Nitric Oxide Pharmacology .

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RECENT TRENDS

IN

PHARMACOLOGY OFNITRIC OXIDE


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OVERVIEW

Nitric oxide(NO)/ Endothelium Derived RelaxingFactor (EDRF)-Properties

Synthesis, Mechanism of action and NO Signalling

Physiological Role- In Body systems

Role in diseases/pathophysiological states, cancer

Pharmacology : NO- related drugs NOS modulating drugs activators and inhibitors

NO Donors : Classification, clinical potential

NO and gene therapy, stem cell-based therapy

and nutraceuticals Future prospects and Conclusion


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Background Information

Prior to 1990: An air pollutant Named Molecule of the Year by Science magazine in 1992

Robert Furchgott, Louis J Ignore, Ferid Murad:

Nobel Prize 1998

Properties of NO:

Small water and lipid soluble gas

Gaseous free radical

Three interchangeable forms:NO: Nitric Oxide

NO+: Nitrosonium cation

NO- : Nitroxyl Radical


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EDRF/NO!

EDRF was claimed to be NO by (Ignarro,

1989, Furchgott, 1990 and Skvaril,

2000,.others).

EDFR/NO system presented in manytissues, is a regulatory system likely to be

important physiologically.


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NOSs, is a family of related enzymes encoded

by separate genes. It is one of the most

regulated enzymes in biology.

Three known isoforms, two are constitutive(cNOS) and the third is inducible (iNOS)

(NOS2).

Nitric Oxide Synthases

Source: (Majano et al., 1998) (Tylor et al., 1997) (Freid Murad.1998 )


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NOSs

Constitutive

Neuornal

NOS1

bcNOS

Endothelial

NOS3

ecNOS

Inducible

NOS2

iNOS

Nitric Oxide

Synthases


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Nitric oxide synthesis involves

arginine, oxygen, and nicotinamideadenine dinucleotide phosphate

(NADPH).

Nitric Oxide Biosynthesis


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L-arginine

NOSsL-

Citrulline

Nitric Oxide Biosynthesis

Nitrite (NO2-)Nitrate (NO3-)


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Synthesis of Nitric Acid
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Nitric Oxide Synthase oxidizes the quanidine

group of L-arginine in a process that consumes

five electrons and results in the formation of NO

with stoichiometric formation of L-citrulline.

The process involves the oxidation of NADPHand the reduction of molecular oxygen.

The transformation occurs at a catalytic siteadjacent to a specific binding site of L-arginine.

Nitric Oxide Synthesis

Source: (Ignarro, 2001)


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Activation of NOS

Glutamate neurotransmitter binds to NMDA receptors

Ca++ channels open causing Ca influx into cell

Activation of calmodulin, which activates NOS

Mechanism for start of synthesis dependent on body

system

NO synthesis takes place in endothelial cells, lung cells,

and neuronal cells


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Http://www.kumc.edu/research/medicine/biochemistry/bioc800/sig02-06.


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Types of NOS

NOS I

Central and peripheral neuronal cells

Ca+2 dependent, used for neuronal communication

NOS II

Most nucleated cells, particularly macrophages

Independent of intracellular Ca+2

Inducible in presence of inflammatory cytokines

NOS III Vascular endothelial cells

Ca+2 dependent

Vascular regulation


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Constitutive Inducible

Cytosolic

NADPH dependent

Dioxygenase

Inhibited by L-arginineanalogues

Ca2+/calmodulin dependent

Picomoles NO released

Short-lasting release

Unaffected by glucocorticoids

Cytosolic

NADPH dependent

Dioxygenase

Inhibited by L-arginineanalogues

Ca2+/calmodulin independent

Nanomoles NO released

Long-lasting release

Induction inhibited by

glucocorticoids

Source: (Moncada et al., 1991)

cNOS/iNOS


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Neuronal NOS

(nNOS or NOS1)

Inducible NOS

(iNOS or NOS2)

Endothelial NOS

(eNOS or NOS3)

Originally cloned

from

Neuronal Cell Macrophage Endothelial Cell

Chromosome

localization

NOS1,

Chromosome 12

12q24.2

NOS2,

Chromosome 17

17 cen-q11.2

NOS3, Chromosome

7

7q35-7q36

Ca dependent Ca dependent

(Ca-dystrophin)

Ca-Calmodulin

independent

Ca dependent

(Ca-Calmodulin)

Ca independent

eNOS/nNOS/iNOS


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Nitric Oxide Signaling

Enzyme Gene No. of

exons

No. of

residues

Subcellular

location

Regulation

nNOS NOS1 29 1429-

1433

Mainly

soluble(brain);

Ca2+/CaM

iNOS NOS2 27 1144-

1153

Mainly

soluble

Ca2+

independent

eNOS NOS3 26 1203-

1205

Mainly

particulate

Ca2+/CaM


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Neuronal Nitric Oxide Synthase (nNOS)


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Epithelial Nitric Oxide Synthase (eNOS)


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Inducible Nitric Oxide Synthase (iNOS)


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Mechanism of Action of NO

Various stimuli5

- HTAcetylcholineThrombinCalcium ionophore A23187Arachidonic AcidChanges in AP &ES

NO Release

Platelet antiaggregation &Vasorelaxation effect

Prostacyclin


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Contd NO

NO bind to Fe 2+haem groupof Guanylyl Cyclase

Active Guanylate Cyclase

Increased cGMP

Increased intracellular Ca 2+

Relaxes muscle

Dilating the vessel &

lowering B.P.


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Under normal basal conditions in blood vessels,NO is continually being produced by cNOS but the

activity of iNOS is very low.

During inflammation the amount of NO producedby iNOS may be a 1,000-fold greater than that

produced by cNOS. The activity of iNOS isstimulated during inflammation by bacterial

endotoxins (e.g., lipopolysaccharide) and cytokines

such as tumor necrosis factor (TNF) and

interleukins. Source: (Archer, 1993) (Davies et al., 1995)

Nitric Oxide Synthesis


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The chemical effect of NO n biologicalsystems is

extensive and complex, it is divided into twomajor categories:

Direct Those reactions fast enough to occur between NO and

specific biological molecules.

Indirect Do not involve NO, but rather are mediated by reactive

nitrogen oxide species (RNOS) formed from the reactionof NO either with oxygen or superoxide. RNOS formedfrom NO can mediate either nitrosative or oxidative

stress. Source: (Wink and Mitchell, 1998)

Nitric Oxide


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Oxidation of iron containing proteins such as

ribonucleotide reductase and aconitase,

Activation of the soluble guanylate cyclase,

ADP ribosylation of proteins,

Protein sulphhydryl group nitrosylation, and iron

regulatory factor activation (Shami et al., 1995).

.

Mechanism of Action

(Source: Shami et al., 1995)


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NO acts through the stimulation of thesoluble guanylate cyclase which is a

heterodimeric enzyme withsubsequent formation of cyclic GMP.

Cyclic GMP activates protein kinasesand leads ultimately to the

dephosphorylation of the myosine light

chain. Source: (Denninger and Marletta, 1999)

Mechanism of Action


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Intracellular calciumNitric Oxide SynthaseNitric OxideGuanylate cyclaseCyclic GMPProtein kinase GProtein phosphatase

Phosphodiestrase

NO/cGMP signaling processes (Davies et al., 1997)

Nitric Oxide


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NO is an important messenger moleculeinvolved in many physiological and

pathological processes within themammalian body both beneficial and

detrimental.

Source: (Kane et al., 1997)

Nitric Oxide


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Functions as a signaling molecule thattells the body to make blood vessels

relax and widen. This physiologicalreaction is important when the bodyneeds more blood.

Works as a signaling molecule in thecardiovascular system, the nervoussystem, and in other tissues,..

Nitric Oxide: Signaling Molecules

Source: (Kuwana, 1998)


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Appropriate levels of NO production are

important in protecting an organ such as theliver from ischemic damage.

Sustained levels of NO production result indirect tissue toxicity and contribute to thevascular collapse associated with septicshock.

Chronic expression of NO is associatedwith various carcinomas and inflammatoryconditions, including juvenile diabetes,multiple sclerosis, arthritis and ulcerativecolitis,.. Source: (Tylor etal., 1997)

Nitric Oxide


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The synthesis of NO by vascular endothelium is responsiblefor the vasodilator tone that is essential for the regulation ofblood pressure.

NO also contributes to the control of platelet aggregation and

the regulation of cardiac contractility. It is now established that NO is the physiological mediator ofpenile erection.

In the central nervous system, NO is a neurotransmitter thatunderlines several functions including the formation ofmemory.

In the periphery, there is a widespread network of nerves,previously recognized as nonadrenergic and noncholinergic,that operate through a NO dependent mechanism to mediatesome forms of neurogenic vasodilatation and regulate variousgastrointestinal, respiratory, and genitourinary tract functions.

Physiological Role

Source:(Moncada and Higgs, 1993)


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Nitric Oxide cGMP Pathway


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Physiology of Nitric oxide

NO play important role :

Penile erection

Lung vasodilatation

Physiological stimuli for generation of NO are not fullyunderstood, but pulsatile flow and shear forces may be themain determinant.

In biological system NO is not stored and diffuses freely to its

site of action where it bind covalently to its effectors (t1/2=3-5second)

In coronary artery disease, basal level of NO as well asstimulated release of NO reduced


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What is the role of Nitric Oxide in

the human body? Nitric Oxide in the human body has

many uses which are best

summarized under five categories.

NO in the nervous system NO in the circulatory system

NO in the muscular system

NO in the immune system NO in the digestive system


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Nitric Oxide in the Nervous

System

Nitric oxide as a neurotransmitter

NO is a signaling molecule, but not necessarily a neurotransmitter

NO signals inhibition of smooth muscle contraction, adaptive

relaxation, and localized vasodilation

Nitric oxide believed to play a role in long term memory

Memory mechanism proposed is a retrograde messenger that

facilitates long term potentiation of neurons (memory)

Synthesis mechanism involving Ca/Calmodulin activates NOS-I

NO travels from postsynaptic neuron back to presynaptic neuronwhich activates guanylyl cyclase, the enzyme that catalyzes cGMP

production

This starts a cycle of nerve action potentials driven by NO


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Is Nitric Oxide a

neurotransmitter?

NO serves in the body as a neurotransmitter, but there

are definite differences between other neurotransmitters

used commonly in the body

NO is synthesized on demand vs. constant synthesis

NO diffuses out of the cells making it vs. storage in vesicles and release

by exocytosis

NO does not bind to surface receptors, but instead exits cytoplasm,

enters the target cell, and binds with intracellular guanylyl cyclase

Similarities to normal NTs Present in presynaptic terminal

Natural removal from synaptic junction


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Nitric Oxide in the Circulatory

System

NO serves as a vasodilator

Released in response to high blood flow rate and signaling

molecules (Ach and bradykinin)

Highly localized and effects are brief

If NO synthesis is inhibited, blood pressure skyrockets (Diagram of vasodilation mechanism after muscular system)

NO aids in gas exchange between hemoglobin and cells

Hemoglobin is a vasoconstrictor, Fe scavenges NO

NO is protected by cysteine group when O2 binds to hemoglobin

During O2 delivery, NO locally dilates blood vessels to aid in gas

exchange

Excess NO is picked up by HGB with CO2


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Nitric Oxide in the Muscular

System NO was orginally called EDRF (endothelium

derived relaxation factor)

NO signals inhibition of smooth muscle contraction

Ca+2 is released from the vascular lumen activating NOS

NO is synthesized from NOS III in vascular endothelialcells

This causes guanylyl cyclase to produce cGMP

A rise in cGMP causes Ca+2 pumps to be activated, thus

reducing Ca+2 concentration in the cell

This causes muscle relaxation


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Http://www.kumc.edu/research/medicine/biochemistry/bioc800/sig02-1


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Nitric Oxide in the Immune

System

NOS II catalyzes synthesis of NO used in host defense

reactions

Activation of NOS II is independent of Ca+2 in the cell

Synthesis of NO happens in most nucleated cells,particularly macrophages

NO is a potent inhibitor of viral replication

NO is a bactericidal agent

NO is created from the nitrates extracted from food near thegums

This kills bacteria in the mouth that may be harmful to the

body


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Nitric Oxide in the Digestive

System

NO is used in adaptive relaxation

NO promotes the stretching of the stomach inresponse to filling.

When the stomach gets full, stretch receptors

trigger smooth muscle relaxation through NO

releasing neurons


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New research ideas involving

Nitric Oxide

The role NO might play in neuronal

development

The mechanism of NO inhibiting the different

forms of NOS

Diazeniumdiolates as NO releasing drugs

Excessive NO release as the cause of most

brain damage after stroke


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Cond.

NO inhibitor of platelet activation

Alteration in formation of NO

Vasoconstriction, Platelet adhesion and Aggregation


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Contd

Isosorbide dinitrate

NITRIC OXIDE

Reduced Platelet deposition & Increased survival timein patients with peripheral vascular disease

Nit i O id d Di


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NO

HypertensionAtherosclerosis

Diabetes

NANCdysfunction

Inflammati

on

Coagulopathies

Organdysfunction

Vascularinjury

Ischemia

reperfusioninjury

Vasospasm

Microcirculatory

dysfunction

Neuronalfunction

Nitric Oxide and Diseases

++

+

+

+

+

+++

+

+

+


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Vascular actions of NO

Direct vasodilation (flow dependent and receptormediated)

Indirect vasodilation by inhibiting vasoconstrictor

influences (e.g., inhibits angiotensin

IIand sympathetic vasoconstriction) Anti-thrombotic effect - inhibits platelet adhesion to

the vascular endothelium

Anti-inflammatory effect - inhibits leukocyte

adhesion to vascular endothelium; scavengessuperoxide anion

Anti-proliferative effect - inhibits smooth muscle

hyperplasia

NO when its production is C
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NO, when its production is

impaired or its bioavailability is

reduced, the following can

result:

Vasoconstriction (e.g.,coronary vasospasm, elevated

systemic vascular resistance,

hypertension)

Thrombosis due to platelet

aggregation and adhesion tovascular endothelium

Inflammation due to

upregulation of leukocyte and

endothelial adhesion

molecules Vascular hypertrophy and

stenosis

Conditions Associated with

Abnormal NO Production

and Bioavailability

Hypertension

Obesity

Dyslipidemias (particularly

hypercholesterolemia and

hypertriglyceridemia)

Diabetes (both type I andII)

Heart failure

Atherosclerosis

Aging

Cigarette smoking


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NO, plays a variety of roles, which are at timescontradictory.

NO, has a dual complex action, at least dual, ontumor growth that may depend on the local

concentration of NO.

Additional factors such as the presence of ROS,and the type of tumor and its susceptibility to NO.

Nitric Oxide and Cancer

Source: (Jenkins et al., 1995) (Wink et al., 1998)


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Low NO concentration

Pro-angiogenic and protumor growth

Higher NO concentration Inhibit mitochondrial respiration, the citric acid cycle

glycolysis, and DNA replication. Locally high levels of

reactive oxygen species (ROS), insufficient oxygen supply

to the tumor tissue, may exacerbate these toxic effects by

generating even more reactive compounds, such asperoxynitrite (ONOO-). The latter compound arises from

the diffusion limited interaction of NO and O2 and is even

more reactive than NO.

Source: (Vamvakas and Schmidt, 1997 and Masuda et al., 2002)

Nitric Oxide


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Nitric Oxide


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Inhalation of 25 ppm of mixed nitrogenoxide, the recommended threshold

limit, may cause pulmonary irritation.

Higher doses of NO may cause

minimal irritation initially but result inhemorrhagic pulmonary edema

several days later.

Toxicology of NO


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Individuals exposed to nitrogen oxide

should be carefully monitored and receive

supportive care, including supplemental O2,

morphine and steroid therapy.

NO must be handled with extreme caution.

On contact with air NO interacts with O2,producing a dimeric form of nitrogen

dioxide, a reddish- brown gas (Archer.,

1993).Source: (Archer., 1993)

Nitric Oxide


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More about NO

Nitric oxide and hypertension (Leclercq et al., 2002) Nitric oxide and pulmonary system ( Persson et al.,1994)

Nitric oxide and the nervous system (Kuwana, 1998) Nitric oxide and gastrointestinal tract (Miller and

Sandoval, 1999) Nitric oxide in liver failure (Tomas et al., 1992) Nitric oxide levels in patients after trauma and during

sepsis (Tylor et al., 1997).

Nitric oxide as a cytostatic and cytotoxic agent(Moncada and Higgs, 1993).

Nitric oxide in immunity and inflammation (Hadas et al.,2002)

Nitric oxide and cancer. ..


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Arg NO

GTP cGMP

5) NO binds to Guanyly l c yclase

Relaxationof smooth muscle

NO

Smooth muscle cellblood vessel wall

4)NO diffuses

across membranes

2) AChbinds to receptorson endothelial cells

3)Activate NO syn thase

1)Stimulated nerve releases

Acety lchol ine(ACh) atNerve

terminal



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NO in Ischemic myocardium:

ACE inhibitor

Inhibition in degradation of Bradykinin

Accumulation of Bradykinin and NO

Prevent coronary Vasoconstriction

Increase in coronary blood flow

1.Stimulation of Bradykinin

Receptor

2. Inhibit Kininase II

Reduced Degdn. OfBradykinin


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Contd

Kitakaze et al.(2000) ACE I attenuate both reversible andirreversible myocardial cellular injury via bradykinin/ NO- dependent

manner

ACE I, enalaprilat, improves transmural myocardial perfusion at rest

and after stress and restore impaired sub endothelial coronary flow

and vasodilator reserve .

The effect of Enalaprilat is bradykinin and NO dependent.

ACE I increase Bradykinin and NO:

Potent cardio protection


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Role of NO inHypertension

In hypertension, morphological vascular alterationaffecting

Endothelium

Intima Vascular smooth muscle

Abnormalities of endothelial cells-- vascular resistanceincrease in Arterial Pressure.

Endothelium produce contracting substances: O 2-

Thromboxane A2

Endothelin-1(Peptide)

Endothelin-1: Potent vasoconstrictor


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Contd

Increase in endothelin plasma conc. observed in patients with

primary hypertension compared to normal.

Mitogenic activation described in hypertension is induced by :

Increase in sympathetic activity

Release of vasoactive agents such as endothelin,

Angiotensin II, PG

Basal formation of NO decreased in Hypertension.

Recently Das,U. N. (2004), the overall role of NO and O2 (superoxide anion ) in hypertension

Patient with hypertension have elevated conc. Of super oxideanion , H2O2 ,Lipid peroxides, endothelin, with simultaneousdecrease in eNO, SOD, Vit E and LCPUFAs.

Nitroglycerine was used for many years to treat

" i " ( h i ) d d d bl d fl


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"angina" (chest pain) due to reduced blood flow

in heart arteries without any knowledge of mechanism

Lumen diameter increasesand resistance to blood

flow decreases

Heart

("coronary")

artery

NO

N

O O

O

N

O O

O

N

O O

O

C C C

H H H H H H

N-ONitro

glycerine

We now know nitroglycerine does notact directly but is degraded to NO

NO


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Nitric oxide (NO) is a gaseous signaling

molecule that readily diffuses across cellmembranes and regulates a wide range of

physiologic and pathophysiologic processes

including cardiovascular, inflammation,

immune, and neuronal functions.

Nitric oxide should not be confused withnitrous oxide (N2O), an anesthetic gas.

DISCOVERY OF ENDOGENOUSLY GENERATED NITRIC


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DISCOVERY OF ENDOGENOUSLY GENERATED NITRIC

OXIDE

The first observations of the biologic role ofendogenously generated NO -in rodent macrophagesand neutrophils:

In vitro exposure of these cells to endotoxinlipopolysaccharide resulted in the accumulation ofsignificant amounts of nitrite and nitrate in the cellculture medium.

Furthermore, injection of endotoxin in animalselevated urinary nitrite and nitrate, the two oxidationproducts of NO.

The second observation was made by investigators in


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The second observation was made by investigators in1980 who found that the ability of acetylcholine toelicit relaxation of isolated strips of rabbit aorta was

entirely dependent on the presence of theendothelium.

If the endothelium was removed, the vessel stillexhibited normal relaxation responses to

nitroglycerin, but not to acetylcholine or carbachol. They discovered that following stimulation with

acetylcholine or carbachol, the endothelium releaseda short-lived molecule that resulted in relaxation and

dilation of surrounding vascular smooth muscle. The synthesis of this factor was not affected by

cyclooxygenase inhibitors, indicating that it wasdistinct from endothelium-derived prostacyclin..


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Synthesis


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Synthesis

NO, written as NO to indicate an unpaired electron in itschemical structure, or simply NO, is a highly reactive signaling

molecule that is made in a wide variety of cells, mostprominently neurons, skeletal muscle, endothelial cells, and

certain immune system cells.

In these cells, NO is synthesized by one or more of three

closely related NO synthase (NOS) isoenzymes, each of whichis encoded by a separate gene and named for the initial cell

type in which it was isolated

These enzymes, neuronal NOS (nNOS or NOS-1),

macrophage or inducible NOS (iNOS or NOS-2), andendothelial NOS (eNOS or NOS-3), despite their names, areeach expressed in a wide variety of cell types, often with anoverlapping distribution.


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These isoforms generate NO from the amino acid L-


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garginine in an O2- and NADPH-dependent reaction

This enzymatic reaction involves enzyme-bound

cofactors, including heme, tetrahydrobiopterin, andflavin adenine dinucleotide.

In the case of nNOS and eNOS, NO synthesis is evoked byagents and processes that increase cytosolic calcium

concentrations. Binding of calcium-calmodulin complexes to eNOS and

nNOS leads to enzyme activation.

On the other hand, iNOS is not regulated by calcium, but

is inducible. In macrophages and several other cell types,

inflammatory mediators induce the transcriptionalactivation of the iNOSgene, resulting in accumulation of

iNOS and generation of increased quantities of NO.

Nitric oxide generation from L-arginine and nitric oxide donors and the


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formation of cGMP.


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Signaling Mechanismsof NO


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NO mediates its effects by covalent modification of proteins.

There are three major effector targets of NO :

Metalloproteins

Thiols

Tyrosine Nitration

Metalloproteins NO interacts with metals, especially iron in heme.


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, p y

Soluble guanylyl cyclase (sGC), an enzyme that generatescyclic GMP from guanosine triphosphate (GTP), containsheme, which binds readily to NO.

NO binding to heme results in activation of sGC andelevation in intracellular cGMP levels.

cGMP activates protein kinase G (PKG), whichphosphorylates specific proteins.

Effects ,mediated :

Vasodilatory effects, which are largely mediated by NO-dependent elevations in cGMP and PKG activity.

Inhibitory effect on enzymes that contain iron-sulfurclusters such as the tricarboxylic acid cycle enzymeaconitase.

Inhibits mitochondrial respiration by inhibition ofcytochrome oxidase.

Inhibition of the heme-containing cytochrome P450enzymes - major pathogenic mechanism in inflammatoryliver disease.

Thiols

NO t ith thi l ( d t i i th SH )


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NO reacts with thiols (compounds containing the SH group)

to form nitrosothiols.

In proteins, the thiol moiety is found in amino acid cysteine.

Upon exposure to NO, certain proteins are found toaccumulate nitrosothiols, which can activate or inhibit the

activity of these proteins.

This posttranslational modification, termed S-nitrosylation,

is reversed by chemical reduction by intracellular reducingagents.

The formation of nitrosothiols is not mediated by directreaction of NO with thiols, but rather requires either metals

or oxygen to catalyze the formation of this adduct. NO undergoes both oxidative and reductive reactions,

resulting in the formation of a variety of oxides of nitrogen

that can nitrosylate thiols, nitrate tyrosines,are stable

oxidation products


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Glutathione a major intracellular sulfhydryl-


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Glutathione, a major intracellular sulfhydrylcontaining compound, also interacts with NOunder physiologic conditions to generate S-

nitrosoglutathione, a more stable form of NO.

Nitrosoglutathione may serve as an endogenouslong-lived adduct or carrier of NO.

Vascular glutathione is decreased in diabetesmellitus and atherosclerosis, and this mayaccount for the increased incidence of

cardiovascular complications in theseconditions.

Tyrosine Nitration

NO ffi i l i h id f i i


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NO reacts very efficiently with superoxide to form peroxynitrite(ONOO), a powerful oxidant that leads to DNA damage,irreversible nitration of tyrosine, and oxidation of cysteine todisulfides or to various oxides (SOX).

In several diseases, cellular degeneration, due to apoptoticmechanisms or due to ischemia, leads to excess superoxideproduction, and a consequent increase in peroxynitrite levels.

Numerous proteins have been found to contain nitrotyrosines, andthis modification can be associated with either activation or

inhibition of protein function. However, it is not yet clear whether tyrosine nitration has essential

roles in either physiologic signaling or in the pathology of anydisease.

Protein tyrosine nitration is also used as a marker for the presenceof oxidative and nitrosative stress.

Peroxynitrite-mediated protein modification is regulated by thecellular content of glutathione, which can protect against tissuedamage by scavenging peroxynitrite.

Factors that regulate the biosynthesis and decomposition ofglutathione may have important consequences on the toxicity of

NO.

Inactivation


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Inactivation

The lability of NO is related to its rapid reactionswith metals and reactive oxygen species.

Thus, NO reacts with heme and hemoproteins,including oxyhemoglobin, which catalyzes NOoxidation to nitrate.

NO reactions with hemoglobin may also result inpartial S-nitrosylation of hemoglobin, resultingin transport of NO throughout the vasculature.

NO is also inactivated by superoxide, and

scavengers of superoxide anion such assuperoxide dismutase may protect NO,enhancing its potency and prolonging itsduration of action.

NITRIC OXIDE IN DISEASE


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VASCULAR EFFECTS

Apart from being a vasodilator, NO protects against thrombosis andatherogenesis through several mechanisms

The antithrombotic effects of NO are also mediated by NO-dependent inhibitionof platelet aggregation. Both endothelial cells and platelets themselves contain

eNOS, which acts to regulate thrombus formation

Thus, endothelial dysfunction and the associated decrease in NO generation mayresult in abnormal platelet function. As in vascular smooth muscle, cGMP

mediates the effect of NO in platelets.

an additional inhibitory effect on blood coagulation by enhancing fibrinolysis viaan effect on plasminogen.

reduces endothelial adhesion of monocytes and leukocytes, key features of the

early development of atheromatous plaques.

may act as an antioxidant, blocking the oxidation of low-density lipoproteins andthus preventing or reducing the formation of foam cells in the vascular wall.

. Atherosclerosis risk factors, such as smoking, hyperlipidemia, diabetes, andhypertension, are associated with decreased endothelial NO production, and thusenhance atherogenesis.


SEPTIC SHOCK


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SEPTIC SHOCK

Increased urinary excretion of nitrate, the oxidative productof NO, is a feature of gram-negative bacterial infection.

Lipopolysaccharide components from the bacterial wallinduce synthesis of iNOS, resulting in exaggeratedhypotension, shock, and, in some cases, death.

This hypotension is reversed by NOS inhibitors such as L-NMMA (in humans as well as in animal models.

A similar reversal of hypotension is produced by compoundsthat prevent the action of NO (such as methylene blue), aswell as by scavengers of NO (such as hemoglobin).

However, thus far there has been no correlation between thehemodynamic effects of relatively nonselective NOS

inhibitors and survival rate in gram-negative sepsis. The absence of benefit may reflect the inability of the NOS

inhibitors to differentiate between NOS isoforms or mayreflect concurrent inhibition of beneficial aspects of iNOSsignaling.


INFLAMMATION


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NO is an important microbicide and may have important roles in tissue adapting

to inflammatory states.

However, overproduction of NO may exacerbate tissue injury in both acute and

chronic inflammatory conditions. NO generated during inflammation is involvedin the vasodilation associated with acute inflammation and can interact withsuperoxide to generate peroxynitrite and subsequently modify proteins, lipids,

and nucleotides.

In experimental models of acute inflammation, inhibitors of iNOS have a dose-dependent protective effect, suggesting that NO promotes edema and vascular

permeability.

NO has a detrimental effect in chronic models of arthritis; dietary L-argininesupplementation exacerbates arthritis, whereas protection is seen with iNOS

inhibitors.

Recent studies have shown that NO stimulates the synthesis of inflammatory

prostaglandins by activating cyclooxygenase isoenzyme II (COX-2). Thus,inhibition of the NO pathway may have a beneficial effect on inflammatorydiseases, including joint diseases.

NITRIC OXIDE IN DISEASETHE CENTRAL NERVOUS SYSTEM


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THE CENTRAL NERVOUS SYSTEM NO has been proposed to have a major role in the central

nervous systemas a neurotransmitter, as a modulator of

ligand-gated receptors, or both. NO synthesis is induced at postsynaptic sites in neurons

upon activation of the NMDA subtype of glutamatereceptor, which results in calcium influx and activation ofnNOS.

In several neuronal subtypes, eNOS is also present andactivated by neurotransmitter pathways that lead tocalcium influx.

NO synthesized postsynaptically may function as aretrograde messenger and diffuse to the presynaptic

terminal to enhance the efficiency of neurotransmitterrelease through a cGMP or S-nitrosylation-dependentmechanism.

It has been suggested that a major role for NO is in theregulation of synaptic plasticity, the molecular process

that underlies learning and behavior


THE PERIPHERAL NERVOUS SYSTEM


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THE PERIPHERAL NERVOUS SYSTEM

Nonadrenergic, noncholinergic (NANC) neurons are widelydistributed in peripheral tissues, especially the gastrointestinal andreproductive tracts

NO as a mediator of certain NANC actions, and some NANC neuronsappear to release NO.

Penile erection is thought to be caused by the release of NO fromNANC neurons; it is well documented that NO promotes relaxationof the smooth muscle in the corpora cavernosathe initiating factor

in penile erectionand inhibitors of NOS have been shown toprevent erection caused by pelvic nerve stimulation in the rat.

Thus, impotence is a possible clinical indication for the use of a NOdonor, and trials have been carried out with nitroglycerin ointmentand the nitroglycerin patch.

An established approach is to inhibit the breakdown of cGMP by thephosphodiesterase (PDE isoform 5) present in the smooth muscle ofthe corpora cavernosa with drugs such as sildenafil , tadanafil


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NITRIC OXIDE IN DISEASERESPIRATORY DISORDERS

NO has been shown to improve cardiopulmonaryfunction in adult patients with pulmonary arteryhypertension

It s administered by inhalation. It has also beenadministered by inhalation to newborns with

pulmonary hypertension and acute respiratorydistress syndrome.

NO may have an additional role in relaxing airwaysmooth muscle and thus acting as a bronchodilator.

For these reasons, NO inhalation therapy is beingwidely tested in both infants and adults with acuterespiratory distress syndrome. The adverse effects ofthis use of NO are being assessed.

PHARMACOLOGIC MANIPULATION OF


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NITRIC OXIDE

NITRIC OXIDE MODULATORS Inhibitors of Nitric Oxide Synthesis

Nitric Oxide Donors

Nitric oxide supplements


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Different Class of Nitric Oxide Donors


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SR Deshpandeet al, 2012

NITRIC OXIDE DONORS

NO donors which release NO or related NO species are
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NO donors, which release NO or related NO species, areused to elicit smooth muscle relaxation..

Organic Nitrates

Nitroglycerin,which dilates veins and coronary arteries, ismetabolized to NO by mitochondrial aldehyde reductase,an enzyme enriched in venous smooth muscle, accountingfor the potent venodilating activity of this molecule.

Other organic nitrates, such as isosorbide dinitrate aremetabolized to an NO-releasing species through acurrently unidentified enzyme.

Organic nitrates have less significant effects onaggregation of platelets, which appear to lack theenzymatic pathways necessary for rapid metabolicactivation.

Organic nitrates are limited by the loss of therapeuticeffect during continuous administration. This nitratetolerance may derive from NO-mediated inhibition ofmitochondrial aldehyde reductase.

Organic Nitrites


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g

Organic nitrites, such as the volatile

antianginal isoamylnitrite, also requiremetabolic activation to elicit vasorelaxation,

although the responsible enzyme has not

been identified.

Nitrites are arterial vasodilators and do notexhibit the rapid tolerance seen with nitrates.


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NO Gas InhalationNO itself can be sed therape ticall


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NO itself can be used therapeutically. Inhalation of NO results in reduced pulmonary artery

pressure and improved perfusion of ventilated areas ofthe lung.

Inhaled NO has been used for acute respiratorydistress syndrome, acute hypoxemia, andcardiopulmonary resuscitation with evidence for

short-term improvements in pulmonary function.Alternate Strategies Another mechanism to enhance the activity of NO is

to enhance the downstream NO signaling pathway.

Sildenafil, an inhibitor of type 5 phosphodiesterase,results in prolongation of the duration of NO-inducedcGMP elevations in a variety of tissues pulmonaryhypertension in dogs..?

Different strategies to achieve NO-donating anti-


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Different strategies to achieve NO donating anti

inflammatory drugs (CINOD)

Ennio Ongini and Manlio Bolla, 2006

NO donor drugs


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g NO gas is notoriously difficult to handle on account of the

problems associated with complete exclusion of oxygen to

prevent oxidation to nitrogen dioxide. Nevertheless, the gas itself can be used therapeutically,

particularly in pulmonary hypertension (Griffiths and Evans,

2005) and in neonates (Greenough, 2000), where it is delivered

to the lungs via inhalation.

.

ORGANIC NITRATES
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Most commonly used NO donor drugs.

Glyceryl trinitrate (GTN; also known as nitroglycerin;) is the

best-studied nitrate, used mainly in acute relief of painassociated with angina, whereas other slower release

preparations, such as isosorbide mononitrate (ISMN), are

used for the treatment of chronic angina.

GTN ointments are also routinely used for the treatment of anal

fissure (Fenton et al., 2006), transdermal patches in heartfailure and chronic angina, whereas nebulized GTN may have

benefits in certain subgroups with pulmonary hypertension

Sodium nitroprusside (SNP).

Used to provide rapid lowering of blood pressure in

hypertensive crises. Relatively stable and does not release NO spontaneously in the

physiological environment; instead, NO generation requires

either light or a tissue-specific mode of release
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The toxicity of by-products needs to be more fully confirmed

(Lam et al., 2003), especially as subsequent reactions

between decomposition products could lead to the formation

of carcinogenic nitrosamines (Maragos et al., 1991).

Incorporation of NONOates into polymers may represent a

means of preventing the leaching of by-products (Mowery et

al., 2000).

At present, conjugated NONOates hold a great deal of

promise, especially for the treatment of certain cancers,

although further characterization of these drugs is essential

before they reach larger clinical trials. The potential for oral

preparations of NONOates

S-nitrosothiols contain a single chemical bond between a thiol (sulphydryl) group
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g ( p y y ) g p

(R-SH) and the NO moiety.

Biological activity of S-nitrosothiols is highly influenced by the

molecular environment of the parent thiol. That said, the complex chemistry of NO release from even the

most basic S-nitrosothiol gives these compounds several means

by which they can confer NO bioactivity.

For instance, S-nitrosothiols are considered to be NO+donors (see

below) and transfer of NO+ across the plasma membrane viaprotein disulphide isomerases (Zai et al., 1999) may allow even

large molecule weight S-nitrosothiols to transfer oxides of nitrogen

across cell membranes to subcellular targets.

A vast number of factors are capable of releasing NO from S-

nitrosothiols, including light, heat, transition metals, thiols,superoxide (Williams, 1999; Al-Sa'doni and Ferro, 2000; Megson

and Webb, 2002). and enzymes such as xanthine oxidase

(Trujillo et al., 1998), superoxide dismutase (Jourd'heuil et al.,

1999), protein disulphide isomerase (Ramachandran et al., 2001)

and various dehydrogenases (Liu et al., 2001).

S Nitrosothiols
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S-Nitrosothiols

Potential advantages over other classes of NO donor.

Firstly, some examples show tissue selectivity: S-nitroso-

glutathione (GSNO; ) is selective for arteries over veins,

giving them a different haemodynamic profile of action than

those of classical organic nitrates.

Additionally, S-nitrosothiols are potent antiplatelet agents,inhibiting aggregation at doses that do not influence vascular

tone (de Belder et al., 1994; Ramsay et al., 1995).

Furthermore, the ability of S-nitrosothiols to directly transfer

NO+ species allows biological activity to be passed on

through a chain of other thiols without the release of free NO. This mechanism of bioactivation may make S-nitrosothiols

less susceptible to conditions of oxidative stress by effectively

protecting the NO moiety from attack by oxygen-centred free

radicals.

GSNO has at least the potential to concurrently boost

NO hybrid drugs (Hybrid NO donor drugs)
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y g ( y g )

Represent a novel approach to the design of NO-releasing

compounds.

Structurally modified to incorporate NO-containing molecules.

The aim of this strategy is to synthesize drugs that retain the

pharmacological activity of the parent compound, but also

have the biological actions of NO. Importantly, the release of NO must be balanced to provide

sufficient activity within the concentration range of the parent

compound (Bandarage et al., 2000

NO-NSAIDs
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Low-dose aspirin is also routinely used prophylactically to

reduce the risk of thrombotic events associated with a wide

range of cardiovascular conditions. However, prolonged use ofaspirin leads to serious side effects in the gastrointestinal tract

that have been reported to cause 16 000 deaths each year in

the USA (Keeble and Moore, 2002).

A further increase in the risk of upper gastrointestinal bleeding

attributed to the co-administration of multiple antithrombotictherapies regularly prescribed for cardiovascular conditions

(Hallas et al., 2006).

NO has a number of effects in the gastrointestinal tract that

could counteract the loss of protective prostanoids caused by

aspirin. NO increases secretion of protective gastric mucus(Brown et al., 1993), increases blood flow to the gastric

mucosa, promoting repair and removal of toxins (Hallas et al.,

2006), decreases interaction of neutrophils with the gastric

microcirculation (Wallace, 1997) and may also promote the

healing of gastric ulcers (Ma and Wallace, 2000). Therefore,
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The first NO-NSAID compounds designed and releasedcommercially were the NicOx compounds, NCX4016 and

NCX4215.

Both are derivatives of aspirin (often referred to as

nitroaspirins')adapted to contain a nitrate group.

These compounds have been shown to retain the ability ofaspirin to inhibit inflammation and nociception without causing

gastric ulcers seen with equivalent concentrations of aspirin

(del Soldato et al., 1999; Fiorucci et al., 2003; Turnbull et al.,

2006b).

Also, several studies have shown that these compounds havecomparable or greater antiplatelet effects than the parent

NSAID, without causing excessive vasodilatation or

hypotension (Lechi et al., 1996; del Soldato et al.,

1999;Wallace et al., 1999a; Momi et al., 2000).

Emerging novel NO-NSAID compounds.
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In the past 5 years, there has been considerable investigation

into the mechanism that underpins the anti-inflammatory

properties of NO generated from nitroaspirins (Keeble and

Moore, 2002). Caspases are a family of proteases involved in

cytokine release and apoptosis.

NO from NCX4016 inhibits the action of capsase-1, and,

subsequently, the propagation of other cytokines such as IL-

1and IL-8 (Fiorucci et al., 2000).

NCX4016 induced inhibition of capsase-1 is mediated

through S-nitrosylation of a sulphydryl group (Dimmeler et al.,

1997), therefore, other NO-NSAIDs, such as S-nitroso-

diclofenac (see Figure 6a) may be more effective inhibitors of

capsase-1 through transnitrosation reactions.

Nitroaspirins also inhibit the release of TNF- from

lipopolysaccharide-stimulated macrophages (Minuz et al.,

2001), although it is difficult to determine whether this is a

direct effect of NO or throu h inhibition of other c tokines.
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NO-NSAIDs have attractive properties in a number of

cardiovascular conditions.

On top of the antiplatelet actions of NO-NSAIDs, the NO-

mediated anti-inflammatory properties would be useful in

vascular injury and atherosclerosis, given the central role of

inflammatory cells in the process (Ross, 1999).

NCX4016, but not aspirin, has been shown to reduce

experimental restenosis in hypercholesterolemic (Napoli et

al., 2001) and aged (Napoli et al., 2002) mice.

NCX4016 also reduces infarct size in several different models

of myocardial ischaemia-reperfusion injury (Rossoni et al.,2000,2001; Wainwright et al., 2002; Burke et al., 2006) and

has been shown to reduce plateletmonocyte interaction in

humans to a greater extent than aspirin alone (Fiorucci et al.,

2004).

Nitroaspirins
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Nitroaspirins

also show potential in cancer therapy. Upregulation of

cyclooxygenase-2 leading to enhanced prostaglandin output

is a feature of a number of cancers (Baron, 1995). Both the

gastro-sparing properties of nitroaspirins and the direct effect

of NO on cell proliferation could be beneficial, although

obtaining suitable balance between the different facets of a

nitroaspirin might prove difficult. That said, NCX4016 havebeen shown to be 2506000-fold more effective at inhibiting

the growth of a number of different cancer cell lines (Kashfi

and Rigas, 2005). Additionally, the compound also reduced

tumour growth in an in vivo rat model of colonic

adenocarcinoma to a greater extent than aspirin itself (Bak etal., 1998). Aside from cancer, NO-NSAIDs may have

applications in other areas of the body (Keeble and Moore,

2002). A NO-releasing derivative of flurbiprofen has been

shown to have beneficial actions in models of renal ablation

(Fujihara et al., 1998), bone degeneration (Armour et al.,'
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Given the tolerance issues associated with organic nitrates, it

is surprising that the majority of nitroaspirins investigated so

far exploit the same NO donor moiety, especially as it has

been shown for at least one example that the mechanism of

NO release is the same in hybrid drugs (Turnbull et al.,

2006a).

Many new NSAIDs/anti-inflammatory/analgesic agents with

nitrates groups

Paracetamol (Marshall et al., 2006), flurbiprofen (Fujihara et

al., 1998), naproxen (Young et al., 2005), mesalamine

(Wallace et al., 1999b), gabapentin (Wu et al., 2004),

predisolone and other steroids (Tallet et al., 2002). However,

the nitrate ester of nitroaspirin has been replaced with a

furoxan moiety (Cena et al., 2003; Turnbull et al., 2006a)

and S-nitroso- (Bandarage et al., 2000) and diazeniumdiolate

(Velazquez et al., 2005) forms of other NSAID drugs (e.g.

aspirin, diclofenac, indomethacin and ibuprofen) have also
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