Abstract
In the past two decades, normal endothelial function has been identified as integral to vascular health. The endothelium produces numerous vasodilator and vasoconstrictor compounds that regulate vascular tone; the vasodilator, nitric oxide (NO), has additional antiatherogenic properties, is probably the most important and best characterised mediator, and its intrinsic vasodilator function is commonly used as a surrogate index of endothelial function. Many conditions, including atherosclerosis, diabetes mellitus and even vascular risk factors, are associated with endothelial dysfunction, which, in turn, correlates with cardiovascular mortality. Furthermore, clinical benefit and improved endothelial function 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 fully resolved, exercise training involving repetitive bouts of exercise over weeks or months up-regulates endothelial NO bioactivity. Animal studies have found improved endothelium-dependent vasodilation after as few as 7 days of exercise. Consequent changes in vasodilator function appear to persist for several weeks but may regress with long-term training, perhaps reflecting progression to structural adaptation which may, however, have been partly endothelium-dependent. The increase in blood flow, and change in haemodynamics that occur during acute exercise may, therefore, provide a stimulus for both acute and chronic changes in vascular function. Substantial differences within species and within the vasculature appear to exist. In humans, exercise training improves endothelium-dependent vasodilator function, not only as a localised phenomenon in the active muscle group, but also as a systemic response when a relatively large mass of muscle is activated regularly during an exercise training programme. Individuals with initially impaired endothelial function at baseline appear to be more responsive to exercise training than healthy individuals; that is, it is more difficult to improve already normal vascular function. While improvement is reflected in increased NO bioactivity, the detail of mechanisms, for example the relative importance of up-regulation of mediators and antioxidant effects, is unclear. Optimum training schedules, possible sequential changes and the duration of benefit under various conditions also remain largely unresolved.
In summary, epidemiological evidence strongly suggests that regular exercise confers beneficial effects on cardiovascular health. Shear stress-mediated improvement in endothelial function provides one plausible explanation for the cardioprotective benefits of exercise training.
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References
Hakin AA, Curb JD, Petrovich H, et al. Effects of walking on coronary heart disease in elderly men: the Honolulu Heart Program. Circulation 1999; 100: 9–13
Sesso H, Paffenbarger R, Lee I. Physical activity and coronary heart disease in men: the Harvard Alumini Health Study. Circulation 2000; 102: 975–80
Myers J, Prakash M, Froelicher V, et al. Exercise capacity and mortality among men referred for exercise testing. N Engl J Med 2002; 346: 793–801
Jolliffe JA, Rees K, Taylor RS, et al. Exercise-based rehabilitation for coronary heart disease. Available in The Cochrane Library [database on disk and CD ROM]. Updated quarterly. The Cochrane Collaboration; issue 3. Oxford: Update Software, 2003
Blair S. Evidence for success of exercise in weight loss and control. Ann Intern Med 1993; 119: 702–6
Tran Z, Weltman A. Differential effects of exercise on serum lipid and lipoprotein levels seen with changes in body weight: a meta-analysis. JAMA 1985; 254: 919–24
Williams P. High-density lipoprotein cholesterol and other risk factors for coronary heart disease in female runners. N Engl J Med 1996; 334: 1298–303
Holloszy J, Schultz J, Kusnierkiewicz J, et al. Effects of exercise on glucose tolerance and insulin resistance. Acta Med Scand Suppl 1986; 711: 55–65
Blair S, Goodyear N, Gibbons L. Physical activity and incidence of hypertension in healthy normotensive men and women. JAMA 1984; 252: 487–90
Kelley G. Aerobic exercise and resting blood pressure among women: a meta-analysis of randomised controlled trials. Prev Med 1999; 28: 264–75
Malfattoo G, Facchini M, Sala L, et al. Effects of cardiac rehabilitation and beta-blocker therapy on heart-rate variability after first acute myocardial infarction. Am J Cardiol 1998; 81: 834–40
El-Sayed MS, Sale C, Jones PG, et al. Blood hemostasis in exercise and training. Med Sci Sports Exerc 2000; 32: 918–25
Smith J, Dykes R, Douglas J, et al. Long-term exercise and atherogenic activity of blood mononuclear cells in persons at risk of developing ischaemic heart disease. JAMA 1999; 281: 1722–7
Garg UC, Hassid A. Nitric-oxide generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest 1989; 83: 1774–7
Kubes P, Suzuki M, Granger D. Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci U S A 1991; 88: 4651–5
Rubanyi G. The role of endothelium in cardiovascular homeostasis and diseases. J Cardiovasc Pharmacol 1993; 22: S1–S14
Moncada S, Vane J. Pharmacology and endogenous roles or prostaglandin endoperoxides, thromboxane A2, and prostacyclin. Pharmacol Rev 1978; 30: 293–331
Cohen R, Vanhoutte P. Endothelium-dependent hyperpolarization: beyond nitric oxide and cyclic GMP. Circulation 1995; 92: 3337–49
Muller-Estrl W. Kininogen, kinins and kinships. Thromb Haemost 1989; 61: 2–6
Ignarro L. Endothelium-derived nitric oxide: actions and properties. FASEB J 1989; 3: 31–6
Dzau VJ. Circulating versus local renin-angiotensin system in cardiovascular homeostasis. Circulation 1988; 77: I4–13
Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988; 332: 411–5
Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980; 288: 373–6
Palmer RMJ, Rees DD, Ashton DS, et al. L-arginine is the physiological precursor for the formation of nitric oxide in endothelium-dependent relaxation. Biochem Biophys Res Commun 1988; 153: 1251–6
Ignarro LJ, Adams JB, Horwitz PM, et al. Activation of soluble guanylate cyclase by NO-hemoproteins involves NO-heme exchange. J Biol Chem 1986; 261: 4997–5002
Furchgott R, Jothianandan D. Endothelium-dependent and — independent vasodilation involving cyclic GMP: relaxation induced by nitric oxide, carbon monoxide and light. Blood Vessels 1991; 28: 52–61
Vallance P, Collier J, Moncada S. Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet 1989; II(8670): 997–1000
Lefroy DC, Crake T, Uren NG, et al. Coronary and peripheral blood flow: effect of inhibition of nitric oxide synthesis on epicardial coronary artery caliber and coronary blood flow in humans. Circulation 1993; 88: 43–54
Duffy SJ, Castle SF, Harper RW, et al. Contribution of vasodilator prostanoids and nitric oxide to resting flow, metabolic vasodilation, and flow-mediated dilation in human coronary circulation. Circulation 1999; 100: 1951–7
Loscalzo J, Welch G. Nitric oxide and its role in the cardiovascular system. Prog Cardiovasc Dis 1995; 38: 87–104
Hutcheson IR, Griffith TM. Release of endothelium-derived relaxing factor is modulated both by frequency and amplitude of pulsatile flow. Am J Physiol 1991; 261: H257–62
Rubanyi GM, Romero JC, Vanhoutte PM. Flow-induced release of endothelium-derived relaxing factor. Am J Physiol 1986; 250: H1145–9
Olesen SP, Clapham DE, Davies PF. Haemodynamic shear stress activates a K+ current in vascular endothelial cells. Nature 1988; 331: 168–70
Guharay F, Sachs F. Stretch activated single ion channel currents in tissue cultured embryonic chick skeletal muscle cells. J Physiol 1984; 352: 685–701
Cooke JP, Rossitch EJ, Andon NA, et al. Flow activates an endothelial potassium channel to release an endogenous nitrovasodilator. J Clin Invest 1991; 88: 1663–71
Dull RO, Davies PF. Flow modulation of agonist (ATP)-response (Ca2+) coupling in vascular endothelial cells. Am J Physiol 1991; 261: H149–54
Mo M, Eskin SG, Schilling WP. Flow-induced changes in Ca2+ signalling of vascular endothelial cells. Am J Physiol 1991; 260: 1698–707
Falcone JC, Kuo L, Meininger GA. Endothelial cell calcium increases during flow-induced dilation in isolated arterioles. Am J Physiol 1993; 264: H653–9
Hecker M, Bara AT, Busse R. Angiotensin-converting enzyme inhibitors unmask endogenous kinin production by bovine coronary artery endothelium. Eur Heart J 1993; 14: 161–3
Groves P, Kursz S, Just H, et al. Role of endogenous bradykinin in human coronary vasomotor control. Circulation 1995; 92: 3424–30
Dimmeler S, Fleming I, Fisslthaler B, et al. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature 1999; 399: 601–5
Joannides R, Haefeli WE, Linder L, et al. Nitric oxide is responsible for flow-dependent dilatation of human peripheral conduit arteries in vivo. Circulation 1995; 91: 1314–9
Okumura K, Yasue H, Matsuyama K, et al. Effect of acetylcholine on the highly stenotic coronary artery: difference between the constrictor response of the infarct-related coronary artery and that of the noninfarct-related artery. J Am Coll Cardiol 1992; 19: 752–8
Bogaty P, Hackett D, Davies G, et al. Vasoreactivity of the culprit lesion in unstable angina. Circulation 1994; 90: 5–11
Nishikawa Y, Ogawa S. Importance of nitric oxide in the coronary artery at rest and during pacing in humans. J Am Coll Cardiol 1997; 29: 85–92
Ohara Y, Peterson TE, Harrison DG. Hypercholesterolemia increases endothelial Superoxide anion production. J Clin Invest 1993; 91: 2546–51
Berliner JA, Navab M, Fogelman AB. Atherosclerosis: basic mechanisms: oxidation, inflammation, and genetics. Circulation 1995; 91: 2488–96
Kojda G, Harrison D. Interactions between NO and reactive oxygen species: pathophysiological importance in atherosclerosis, hypertension, diabetes and heart failure. Cardiovasc Res 1999; 43: 562–71
McLenachan JM, Vita J, Fish DR, et al. Early evidence of endothelial vasodilator dysfunction at coronary branch points. Circulation 1990; 82: 1169–73
Celermajer DS, Sorensen KE, Georgakopoulos D, et al. Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults. Circulation 1993; 88: 2149–55
Anderson TJ, Meredith IT, Yeung AC, et al. The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion. N Engl J Med 1995; 332: 488–93
Green DJ, O’Driscoll GJ, Rankin JM, et al. Beneficial effect of vitamin E administration on nitric oxide function in subjects with hypercholesterolaemia. Clin Sci 1998; 95: 361–7
DeSouza CA, Shapiro LF, Clevenger C, et al. Regular aerobic exercise prevents and restores age-related declines in endothelium-dependent vasodilation in healthy men. Circulation 2000; 102: 1351–7
O’Driscoll G, Green D, Taylor R. Simvastatin, an HMG-Coenzyme A reductase inhibitor, improves endothelial function within 1 month. Circulation 1997; 95: 1126–31
O’Driscoll JG, Green DJ, Maiorana A, et al. Improvement in endothelial function by ACE inhibition in non-insulin-dependent diabetes mellitus. J Am Coll Cardiol 1999; 33: 1506–11
Dagenais G, Yusuf S, Bourassa M, et al. Effects of ramapril on coronary events in high-risk persons: results of the Heart Outcomes Prevention Evaluation Study. Circulation 2001; 104: 522–6
Celermajer DS, Sorensen KE, Gooch VM, et al. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 1992; 340: 1111–5
Vita J, Treasure C, Nabel E, et al. Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease. Circulation 1990; 81: 491–7
Egashira K, Inou T, Hirooka Y, et al. Effects of age on endothelium-dependent vasodilation of resistance coronary artery by acetylcholine in humans. Circulation 1993; 88: 77–81
Taddei S, Virdis A, Mattel P, et al. Aging and endothelial function in normotensive subjects and patients with essential hypertension. Circulation 1995; 91: 1981–7
Gerhard M, Roddy M-A, Creager SJ, et al. Aging progressively impairs endothelium-dependent vasodilation in forearm resistance vessels of humans. Hypertension 1996; 27: 849–53
Yasue H, Matsuyama K, Matsuyama K, et al. Responses of angiographically normal human coronary arteries to intracoronary injection of acetylcholine by age and segment: possible role of early coronary athersclerosis. Circulation 1990; 81: 482–90
Woo KS, Chook P, Leong HC, et al. The impact of heavy passive smoking on arterial endothelial dysfunction in modernized Chinese. J Am Coll Cardiol 2000; 36: 1228–32
Nitenberg A, Antony I, Foult JM. Acetylcholine-induced coronary vasoconstriction in young, heavy smokers with normal coronary arteriographic findings. Am J Med 1993; 95: 71–7
Drexler H, Zeiher K, Meinzer K, et al. Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolaemic patients by L-arginine. Lancet 1991; 338: 1546–50
Creager MA, Cooke JP, Mendelhson ME, et al. Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans. J Clin Invest 1990; 86: 228–34
Chowienczyk PJ, Watts GF, Cockcroft JR, et al. Impaired endothelium-dependent vasodilation of forearm resistance vessels in hypercholesterolaemia. Lancet 1992; 340: 1430–2
Casino PR, Kilcoyne CM, Quyyumi AA, et al. Role of nitric oxide in endothelium-dependent vasodilation of hypercholes-terolemic patients. Circulation 1993; 88: 2541–7
Sorensen KE, Celermajer DS, Georgakopoulos D, et al. Impairment of endothelium-dependent dilation is an early event in children with familial hypercholesterolemia and is related to the lipoprotein (a) level. J Clin Invest 1994; 93: 50–5
Zhao SP, Liu L, Gao M, et al. Impairment of endothelial function after a high-fat meal in patients with coronary artery disease. Coron Artery Dis 2001; 7: 561–5
Tamai O, Matsuoka H, Itabe H, et al. Single LDL apheresis improves endothelium-dependent vasodilatation in hypercholesterolemic humans. Circulation 1997; 95: 76–82
Panza J, Quyyumi A, Brush J, et al. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med 1990; 323: 22–7
Higashi Y, Oshima T, Ozono R, et al. Aging and severity of hypertension attenuate endothelium-dependent renal vascular relaxation in humans. Hypertension 1997; 30: 252–8
Treasure C, Manoukian S, Klein J, et al. Epicardial coronary artery responses to acetylcholine are impaired in hypertensive patients. Circ Res 1992; 71: 776–81
Brush JE, Faxon DP, Salmon S, et al. Abnormal endothelium-dependent coronary vasomotion in hypertensive patients. J Am Coll Cardiol 1992; 19: 809–15
Egashira K, Suzuki S, Hirooka Y, et al. Impaired endothelium-dependent vasodilation in large epicardial and resistance arteries in patients with essential hypertension: different responses to acetylcholine and substance P. Hypertension 1995; 25: 201–6
Perticone F, Ceravolo R, Pujia A, et al. Prognostic significance of endothelial dysfunction in hypertensive patients. Circulation 2001; 104: 191–6
Anderson TJ, Overhiser RW, Haber H, et al. A comparative study of four anti-hypertensive agents on endothelial function in patients with coronary disease. J Am Coll Cardiol 1998; 31Suppl. A: 327A
Bosch J, Yusuf S, Pogue J, et al. Use of ramapril in preventing stroke: double blind randomised trial. BMJ 2002; 324: 699–702
Sleight P, Yusuf S, Pogue J, et al. Blood pressure reduction and cardiovascular risk in HOPE study. Lancet 2001; 358: 2130–1
Hubert HB, Feinlab M, McNamara PM, et al. Obesity was an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study. Circulation 1983; 67: 968–77
Arcaro G, Zamboni M, Rossi L, et al. Body fat distribution predicts degree of endothelial dysfunction in uncomplicated obesity. Int J Obes 1999; 23: 9936–42
Perticone F, Ceravolo R, Candigliota M, et al. Obesity and body fat distribution induce endothelial dysfunction by oxidative stress: protective effect of vitamin C. Diabetes 2001; 50: 159–65
Al Suwaidi J, Higano ST, Holmes DR, et al. Obesity is independently associated with coronary endothelial dysfunction in patients with normal or mildly diseased coronary arteries. J Am Coll Cardiol 2001; 37: 1523–8
Standl E, Balletshofer B, Dahl B, et al. Predictors of 10-year macrovascular and overall mortality in patients with NIDDM: the Munich General Practitioners Project. Diabetologia 1996; 39: 1540–5
Calles-Escandon J, Cipolla M. Diabetes and endothelial dysfunction: a clinical perspective. Endocr Rev 2001; 22: 36–52
McVeigh GE, Brennan GM, Johnston GD, et al. Impaired endothelium-dependent and independent vasodilation in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 1992; 35: 771–6
Karusa C, Socul H, Altan VM. Effects of non-insulin dependent diabetes mellitus on the reactivity of human internal mammary artery and human saphenous vein. Life Sci 1995; 57: 103–12
Williams SB, Cusco JA, Roddy MA, et al. Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus. J Am Coll Cardiol 1996; 27: 567–74
Watts G, O’Brien S, Silvester W, et al. Impaired endothelium-dependent and independent dilation of forearm resistance vessels in men with diet-treated non-insulin-dependent diabetes: role of dyslipidemia. Clin Sci 1996; 91: 567–73
Ting HH, Timimi FK, Boles KS, et al. Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus. J Clin Invest 1996; 97: 22–8
Avogaro A, Piarulli F, Valerio A, et al. Forearm nitric oxide balance, vascular relaxation, and glucose metabolism in NIDDM patients. Diabetes 1997; 46: 1040–6
Calver A, Collier J, Vallance P. Inhibition and stimulation of nitric oxide synthesis in the human forearm arterial bed of patients with insulin-dependent diabetes. J Clin Invest 1992; 90: 2548–54
Johnstone MT, Creager SJ, Scales KM, et al. Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. Circulation 1993; 88: 2510–6
McNally P, Watt P, Rimmer T, et al. Impaired contraction and endothelium-dependent relaxation in isolated resistance vessels from patients with insulin dependent diabetes mellitus. Clin Sci 1994; 87: 31–6
O’Driscoll G, Green D, Rankin J, et al. Improvement in endothelial function by angiotensin converting enzyme inhibition in insulin-dependent diabetes mellitus. J Clin Invest 1997; 100: 678–84
Ludmer P, Selwyn A, Shook T, et al. Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med 1986; 315: 1046–51
Anderson TJ, Uehata A, Gerhard MD, et al. Close relationship of endothelial function in the human coronary and peripheral circulations. J Am Coll Cardiol 1995; 26: 1235–41
Neunteufl T, Katzenschlager R, Hassan A, et al. Systemic endothelial dysfunction is related to the extent and severity of coronary artery disease. Atherosclerosis 1997; 129: 111–8
Al Suwaidi J, Hamasaki S, Higano S, et al. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation 2000; 101: 948–54
Schachinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 2000; 101: 1899–906
Halcox JPJ, Schenke WH, Zalos G, et al. Prognostic value of coronary vascular endothelial dysfunction. Circulation 2002; 106: 653–8
Neunteufl T, Heher S, Katzenschlager R, et al. Late prognostic value of flow-mediated dilation in the brachial artery of patients with chest pain. Am J Cardiol 2000; 86: 207–10
Gokce N, Keaney JF, Hunter LM, et al. Risk stratification for postoperative cardiovascular events via noninvasive assessment of endothelial function: a prospective study. Circulation 2002; 105: 1567–72
Cohn JN, Johnson GR, Shabetai R, et al. Ejection fraction, peak exercise oxygen consumption, cardiothoracic ratio, ventricular arrhythmias, and plasma norepinephrine as determinants of prognosis in heart failure. The V-HeFT VA Cooperative Studies Group. Circulation 1993; 87: V15–6
Katz SD, Krum H, Kahn T, et al. Exercise-induced vasodilation in forearm circulation of normal subjects and patients with congestive heart failure: role of endothelium-derived nitric oxide. J Am Coll Cardiol 1996; 28: 585–90
Jondeau G, Katz D, Zohman M, et al. Active skeletal muscle mass and cardiopulmonary reserve: failure to attain peak aerobic capacity during maximal exercise in patients with congestive heart failure. Circulation 1992; 86: 1352–6
LeJemtel T, Maskin D, Lucido D, et al. Failure to augment maximal blood flow in response to one-leg versus two-leg exercise in patients with congestive heart failure. Circulation 1986; 74: 245–51
Treasure CB, Vita JA, Cox DA. Endothelium-dependent dilation of the coronary microvasculature is impaired in dilated cardiomyopathy. Circulation 1990; 81: 772–9
Drexler H, Hayoz D, Munzel T, et al. Endothelial function in chronic congestive heart failure. Am J Cardiol 1992; 69: 1596–601
Katz SD, Schwarz M, Yuen J, et al. Impaired acetylcholine-mediated vasodilation in patients with congestive heart failure. Circulation 1993; 88: 55–61
Kubo SH, Rector TS, Bank AJ, et al. Endothelium-dependent vasodilation is attenuated in patients with heart failure. Circulation 1991; 84: 1589–96
Katz SD, Biasucci L, Sabba C, et al. Impaired endothelium-mediated vasodilation in the peripheral vasculature of patients with congestive heart failure. J Am Coll Cardiol 1992; 19: 918–25
Nakamura M, Yoshida H, Arakawa N, et al. Endothelium-dependent vasodilation is not selectively impaired in patients with chronic heart failure secondary to valvular heart disease and congenital heart disease. Eur Heart J 1996; 17: 1875–81
Lindsay D, Holdright D, Clarke D, et al. Endothelial control of lower limb blood flow in chronic heart failure. Heart 1996; 75: 469–76
Andersen P. Maximal perfusion of skeletal muscle in man. J Physiol 1985; 366: 233–49
Walloe L, Wesche J. Time course and magnitude of blood flow changes in the human quadriceps muscles during and following rhythmic exercise. J Physiol 1988; 405: 257–73
Laughlin MH. Skeletal muscle blood flow capacity: role of muscle pump in exercise hyperaemia. Am J Physiol 1987; 253: H993–1004
Keins B, Saltin B, Walloe L, et al. Temporal relationship between blood flow changes and release of ions and metabolites from muscles upon single weak contractions. Acta Physiol Scand 1989; 136: 551–9
Hester R, Guyton A, Barber B. Reactive and exercise hyperaemia during high levels of adenosine infusion. Am J Physiol 1982; 243: H181–6
Kobzik L, Reid MB, Bredt DS, et al. Nitric oxide in skeletal muscle. Nature 1994; 372: 546–8
Joyner M, Nausss L, Warner M, et al. Sympathetic modulation of blood flow and O2 uptake in rhythmically contracting human forearm muscles. Am J Physiol 1992; 263: H1078–83
Gow A, Stamler J. Reactions between nitric oxide and haemoglobin under physiological conditions. Nature 1998; 391: 169–73
Segal SS, Kurjiaka DT. Coordination of blood flow control in the resistance vasculature of skeletal muscle. Med Sci Sports Exerc 1995; 27: 1158–64
Segal SS. Communication among endothelial and smooth muscle cells coordinates blood flow control during exercise. News Physiol Sci 1992; 7: 152–6
Green DJ, O’Driscoll JG, Blanksby BA, et al. Control of skeletal muscle blood flow during dynamic exercise. Sports Med 1996; 21: 119–46
Folkow B, Sonnenschein RR, Wright DL. Loci of neurogenic and metabolic effects on precapillary vessels of skeletal muscle. Acta Physiol Scand 1971; 81: 459–71
Koller A, Kaley G. Endothelial regulation of wall shear stress and blood flow in skeletal muscle microcirculation. Am J Physiol 1991; 260: H862–8
Falcone JC, Davis MJ, Meininger GA. Endothelial independence of myogenic response in isolated skeletal muscle arterioles. Am J Physiol 1991; 260: H130–5
Segal SS, Damon DN, Duling BR. Propagation of vasomotor responses coordinates arteriolar resistances. Am J Physiol 1989; 256: H832–7
Delp MD, Laughlin MH. Regulation of skeletal muscle perfusion during exercise. Acta Physiol Scand 1998; 162: 411–9
Shen W, Lundborg M, Wang J, et al. Role of EDRF in the regional blood flow and vascular resistance at rest and during exercise in conscious dogs. J Appl Physiol 1994; 77: 165–72
Hirai T, Visneski MD, Kearns KJ, et al. Effects of NO synthase inhibition on the muscular blood flow response to treadmill exercise in rats. J Appl Physiol 1994; 77(3): 1288–93
Berdeaux A, Ghaleh B, Dubois-Randé JL, et al. Role of vascular endothelium in exercise-induced dilation of large epicardial coronary arteries in conscious dogs. Circulation 1994; 89: 2799–808
Persson MG, Wiklund NP, Gustafsson LE. Nitric oxide requirement for vasomotor nerve-induced vasodilatation and modulation of resting blood flow in muscle microcirculation. Acta Physiol Scand 1991; 141: 49–56
Saito Y, Eraslan A, Hester RL. Role of EDRFs in the control of arteriolar diameter during increased metabolism of striated muscle. Am J Physiol 1994; 267: H195–200
Kingwell BA. Nitric oxide as a metabolic regulator during exercise: effects of training in health and disease. Clin Exp Pharmacol Physiol 2000; 27: 239–50
Ambring A, Benthin G, Petersson A-S, et al. Indirect evidence of increased expression of NO synthase in marathon runners, and upregulation of NO synthase activity during running [abstract]. Circulation 1994; 90: 1–137
Bode-Böger SM, Böger RH, Scroder EP, et al. Exercise increases systemic nitric oxide production in men. J Cardiovasc Risk 1994; 1: 173–8
Wilson JR, Kapoor S. Contribution of endothelium-derived relaxing factor to exercise-induced vasodilation in humans. J Appl Physiol 1993; 75: 2740–4
Endo T, Imaizumi T, Tagawa T, et al. Role of nitric oxide in exercise-induced vasodilation of the forearm. Circulation 1994; 90: 2886–90
Joyner MJ, Dietz NM. Nitric oxide and vasodilation in human limbs. J Appl Physiol 1997; 83: 1785–96
Brock RW, Tschakovsky ME, Shoemaker JK, et al. Effects of acetylcholine and nitric oxide on forearm blood flow at rest and after a single muscle contraction. Am J Physiol 1998; 85: 2249–54
Gilligan DM, Panza JA, Kilcoyne CM, et al. Contribution of endothelium-derived nitric oxide to exercise-induced vasodilation. Circulation 1994; 90: 2853–8
Dyke CK, Proctor DN, Deitz NM, et al. Role of nitric oxide in exercise hyperemia during prolonged rhythmic handgripping in humans. J Physiol 1995; 488: 259–65
Duffy SJ, Gishel N, Tran BT, et al. Relative contribution of vasodilator prostanoids and NO to metabolic vasodilation in the human forearm. Am J Physiol 1999; 45: H663–70
Hickner R, Fisher J, Ehsani A, et al. Role of nitric oxide in skeletal muscle blood flow at rest and during dynamic exercise in humans. Am J Physiol 1997; 273: H405–10
Radegran G, Saltin B. Nitric oxide in the regulation of vasomotor tone in human skeletal muscle. Am J Physiol 1999; 276: H1951–60
Bradley SJ, Kingwell BA, McConnell GK. Nitric oxide synthase inhibition reduces leg glucose uptake but not blood flow during dynamic exercise in humans. Diabetes 1999; 48: 1815–21
Scherrer U, Pryor SL, Bertocci LA, et al. Arterial baroreflex buffering of sympathetic activation during exercise-induced elevations in arterial pressure. J Clin Invest 1990; 86: 1855–61
Sheriff DD, Nelson CD, Sundermann RK. Does autonomic blockade reveal a potent contribution of nitric oxide to locomotion-induced vasodilation? Am J Physiol 2000; 279: H726–32
Radegran G, Saltin B. Muscle blood flow at the onset of dynamic exercise in humans. Am J Physiol 1998; 274: H314–22
Green D, Cheetham C, Mavaddat L, et al. Effect of lower limb exercise on forearm vascular function: contribution of nitric oxide. Am J Physiol 2002; 283: H899–907
Green D, Cheetham C, Henderson C, et al. Effect of cardiac pacing on forearm vascular function. Am J Physiol 2002; 283: H1354–60
Minamino T, Kitakaze M, Matsumura Y, et al. Impact of coronary risk factors on contribution of nitric oxide and adenosine to metabolic coronary vasodilation in humans. J Am Coll Cardiol 1998; 31: 1274–9
Quyyumi AA, Dakak N, Andrews NP, et al. Contribution of nitric oxide to metabolic coronary vasodilation in the human heart. Circulation 1995; 92: 320–6
Tousoulis D, Tentolouris C, Crake T, et al. Basal and flow-mediated nitric oxide production by atheromatous coronary arteries. J Am Coll Cardiol 1997; 29: 1256–62
Egashira K, Katsuda Y, Mohri M, et al. Role of endothelium-derived nitric-oxide in coronary vasodilation induced by pacing tachycardia in humans. Circ Res 1996; 79: 331–5
Shiode N, Morishima N, Nakayama K, et al. Flow-mediated vasodilation of human epicardial coronary arteries: effect of inhibition of nitric oxide synthesis. J Am Coll Cardiol 1996; 27: 304–10
Quyyumi AA, Dakak N, Andrews NP, et al. Nitric oxide activity in the human coronary circulation. J Clin Invest 1995; 95: 1747–55
Sinoway LI, Musch TI, Minotti JR, et al. Enhanced maximal metabolic vasodilation in the dominant forearms of tennis players. J Appl Physiol 1986; 61: 673–8
Sinoway LI, Shenberger J, Wilson J, et al. A 30-day forearm work protocol increases maximal forearm blood flow. J Appl Physiol 1987; 62: 1063–7
Lee I, Sesso H, Paffenbarger RS. Physical activity and coronary heart disease risk in men; does the duration of exercise episodes predict risk? Circulation 2000; 102: 981–6
Sun D, Huang A, Koller A, et al. Short-term daily exercise activity enhances endothelial NO synthesis in skeletal muscle arterioles of rats. J Appl Physiol 1994; 76: 2241–7
Koller A, Huang A, Sun D, et al. Exercise training augments flow-dependent dilation in rat skeletal muscle arterioles. Circ Res 1995; 76: 544–50
Sun D, Huang A, Koller A, et al. Adaptation of flow-induced dilation of arterioles to daily exercise. Microvasc Res 1998; 56: 54–61
McAllister RM, Laughlin MH. Short-term exercise training alters responses of porcine femoral and brachial arteries. J Appl Physiol 1997; 82: 1438–44
Delp MD, Laughlin MH. Time course of enhanced endothelium-mediated dilation in aorta of trained rats. Med Sci Sports Exerc 1997; 29: 1454–61
Delp MD, McAllister RM, Laughlin MH. Exercise training alters endothelium-dependent vasoreactivity of rat abdominal aorta. J Appl Physiol 1993; 75: 1354–63
Chen H, Li H-T. Physical conditioning can modulate endothelium-dependent vasorelaxation in rabbits. Arterioscler Thromb 1993; 13: 852–6
McAllister RM, Kimani JK, Webster JL, et al. Effects of exercise training on peripheral and visceral arteries in swine. J Appl Physiol 1996; 80: 216–5
Kingwell B, Arnold P, Jennings G, et al. Spontaneous running increases aortic compliance in Wistar-Kyoto rats. Cardiovasc Res 1997; 35: 132–7
Johnson LR, Rush JWE, Turk JR, et al. Short-term exercise training increases ACh-induced relaxation and eNOS protein in porcine pulmonary arteries. J Appl Physiol 2001; 90: 1102–10
Johnson LR, Laughlin MH. Chronic exercise training does not alter pulmonary vasorelaxation in normal pigs. J Appl Physiol 2000; 88: 2008–16
Leon AS, Bloor CM. Effects of exercise and its cessation on the heart and its blood supply. J Appl Physiol 1968; 24: 485–90
Kramsch DM, Aspen AJ, Abramowitz BM, et al. Reduction of coronary atherosclerosis by moderate conditioning exercise in monkeys on an atherogenic diet. N Engl J Med 1981; 305: 1483–9
Wyatt HL, Mitchell J. Influences of physical conditioning and deconditioning on coronary vasculature of dogs. J Appl Physiol 1978; 45: 619–25
Lash J, Bohlen H. Functional adaptations of rat skeletal muscle arterioles to aerobic exercise training. J Appl Physiol 1992; 72: 2052–62
Kamiya A, Togawa T. Adaptive regulation of wall shear stress to flow change in the canine carotid artery. Am J Physiol 1980; 239: H14–21
Langille BL, O’Donnell F. Reductions in arterial diameter produced by chronic decreases in blood flow are endothelium-dependent. Nature 1986; 231: 405–7
Zarins CK, Zatina MA, Giddens DP, et al. Shear stress regulation of artery lumen diameter in experimental atherosclerosis. J Vasc Surg 1987; 5: 413–20
Gibbons G, Dzau V. The emerging concept of vascular remodelling. N Engl J Med 1994; 330: 1431–8
Rudic R, Sheseley E, Maeda N, et al. Direct evidence for the importance of endothelium-derived nitric oxide in vascular remodeling. J Clin Invest 1998; 101: 731–6
Prior BM, Lloyd PG, Yang HT, et al. Exercise-induced vascular remodelling. Exerc Sports Sci Rev 2003; 31: 26–33
DiCarlo SE, Blair RW, Bishop VS, et al. Daily exercise enhances coronary resistance vessel sensitivity to pharmacological activation. J Appl Physiol 1989; 66: 421–8
Laughlin M, Overholser K, Bhatte M. Exercise training increases coronary transport reserve in miniature swine. J Appl Physiol 1989; 67: 1140–9
Wang J, Wolin MS, Hintze TH. Chronic exercise enhances endothelium-mediated dilation of epicardial coronary artery in conscious dogs. Circ Res 1993; 73: 829–38
Sessa WC, Pritchard K, Seyedi N, et al. Chronic exercise in dogs increases coronary vascular nitric oxide synthase production and endothelial cell nitric oxide synthase gene expression. Circ Res 1994; 74: 349–53
Woodman CR, Muller JM, Laughlin MH. Induction of nitric oxide synthase mRNA in coronary resistance arteries isolated from exercise-trained pigs. Am J Physiol 1997; 273: H1–5
Muller JD, Myers PR, Laughlin MH. Vasodilator responses of coronary resistance arteries of exercise-trained pigs. Circulation 1994; 89: 2308–14
Oltman C, Parker J, Adams H, et al. Effects of exercise training on vasomotor reactivity of porcine coronary arteries. Am J Physiol 1992; 263: H372–82
Maxwell AJ, Schauble E, Berstein D, et al. Limb blood flow during exercise is dependent on nitric oxide. Circulation 1998; 98: 369–74
Niebauer J, Maxwell A, Lin P, et al. Impaired aerobic capacity in hypercholesterolemic mice: partial reversal by exercise training. Am J Physiol 1999; 276: H1346–54
Yen MH, Yang JH, Sheu JR, et al. Chronic exercise enhances endothelium-mediated dilation in spontaneously hypertensive rats. Life Sci 1995; 57: 2205–13
Chen HI, Chiang IP. Chronic exercise decreases adrenergic agonist-induced vasoconstriction in spontaneously hypertensive rats. Am J Physiol 1996; 271: H977–83
Jonsdottir I, Jungersten J, Johansson C, et al. Increase in nitric oxide formation after chronic voluntary exercise in spontaneously hypertensive rats. Acta Physiol Scand 1998; 162: 149–53
Sakamoto S, Kazushi M, Niwa Y, et al. Effect of exercise training and food restriction on endothelium-dependent relaxation in the Otsuka Long-Evans Tokushima Fatty Rat, a model of spontaneous NIDDM. Diabetes 1998; 47: 82–6
Lindsay DC, Jiang C, Brunotte F, et al. Impairment of endothelium-dependent responses in a rat model of chronic heart failure: effects of an exercise training protocol. Cardiovasc Res 1992; 26: 694–7
Wang J, Yi G, Knecht M, et al. Physical training alters the pathogenesis of pacing-induced heart failure through endothelium-mediated mechanisms in awake dogs. Circulation 1997; 96: 2683–92
Silber DH, Sinoway LI. Reversible impairment of forearm vasodilation after forearm casting. J Appl Physiol 1990; 68: 1945–9
Haskell WL, Sims C, Myell J, et al. Coronary artery size and dilating capacity in ultradistance runners. Circulation 1993; 87: 1076–82
Maeda S, Miyauchi T, Kakiyama T, et al. Effects of exercise training of 8 weeks and detraining on plasma levels of endothelium-derived factors, endothein-1 and nitric oxide, in healthy young humans. Life Sci 2001; 69: 1005–16
Green DJ, Cable NT, Fox C, et al. Modification of forearm resistance vessels by exercise training in young men. J Appl Physiol 1994; 77: 1829–33
Green DJ, Fowler DT, O’Driscoll JG, et al. Endothelium-derived nitric oxide activity in forearm vessels of tennis players. J Appl Physiol 1996; 81: 943–8
Green DJ, O’Driscoll JG, Blanksby BA, et al. Effect of casting on forearm resistance vessels in young men. Med Sci Sports Exerc 1997; 29: 1325–31
Franke WD, Stephens GM, Schmid PG. Effects of intense exercise training on endothelium-dependent exercise induced vasodilatation. Clin Physiol 1998; 18: 521–8
Kingwell BA, Sherrard B, Jennings GL, et al. Four weeks of cycle training increases basal production of nitric oxide from the forearm. Am J Physiol 1997; 272: H1070–7
Clarkson P, Montgomery HE, Mullen MJ, et al. Exercise training enhances endothelial function in young men. J Am Coll Cardiol 1999; 33: 1379–85
Maiorana A, O’Driscoll G, Cheetham C, et al. The effect of combined aerobic and resistance exercise training on vascular function in type 2 diabetes. J Am Coll Cardiol 2001; 38: 860–6
Walsh JH, Bilsborough W, Maiorana A, et al. Exercise training improves conduit vessel function in patients with coronary artery disease. J Appl Physiol 2003; 95: 20–5
Walsh J, Yong G, Cheetham C, et al. Effect of exercise training on conduit and resistance vessel function in medicated and unmedicated hypercholesterolaemic patients. Eur Heart J 2003; 24(18): 1681–9
Maiorana A, O’Driscoll G, Dembo L, et al. Exercise training, vascular function, and functional capacity in middle-aged subjects. Med Sci Sports Exerc 2001; 33: 2022–8
Maiorana A, O’Driscoll G, Dembo L, et al. Effect of aerobic and resistance exercise training on vascular function in heart failure. Am J Physiol 2000; 279: H1999–2005
Taddei S, Galetta F, Virdis A, et al. Physical activity prevents age-related impairment in nitric oxide availability in elderly athletes. Circulation 2000; 101: 2896–901
Bergholm R, Makimattila S, Valkonen N, et al. Intense physical training decreases circulating antioxidants and endothelium-dependent vasodilation in vivo. Atherosclerosis 1999; 145: 141–9
Goto C, Higashi Y, Kimura M, et al. Effect of different intensities of exercise on endothelium-dependent vasodilation in humans; role of endothelium-dependent nitric oxide and oxidative stress. Circulation 2003; 108: 530–5
Lewis TV, Dart AM, Chin-Dusting JPF, et al. Exercise training increases basal nitric oxide production from the forearm in hypercholesterolemic patients. Arterioscler Thromb Vasc Biol 1999; 19: 2782–7
Jodoin I, Bussieres LM, Tardif JC, et al. Effect of a short-term primary prevention program on endothelium-dependent vasodilation in adults at risk for atherosclerosis. Can J Cardiol 1999; 15: 83–9
Bates K, Ruggeroli C, Goldman S, et al. Simvastatin restores endothelial NO-mediated vasorelaxation in large arteries after myocardial infarction. Am J Physiol 2002; 283: H768–75
Griffin K, Woodman C, Price E, et al. Endothelium-mediated relaxation of porcine collateral-dependent arterioles is improved by exercise training. Circulation 2001; 103: 2839–44
Carneado J, Alvarez de Sotomayor M, Perez-Guerrero C, et al. Simvastatin improves endothelial function in spontaneously hypertensive rats through a Superoxide dismutase mediated antioxidant effect. J Hypertens 2002; 20: 429–37
Powers S, Ji L, Leeuwenburgh C. Exercise training-induced alterations in skeletal muscle antioxidant capacity: a brief review. Med Sci Sports Exerc 1999; 31: 987–97
Higashi Y, Sasaki S, Sasaki N, et al. Daily aerobic exercise improves reactive hyperaemia in patients with essential hypertension. Hypertension 1999; 33: 591–7
Higashi Y, Sasaki S, Kurisu S, et al. Regular aerobic exercise augments endothelium-dependent vascular relaxation in normotensive as well as hypertensive subjects. Circulation 1999; 100: 1194–202
Sciacqua A, Candigliota M, Ceravolo R, et al. Weight loss in combination with physical activity improves endothelial dysfunction in human obesity. Diabetes Care 2003; 26: 1673–8
Watts K, Beye P, Siafarikas A, et al. Exercise training normalises vascular dysfunction and improves central adiposity in obese adolescents. J Am Coll Cardiol. In press
Fuchsjager-Mayrl G, Pleiner J, Wiesinger GF, et al. Exercise training improves vascular endothelial function in patients with type 1 diabetes. Diabetes Care 2002; 25: 1795–801
US Department of Health and Human Services. Physical activity and health: a report of the Surgeon General. Atlanta (GA): US Department of Health and Human Services, Centres for Disease Control and Prevention, National Centre for Chronic Disease Prevention and Health Promotion, 1996
Hambrecht R, Wolf A, Geilen S, et al. Effect of exercise on coronary endothelial function in patients with coronary artery disease. N Engl J Med 2000; 342: 454–60
Gielen S, Erbs S, Linke A, et al. Home-based versus hospital-based exercise programs in patients with coronary artery disease: effects on coronary vasomotion. Am Heart J 2003; 145: e3
Gokce N, Vita J, Bader D, et al. Effect of exercise on upper and lower extremity endothelial function in patients with coronary artery disease. J Am Coll Cardiol 2002; 90: 124–7
Hambrecht R, Adams V, Erbs S, et al. Regular physical activity improves endothelial function in patients with coronary artery disease by increasing phosphorylation of endothelial nitric oxide synthase. Circulation 2003; 107: 3152–8
Ehsani A, Heath G, Hagberg J, et al. Effects of 12 months of intense exercise training on ischaemic ST-segment depression in patients with coronary artery disease. Circulation 1981; 64: 1116–24
Schuler G, Hambrecht R, Schlierf G. Regular physical exercise and low-fat diet: effects on progression of coronary artery disease. Circulation 1992; 86: 1–11
Wilson JR, Martin JL, Schwartz D, et al. Exercise intolerance in patients with chronic heart failure: role of impaired nutritive flow to skeletal muscle. Circulation 1984; 69: 1079–87
Kraemer MD, Kubo SH, Rector TS, et al. Pulmonary and peripheral vascular factors are important determinants of peak exercise oxygen uptake in patients with heart failure. J Am Coll Cardiol 1993; 21: 641–8
Mancini DM, Eisen H, Kussmaul W, et al. Value of peak exercise oxygen consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure. Circulation 1991; 83: 778–86
Myers J, Gullestad L, Vagelos R, et al. Clinical, hemodynamic, and cardiopulmonary exercise test determinants of survival in patients referred for evaluation of heart failure. Ann Intern Med 1998; 129: 286–93
Hornig B, Maier V, Drexler H. Physical training improves endothelial function in patients with chronic heart failure. Circulation 1996; 93: 210–4
Hambrecht R, Hilbrich L, Erbs S, et al. Correction of endothelial dysfunction in chronic heart failure: additional effects of exercise training and oral L-arginine supplementation. J Am Coll Cardiol 2000; 35: 706–13
Katz SD, Yuen J, Bijou R, et al. Training improves endothelium-dependent vasodilation in resistance vessels of patients with heart failure. J Appl Physiol 1997; 82: 1488–92
Minotti JR, Johnson EC, Hudson TL, et al. Skeletal muscle response to exercise training in congestive heart failure. J Clin Invest 1990; 86: 751–8
Bank AJ, Shammas RA, Mullen K, et al. Effects of short-term forearm exercise training on resistance vessel endothelial function in normal subjects and patients with heart failure. J Card Fail 1998; 4: 193–201
Demopoulos L, Bijou R, Fergus I, et al. Exercise training in patients with severe congestive heart failure: enhancing peak aerobic capacity while minimizing the increase in ventricular wall stress. J Am Coll Cardiol 1997; 29: 597–603
Hambrecht R, Fiehn E, Weigl C, et al. Regular physical exercise corrects endothelial dysfunction and improves exercise capacity in patients with chronic heart failure. Circulation 1998; 98: 2709–15
Linke A, Schoene N, Gielen S, et al. Endothelial dysfunction in patients with chronic heart failure: systemic effects of lower-limb exercise training. J Am Coll Cardiol 2001; 37: 392–7
Hambrecht R, Gielen S, Linke A, et al. Effects of exercise training on left ventricular function and peripheral resistance in patients with chronic heart failure. JAMA 2000; 283: 3095–101
Patterson GC, Whelan RF. Reactive hyperaemia in the human forearm. Clin Sci 1955; 14: 197–211
Schmidt A, Pleiner J, Bayerle-Eder M, et al. Regular physical exercise improves endothelial function in heart transplant recipients. Clin Transplant 2002; 16: 137–43
Maiorana A, O’Driscoll G, Cheetham C, et al. Combined aerobic and resistance exercise training improves functional capacity and strength in CHF. J Appl Physiol 2000; 88: 1565–70
Miyachi M, Tanaka H, Yamamoto K, et al. Effects of one-legged endurance training on femoral arterial and venous size in healthy humans. J Appl Physiol 2001; 90: 2439–44
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The authors wish to thank Paul Ricketts, Multimedia Designer, DUIT Multimedia, for constructing the diagram that appears in this manuscript. No sources of funding were used to assist in the preparation of this manuscript. The authors have no conflicts of interest that are directly relevant to the content of this manuscript.
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Maiorana, A., O’Driscoll, G., Taylor, R. et al. Exercise and the Nitric Oxide Vasodilator System. Sports Med 33, 1013–1035 (2003). https://doi.org/10.2165/00007256-200333140-00001
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DOI: https://doi.org/10.2165/00007256-200333140-00001