insight from redoxbehaviorrdquo Journal of Cardiovascular Pharmacology vol 30supplement 2 pp S28ndashS30 1997
[205] P G Cristofori F A Crivellente I Faustinelli et al ldquoInvolve-ment of the nitric oxide system in the anti-atheroscleroticpotential of lacidipine in the apoE-deficient mouse a mor-phological functional and electrochemical studyrdquo ToxicologicPathology vol 32 no 4 pp 493ndash499 2004
[206] X-P Zhang E L Kit S Mital S Chahwala and T HHintze ldquoParadoxical release of nitric oxide by an L-type calciumchannel antagonist the R+ enantiomer of amlodipinerdquo Journalof Cardiovascular Pharmacology vol 39 no 2 pp 208ndash2142002
[207] F Franzoni G Santoro F Regoli et al ldquoAn in vitro study of theperoxyl and hydroxyl radical scavenging capacity of the calciumantagonist amlodipinerdquo Biomedicine and Pharmacotherapy vol58 no 8 pp 423ndash426 2004
[208] S V Gatsura ldquoOxygen-dependent mechanisms underlying theantiischemic effect of verapamil and amlodipinerdquo Bulletin ofExperimental Biology and Medicine vol 137 no 1 pp 40ndash422004
[209] Y Hirooka Y Kimura M Nozoe Y Sagara K Ito and KSunagawa ldquoAmlodipine-induced reduction of oxidative stressin the brain is associated with sympatho-inhibitory effects instroke-prone spontaneously hypertensive ratsrdquo HypertensionResearch vol 29 no 1 pp 49ndash56 2006
[210] B Tomlinson and I F F Benzie ldquoAntioxidant effect of lercani-dipine (note)rdquo Hypertension vol 42 no 4 pp e10ndashe11 2003
[211] A A Faraqui ldquoNeurochemical aspects of 4-hydroxynonenalrdquoin Lipid Mediators and Their Metabolism in the Brain A AFaraqui Ed chapter 6 pp 159ndash191 Springer New York NYUSA 2011
[212] V S NascimentoM S DrsquoAlva A AOliveira et al ldquoAntioxidanteffect of nimodipine in young rats after pilocarpine-inducedseizuresrdquo Pharmacology Biochemistry and Behavior vol 82 no1 pp 11ndash16 2005
[213] O Ismailoglu P Atilla S Palaoglu et al ldquoThe therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjuryrdquo Turkish Neurosurgery vol 22 no 6 pp 740ndash746 2012
[214] M Matsubara and K Hasegawa ldquoBenidipine a dihydropy-ridine-calcium channel blocker prevents lysophosphatidyl-choline-induced injury and reactive oxygen species productionin human aortic endothelial cellsrdquo Atherosclerosis vol 178 no1 pp 57ndash66 2005
[215] M Matsubara K Yao and K Hasegawa ldquoBenidipine adihydropyridine-calcium channel blocker inhibits lysophos-phatidylcholine-induced endothelial injury via stimulation ofnitric oxide releaserdquo Pharmacological Research vol 53 no 1 pp35ndash43 2006
[216] MMatsubara and K Hasegawa ldquoEffects of benidipine a dihyd-ropyridine-Ca2+ channel blocker on expression of cytokine-induced adhesion molecules and chemoattractants in humanaortic endothelial cellsrdquo European Journal of Pharmacology vol498 no 1ndash3 pp 303ndash314 2004
[217] M Matsubara O Akizuki J-I Ikeda K Saeki K Yao and KSasaki ldquoBenidipine an anti-hypertensive drug inhibits reactiveoxygen species production in polymorphonuclear leukocytesand oxidative stress in salt-loaded stroke-prone spontaneouslyhypertensive ratsrdquo European Journal of Pharmacology vol 580no 1-2 pp 201ndash213 2008
[218] A C Rosenkranz H Lob T Breitenbach R Berkels and RRoesen ldquoEndothelial antioxidant actions of dihydropyridines
and angiotensin converting enzyme inhibitorsrdquo European Jour-nal of Pharmacology vol 529 no 1ndash3 pp 55ndash62 2006
[219] V Kain S Kumar and S L Sitasawad ldquoAzelnidipine preventscardiac dysfunction in streptozotocin-diabetic rats by reducingintracellular calcium accumulation oxidative stress and apop-tosisrdquo Cardiovascular Diabetology vol 10 article 97 2011
[220] K Nakamura S Yamagishi and H Inoue ldquoUnique atheropro-tective property of azelnidipine a dihydropyridine-based cal-cium antagonistrdquoMedical Hypotheses vol 65 no 1 pp 155ndash1572005
[221] TMatsui S Yamagishi K Nakamura S Kikuchi andH InoueldquoAzelnidipine a dihydropyridine-based calcium antagonistinhibits angiotensin II-induced oxidative stress generation anddownregulation of pigment epithelium-derived factor mRNAlevels in microvascular endothelial cellsrdquo Drugs under Experi-mental and Clinical Research vol 31 no 5-6 pp 215ndash219 2005
[222] C Ohmura H Watada T Shimizu et al ldquoCalcium channelblocker azelnidipine reduces lipid hydroperoxides in patientswith type 2 diabetes independent of blood pressurerdquo EndocrineJournal vol 54 no 5 pp 805ndash811 2007
[223] H Daikuhara F Kikuchi and T Ishida ldquoThe combination ofOLmesartan and a CAlcium channel blocker (azelnidipine) orcandesartan and a calcium channel blocker (amlodipine) intype 2 diabetic hypertensive patients theOLCA studyrdquoDiabetesand Vascular Disease Research vol 9 no 4 pp 280ndash286 2012
[224] MAbe NMaruyama KOkada SMatsumoto KMatsumotoand M Soma ldquoAdditive antioxidative effects of azelnidipine onangiotensin receptor blocker olmesartan treatment for type 2diabetic patients with albuminuriardquoHypertension Research vol34 no 8 pp 935ndash941 2011
[225] K Mizushige ldquoAntioxidative activities of thiazolidinedionesand dihydropyridine-type calcium antagonistsrdquo IRYOmdashJapa-nese Journal of National Medical Services vol 59 no 11 pp 581ndash592 2005
[226] S Manabe T Okura T Fukuoka and J Higaki ldquoAntioxidativeeffects of azelnidipine on mesangial cell proliferation inducedby highly concentrated insulinrdquo European Journal of Pharma-cology vol 567 no 3 pp 252ndash257 2007
[227] Y Koyama Y Takeishi H Takahashi et al ldquoAzelnidipine inhi-bits H
2O2-induced cell death in neonatal rat cardiomyocytesrdquo
CardiovascularDrugs andTherapy vol 21 no 1 pp 69ndash72 2007[228] K Shinomiya K Mizushige M Fukunaga et al ldquoAntioxidant
effect of a new calcium antagonist azelnipidine in culturedhuman arterial endothelial cellsrdquo Journal of International Med-ical Research vol 32 no 2 pp 170ndash175 2004
[229] T Ohyama K Sato K Kishimoto et al ldquoAzelnidipine is acalcium blocker that attenuates liver fibrosis and may increaseantioxidant defencerdquo British Journal of Pharmacology vol 165no 4 pp 1173ndash1187 2012
[230] L A Calo F Zaghetto E Pagnin P A Davis A Sempliciniand A C Pessina ldquoEffect of manidipine on gene expressionand protein level of oxidative stress-related proteins p22phoxand HO-1 Relevance for antihypertensive and anti-remodelingeffectsrdquo Journal of Cardiovascular Pharmacology vol 43 no 4pp 531ndash538 2004
[231] R Ghyasi G Sepehri M Mohammadi R Badalzadeh and AGhyasi ldquoEffect of mebudipine on oxidative stress and lipid per-oxidation in myocardial ischemic-reperfusion injury in maleratrdquo Journal of Research in Medical Sciences vol 17 no 12 pp1150ndash1155 2012
Oxidative Medicine and Cellular Longevity 35
[232] DCAndersson J Fauconnier T Yamada et al ldquoMitochondrialproduction of reactive oxygen species contributes to the 120573-adrenergic stimulation of mouse cardiomycytesrdquoThe Journal ofPhysiology vol 589 no 7 pp 1791ndash1801 2011
[233] A F Ceylan-Isik N Ari M Stefek et al ldquoEffects of a long-term treatment with an antioxidant pyridoindole on vascularresponsiveness in diabetes-induced aging ratsrdquo Current AgingScience vol 4 no 2 pp 150ndash157 2011
[234] S Saponara G Sgaragli and F Fusi ldquoQuercetin antagonismof Bay K 8644 effects on rat tail artery L-type Ca2+ channelsrdquoEuropean Journal of Pharmacology vol 598 no 1ndash3 pp 75ndash802008
[235] D A Sica ldquoInteraction of grapefruit juice and calcium channelblockersrdquo American Journal of Hypertension vol 19 no 7 pp768ndash773 2006
[236] P Mulder G Litwinienko S Lin P D MacLean L R CBarclay and K U Ingold ldquoThe L-type calcium channel block-ers Hantzsch 14-dihydropyridines are not peroxyl radical-trapping chain-breaking antioxidantsrdquo Chemical Research inToxicology vol 19 no 1 pp 79ndash85 2006
[237] L J Nunez-Vergara R Salazar C Camargo et al ldquoOxidation ofC4-hydroxyphenyl 14-dihydropyridines in dimethylsulfoxideand its reactivity towards alkylperoxyl radicals in aqueousmediumrdquo Bioorganic and Medicinal Chemistry vol 15 no 12pp 4318ndash4326 2007
[238] M E Ortiz L J Nunez-Vergara and J A Squella ldquoRelativereactivity of dihydropyridine derivatives to electrogeneratedsuperoxide ion in DMSO solutions a voltammetric approachrdquoPharmaceutical Research vol 20 no 2 pp 292ndash296 2003
[239] M E Ortiz L J Nunez-Vergara C Camargo and J A SquellaldquoOxidation of Hantzsch 14-dihydropyridines of pharmacolog-ical significance by electrogenerated superoxiderdquo Pharmaceuti-cal Research vol 21 no 3 pp 428ndash435 2004
[240] R S Raghuvanshi and K N Singh ldquoSuperoxide induced oxida-tive aromatization of Hantzsch 14-dihydropyridinesrdquo IndianJournal of Chemistry Section B Organic and Medicinal Chem-istry vol 47 no 11 pp 1735ndash1738 2008
[241] I Kruk A Kladna K Lichszteld et al ldquoAntioxidant activityof 4-flavonil-14-dihydropyridine derivativesrdquo Biopolymers vol62 no 3 pp 163ndash167 2001
[242] G D Tirzit I M Byteva K I Salokhiddinov G P Gurinovichand G Y Dubur ldquo14-Dihydropyridine derivatives as deactiva-tors of singlet oxygenrdquo Chemistry of Heterocyclic Compoundsvol 17 no 7 pp 682ndash684 1981
[243] G D Tirzit E Y Kazush and G Y Dubur ldquoInfluence of14-dihydropyridine derivatives on the generation of hydroxylradicalsrdquo Chemistry of Heterocyclic Compounds vol 28 no 4pp 435ndash437 1992
[244] N A Pizarro-Urzua and L J Nunez-Vergara ldquoNifedipine andnitrendipine reactivity toward singlet oxygenrdquo Journal of Photo-chemistry and Photobiology A Chemistry vol 175 no 2-3 pp129ndash137 2005
[245] L-F Wang H-Y Zhang L Konga Z-W Chena and J-G ShildquoDFT calculations indicate that 14-dihydropyridine is a promis-ing lead antioxidantrdquo Helvetica Chimica Acta vol 87 no 6 pp1515ndash1521 2004
[246] P Mulder H-G Korth and K U Ingold ldquoWhy quantum-thermochemical calculations must be used with caution toindicate lsquoa promising lead antioxidantrsquordquoHelvetica Chimica Actavol 88 no 2 pp 370ndash374 2005
[247] K Yao Y Ina K Nagashima K Ohmori and T Ohno ldquoAntiox-idant effects of calcium antagonists in rat brain homogenatesrdquo
Biological and Pharmaceutical Bulletin vol 23 no 6 pp 766ndash769 2000
[248] T Matsui S-I Yamagishi K Nakamura and H Inoue ldquoBayw 9798 a dihydropyridine structurally related to nifedipinewith no calcium channel-blocking properties inhibits tumournecrosis factor-120572-induced vascular cell adhesion molecule-1expression in endothelial cells by suppressing reactive oxygenspecies generationrdquo Journal of International Medical Researchvol 35 no 6 pp 886ndash891 2007
[249] K AMitrega B VargheseM Porc and T F Krzeminski ldquoAnti-arrhythmic and hemodynamic effects of oxy nifedipine oxynimodipine oxy nitrendipine and oxy nisoldipinerdquo Pharmaco-logical Research vol 66 no 4 pp 300ndash308 2012
[250] V Herbert ldquoSymposium prooxidant effects of antioxidantvitamins Introductionrdquo The Journal of Nutrition vol 126 no4 supplement pp 1197Sndash1200S 1996 httpjnnutritionorgcontent1264 Suppl1197Sfullpdf
[251] B Halliwell ldquoAre polyphenols antioxidants or pro-oxidantsWhat do we learn from cell culture and in vivo studiesrdquoArchives of Biochemistry and Biophysics vol 476 no 2 pp 107ndash112 2008
[252] C Winterbourn Pro-Oxidants or Antioxidants ChristchurchSchool of Medicine Depatment of Pathology Free RadicalSchool SFRBMUniversity of Otago San Francisco Calif USA2009 httpwwwsfrbmorgfrsWinterbournpdf
[253] A Morakinyo B Iranloye and O Adegoke ldquoCalcium antag-onists modulate oxidative stress and acrosomal reaction in ratspermatozoardquo Archives of Medical Science vol 7 no 4 pp 613ndash618 2011
[254] The Alpha-Tocopherol Beta Carotene Cancer Prevention StudyGroup ldquoThe effect of vitamin E and beta carotene on theincidence of lung cancer and other cancers in male smokersrdquoTheNew England Journal of Medicine vol 330 no 15 pp 1029ndash1035 1994
[255] B Poljsak ldquoStrategies for reducing or preventing the generationof oxidative stressrdquo Oxidative Medicine and Cellular Longevityvol 2011 Article ID 194586 15 pages 2011
[256] B Poljsak and I Milisav ldquoThe neglected significance of lsquoanti-oxidative stressrsquordquoOxidativeMedicine and Cellular Longevity vol2012 Article ID 480895 12 pages 2012
[257] T Godfraind and S Salomone ldquoAmbiguities in dietary antiox-idant supplementation compared to calcium channel blockerstherapyrdquo Frontiers in Pharmacology vol 6 article 10 2015
[258] H Wagner H Norr and H Winterhoff ldquoDrugs with adap-togenic effects for strengthening the powers of resistancerdquoZeitschrift fur Phytotherapie vol 13 no 2 pp 42ndash54 1992
34 Oxidative Medicine and Cellular Longevity
[204] F Ursini ldquoTissue protection by lacidipine insight from redoxbehaviorrdquo Journal of Cardiovascular Pharmacology vol 30supplement 2 pp S28ndashS30 1997
[205] P G Cristofori F A Crivellente I Faustinelli et al ldquoInvolve-ment of the nitric oxide system in the anti-atheroscleroticpotential of lacidipine in the apoE-deficient mouse a mor-phological functional and electrochemical studyrdquo ToxicologicPathology vol 32 no 4 pp 493ndash499 2004
[206] X-P Zhang E L Kit S Mital S Chahwala and T HHintze ldquoParadoxical release of nitric oxide by an L-type calciumchannel antagonist the R+ enantiomer of amlodipinerdquo Journalof Cardiovascular Pharmacology vol 39 no 2 pp 208ndash2142002
[207] F Franzoni G Santoro F Regoli et al ldquoAn in vitro study of theperoxyl and hydroxyl radical scavenging capacity of the calciumantagonist amlodipinerdquo Biomedicine and Pharmacotherapy vol58 no 8 pp 423ndash426 2004
[208] S V Gatsura ldquoOxygen-dependent mechanisms underlying theantiischemic effect of verapamil and amlodipinerdquo Bulletin ofExperimental Biology and Medicine vol 137 no 1 pp 40ndash422004
[209] Y Hirooka Y Kimura M Nozoe Y Sagara K Ito and KSunagawa ldquoAmlodipine-induced reduction of oxidative stressin the brain is associated with sympatho-inhibitory effects instroke-prone spontaneously hypertensive ratsrdquo HypertensionResearch vol 29 no 1 pp 49ndash56 2006
[210] B Tomlinson and I F F Benzie ldquoAntioxidant effect of lercani-dipine (note)rdquo Hypertension vol 42 no 4 pp e10ndashe11 2003
[211] A A Faraqui ldquoNeurochemical aspects of 4-hydroxynonenalrdquoin Lipid Mediators and Their Metabolism in the Brain A AFaraqui Ed chapter 6 pp 159ndash191 Springer New York NYUSA 2011
[212] V S NascimentoM S DrsquoAlva A AOliveira et al ldquoAntioxidanteffect of nimodipine in young rats after pilocarpine-inducedseizuresrdquo Pharmacology Biochemistry and Behavior vol 82 no1 pp 11ndash16 2005
[213] O Ismailoglu P Atilla S Palaoglu et al ldquoThe therapeutic effectsof melatonin and nimodipine in rats after cerebral corticalinjuryrdquo Turkish Neurosurgery vol 22 no 6 pp 740ndash746 2012
[214] M Matsubara and K Hasegawa ldquoBenidipine a dihydropy-ridine-calcium channel blocker prevents lysophosphatidyl-choline-induced injury and reactive oxygen species productionin human aortic endothelial cellsrdquo Atherosclerosis vol 178 no1 pp 57ndash66 2005
[215] M Matsubara K Yao and K Hasegawa ldquoBenidipine adihydropyridine-calcium channel blocker inhibits lysophos-phatidylcholine-induced endothelial injury via stimulation ofnitric oxide releaserdquo Pharmacological Research vol 53 no 1 pp35ndash43 2006
[216] MMatsubara and K Hasegawa ldquoEffects of benidipine a dihyd-ropyridine-Ca2+ channel blocker on expression of cytokine-induced adhesion molecules and chemoattractants in humanaortic endothelial cellsrdquo European Journal of Pharmacology vol498 no 1ndash3 pp 303ndash314 2004
[217] M Matsubara O Akizuki J-I Ikeda K Saeki K Yao and KSasaki ldquoBenidipine an anti-hypertensive drug inhibits reactiveoxygen species production in polymorphonuclear leukocytesand oxidative stress in salt-loaded stroke-prone spontaneouslyhypertensive ratsrdquo European Journal of Pharmacology vol 580no 1-2 pp 201ndash213 2008
[218] A C Rosenkranz H Lob T Breitenbach R Berkels and RRoesen ldquoEndothelial antioxidant actions of dihydropyridines
and angiotensin converting enzyme inhibitorsrdquo European Jour-nal of Pharmacology vol 529 no 1ndash3 pp 55ndash62 2006
[219] V Kain S Kumar and S L Sitasawad ldquoAzelnidipine preventscardiac dysfunction in streptozotocin-diabetic rats by reducingintracellular calcium accumulation oxidative stress and apop-tosisrdquo Cardiovascular Diabetology vol 10 article 97 2011
[220] K Nakamura S Yamagishi and H Inoue ldquoUnique atheropro-tective property of azelnidipine a dihydropyridine-based cal-cium antagonistrdquoMedical Hypotheses vol 65 no 1 pp 155ndash1572005
[221] TMatsui S Yamagishi K Nakamura S Kikuchi andH InoueldquoAzelnidipine a dihydropyridine-based calcium antagonistinhibits angiotensin II-induced oxidative stress generation anddownregulation of pigment epithelium-derived factor mRNAlevels in microvascular endothelial cellsrdquo Drugs under Experi-mental and Clinical Research vol 31 no 5-6 pp 215ndash219 2005
[222] C Ohmura H Watada T Shimizu et al ldquoCalcium channelblocker azelnidipine reduces lipid hydroperoxides in patientswith type 2 diabetes independent of blood pressurerdquo EndocrineJournal vol 54 no 5 pp 805ndash811 2007
[223] H Daikuhara F Kikuchi and T Ishida ldquoThe combination ofOLmesartan and a CAlcium channel blocker (azelnidipine) orcandesartan and a calcium channel blocker (amlodipine) intype 2 diabetic hypertensive patients theOLCA studyrdquoDiabetesand Vascular Disease Research vol 9 no 4 pp 280ndash286 2012
[224] MAbe NMaruyama KOkada SMatsumoto KMatsumotoand M Soma ldquoAdditive antioxidative effects of azelnidipine onangiotensin receptor blocker olmesartan treatment for type 2diabetic patients with albuminuriardquoHypertension Research vol34 no 8 pp 935ndash941 2011
[225] K Mizushige ldquoAntioxidative activities of thiazolidinedionesand dihydropyridine-type calcium antagonistsrdquo IRYOmdashJapa-nese Journal of National Medical Services vol 59 no 11 pp 581ndash592 2005
[226] S Manabe T Okura T Fukuoka and J Higaki ldquoAntioxidativeeffects of azelnidipine on mesangial cell proliferation inducedby highly concentrated insulinrdquo European Journal of Pharma-cology vol 567 no 3 pp 252ndash257 2007
[227] Y Koyama Y Takeishi H Takahashi et al ldquoAzelnidipine inhi-bits H
2O2-induced cell death in neonatal rat cardiomyocytesrdquo
CardiovascularDrugs andTherapy vol 21 no 1 pp 69ndash72 2007[228] K Shinomiya K Mizushige M Fukunaga et al ldquoAntioxidant
effect of a new calcium antagonist azelnipidine in culturedhuman arterial endothelial cellsrdquo Journal of International Med-ical Research vol 32 no 2 pp 170ndash175 2004
[229] T Ohyama K Sato K Kishimoto et al ldquoAzelnidipine is acalcium blocker that attenuates liver fibrosis and may increaseantioxidant defencerdquo British Journal of Pharmacology vol 165no 4 pp 1173ndash1187 2012
[230] L A Calo F Zaghetto E Pagnin P A Davis A Sempliciniand A C Pessina ldquoEffect of manidipine on gene expressionand protein level of oxidative stress-related proteins p22phoxand HO-1 Relevance for antihypertensive and anti-remodelingeffectsrdquo Journal of Cardiovascular Pharmacology vol 43 no 4pp 531ndash538 2004
[231] R Ghyasi G Sepehri M Mohammadi R Badalzadeh and AGhyasi ldquoEffect of mebudipine on oxidative stress and lipid per-oxidation in myocardial ischemic-reperfusion injury in maleratrdquo Journal of Research in Medical Sciences vol 17 no 12 pp1150ndash1155 2012
Oxidative Medicine and Cellular Longevity 35
[232] DCAndersson J Fauconnier T Yamada et al ldquoMitochondrialproduction of reactive oxygen species contributes to the 120573-adrenergic stimulation of mouse cardiomycytesrdquoThe Journal ofPhysiology vol 589 no 7 pp 1791ndash1801 2011
[233] A F Ceylan-Isik N Ari M Stefek et al ldquoEffects of a long-term treatment with an antioxidant pyridoindole on vascularresponsiveness in diabetes-induced aging ratsrdquo Current AgingScience vol 4 no 2 pp 150ndash157 2011
[234] S Saponara G Sgaragli and F Fusi ldquoQuercetin antagonismof Bay K 8644 effects on rat tail artery L-type Ca2+ channelsrdquoEuropean Journal of Pharmacology vol 598 no 1ndash3 pp 75ndash802008
[235] D A Sica ldquoInteraction of grapefruit juice and calcium channelblockersrdquo American Journal of Hypertension vol 19 no 7 pp768ndash773 2006
[236] P Mulder G Litwinienko S Lin P D MacLean L R CBarclay and K U Ingold ldquoThe L-type calcium channel block-ers Hantzsch 14-dihydropyridines are not peroxyl radical-trapping chain-breaking antioxidantsrdquo Chemical Research inToxicology vol 19 no 1 pp 79ndash85 2006
[237] L J Nunez-Vergara R Salazar C Camargo et al ldquoOxidation ofC4-hydroxyphenyl 14-dihydropyridines in dimethylsulfoxideand its reactivity towards alkylperoxyl radicals in aqueousmediumrdquo Bioorganic and Medicinal Chemistry vol 15 no 12pp 4318ndash4326 2007
[238] M E Ortiz L J Nunez-Vergara and J A Squella ldquoRelativereactivity of dihydropyridine derivatives to electrogeneratedsuperoxide ion in DMSO solutions a voltammetric approachrdquoPharmaceutical Research vol 20 no 2 pp 292ndash296 2003
[239] M E Ortiz L J Nunez-Vergara C Camargo and J A SquellaldquoOxidation of Hantzsch 14-dihydropyridines of pharmacolog-ical significance by electrogenerated superoxiderdquo Pharmaceuti-cal Research vol 21 no 3 pp 428ndash435 2004
[240] R S Raghuvanshi and K N Singh ldquoSuperoxide induced oxida-tive aromatization of Hantzsch 14-dihydropyridinesrdquo IndianJournal of Chemistry Section B Organic and Medicinal Chem-istry vol 47 no 11 pp 1735ndash1738 2008
[241] I Kruk A Kladna K Lichszteld et al ldquoAntioxidant activityof 4-flavonil-14-dihydropyridine derivativesrdquo Biopolymers vol62 no 3 pp 163ndash167 2001
[242] G D Tirzit I M Byteva K I Salokhiddinov G P Gurinovichand G Y Dubur ldquo14-Dihydropyridine derivatives as deactiva-tors of singlet oxygenrdquo Chemistry of Heterocyclic Compoundsvol 17 no 7 pp 682ndash684 1981
[243] G D Tirzit E Y Kazush and G Y Dubur ldquoInfluence of14-dihydropyridine derivatives on the generation of hydroxylradicalsrdquo Chemistry of Heterocyclic Compounds vol 28 no 4pp 435ndash437 1992
[244] N A Pizarro-Urzua and L J Nunez-Vergara ldquoNifedipine andnitrendipine reactivity toward singlet oxygenrdquo Journal of Photo-chemistry and Photobiology A Chemistry vol 175 no 2-3 pp129ndash137 2005
[245] L-F Wang H-Y Zhang L Konga Z-W Chena and J-G ShildquoDFT calculations indicate that 14-dihydropyridine is a promis-ing lead antioxidantrdquo Helvetica Chimica Acta vol 87 no 6 pp1515ndash1521 2004
[246] P Mulder H-G Korth and K U Ingold ldquoWhy quantum-thermochemical calculations must be used with caution toindicate lsquoa promising lead antioxidantrsquordquoHelvetica Chimica Actavol 88 no 2 pp 370ndash374 2005
[247] K Yao Y Ina K Nagashima K Ohmori and T Ohno ldquoAntiox-idant effects of calcium antagonists in rat brain homogenatesrdquo
Biological and Pharmaceutical Bulletin vol 23 no 6 pp 766ndash769 2000
[248] T Matsui S-I Yamagishi K Nakamura and H Inoue ldquoBayw 9798 a dihydropyridine structurally related to nifedipinewith no calcium channel-blocking properties inhibits tumournecrosis factor-120572-induced vascular cell adhesion molecule-1expression in endothelial cells by suppressing reactive oxygenspecies generationrdquo Journal of International Medical Researchvol 35 no 6 pp 886ndash891 2007
[249] K AMitrega B VargheseM Porc and T F Krzeminski ldquoAnti-arrhythmic and hemodynamic effects of oxy nifedipine oxynimodipine oxy nitrendipine and oxy nisoldipinerdquo Pharmaco-logical Research vol 66 no 4 pp 300ndash308 2012
[250] V Herbert ldquoSymposium prooxidant effects of antioxidantvitamins Introductionrdquo The Journal of Nutrition vol 126 no4 supplement pp 1197Sndash1200S 1996 httpjnnutritionorgcontent1264 Suppl1197Sfullpdf
[251] B Halliwell ldquoAre polyphenols antioxidants or pro-oxidantsWhat do we learn from cell culture and in vivo studiesrdquoArchives of Biochemistry and Biophysics vol 476 no 2 pp 107ndash112 2008
[252] C Winterbourn Pro-Oxidants or Antioxidants ChristchurchSchool of Medicine Depatment of Pathology Free RadicalSchool SFRBMUniversity of Otago San Francisco Calif USA2009 httpwwwsfrbmorgfrsWinterbournpdf
[253] A Morakinyo B Iranloye and O Adegoke ldquoCalcium antag-onists modulate oxidative stress and acrosomal reaction in ratspermatozoardquo Archives of Medical Science vol 7 no 4 pp 613ndash618 2011
[254] The Alpha-Tocopherol Beta Carotene Cancer Prevention StudyGroup ldquoThe effect of vitamin E and beta carotene on theincidence of lung cancer and other cancers in male smokersrdquoTheNew England Journal of Medicine vol 330 no 15 pp 1029ndash1035 1994
[255] B Poljsak ldquoStrategies for reducing or preventing the generationof oxidative stressrdquo Oxidative Medicine and Cellular Longevityvol 2011 Article ID 194586 15 pages 2011
[256] B Poljsak and I Milisav ldquoThe neglected significance of lsquoanti-oxidative stressrsquordquoOxidativeMedicine and Cellular Longevity vol2012 Article ID 480895 12 pages 2012
[257] T Godfraind and S Salomone ldquoAmbiguities in dietary antiox-idant supplementation compared to calcium channel blockerstherapyrdquo Frontiers in Pharmacology vol 6 article 10 2015
[258] H Wagner H Norr and H Winterhoff ldquoDrugs with adap-togenic effects for strengthening the powers of resistancerdquoZeitschrift fur Phytotherapie vol 13 no 2 pp 42ndash54 1992
Oxidative Medicine and Cellular Longevity 35
[232] DCAndersson J Fauconnier T Yamada et al ldquoMitochondrialproduction of reactive oxygen species contributes to the 120573-adrenergic stimulation of mouse cardiomycytesrdquoThe Journal ofPhysiology vol 589 no 7 pp 1791ndash1801 2011
[233] A F Ceylan-Isik N Ari M Stefek et al ldquoEffects of a long-term treatment with an antioxidant pyridoindole on vascularresponsiveness in diabetes-induced aging ratsrdquo Current AgingScience vol 4 no 2 pp 150ndash157 2011
[234] S Saponara G Sgaragli and F Fusi ldquoQuercetin antagonismof Bay K 8644 effects on rat tail artery L-type Ca2+ channelsrdquoEuropean Journal of Pharmacology vol 598 no 1ndash3 pp 75ndash802008
[235] D A Sica ldquoInteraction of grapefruit juice and calcium channelblockersrdquo American Journal of Hypertension vol 19 no 7 pp768ndash773 2006
[236] P Mulder G Litwinienko S Lin P D MacLean L R CBarclay and K U Ingold ldquoThe L-type calcium channel block-ers Hantzsch 14-dihydropyridines are not peroxyl radical-trapping chain-breaking antioxidantsrdquo Chemical Research inToxicology vol 19 no 1 pp 79ndash85 2006
[237] L J Nunez-Vergara R Salazar C Camargo et al ldquoOxidation ofC4-hydroxyphenyl 14-dihydropyridines in dimethylsulfoxideand its reactivity towards alkylperoxyl radicals in aqueousmediumrdquo Bioorganic and Medicinal Chemistry vol 15 no 12pp 4318ndash4326 2007
[238] M E Ortiz L J Nunez-Vergara and J A Squella ldquoRelativereactivity of dihydropyridine derivatives to electrogeneratedsuperoxide ion in DMSO solutions a voltammetric approachrdquoPharmaceutical Research vol 20 no 2 pp 292ndash296 2003
[239] M E Ortiz L J Nunez-Vergara C Camargo and J A SquellaldquoOxidation of Hantzsch 14-dihydropyridines of pharmacolog-ical significance by electrogenerated superoxiderdquo Pharmaceuti-cal Research vol 21 no 3 pp 428ndash435 2004
[240] R S Raghuvanshi and K N Singh ldquoSuperoxide induced oxida-tive aromatization of Hantzsch 14-dihydropyridinesrdquo IndianJournal of Chemistry Section B Organic and Medicinal Chem-istry vol 47 no 11 pp 1735ndash1738 2008
[241] I Kruk A Kladna K Lichszteld et al ldquoAntioxidant activityof 4-flavonil-14-dihydropyridine derivativesrdquo Biopolymers vol62 no 3 pp 163ndash167 2001
[242] G D Tirzit I M Byteva K I Salokhiddinov G P Gurinovichand G Y Dubur ldquo14-Dihydropyridine derivatives as deactiva-tors of singlet oxygenrdquo Chemistry of Heterocyclic Compoundsvol 17 no 7 pp 682ndash684 1981
[243] G D Tirzit E Y Kazush and G Y Dubur ldquoInfluence of14-dihydropyridine derivatives on the generation of hydroxylradicalsrdquo Chemistry of Heterocyclic Compounds vol 28 no 4pp 435ndash437 1992
[244] N A Pizarro-Urzua and L J Nunez-Vergara ldquoNifedipine andnitrendipine reactivity toward singlet oxygenrdquo Journal of Photo-chemistry and Photobiology A Chemistry vol 175 no 2-3 pp129ndash137 2005
[245] L-F Wang H-Y Zhang L Konga Z-W Chena and J-G ShildquoDFT calculations indicate that 14-dihydropyridine is a promis-ing lead antioxidantrdquo Helvetica Chimica Acta vol 87 no 6 pp1515ndash1521 2004
[246] P Mulder H-G Korth and K U Ingold ldquoWhy quantum-thermochemical calculations must be used with caution toindicate lsquoa promising lead antioxidantrsquordquoHelvetica Chimica Actavol 88 no 2 pp 370ndash374 2005
[247] K Yao Y Ina K Nagashima K Ohmori and T Ohno ldquoAntiox-idant effects of calcium antagonists in rat brain homogenatesrdquo
Biological and Pharmaceutical Bulletin vol 23 no 6 pp 766ndash769 2000
[248] T Matsui S-I Yamagishi K Nakamura and H Inoue ldquoBayw 9798 a dihydropyridine structurally related to nifedipinewith no calcium channel-blocking properties inhibits tumournecrosis factor-120572-induced vascular cell adhesion molecule-1expression in endothelial cells by suppressing reactive oxygenspecies generationrdquo Journal of International Medical Researchvol 35 no 6 pp 886ndash891 2007
[249] K AMitrega B VargheseM Porc and T F Krzeminski ldquoAnti-arrhythmic and hemodynamic effects of oxy nifedipine oxynimodipine oxy nitrendipine and oxy nisoldipinerdquo Pharmaco-logical Research vol 66 no 4 pp 300ndash308 2012
[250] V Herbert ldquoSymposium prooxidant effects of antioxidantvitamins Introductionrdquo The Journal of Nutrition vol 126 no4 supplement pp 1197Sndash1200S 1996 httpjnnutritionorgcontent1264 Suppl1197Sfullpdf
[251] B Halliwell ldquoAre polyphenols antioxidants or pro-oxidantsWhat do we learn from cell culture and in vivo studiesrdquoArchives of Biochemistry and Biophysics vol 476 no 2 pp 107ndash112 2008
[252] C Winterbourn Pro-Oxidants or Antioxidants ChristchurchSchool of Medicine Depatment of Pathology Free RadicalSchool SFRBMUniversity of Otago San Francisco Calif USA2009 httpwwwsfrbmorgfrsWinterbournpdf
[253] A Morakinyo B Iranloye and O Adegoke ldquoCalcium antag-onists modulate oxidative stress and acrosomal reaction in ratspermatozoardquo Archives of Medical Science vol 7 no 4 pp 613ndash618 2011
[254] The Alpha-Tocopherol Beta Carotene Cancer Prevention StudyGroup ldquoThe effect of vitamin E and beta carotene on theincidence of lung cancer and other cancers in male smokersrdquoTheNew England Journal of Medicine vol 330 no 15 pp 1029ndash1035 1994
[255] B Poljsak ldquoStrategies for reducing or preventing the generationof oxidative stressrdquo Oxidative Medicine and Cellular Longevityvol 2011 Article ID 194586 15 pages 2011
[256] B Poljsak and I Milisav ldquoThe neglected significance of lsquoanti-oxidative stressrsquordquoOxidativeMedicine and Cellular Longevity vol2012 Article ID 480895 12 pages 2012
[257] T Godfraind and S Salomone ldquoAmbiguities in dietary antiox-idant supplementation compared to calcium channel blockerstherapyrdquo Frontiers in Pharmacology vol 6 article 10 2015
[258] H Wagner H Norr and H Winterhoff ldquoDrugs with adap-togenic effects for strengthening the powers of resistancerdquoZeitschrift fur Phytotherapie vol 13 no 2 pp 42ndash54 1992
![Functional Group Transformations in Derivatives of 1,4 ... · benzo[1,2,4]triazinyl radicals 1 and also prepared 7-iodo derivatives 2a and 2d26 and report an attempted synthesis of](https://static.documents.pub/doc/80x56/5ec4216e6032f166801559b7/functional-group-transformations-in-derivatives-of-14-benzo124triazinyl.jpg)
