Exercise and the Nitric Oxide Vasodilator System

Sports Med 2003; 33 (14): 1013-1035LEADING ARTICLE 0112-1642/03/0014-1013/$30.00/0

Adis Data Information BV 2003. All rights reserved.

Exercise and the Nitric OxideVasodilator SystemAndrew Maiorana,1,2,3 Gerard O’Driscoll,3,4 Roger Taylor2,4 and Daniel Green1,3,4

1 Department of Human Movement and Exercise Science, The University of Western Australia,Crawley, Western Australia, Australia

2 Department of Medicine, The University of Western Australia, Crawley, WesternAustralia, Australia

3 Cardiac Transplant Unit, Royal Perth Hospital and West Australian Heart Research Institute,Perth, Western Australia, Australia

4 Department of Cardiology, Royal Perth Hospital and West Australian Heart ResearchInstitute, Perth, Western Australia, Australia

In the past two decades, normal endothelial function has been identified asAbstractintegral to vascular health. The endothelium produces numerous vasodilator andvasoconstrictor compounds that regulate vascular tone; the vasodilator, nitricoxide (NO), has additional antiatherogenic properties, is probably the mostimportant and best characterised mediator, and its intrinsic vasodilator function iscommonly used as a surrogate index of endothelial function. Many conditions,including atherosclerosis, diabetes mellitus and even vascular risk factors, areassociated with endothelial dysfunction, which, in turn, correlates with cardio-vascular mortality. Furthermore, clinical benefit and improved endothelial func-tion tend to be associated in response to interventions.

Shear stress on endothelial cells is a potent stimulus for NO production.Although the role of endothelium-derived NO in acute exercise has not been fullyresolved, exercise training involving repetitive bouts of exercise over weeks ormonths up-regulates endothelial NO bioactivity. Animal studies have foundimproved endothelium-dependent vasodilation after as few as 7 days of exercise.Consequent changes in vasodilator function appear to persist for several weeks butmay regress with long-term training, perhaps reflecting progression to structuraladaptation which may, however, have been partly endothelium-dependent. Theincrease in blood flow, and change in haemodynamics that occur during acuteexercise may, therefore, provide a stimulus for both acute and chronic changes invascular function. Substantial differences within species and within the vascula-ture appear to exist. In humans, exercise training improves endotheli-um-dependent vasodilator function, not only as a localised phenomenon in theactive muscle group, but also as a systemic response when a relatively large massof muscle is activated regularly during an exercise training programme. Individu-als with initially impaired endothelial function at baseline appear to be moreresponsive to exercise training than healthy individuals; that is, it is more difficultto improve already normal vascular function. While improvement is reflected inincreased NO bioactivity, the detail of mechanisms, for example the relative

1014 Maiorana et al.

importance of up-regulation of mediators and antioxidant effects, is unclear.Optimum training schedules, possible sequential changes and the duration ofbenefit under various conditions also remain largely unresolved.

In summary, epidemiological evidence strongly suggests that regular exerciseconfers beneficial effects on cardiovascular health. Shear stress-mediatedimprovement in endothelial function provides one plausible explanation for thecardioprotective benefits of exercise training.

Repeated physical activity induces physiological This review will briefly consider the importanceadaptations to the cardiovascular system that im- of the endothelium in the maintenance of normalprove physical fitness and reduce primary[1-3] and vascular function, identify conditions associatedsecondary cardiovascular events.[4] The mechanisms with impaired endothelial function, and discuss theinvolved are multifactorial and probably include effect of exercise training on endothelium-depen-modification of established risk factors, such as dent vasodilator capacity in healthy individuals,improved weight control,[5] blood lipid profile[6,7] those with risk factors for cardiovascular diseaseand glucose tolerance,[8] and blood pressure.[9,10] and those with overt manifestations of cardio-Furthermore, the positive effects of regular exercise vascular disease.on autonomic tone,[11] blood coagulation[12] and in-flammation[13] are likely to contribute to improved 1. How Does the Vascular Endotheliumvascular health. Influence Vasodilator Function?

A growing body of research has identified thevascular endothelium as another therapeutic target

The vascular endothelium produces an array offor cardiovascular risk reduction. Strategically lo-molecules that influence vascular tone, blood flow,cated at the interface of the circulating blood and theviscosity and cell wall interactions. Some of these,vascular wall, the endothelium is ideally positionedincluding prostacyclin,[17] putative endothelium-de-to respond to changes in haemodynamics and torived hyperpolarising factor,[18] bradykinin[19] andmaintain circulatory homeostasis. Originally con-nitric oxide (NO)[20] possess vasodilator propertiessidered a passive layer of inert cells, the endotheli-while others, such as angiotensin II[21] and endothe-um is now regarded as an important endocrine organlin,[22] are vasoconstrictor agents.capable of producing and responding to an array of

Of the vasoactive agents produced by the endo-chemical and physical stimuli. Normal endothelialthelium, NO has been the most comprehensivelyfunction is not only critical to regulating vascularstudied and is the focus of this review. An endotheli-tone but also to mediating antiatherogenic propertiesum-derived relaxing factor was first identified in aincluding inhibition of cell growth and prolifera-landmark study by Furchgott and Zawadski[23] whotion,[14] reduced leucocyte and platelet adhesion toestablished that the vasodilator effect of acetylcho-the vessel wall[15] and antithrombotic and fibrinolyt-line (ACh) was only evident in blood vessels with anic properties.[16] The loss of these protective attrib-intact endothelial lining. The compound was subse-utes due to endothelial dysfunction may be an inte-quently established to be NO, synthesised in endo-gral part of, and may contribute to, the pathophysio-thelial cells from the amino-acid L-arginine throughlogy of atherosclerosis. This link betweenthe action of endothelial nitric oxide synthaseendothelial dysfunction and clinical vascular disease(eNOS).[24] NO is lipid soluble and rapidly diffuseshighlights the therapeutic potential of interventionsinto the vascular smooth muscle of the tunica mediathat improve endothelial function and provides awhere it binds to the enzyme guanylate cyclase.[25]plausible explanation for a reduction in coronaryThe resulting increase in cyclic guanosine mono-events associated with these interventions.

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Exercise Training and Endothelial Function 1015

phosphate induces smooth muscle relaxation and such as the brachial or femoral artery, a responsealmost exclusively mediated by NO[42] can be in-vascular dilation.[26]

duced by the increased flow associated with theNO importantly influences basal vasomotor tonetransient hyperaemia following a period of ischae-in the coronary and peripheral circulation.[27-30] Themia, known as flow-mediated dilation (FMD). Totone of the vasculature is determined by the balanceinvestigate the vascular smooth muscle componentbetween dilator and constrictor influences. At rest,of the NO-dilator pathway, the responses to endo-low levels of NO are continuously released. Inthelium-independent vasodilators, such as sodiumhumans, this phenomenon was initially identified bynitroprusside (SNP) or glyceryl trinitrate (GTN),Vallance et al. who infused the arginine analoguewhich release NO to act directly on the smoothNG-monomethyl-L-arginine (L-NMMA) into themuscle, are determined. Evaluating the responses toforearm vascular bed to inhibit eNOS and the syn-endothelium-dependent and -independent vasodila-thesis of NO, resulting in vasoconstriction.[27] NOtors provides information about the contribution tobioactivity can be stimulated by pharmacologicalblood-flow control of different components of theand physiological stimuli. During exercise, for ex-NO-dilator system.ample, shear stress is imparted to the vascular wall.

The endothelium acts as a mechanotransducer[31,32]

2. Endothelial Dysfunctionand increases vasodilator mechanisms, tending tonormalise the high shear stress. Although the signal-

NO-related endothelial dysfunction is foundling cascade linking mechanical stimulation to the

under diverse conditions and, while it is usuallyrelease of vasoactive molecules has not been fully

apparent in both conduit and resistance vessels andclarified, a number of mechanisms have been pro- in various vascular beds, differential effects on theposed. Endothelial potassium channel activation by many vascular beds might occur under specific con-flow,[33] possibly as a result of shear stress-mediated ditions, for example, within the coronary circula-deformation of cytoskeletal elements,[34] may lead to tion.[43-45] The mechanisms proposed to explain de-release of NO, as found in rabbit iliac arteries.[35]

pressed NO activity include a loss of endothelialOther investigators have identified that flow in- synthesis of NO and a reduction in NO bioavailabil-creases calcium influx in endothelial cells,[36-38] an ity due to quenching by superoxide anions asso-effect that is necessary for the synthesis and release ciated with an abnormal redox state.[46-48] However,of NO. Flow may also induce the release of brady- the mechanisms are not well defined and probablykinin from endothelial cells[39] and, in turn, stimulate depend upon the cause.bradykinin receptors on the endothelial cell to in- Several lines of evidence suggest that endothelialcrease NO bioactivity.[40] More recently, shear stress dysfunction, along with depressed NO bioactivity, ishas been shown to induce phosphorylation of a an important and integral component of ather-serine residue, altering eNOS sensitivity to intracell- ogenesis although the exact relationship is debated.ular calcium levels resulting in increased NO pro- Endothelial dysfunction occurs initially at coronaryduction.[41]

branch points,[49] as do atherosclerotic plaques. TheIn humans, NO bioactivity is used as a practical endothelium loses its protective effect on the vascu-

surrogate for endothelial function while, obviously, lar system, which is likely to facilitate the develop-it does not constitute a comprehensive evaluation. ment and progression of atherosclerosis. However,Inhibitors of eNOS are used to examine ambient NO endothelial dysfunction seems reversible to somebioactivity while endothelium-dependent vasodila- extent and numerous interventions that improvetors, such as ACh, are used to stimulate the release cardiovascular risk factors and reduce cardio-of NO from endothelial cells with resultant vasodila- vascular morbidity and mortality also enhance endo-tion. These drugs are commonly used to assess the thelial function,[50-56] further emphasising the poten-responses of resistance vessels. In conduit vessels, tial role of endothelial function in atherosclerosis.



2.1 Endothelial Dysfunction and Risk Factors control alone;[78] enhanced endothelial function isfor Atherosclerosis likely to be a major influence,[79,80] perhaps through

reduced superoxide production and NO quench-Impaired responses to endothelium-dependent ing.[48]

stimuli have been reported in individuals without2.1.5 Obesityobvious atherosclerosis but with conventionalEndothelial dysfunction in the obese may con-cardiovascular risk factors,[57] related to the number

tribute to the increased risk of cardiovascular dis-of risk factors present.[58]

ease in these individuals.[81] It may be particularly2.1.1 Aging associated with central obesity and insulin resis-Aging has been highlighted as a significant pre- tance[81-83] and has been found in the coronary circu-

dictor of impaired endothelial function,[59,60] func- lation, in addition to the systemic circulation intion declining with age.[61] Dysfunction has been individuals with normal or only mildly diseasedidentified as early as 30 years.[62]

arteries.[84]

2.1.2 Smoking 2.1.6 Diabetes MellitusCigarette smoking is a major risk factor for ath- Mortality from diabetes is largely attributable to

erosclerosis. Endothelial dysfunction has been iden- atherosclerotic macrovascular complications, whiletified in systemic vessels[50,63] and variably in coro- microvascular dysfunction and consequent reti-nary vessels[58,64] of smokers. It has even been re- nopathy, neuropathy and nephropathy contributeported in young smokers, dependent upon the significantly to morbidity.[85,86] Short of these obvi-amount smoked,[50] and also associated with passive ous complications, recent evidence suggests thatsmoking.[63] It may be at least partially reversible insulin resistance is inextricably linked to endotheli-when smoking is ceased.[50]

al dysfunction, endothelial dysfunction contributingto insulin resistance and vice versa.[86] Impaired2.1.3 Hypercholesterolaemiaendothelial function has been identified in type 2In hypercholesterolaemia, endothelial dysfunc-diabetes,[55,87-91] although not in all studies;[92] diabe-tion has been identified in both the coronary[58,65]

tic control was better in the latter study. In type 1and peripheral circulations,[66-68] and can appear indiabetes, while one study suggested that the abnor-childhood.[69] The mechanism responsible shouldmality in vasodilator function may lie within theaccommodate the fact that NO-related endothelialsmooth muscle,[93] most have implicated endothelialfunction is responsive to acute elevation[70] or reduc-rather than smooth muscle dysfunction.[94-96]

tion[71] of plasma cholesterol. NO inactivation bysuperoxide production may be partially responsi-

2.2 Endothelial Dysfunction in Establishedble.[46]

Cardiovascular Disease2.1.4 Hypertension

2.2.1 Coronary Artery Disease (CAD)Abnormal endothelial function has also been im-plicated in the pathophysiology of hypertension. It In patients with advanced coronary stenosis, in-has been identified in several peripheral vascular tracoronary ACh causes constriction rather than thebeds[72,73] and the coronary circulation,[74-76] and vasodilation of angiographically normal vessels,more recently reported to be an independent marker while arteries of individuals with early atherosclero-for future cardiovascular morbidity in hypertensive sis demonstrate a heterogenous response.[97] Fur-individuals.[77] The nexus between hypertension and thermore, endothelial dysfunction in systemic ves-endothelial dysfunction is unclear. For example, sels correlates with the extent ofobstructive corona-improved cardiovascular outcomes as a result of ry artery disease (CAD) and with coronaryangiotensin-converting enzyme-inhibitor therapy endothelial dysfunction[98,99] reflecting the general-seem greater than expected from blood pressure ised nature of endothelial dysfunction. However,



there can be regional differences within a vascular skeletal muscle creates a ‘muscle-pump’, whichbed; basal NO function was impaired in large epi- causes an immediate increase in blood flow to thecardial arteries but normal in small epicardial and working muscle.[118] As muscle activity continues,resistance vessels,[45] suggesting that the proximal metabolites with vasoactive properties are releasedsegment is not only more prone to atherosclerosis from the muscle into the interstitial fluid and actbut also to endothelial dysfunction. Additionally, directly on terminal arterioles. Substances proposedpatients who have experienced recent cardiac events to be involved in this ‘metabolic’ vasodilation in-have worse endothelial dysfunction than clinically clude potassium ions,[119] metabolites such as adeno-stable patients.[43,44] sine,[120] and, more recently, NO released from the

Clinical outcomes in patients submitted to coro- active muscle.[121] Furthermore, NO transported vianary angiography have been related to coronary the blood bound to haemoglobin,[122,123] and acetyl-endothelial dysfunction by several authors.[100-102] choline spill-over from motor neurones[124] may in-Brachial endothelial dysfunction has also been duce vasodilation of the terminal arterioles.found to predict future cardiac events in patients Blood-flow changes due to metabolic vasodila-with chest pain,[103] and short-term events in high-

tion alone are insufficient to account for the dramat-risk patients undergoing surgery for vascular dis-

ic increases that occur during exercise.[125] There-ease.[104]

fore, it is clear that a coordinated dilation of small2.2.2 Chronic Heart Failure and large vessels must occur as metabolic demandWhile a decrease in cardiac function initiates increases. The structure of the arterial network facil-

chronic heart failure (CHF), functional capacity is itates such a response to increased local blood flowpoorly correlated with central haemodynamics[105] because terminal arterioles arise, in series, fromand is closely associated with abnormalities of the progressively larger vessels. The principle of ‘as-peripheral circulation, including impaired vasodila- cending vasodilation’ has been proposed to explaintor response.[106] Furthermore, systemic vaso- the phenomenon of vasodilation which begins in theconstriction increases left ventricular impedance microvessels and is then transmitted proximally toand ultimately leads to further deterioration in left larger feed arteries.[125,126] One explanation for as-ventricular function.[107,108] Endothelial dysfunction cending vasodilation proposes that, following thehas been found in the coronary circulation[109] and in onset of exercise, terminal vessels bathed in intersti-peripheral resistance,[110-112] and conduit[113] vessels tial fluid and in contact with by-products of meta-in individuals with CHF of various aetiologies. bolism dilate, increasing blood-flow velocityBlood-flow responses to GTN, that is, endothelium- through the upstream feed arteries.[127] This increaseindependent NO-related responses, have also been in flow increases shear stress on the endotheli-reported to be impaired perhaps reflecting more um,[128] stimulating NO bioactivity and inducingsevere vascular abnormalities and advanced feed artery vasodilation. This hypothetical paradigmCHF.[114,115]

explains the observed magnitude of exercise hyper-aemia by linking downstream metabolic dilation

3. Endothelium-Derived Nitric Oxidewith dilution of upstream vessels that are not in(NO) and Exercise Hyperaemiacontact with the by-products of metabolism, butwhich respond to changes in localised haemodyna-Exercise training involves recurrent exposure tomics. Certainly, what is now commonly nameddramatic changes in cardiovascular haemodynamicsFMD, a dilator response of conduit arteries in res-that occur with bouts of physical activity. In res-ponse to muscle ischaemia, is predominantly depen-ponse to acute exercise, numerous phenomena inter-dent upon an increase in NO bioactivity in theseact to increase blood flow to active muscles as muchlarger arteries.[42] However, the coordinated dilationas 50- to 100-fold.[116,117] At the onset of exercise,of large and small vessels can occur independentlythe mechanical action of contracting and relaxing



of changes in endothelial wall shear stress and NO bition could be explained by changes in restingproduction,[129,130] suggesting that redundant mech- flow.[141] However, both of these studies measuredanisms may be involved. blood flow after the cessation of muscular contrac-

tion and blood flow during recovery may be under3.1 Animal Studies different control to that during exercise.[142]

The role of NO may increase with the duration ofA comprehensive account of blood-flow controlexercise. While it is unlikely that NO plays a majorduring acute exercise in animals is provided in anrole in the dilator response to a single muscle con-excellent review by Delp and Laughlin.[131] Animaltraction,[143] it may be important during prolongedstudies offer equivocal support for a major role ofexercise. L-NMMA infusion during intermittentNO in exercise-induced local hyperaemia. NO regu-forearm hand-gripping at 15%, 30% and 45% oflated regional flow in dogs[132] and rats[133] while, inmaximum grip strength induced a small, but signif-the coronary circulation of dogs, endothelial denu-icant, reduction in exercise-induced vasodila-dation caused the normal epicardial artery vasodila-tion.[144] Importantly, the greatest effect of L-NM-tion during exercise to be replaced by constriction.MA was evident at the highest infusion rate of theRestoration of normal epicardial vasodilation corre-drug, indicating that the dose of an antagonist maylated with normalisation of the response to ACh andbe critical during an exercise study, when increasedto reactive hyperaemia.[134] However, NO inhibitionblood flow effectively dilutes a constant dose deliv-did not alter the hind-limb skeletal muscle microcir-ery. Indeed, Katz et al. indicated that the effect of L-culation responses of rabbits[135] or arterial dilationNMMA decreased with increasing intensity of exer-in response to metabolic stimulation of hamstercise.[106] In another study, L-NMMA infusion atten-skeletal muscle.[136]

uated the blood-flow response to prolonged forearmIn summary, the majority of animal studies sug-hand-gripping by 20–30%.[145] Furthermore, Duffygest a role for NO in exercise-induced vasodila-et al. recently confirmed a role for both NO andtion,[137] but it is likely that interspecies differencesvasodilator prostanoids in mediating hyperaemia inexist and human studies are important.response to forearm handgrip exercise.[29,146] How-ever, sequential inhibition of these two vasodilators3.2 Human Studieshad no additional effect on reducing blood flow overand above that induced by inhibition of one, high-3.2.1 Skeletal Musclelighting the possibility that redundant mechanismsIndirect evidence for a role of NO in exercisemay contribute to blood-flow control during contin-hyperaemia in humans is provided by the increaseduous exercise.levels of plasma nitrite[138] and urinary nitrate[139] in

In the lower limbs, Hickner et al.,[147] usingresponse to prolonged aerobic exercise; however,microdialysis probes, measured a reduction in bloodthese measures do not reliably reflect endothelium-flow of 50% following the infusion of L-NMMAderived NO. Therefore, despite technical difficultiesduring continuous dynamic exercise of the vastusassociated with measuring blood flow during exer-lateralis. However, this technique requires furthercise, a number of investigators have attempted tovalidation and these results have not been supporteddetermine NO involvement in the hyperaemic res-by other studies of lower limb exercise. L-NMMAponse to exercise in the peripheral circulation. In anhad no effect on blood flow measured using Dopplerearly study, flow was measured during periods ofultrasound during steady-state submaximal or peakinactivity immediately following two intensities ofvoluntary knee extension exercise.[148] Similarly,wrist flexor exercise and concurrent infusion of L-when blood flow to the lower limbs was determinedNMMA had no significant effect on blood flow.[140]

using femoral thermodilution, L-NMMA did notFurthermore, a small reduction in exercise hyperae-reduce blood flow during supine cycling, despitemia during static hand-gripping following NO inhi-



decreasing glucose flux across the limb.[149] Leg during muscular contraction but have indicated aneffect at rest and during recovery.exercise is associated with a high perfusion-to-

Contrary to this essentially negative conclusionmuscle mass ratio, and flow may be increased overfor an additional role of NO during exercise in the10-fold. Possibly, this hyperaemia dilutes L-NMMAactive muscle bed, a recent study examined brachialconcentration to an inadequate blocking level. Usingartery blood flow during lower limb exercise,[153]systemic intravenous infusion of NG-nitro-L-argi-and found that brachial artery infusion of L-NMMAnine methyl ester (L-NAME), a potent inhibitor ofdecreased forearm blood flow during cycling at 60,NO production, leg blood flow during submaximal100, and 160W, compared with the resting state.leg extensor exercise was not reduced, leading theThis finding suggests that systemic production ofauthors to conclude that NO is not essential toNO increases during exercise, even in vascular bedsexercise hyperaemia. However, this interpretationfeeding metabolically inactive tissue. A subsequentmay be considered controversial, since mean arterialstudy found that changes in heart rate alone in thepressure increased and vascular conductance wasabsence of exercise were not associated with this

lower during L-NAME infusion. Furthermore, anphenomenon and, hence, it may be due to pulse

increase in arterial pressure is likely to reduce sym- pressure dynamics stimulating the endotheliumpathetic outflow during exercise,[150] and this may throughout the circulation during exercise.[154]

mask a potential blood-flow reduction due to eNOSinhibition.[151]

3.2.2 Cardiac MuscleIn summary, of the above results in the peripheral Experimentally, an increase in cardiac metabol-

ism is commonly achieved by increasing ventricularcirculation, the evidence for a role of NO in therate using cardiac pacing. Indirect evidence for ahyperaemic response to prolonged exercise in therole of NO in metabolic vasodilation comes from aforearms, having a relatively small muscle mass, isstudy showing an increase in by-products of NO inreasonably convincing. Because the increased bloodcoronary sinus blood following pacing in individu-flow in these studies was modest (3–6 times restingals without CAD risk factors.[155] No increase waslevels), the dilution of constant dose infusion of L-evident in individuals with CAD risk factors butNMMA would be less than with leg exercise. Evi-coronary sinus adenosine was elevated,[155] raisingdence is less compelling from studies involving thethe possibility that adenosine production may be alower limbs, only one out of four published studiescompensatory mechanism maintaining myocardialbeing positive. While this disparity may reflect re-blood flow in the presence of endothelial dysfunc-gional differences between vascular beds, it maytion. L-NMMA abolished pacing-induced epicardial

depend upon greater dilution of L-NMMA duringvessel dilation, indicating that NO contributes to

leg exercise. Further carefully designed studies will vasodilation in these conduit vessels in patients freebe required to clarify this issue. There is also evi- of CAD risk factors[156] and in those with angi-dence that redundancy of mechanisms of vasodila- ographically normal coronary arteries.[157] In an-tion exist so that inhibition of one pathway may other study, L-NMMA reduced pacing-induced dila-result in up-regulation of another. A final problem tion of large epicardial arteries, but not of microves-concerns blood-flow measurement techniques. For sels.[158] However, there have been negative studiesexample, as summarised by Radegran and Saltin,[152]

in those with angiographically normal arteries, per-studies indicating an effect of L-NMMA have most- haps related to the shortcomings of angiogra-ly been undertaken using plethysmography, necessi- phy.[45,159] In yet another study, NO was involved intating measurement of flow during brief rest periods pacing-induced hyperaemia in patients with risk fac-between contractions or exercise bouts. Flows mea- tors for CAD, including some with mildly irregularsured using ultrasound/Doppler actually during ex- arteries[29] despite risk factors leading to a reductionercise have, to date, not supported much role for NO in vasodilation,[156] and an impaired response to



stimulated NO release.[160] In patients with CAD days of endurance training in pigs.[167] Similarly, 4disease, NO production increased by pacing was weeks of training enhanced ACh-induced vasodila-abolished at the sites of stenoses.[157] tion of the rat aorta and increased eNOS protein

In summary, there is strong evidence for a role of levels in aortic tissue.[168,169] In rabbits, 8 weeks ofendothelium-derived NO in the metabolic vasodila- treadmill running increased ACh reactivity in thetion of healthy coronary epicardial vessels, but NO- aorta and pulmonary arteries but not in the carotiddependent vasodilation decreases in the presence of artery, a vessel which is partly protected from dra-risk factors and is absent or much reduced in grossly matic changes in flow and shear stress.[170]

atherosclerotic vessels. In contrast to short to moderate periods of exer-cise training, studies over a longer duration have not4. Does Exercise Training Improveconsistently shown improvement in NO-related en-Endothelial Function?dothelial function. NO-dependent vasodilation wasunaltered after 16–20 weeks of training in pigs,[171]If the endothelium is activated during exercise, itand 16 weeks in rats despite improved arterial com-can be postulated that repetitive exposure to haemo-pliance.[172] This seems to indicate that improvementdynamic and shear stress changes may result in anin endothelium-dependent vasodilator responses inadaptation that up-regulates the NO dilator system.the periphery may be a transient phenomenon that isRegular exercise training is associated with in-lost with long-term training. Altered expression ofcreased vasodilator capacity[161,162] and longitudinaleNOS has been implicated in this time dependence.studies provide convincing evidence for theDaily exercise for 1 week resulted in an increasedantiatherogenic effect of regular physical ac-expression of eNOS protein in porcine pulmonarytivity.[2,3,163] These phenomena may be due, in part,arteries and enhanced ACh-mediated relaxation,[173]to up-regulation of endothelial function.changes not present after 16 weeks of exercise train-

4.1 Exercise Training and NO Function in ing.[174] In various animal models, prolonged exer-Healthy Animals cise training enlarges the diameter of arteries;[175-178]

this vascular remodelling appears to be an endotheli-In peripheral vessels, short-term exercise trainingum and partly NO-dependent phenomenon,[179-184]

in rats, of 2–4 weeks, increased endothelial NObut one which partly supplants the acutely respon-synthesis in skeletal muscle arterioles and increasedsive vasodilator mechanisms.the vasodilator responses to ACh and L-arginine,

In the coronary circulation, early studies reportedbut not to SNP, suggesting enhanced endothelium-exercise training to increase sensitivity to vasodila-dependent function but unchanged smooth muscletor agents in dogs[185] and increase transport capacitycell sensitivity to NO.[164] A subsequent study ofin miniature swine.[186] Evidence that exercise train-similar duration also demonstrated augmented dila-ing enhances NO-mediated dilation was found in ator response in rat muscle arterioles following train-study of short-term (7–10 days) treadmill exerciseing, which was partially abolished by L-NMMAtraining in dogs.[187] This intervention increased di-infusion.[165] Vascular structure was not obviouslylation of the circumflex artery following both AChaltered. These findings suggest that increased pro-infusion and reactive hyperaemia. Infusion of nitro-duction of endothelial NO constitutes an initialL-arginine, an NO-synthase inhibitor, eliminatedphase in the adaptive response to exercise training.these responses. The training did not change theAnother study found that 4 weeks of daily exerciseresponse to SNP. Evidence that eNOS gene expres-in rats improved flow-induced dilation in skeletalsion is enhanced in the coronary vasculature bymuscle arteries, but not in mesenteric vessels, whichexercise training was first published by Sessa etare not subject to exercise hyperaemia.[166] In largeal.,[188] who found that nitrite and NO production,conduit vessels, improved endothelium-dependent

vasodilation has been observed after as few as 7 and eNOS gene expression, were increased in coro-



nary arterioles following 10 days of training in dogs. onary arteries with longer-term training might bedue, at least in part, to adaptations within smoothSimilarly, in a porcine model, 16 weeks of trainingmuscle.[191]increased eNOS mRNA[189] and increased bradykin-

in induced vasodilation[190] in coronary resistance In summary, animal studies investigating the per-vessels, suggesting that enhanced endothelium-de- ipheral and coronary vasculature suggest the hypo-pendent dilation persists in such vessels for at least 4 thetical adaptation schema diagrammatically repre-months. However, 16–22 weeks of training aug- sented in figure 1. Short-term exercise training en-mented vasodilator responses to adenosine in the hances NO production and bioactivity to bufferlarge epicardial arteries of pigs, even after removal increased shear. After extended training, increasedof the endothelium. This one piece of evidence NO production, and possibly other mediators, in-suggests that changes in vasomotor response in cor- duce structural changes to the vessel resulting in an

c

Fig. 1. Hypothesised response of arteries to increased flow and shear stress following varying duration of exercise training. (a) Untrainedvessel; baseline endothelial release of NO, which diffuses to smooth muscle, activates GC leading to production of cyclic GMP. Cyclic GMPleads to calcium channel opening causing smooth muscle relaxation and vasodilation of the vessel (intermediate steps have beenoverlooked for simplification). Localised fluctuations in release of NO act to homeostatically regulate wall shear. (b) Vessel followingmedium-term exercise training (several weeks); acute increase in shear stress, associated with repetitive exposure to increased flow duringbouts of exercise, stimulates increased endothelial NO production and consequent vasodilation. Up-regulation of the NO-dilator system,including eNOS expression, occurs to buffer increased shear stress. (c) Vessel following long-term exercise training; structural adaptationoccurs, possibly partly due to NO-mediated changes in smooth muscle cells, resulting in chronic increase in vessel calibre. Shear stress isnormalised and NO function returns towards baseline levels. eNOS = endothelial nitric oxide synthase; GC = guanylate cyclase; GMP =guanosine monophosphate; GTP = guanosine triphosphate; NO = nitric oxide.



increase in lumen diameter.[184] Shear stress is hence failure did not improve aortic vasodilation to ago-‘structurally’ normalised and endothelial NO ac- nists of NO.[198] However, treadmill running in dogstivity returns towards initial levels. Whilst the evi- during the development of pacing-induced heartdence upon which this is based is currently limited, failure preserved endothelium-dependent vasodila-these data suggest that functional and structural ad- tion of peripheral and coronary arteries[198,199] andaptations of the vasculature to exercise training may vascular gene expression of eNOS.[199] In these stud-alter with training duration. Further research will be ies, exercise training was initiated before overt CHFrequired to answer this intriguing hypothesis. developed. This is potentially clinically significant

because it demonstrates preservation of endothelial4.2 Exercise Training and NO Function in function despite the development of a failing centralAnimal Models of Pathological States circulation.

In summary, there is preliminary evidence that4.2.1 Hypercholesterolaemia exercise training can improve NO-related endotheli-Hypercholesterolaemia is associated with re- al function in animal models of hypercholesterol-

duced aerobic capacity in mice and this correlates aemia, hypertension, diabetes and heart failure.with impaired endothelium-dependent vascular re-laxation.[192] Four weeks of exercise training in hy- 4.3 Exercise Training and NO Function inpercholesterolaemic mice partially reverses endo- Healthy Volunteersthelial dysfunction, and this is correlated with im-proved aerobic capacity.[193]

Early descriptive studies included the finding that4 weeks of handgrip training improved forearm4.2.2 Hypertensionmaximal blood flow.[162] Due to the relatively smallIn in-vitro preparations of aortic and mesentericmuscle mass involved, the training stimulus wasrings from spontaneously hypertensive rats, ACh-thought insufficient to alter sympathetic tone, sug-induced relaxation was significantly greater follow-gesting the presence of an alternative local mecha-ing exercise training.[194] Furthermore, in the samenism. Supportive studies found enhanced vasodila-model, exercise training was associated with in-tor capacity in the dominant limb of tennis play-creased NO production[195] and an increase in plas-ers[161] and in the forearm with the resumption ofma nitrate.[196]

activity following immobilisation by casting.[200]

4.2.3 DiabetesCross-sectional studies highlight a significantly

Only one animal study has examined the effect of greater capacity for vasodilation among highly-exercise training on endothelial function in type 2 trained middle-aged distance runners than aged-diabetes.[197] Diabetic rats with impaired aortic en- matched inactive men.[201] Furthermore, exercisedothelial function were randomised to sedentary, training increased plasma nitrite and nitrate, persist-exercise-trained and food-restricted groups. Both ing for 4 weeks of detraining but returning to base-exercise training and food restriction reduced plas- line after 8 weeks.[202] An early investigation toma glucose and insulin, and increased insulin sensi- elucidate mechanisms associated with blood-flowtivity, but only exercise training improved endothe- changes following exercise training was conductedlium-dependent relaxation to histamine and inin young males by Green et al.[203] Four weeks ofcreased urinary excretion of nitrite. This suggests hand-grip training reduced minimum vascular resis-that exercise training improves endothelial function tance following an ischaemic stimulus in the trainedindependent of changes in glucose tolerance in this limb but not the untrained contralateral arm, nor inmodel of diabetes. sedentary controls. However, neither the forearm

4.2.4 Heart Failure blood-flow response to the endothelium-dependentAnimal models of heart failure provide conflict- vasodilator methacholine chloride nor to SNP were

ing evidence. Exercise training of rats with heart altered following training. Similar findings were



evident in studies comparing preferred and non- or -independent function.[212] This finding is in con-trast with studies in which an identical mode andpreferred arms of elite tennis players[204] and recov-intensity of training improved endothelium-depen-ery from forearm immobilisation from casting.[205]

dent and independent function in CHF patients[213]In another study, which employed 4 weeks of hand-and endothelium-dependent function in type 2 dia-grip training, exercise-induced vasodilation was in-betes.[209] NO-related endothelial function is im-creased following training. However, neither AChpaired in CHF and type 2 diabetes (discussed earliernor SNP infusion during exercise increased forearmin this review). It is therefore probable that de-vascular conductance above the level observedpressed endothelial function is more capable of aug-during exercise alone, suggesting that exercise train-mentation by moderate exercise training than is theing does not increase the response to these vasodila-well-preserved function of healthy individuals,tors, at least during exercise.[206] On the whole, thesewhich may, however, be improved by more intensestudies suggest that forearm muscle training (i.e.training.localised exercise of a small muscle group) does not

influence endothelial function in apparently healthy Cross-sectional studies suggest that regular phys-individuals, despite demonstrable increased capa- ical activity may partially reduce the age-relatedcity for peak blood flow. decline in NO-related endothelial function. A com-

parison of young and elderly athletes, and aged-Exercise involving large muscle groups of thematched sedentary controls, found that vasodilationlegs is likely to produce systemic changes in vascu-to ACh was not different between young trained andlar haemodynamics not apparent with localised ex-sedentary individuals but was significantly reducedercise of the upper limb. In healthy individuals,in elderly sedentary individuals compared with eld-Kingwell et al.[207] examined the systemic effect of 4erly athletes.[214] Furthermore, L-NMMA reducedweeks of cycling on NO production in the forearm.vasodilation to ACh in elderly athletes comparedFollowing training, L-NMMA-induced vaso-with the untrained. No difference was seen in theconstriction was increased, suggesting enhanced ba-response to SNP between the trained and controlsal NO production. Conversely, there was no signif-individuals. In the elderly control individuals,icant effect of training on the response to ACh orascorbic acid (vitamin C) restored vasoconstrictionSNP, suggesting that stimulated endothelium-de-to L-NMMA, suggesting that the aged-related de-pendent and -independent function were unaltered.cline in NO bioavailability may be due partially toHowever, following a 10-week programme of dailyoxidative stress. DeSouza et al. agreed with theseaerobic and anaerobic exercise training in youngfindings in a study of men aged 22–35 and 50–76military recruits, FMD- but not GTN-mediated va-years who were either sedentary or exercisesodilation of the brachial artery was significantlytrained.[53] Among the sedentary men, the forearmimproved.[208] This study also involved predomin-blood-flow response to ACh was reduced in theantly lower-limb exercise, indicating that the im-older group by 25%. However, there was no age-provement in endothelial function was likely to berelated decline in endothelial function among thesystemic in nature although, despite an intensiveolder men who were endurance trained. In a subsettraining regime, the change in FMD was relativelyof the sedentary older group, 3 months of moderatesmall, increasing from 2.2–3.9%. Even after train-training increased vasodilation to ACh by 30%, toing, these values are lower than commonly reportedlevels similar to those in the young group and olderin healthy individuals,[57,99] the explanation forendurance trained men, suggesting that endothelialwhich is unclear as baseline diameters did not differfunction can be improved by exercise in previouslysubstantially from other studies.[99,209-211] Recently,sedentary older men.in a randomised, crossover study of combined aero-

bic and resistance exercise in healthy middle-aged Two recent studies raise the possibility that theremen, training did not affect endothelium-dependent may be an optimal threshold of training, beyond



which exercise may decrease endothelial function. after 3 months of combined exercise and diet educa-Bergholm et al. reported that 3 months of high- tion in individuals with elevated low-density lipo-intensity running reduced endothelium-dependent protein (LDL)-cholesterol, despite increases infunction but not endothelium-independent func- VO2max and reduction in LDL cholesterol.[218] In ation.[215] The degree of endothelial dysfunction fol- randomised, crossover study, 8 weeks of traininglowing training was significantly correlated with a also failed to alter endothelial function in unmedi-decrease in serum uric acid and was most severe in cated individuals, but improved FMD and ACh re-individuals with the greatest improvement in maxi- sponses in individuals taking hydroxymethyl-mal oxygen uptake (VO2max). The authors postulat- glutaryl-coenzyme A (HMG-CoA) reductase inhibi-ed that the training-induced decrease in circulating tor lipid-lowering therapy. This disparity isantioxidant levels may adversely affect endothelial intriguing; it was probably due to the longer dura-function in the highly-trained or overtrained state. tion and greater severity of hypercholesterolaemiaHowever, this finding is also consistent with a train- in the treated individuals and their depression ofing-induced change in vascular structure as pro-

NO-related vasodilation compared with the untreat-posed earlier and depicted diagrammatically in fig-

ed and healthy individuals, again consistent with theure 1.

greater potential for improving depressed comparedIn a study comparing the effects of different

with normal function. Alternatively, as HMG-CoAintensities of exercise training in healthy young

reductase inhibitors and exercise training have bothmen, moderate intensity (50% VO2max) exercisebeen reported to increase eNOS activity,[219,220] andtraining augmented endothelium-dependent vasodi-perhaps both affect the oxidant state,[221,222] there is alation, but low-intensity (25% VO2max) and high-hypothetical possibility of synergistic benefit fromintensity (75% VO2max) training did not.[216] Thesethe two interventions.findings suggest that low-intensity training may fall

Improvement in basal[217] and stimulated endo-below the threshold for improving endothelial func-tion while the increase in markers of oxidative stress thelial function with exercise training have beenassociated with high-intensity training in this study reported in the absence of a decrease in serum lipids,raise the possibility that increased reactive oxygen and reductions in lipid levels are not necessarilyspecies may reduce NO bioavailability, abolishing associated with improved endothelial function.[218]

any improvement in vascular function as a result of Therefore, exercise-induced improvements in endo-increased NO production. thelial function in hypercholesterolaemia appear to

result from mechanisms independent of the effect ofexercise training on serum cholesterol reduction.4.4 Exercise Training and NO Function in

Pathological States in Humans Another interesting outcome of the study byWalsh et al. is that, in the hypercholesterolaemicpatients receiving statin therapy, both endothelium-4.4.1 Hypercholesterolaemiadependent (FMD) and endothelium-independentHypercholesterolaemia is associated with im-(GTN) responses were impaired at the outset of thepaired NO-related endothelium-dependent vasodila-study compared with matched healthy controls. Ex-tion[67,68] and is an important cardiovascular riskercise training improved endothelium-dependent va-factor. Several studies have examined the effect ofsodilation but not the impaired smooth muscle func-exercise training on endothelial function in thistion. This is consistent with findings from severalgroup. Four weeks of cycle training in unmedicatedanimal studies, which suggest that exercise training-individuals enhanced basal NO bioactivity but didmediated improvement in endothelial function pre-not alter ACh-stimulated vasodilation nor smoothcedes improvements in structure and function in themuscle sensitivity to SNP in the forearm.[217] Un-

changed endothelium-dependent function was found medial layer.[167,171-174,176]



4.4.2 Hypertension 4.4.4 DiabetesOne recently published trial has examined theTwelve weeks of daily walking increased fore-

effects of combined, predominantly lower limb, re-arm reactive hyperaemia[223] and the blood-flow res-sistance and aerobic exercise training on vascularponse to ACh[224] in essential hypertension. Thesefunction in type 2 diabetes.[209] Despite the avoid-effects were abolished by L-NMMA, indicating thatance of forearm muscle contractions, exercise train-the improvement following training was due to aug-ing enhanced endothelium-dependent reactivity tomented bioactivity of NO. There was a reduction inACh and FMD in forearm resistance and conduitblood pressure as a result of exercise training in thisvessels, respectively, without a change in endotheli-

study, but it did not correlate with improved endo-um-independent response. This improvement in en-

thelial function.dothelial function appears, therefore, to be a system-ic adaptation. Changes in conduit and resistance

4.4.3 Obesity vessel endothelial function were not significantlyThe combined effects of exercise training and related to changes in fasting blood glucose or glycat-

dietary restriction on vascular endothelial function ed haemoglobin, suggesting that improved endothe-have been investigated in a non-randomised study in lial function occurs independently of glycaemicobese adults.[225] Following the weight loss interven- control.tion, ACh responses significantly improved and the In keeping with a systemic effect of exercisemagnitude of this improvement was significantly training, 4 months of cycle training in patients with

long-standing type 1 diabetes also increased FMD ofcorrelated with changes in body mass index, waistthe brachial artery, and occular fundus pulsationgirth and insulin resistance. No changes were evi-amplitudes to intravenous L-NMMA, effects whichdent in response to SNP. The authors concluded thatwere lost after 8 months of detraining.[227]weight loss may affect endothelial function by im-

proving insulin sensitivity, decreasing oxidative4.4.5 CADstress and increasing NO bioavailability.Physical inactivity is an established risk factorThe effect of exercise training alone has recently

for cardiovascular disease[228] and exercise trainingbeen investigated in obese children (unpublishedhas been associated with a 20–25% reduction in

data) and adolescents.[226] Baseline endothelial func-mortality following a primary cardiac event.[4]

tion was significantly impaired in both groups rela-To date, there appear to be five studies of the

tive to age- and sex-matched controls. Adolescentseffect of exercise training on endothelial function in

performed combined resistance and aerobic exercise patients with established CAD. Four weeks of high-three times a week for 8 weeks and children under- frequency exercise training improved endothelium-took 8 weeks of physically active game play. Exer- dependent vasodilation in epicardial coronary andcise intensity was monitored at 60–85% maximum resistance vessels, but did not alter endothelium-heart rate in both groups. Study participants and independent function.[229] These benefits can betheir guardians were specifically requested not to maintained, albeit to a reduced degree, with home-alter diet intake across the study period and this was based exercise of reduced daily exercise dura-checked using repeated diet diaries. In both groups, tion.[230] Eight weeks of combined resistance andthe exercise intervention was associated with de- aerobic exercise, that did not involve forearmcreased abdominal fat mass (dual-energy x-ray ab- muscle contraction, improved FMD of the brachialsorbtiometry assessment) and improved FMD com- artery in patients with CAD suggesting a systemicpared with an inactive control period. These find- effect of training.[210] In minor contrast, 10 weeks ofings highlight the importance of regular exercise, lower extremity training increased FMD significant-even in the young, in controlling risk factors to ly in the tibial artery by 2%, but the 1.9% increase inreduce the risk of cardiovascular disease later in life. the brachial artery was not statistically signif-



icant.[231] The baseline FMD in the former study[210] change was evident in the untrained contra-lateralwas substantially lower than in the latter,[231] reflect- arm[239] and that comparable training protocols haveing greater impairment of endothelial function, a not altered systemic cardiac output, heart rate orcondition that may be more sensitive to exercise plasma norepinephrine or lactate levels[242] supporttraining. the argument that training adaptations to hand-grip-

An insight into the possible mechanisms respon- ping result from local mechanisms. Because greatersible for improved endothelial function following blood-flow responses to ACh were noted followingexercise training has recently been presented by combined exercise and supplementation with oralHambrecht et al.[232] in a study of patients undergo- L-arginine compared with either treatmenting coronary artery bypass graft surgery. Four alone,[240] increased substrate availability appears toweeks of daily exercise, undertaken immediately compliment shear stress-induced up-regulation ofprior to surgery, improved peak flow velocity in eNOS. However, localised exercise training has notresponse to ACh and FMD in the left internal mam- universally resulted in improved endothelial func-mary artery. No changes were evident in inactive tion. In one study, training increased endothelium-controls. Following surgery, a section of this vessel dependent vasodilation and peak hyperaemic bloodwas harvested and used for in vitro assessment of flow in control individuals but not in CHF pa-endothelial function, immunochemistry, and quanti- tients;[243] however, the negative results may reflectfication of mRNA and protein expression. eNOS the low intensity of training undertaken. On balance,mRNA and vascular protein expression were higher the preceding findings provide good support for thein trained individuals and increased eNOS phospho- efficacy of exercise training, involving relativelyrylation was significantly correlated with the change small muscle mass (i.e. the forearm), in stimulatingin ACh-induced average peak flow velocity follow- a localised improvement in endothelium-dependenting training. These important findings support the vasodilation in patients with CHF, who initiallyhypothesis that an increase in eNOS protein may exhibit endothelial dysfunction.mediate an improvement in endothelial function

The vascular effects of exercise training involv-through shear stress-induced phosphorylation.ing a large muscle mass have been examined inIn summary, exercise training can improve endo-several studies in patients with CHF.[213,244-246]

thelial function both locally and systemically inTwelve weeks of low intensity cycling (<50%patients with existing CAD. This may enhance myo-VO2max) significantly increased peak reactive hy-cardial perfusion and contribute to the well-docu-peraemia locally in the calf, but did not provide amented benefits of exercise training, such as reduc-systemic effect assessed in the forearm.[244] A local-tion in the incidence and severity of exercise-in-ised training effect on basal and stimulated NO-duced myocardial ischaemia.[233,234]

related dilation of the femoral artery was also evi-dent following 6 months of cycle training without a4.4.6 Chronic Heart Failurechange in the smooth muscle response to GTN.[245]Due to the clinical significance of peripheralIncreases in endothelium-dependent vasodilation inabnormalities in CHF, which limit peak oxygenvessels supplying the trained musculature were sig-uptake,[235,236] a strong correlate of prognosis,[237,238]

nificantly correlated with changes in functional ca-the effects of exercise training on endothelial func-pacity in both of these studies.[244,245] Furthermore,tion have been thoroughly investigated. Studiesexercise training was also associated with an in-have examined the effect of localised and systemiccrease in stroke volume, a small but significanttraining protocols in the upper and lower limbs.reduction in left ventricular end diastolic diameterHandgrip training improved NO-related function inand volume, and a reduction in total peripheralconduit[239,240] and resistance vessels[241] following 4resistance at rest and during peak exercise, the latterand 8 weeks, respectively, without altering endothe-correlating with ACh-enhanced blood flow in thelium-independent function. The observations that no



lower limb.[247] This is consistent with exercise- 5. Conclusionsinduced improvement in endothelium-dependent

It should be emphasised that NO-related vasodi-function in the peripheral circulation benefitinglation is only one of the endothelium-related effectsafterload and cardiac function.of NO, and that NO is only one of many mediatorsSystemic changes in vascular NO bioactivityproduced by the endothelium. However, NO plays ahave been identified in two lower body exercisekey role in endothelial function and its vasodilatortraining studies in CHF patients.[213,246] In a random-function provides a practical index of endothelialised, crossover study, combined aerobic and resis-function.tance exercise, which specifically avoided forearm

Acute bouts of exercise produce changes inexercise, improved forearm resistance vessel func-haemodynamics that act directly on the endotheli-tion in CHF patients,[213] suggesting a systemic ef-um. Recurrent exposure to these forces can result infect. Although the response to training was predom-endothelial adaptation, including up-regulation ofinantly endothelium-dependent, there was a slightNO bioactivity and an increased capacity for vasodi-improvement in endothelium-independent dilationlation. Exercise training involving relatively smalland an increase in reactive hyperaemia, which sug-muscle groups, such as hand-gripping, can improvegests a change in smooth muscle function and/orvasodilator function locally;[239,241] whilst exercisevascular structure.[201,248] Cycle training has alsoinvolving a large area of active muscle, such asbeen associated with a systemic effect on endotheli-cycling or jogging, causes heart rate and pulse pres-al function in CHF patients after 4 weeks[246] andsure to rise, resulting in increased pulsatile flow andheart transplant recipients after 6 months.[249] Thesepulse pressure systemically.[153] This increases vas-findings suggest that the endothelial dysfunctioncular shear stress and recurrent exposure to thisevident in CHF may be improved throughout thestimulus, by way of exercise training, can enhancevasculature with exercise training protocols that ac-endothelial NO-related vasodilator capacity both lo-tivate sufficient muscle mass to increase pulse wavecally[231,245] and systemically[208-210,213,246] under adynamics and shear stress. The minimum trainingrange of conditions, although variable results havethreshold for this effect may lie between 50%[244]

been found.[203,206,212] Importantly, exercise trainingand 70% of VO2max.[246]

effects on the endothelium appear to extend to thecoronary circulation, at least in patients with ex-4.5 Exercise Cessation and Detrainingisting CAD.[229]

It appears that a greater training load is requiredLocalised and systemic exercise-inducedto improve ‘normal’ endothelial function in thechanges in endothelial function are quickly lost fol-young and healthy,[208] for which evidence is equiv-lowing the cessation of relatively short durationocal, than in conditions associated with endothelialtraining. Six weeks after training was ceased indysfunction,[250] or to prevent age-related decline inpatients with CHF, radial artery diameters had re-endothelial function.[53] This raises the intriguingturned to pre-training size.[239] Similarly, endothelialpossibility of a threshold effect for training on endo-function returned to baseline after 8 weeks in pa-thelial function which may be determined by age,tients with CHF,[213] hypercholesterolaemia and typefitness or pathological state.2 diabetes.[209] This is consistent with the time

course of deconditioning associated with other Endothelial function may improve after as few asphysiological adaptations to exercise training. 7 days in trained animals.[167,187] In healthy humans,Therefore, these data suggest that an exercise pro- 4 weeks of training improved basal NO-related en-gramme, at some level as yet undetermined, would dothelial function in healthy individuals.[207] How-be necessary to maintain vascular benefits. To date, ever, studies that have identified improved stimulat-no data exist on the effect of detraining on endotheli- ed endothelium-dependent vasodilation have pre-al function in healthy individuals. scribed at least 10 weeks of training in healthy



authors have no conflicts of interest that are directly relevantindividuals.[53,208] Pathological states associatedto the content of this manuscript.with depressed NO bioactivity may respond more

rapidly to training, with endothelial function im-Referencesproving after as little as 4 weeks,[229,239] but re-

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Exercise and the Nitric Oxide Vasodilator System

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