Sports Medicine

, Volume 33, Issue 14, pp 1013–1035 | Cite as

Exercise and the Nitric Oxide Vasodilator System

  • Andrew Maiorana
  • Gerard O’Driscoll
  • Roger Taylor
  • Daniel Green
Leading Article

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.

References

  1. 1.
    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: 9–13CrossRefGoogle Scholar
  2. 2.
    Sesso H, Paffenbarger R, Lee I. Physical activity and coronary heart disease in men: the Harvard Alumini Health Study. Circulation 2000; 102: 975–80PubMedCrossRefGoogle Scholar
  3. 3.
    Myers J, Prakash M, Froelicher V, et al. Exercise capacity and mortality among men referred for exercise testing. N Engl J Med 2002; 346: 793–801PubMedCrossRefGoogle Scholar
  4. 4.
    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, 2003Google Scholar
  5. 5.
    Blair S. Evidence for success of exercise in weight loss and control. Ann Intern Med 1993; 119: 702–6PubMedGoogle Scholar
  6. 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: 919–24PubMedCrossRefGoogle Scholar
  7. 7.
    Williams P. High-density lipoprotein cholesterol and other risk factors for coronary heart disease in female runners. N Engl J Med 1996; 334: 1298–303PubMedCrossRefGoogle Scholar
  8. 8.
    Holloszy J, Schultz J, Kusnierkiewicz J, et al. Effects of exercise on glucose tolerance and insulin resistance. Acta Med Scand Suppl 1986; 711: 55–65PubMedGoogle Scholar
  9. 9.
    Blair S, Goodyear N, Gibbons L. Physical activity and incidence of hypertension in healthy normotensive men and women. JAMA 1984; 252: 487–90PubMedCrossRefGoogle Scholar
  10. 10.
    Kelley G. Aerobic exercise and resting blood pressure among women: a meta-analysis of randomised controlled trials. Prev Med 1999; 28: 264–75PubMedCrossRefGoogle Scholar
  11. 11.
    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: 834–40CrossRefGoogle Scholar
  12. 12.
    El-Sayed MS, Sale C, Jones PG, et al. Blood hemostasis in exercise and training. Med Sci Sports Exerc 2000; 32: 918–25PubMedGoogle Scholar
  13. 13.
    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: 1722–7PubMedCrossRefGoogle Scholar
  14. 14.
    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: 1774–7PubMedCrossRefGoogle Scholar
  15. 15.
    Kubes P, Suzuki M, Granger D. Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci U S A 1991; 88: 4651–5PubMedCrossRefGoogle Scholar
  16. 16.
    Rubanyi G. The role of endothelium in cardiovascular homeostasis and diseases. J Cardiovasc Pharmacol 1993; 22: S1–S14PubMedCrossRefGoogle Scholar
  17. 17.
    Moncada S, Vane J. Pharmacology and endogenous roles or prostaglandin endoperoxides, thromboxane A2, and prostacyclin. Pharmacol Rev 1978; 30: 293–331PubMedGoogle Scholar
  18. 18.
    Cohen R, Vanhoutte P. Endothelium-dependent hyperpolarization: beyond nitric oxide and cyclic GMP. Circulation 1995; 92: 3337–49PubMedCrossRefGoogle Scholar
  19. 19.
    Muller-Estrl W. Kininogen, kinins and kinships. Thromb Haemost 1989; 61: 2–6Google Scholar
  20. 20.
    Ignarro L. Endothelium-derived nitric oxide: actions and properties. FASEB J 1989; 3: 31–6PubMedGoogle Scholar
  21. 21.
    Dzau VJ. Circulating versus local renin-angiotensin system in cardiovascular homeostasis. Circulation 1988; 77: I4–13PubMedCrossRefGoogle Scholar
  22. 22.
    Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988; 332: 411–5PubMedCrossRefGoogle Scholar
  23. 23.
    Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980; 288: 373–6PubMedCrossRefGoogle Scholar
  24. 24.
    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: 1251–6PubMedCrossRefGoogle Scholar
  25. 25.
    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: 4997–5002PubMedGoogle Scholar
  26. 26.
    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: 52–61PubMedGoogle Scholar
  27. 27.
    Vallance P, Collier J, Moncada S. Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet 1989; II(8670): 997–1000CrossRefGoogle Scholar
  28. 28.
    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: 43–54PubMedCrossRefGoogle Scholar
  29. 29.
    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: 1951–7PubMedCrossRefGoogle Scholar
  30. 30.
    Loscalzo J, Welch G. Nitric oxide and its role in the cardiovascular system. Prog Cardiovasc Dis 1995; 38: 87–104PubMedCrossRefGoogle Scholar
  31. 31.
    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: H257–62PubMedGoogle Scholar
  32. 32.
    Rubanyi GM, Romero JC, Vanhoutte PM. Flow-induced release of endothelium-derived relaxing factor. Am J Physiol 1986; 250: H1145–9PubMedGoogle Scholar
  33. 33.
    Olesen SP, Clapham DE, Davies PF. Haemodynamic shear stress activates a K+ current in vascular endothelial cells. Nature 1988; 331: 168–70PubMedCrossRefGoogle Scholar
  34. 34.
    Guharay F, Sachs F. Stretch activated single ion channel currents in tissue cultured embryonic chick skeletal muscle cells. J Physiol 1984; 352: 685–701PubMedGoogle Scholar
  35. 35.
    Cooke JP, Rossitch EJ, Andon NA, et al. Flow activates an endothelial potassium channel to release an endogenous nitrovasodilator. J Clin Invest 1991; 88: 1663–71PubMedCrossRefGoogle Scholar
  36. 36.
    Dull RO, Davies PF. Flow modulation of agonist (ATP)-response (Ca2+) coupling in vascular endothelial cells. Am J Physiol 1991; 261: H149–54PubMedGoogle Scholar
  37. 37.
    Mo M, Eskin SG, Schilling WP. Flow-induced changes in Ca2+ signalling of vascular endothelial cells. Am J Physiol 1991; 260: 1698–707Google Scholar
  38. 38.
    Falcone JC, Kuo L, Meininger GA. Endothelial cell calcium increases during flow-induced dilation in isolated arterioles. Am J Physiol 1993; 264: H653–9PubMedGoogle Scholar
  39. 39.
    Hecker M, Bara AT, Busse R. Angiotensin-converting enzyme inhibitors unmask endogenous kinin production by bovine coronary artery endothelium. Eur Heart J 1993; 14: 161–3PubMedCrossRefGoogle Scholar
  40. 40.
    Groves P, Kursz S, Just H, et al. Role of endogenous bradykinin in human coronary vasomotor control. Circulation 1995; 92: 3424–30PubMedCrossRefGoogle Scholar
  41. 41.
    Dimmeler S, Fleming I, Fisslthaler B, et al. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature 1999; 399: 601–5PubMedCrossRefGoogle Scholar
  42. 42.
    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: 1314–9PubMedCrossRefGoogle Scholar
  43. 43.
    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: 752–8PubMedCrossRefGoogle Scholar
  44. 44.
    Bogaty P, Hackett D, Davies G, et al. Vasoreactivity of the culprit lesion in unstable angina. Circulation 1994; 90: 5–11PubMedCrossRefGoogle Scholar
  45. 45.
    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: 85–92PubMedCrossRefGoogle Scholar
  46. 46.
    Ohara Y, Peterson TE, Harrison DG. Hypercholesterolemia increases endothelial Superoxide anion production. J Clin Invest 1993; 91: 2546–51PubMedCrossRefGoogle Scholar
  47. 47.
    Berliner JA, Navab M, Fogelman AB. Atherosclerosis: basic mechanisms: oxidation, inflammation, and genetics. Circulation 1995; 91: 2488–96PubMedCrossRefGoogle Scholar
  48. 48.
    Kojda G, Harrison D. Interactions between NO and reactive oxygen species: pathophysiological importance in atherosclerosis, hypertension, diabetes and heart failure. Cardiovasc Res 1999; 43: 562–71PubMedCrossRefGoogle Scholar
  49. 49.
    McLenachan JM, Vita J, Fish DR, et al. Early evidence of endothelial vasodilator dysfunction at coronary branch points. Circulation 1990; 82: 1169–73PubMedCrossRefGoogle Scholar
  50. 50.
    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: 2149–55PubMedCrossRefGoogle Scholar
  51. 51.
    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: 488–93PubMedCrossRefGoogle Scholar
  52. 52.
    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: 361–7PubMedCrossRefGoogle Scholar
  53. 53.
    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: 1351–7PubMedCrossRefGoogle Scholar
  54. 54.
    O’Driscoll G, Green D, Taylor R. Simvastatin, an HMG-Coenzyme A reductase inhibitor, improves endothelial function within 1 month. Circulation 1997; 95: 1126–31PubMedCrossRefGoogle Scholar
  55. 55.
    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: 1506–11PubMedCrossRefGoogle Scholar
  56. 56.
    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: 522–6PubMedCrossRefGoogle Scholar
  57. 57.
    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: 1111–5PubMedCrossRefGoogle Scholar
  58. 58.
    Vita J, Treasure C, Nabel E, et al. Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease. Circulation 1990; 81: 491–7PubMedCrossRefGoogle Scholar
  59. 59.
    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: 77–81PubMedCrossRefGoogle Scholar
  60. 60.
    Taddei S, Virdis A, Mattel P, et al. Aging and endothelial function in normotensive subjects and patients with essential hypertension. Circulation 1995; 91: 1981–7PubMedCrossRefGoogle Scholar
  61. 61.
    Gerhard M, Roddy M-A, Creager SJ, et al. Aging progressively impairs endothelium-dependent vasodilation in forearm resistance vessels of humans. Hypertension 1996; 27: 849–53PubMedCrossRefGoogle Scholar
  62. 62.
    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: 482–90PubMedCrossRefGoogle Scholar
  63. 63.
    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: 1228–32PubMedCrossRefGoogle Scholar
  64. 64.
    Nitenberg A, Antony I, Foult JM. Acetylcholine-induced coronary vasoconstriction in young, heavy smokers with normal coronary arteriographic findings. Am J Med 1993; 95: 71–7PubMedCrossRefGoogle Scholar
  65. 65.
    Drexler H, Zeiher K, Meinzer K, et al. Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolaemic patients by L-arginine. Lancet 1991; 338: 1546–50PubMedCrossRefGoogle Scholar
  66. 66.
    Creager MA, Cooke JP, Mendelhson ME, et al. Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans. J Clin Invest 1990; 86: 228–34PubMedCrossRefGoogle Scholar
  67. 67.
    Chowienczyk PJ, Watts GF, Cockcroft JR, et al. Impaired endothelium-dependent vasodilation of forearm resistance vessels in hypercholesterolaemia. Lancet 1992; 340: 1430–2PubMedCrossRefGoogle Scholar
  68. 68.
    Casino PR, Kilcoyne CM, Quyyumi AA, et al. Role of nitric oxide in endothelium-dependent vasodilation of hypercholes-terolemic patients. Circulation 1993; 88: 2541–7PubMedCrossRefGoogle Scholar
  69. 69.
    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: 50–5PubMedCrossRefGoogle Scholar
  70. 70.
    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: 561–5CrossRefGoogle Scholar
  71. 71.
    Tamai O, Matsuoka H, Itabe H, et al. Single LDL apheresis improves endothelium-dependent vasodilatation in hypercholesterolemic humans. Circulation 1997; 95: 76–82PubMedCrossRefGoogle Scholar
  72. 72.
    Panza J, Quyyumi A, Brush J, et al. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med 1990; 323: 22–7PubMedCrossRefGoogle Scholar
  73. 73.
    Higashi Y, Oshima T, Ozono R, et al. Aging and severity of hypertension attenuate endothelium-dependent renal vascular relaxation in humans. Hypertension 1997; 30: 252–8PubMedCrossRefGoogle Scholar
  74. 74.
    Treasure C, Manoukian S, Klein J, et al. Epicardial coronary artery responses to acetylcholine are impaired in hypertensive patients. Circ Res 1992; 71: 776–81PubMedCrossRefGoogle Scholar
  75. 75.
    Brush JE, Faxon DP, Salmon S, et al. Abnormal endothelium-dependent coronary vasomotion in hypertensive patients. J Am Coll Cardiol 1992; 19: 809–15PubMedCrossRefGoogle Scholar
  76. 76.
    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: 201–6PubMedCrossRefGoogle Scholar
  77. 77.
    Perticone F, Ceravolo R, Pujia A, et al. Prognostic significance of endothelial dysfunction in hypertensive patients. Circulation 2001; 104: 191–6PubMedCrossRefGoogle Scholar
  78. 78.
    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: 327ACrossRefGoogle Scholar
  79. 79.
    Bosch J, Yusuf S, Pogue J, et al. Use of ramapril in preventing stroke: double blind randomised trial. BMJ 2002; 324: 699–702PubMedCrossRefGoogle Scholar
  80. 80.
    Sleight P, Yusuf S, Pogue J, et al. Blood pressure reduction and cardiovascular risk in HOPE study. Lancet 2001; 358: 2130–1PubMedCrossRefGoogle Scholar
  81. 81.
    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: 968–77PubMedCrossRefGoogle Scholar
  82. 82.
    Arcaro G, Zamboni M, Rossi L, et al. Body fat distribution predicts degree of endothelial dysfunction in uncomplicated obesity. Int J Obes 1999; 23: 9936–42CrossRefGoogle Scholar
  83. 83.
    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: 159–65PubMedCrossRefGoogle Scholar
  84. 84.
    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: 1523–8PubMedCrossRefGoogle Scholar
  85. 85.
    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: 1540–5PubMedCrossRefGoogle Scholar
  86. 86.
    Calles-Escandon J, Cipolla M. Diabetes and endothelial dysfunction: a clinical perspective. Endocr Rev 2001; 22: 36–52PubMedCrossRefGoogle Scholar
  87. 87.
    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: 771–6PubMedGoogle Scholar
  88. 88.
    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: 103–12CrossRefGoogle Scholar
  89. 89.
    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: 567–74PubMedCrossRefGoogle Scholar
  90. 90.
    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: 567–73PubMedGoogle Scholar
  91. 91.
    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: 22–8PubMedCrossRefGoogle Scholar
  92. 92.
    Avogaro A, Piarulli F, Valerio A, et al. Forearm nitric oxide balance, vascular relaxation, and glucose metabolism in NIDDM patients. Diabetes 1997; 46: 1040–6PubMedCrossRefGoogle Scholar
  93. 93.
    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: 2548–54PubMedCrossRefGoogle Scholar
  94. 94.
    Johnstone MT, Creager SJ, Scales KM, et al. Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. Circulation 1993; 88: 2510–6PubMedCrossRefGoogle Scholar
  95. 95.
    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: 31–6PubMedGoogle Scholar
  96. 96.
    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: 678–84PubMedCrossRefGoogle Scholar
  97. 97.
    Ludmer P, Selwyn A, Shook T, et al. Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med 1986; 315: 1046–51PubMedCrossRefGoogle Scholar
  98. 98.
    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: 1235–41PubMedCrossRefGoogle Scholar
  99. 99.
    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: 111–8PubMedCrossRefGoogle Scholar
  100. 100.
    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: 948–54CrossRefGoogle Scholar
  101. 101.
    Schachinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 2000; 101: 1899–906PubMedCrossRefGoogle Scholar
  102. 102.
    Halcox JPJ, Schenke WH, Zalos G, et al. Prognostic value of coronary vascular endothelial dysfunction. Circulation 2002; 106: 653–8PubMedCrossRefGoogle Scholar
  103. 103.
    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: 207–10PubMedCrossRefGoogle Scholar
  104. 104.
    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: 1567–72PubMedCrossRefGoogle Scholar
  105. 105.
    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: V15–6Google Scholar
  106. 106.
    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: 585–90PubMedCrossRefGoogle Scholar
  107. 107.
    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: 1352–6CrossRefGoogle Scholar
  108. 108.
    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: 245–51PubMedCrossRefGoogle Scholar
  109. 109.
    Treasure CB, Vita JA, Cox DA. Endothelium-dependent dilation of the coronary microvasculature is impaired in dilated cardiomyopathy. Circulation 1990; 81: 772–9PubMedCrossRefGoogle Scholar
  110. 110.
    Drexler H, Hayoz D, Munzel T, et al. Endothelial function in chronic congestive heart failure. Am J Cardiol 1992; 69: 1596–601PubMedCrossRefGoogle Scholar
  111. 111.
    Katz SD, Schwarz M, Yuen J, et al. Impaired acetylcholine-mediated vasodilation in patients with congestive heart failure. Circulation 1993; 88: 55–61PubMedCrossRefGoogle Scholar
  112. 112.
    Kubo SH, Rector TS, Bank AJ, et al. Endothelium-dependent vasodilation is attenuated in patients with heart failure. Circulation 1991; 84: 1589–96PubMedCrossRefGoogle Scholar
  113. 113.
    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: 918–25PubMedCrossRefGoogle Scholar
  114. 114.
    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: 1875–81PubMedCrossRefGoogle Scholar
  115. 115.
    Lindsay D, Holdright D, Clarke D, et al. Endothelial control of lower limb blood flow in chronic heart failure. Heart 1996; 75: 469–76PubMedCrossRefGoogle Scholar
  116. 116.
    Andersen P. Maximal perfusion of skeletal muscle in man. J Physiol 1985; 366: 233–49PubMedGoogle Scholar
  117. 117.
    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: 257–73PubMedGoogle Scholar
  118. 118.
    Laughlin MH. Skeletal muscle blood flow capacity: role of muscle pump in exercise hyperaemia. Am J Physiol 1987; 253: H993–1004PubMedGoogle Scholar
  119. 119.
    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: 551–9CrossRefGoogle Scholar
  120. 120.
    Hester R, Guyton A, Barber B. Reactive and exercise hyperaemia during high levels of adenosine infusion. Am J Physiol 1982; 243: H181–6PubMedGoogle Scholar
  121. 121.
    Kobzik L, Reid MB, Bredt DS, et al. Nitric oxide in skeletal muscle. Nature 1994; 372: 546–8PubMedCrossRefGoogle Scholar
  122. 122.
    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: H1078–83PubMedGoogle Scholar
  123. 123.
    Gow A, Stamler J. Reactions between nitric oxide and haemoglobin under physiological conditions. Nature 1998; 391: 169–73PubMedCrossRefGoogle Scholar
  124. 124.
    Segal SS, Kurjiaka DT. Coordination of blood flow control in the resistance vasculature of skeletal muscle. Med Sci Sports Exerc 1995; 27: 1158–64PubMedGoogle Scholar
  125. 125.
    Segal SS. Communication among endothelial and smooth muscle cells coordinates blood flow control during exercise. News Physiol Sci 1992; 7: 152–6Google Scholar
  126. 126.
    Green DJ, O’Driscoll JG, Blanksby BA, et al. Control of skeletal muscle blood flow during dynamic exercise. Sports Med 1996; 21: 119–46PubMedCrossRefGoogle Scholar
  127. 127.
    Folkow B, Sonnenschein RR, Wright DL. Loci of neurogenic and metabolic effects on precapillary vessels of skeletal muscle. Acta Physiol Scand 1971; 81: 459–71PubMedCrossRefGoogle Scholar
  128. 128.
    Koller A, Kaley G. Endothelial regulation of wall shear stress and blood flow in skeletal muscle microcirculation. Am J Physiol 1991; 260: H862–8PubMedGoogle Scholar
  129. 129.
    Falcone JC, Davis MJ, Meininger GA. Endothelial independence of myogenic response in isolated skeletal muscle arterioles. Am J Physiol 1991; 260: H130–5PubMedGoogle Scholar
  130. 130.
    Segal SS, Damon DN, Duling BR. Propagation of vasomotor responses coordinates arteriolar resistances. Am J Physiol 1989; 256: H832–7PubMedGoogle Scholar
  131. 131.
    Delp MD, Laughlin MH. Regulation of skeletal muscle perfusion during exercise. Acta Physiol Scand 1998; 162: 411–9PubMedCrossRefGoogle Scholar
  132. 132.
    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: 165–72PubMedGoogle Scholar
  133. 133.
    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): 1288–93PubMedGoogle Scholar
  134. 134.
    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: 2799–808PubMedCrossRefGoogle Scholar
  135. 135.
    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: 49–56PubMedCrossRefGoogle Scholar
  136. 136.
    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: H195–200PubMedGoogle Scholar
  137. 137.
    Kingwell BA. Nitric oxide as a metabolic regulator during exercise: effects of training in health and disease. Clin Exp Pharmacol Physiol 2000; 27: 239–50PubMedCrossRefGoogle Scholar
  138. 138.
    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: 1–137CrossRefGoogle Scholar
  139. 139.
    Bode-Böger SM, Böger RH, Scroder EP, et al. Exercise increases systemic nitric oxide production in men. J Cardiovasc Risk 1994; 1: 173–8PubMedGoogle Scholar
  140. 140.
    Wilson JR, Kapoor S. Contribution of endothelium-derived relaxing factor to exercise-induced vasodilation in humans. J Appl Physiol 1993; 75: 2740–4PubMedGoogle Scholar
  141. 141.
    Endo T, Imaizumi T, Tagawa T, et al. Role of nitric oxide in exercise-induced vasodilation of the forearm. Circulation 1994; 90: 2886–90PubMedCrossRefGoogle Scholar
  142. 142.
    Joyner MJ, Dietz NM. Nitric oxide and vasodilation in human limbs. J Appl Physiol 1997; 83: 1785–96PubMedGoogle Scholar
  143. 143.
    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: 2249–54Google Scholar
  144. 144.
    Gilligan DM, Panza JA, Kilcoyne CM, et al. Contribution of endothelium-derived nitric oxide to exercise-induced vasodilation. Circulation 1994; 90: 2853–8PubMedCrossRefGoogle Scholar
  145. 145.
    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: 259–65PubMedGoogle Scholar
  146. 146.
    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: H663–70Google Scholar
  147. 147.
    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: H405–10PubMedGoogle Scholar
  148. 148.
    Radegran G, Saltin B. Nitric oxide in the regulation of vasomotor tone in human skeletal muscle. Am J Physiol 1999; 276: H1951–60PubMedGoogle Scholar
  149. 149.
    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: 1815–21PubMedCrossRefGoogle Scholar
  150. 150.
    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: 1855–61PubMedCrossRefGoogle Scholar
  151. 151.
    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: H726–32Google Scholar
  152. 152.
    Radegran G, Saltin B. Muscle blood flow at the onset of dynamic exercise in humans. Am J Physiol 1998; 274: H314–22PubMedGoogle Scholar
  153. 153.
    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: H899–907Google Scholar
  154. 154.
    Green D, Cheetham C, Henderson C, et al. Effect of cardiac pacing on forearm vascular function. Am J Physiol 2002; 283: H1354–60Google Scholar
  155. 155.
    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: 1274–9PubMedCrossRefGoogle Scholar
  156. 156.
    Quyyumi AA, Dakak N, Andrews NP, et al. Contribution of nitric oxide to metabolic coronary vasodilation in the human heart. Circulation 1995; 92: 320–6PubMedCrossRefGoogle Scholar
  157. 157.
    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: 1256–62PubMedCrossRefGoogle Scholar
  158. 158.
    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: 331–5PubMedCrossRefGoogle Scholar
  159. 159.
    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: 304–10PubMedCrossRefGoogle Scholar
  160. 160.
    Quyyumi AA, Dakak N, Andrews NP, et al. Nitric oxide activity in the human coronary circulation. J Clin Invest 1995; 95: 1747–55PubMedCrossRefGoogle Scholar
  161. 161.
    Sinoway LI, Musch TI, Minotti JR, et al. Enhanced maximal metabolic vasodilation in the dominant forearms of tennis players. J Appl Physiol 1986; 61: 673–8PubMedGoogle Scholar
  162. 162.
    Sinoway LI, Shenberger J, Wilson J, et al. A 30-day forearm work protocol increases maximal forearm blood flow. J Appl Physiol 1987; 62: 1063–7PubMedGoogle Scholar
  163. 163.
    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: 981–6PubMedCrossRefGoogle Scholar
  164. 164.
    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: 2241–7PubMedGoogle Scholar
  165. 165.
    Koller A, Huang A, Sun D, et al. Exercise training augments flow-dependent dilation in rat skeletal muscle arterioles. Circ Res 1995; 76: 544–50PubMedCrossRefGoogle Scholar
  166. 166.
    Sun D, Huang A, Koller A, et al. Adaptation of flow-induced dilation of arterioles to daily exercise. Microvasc Res 1998; 56: 54–61PubMedCrossRefGoogle Scholar
  167. 167.
    McAllister RM, Laughlin MH. Short-term exercise training alters responses of porcine femoral and brachial arteries. J Appl Physiol 1997; 82: 1438–44PubMedCrossRefGoogle Scholar
  168. 168.
    Delp MD, Laughlin MH. Time course of enhanced endothelium-mediated dilation in aorta of trained rats. Med Sci Sports Exerc 1997; 29: 1454–61PubMedCrossRefGoogle Scholar
  169. 169.
    Delp MD, McAllister RM, Laughlin MH. Exercise training alters endothelium-dependent vasoreactivity of rat abdominal aorta. J Appl Physiol 1993; 75: 1354–63PubMedGoogle Scholar
  170. 170.
    Chen H, Li H-T. Physical conditioning can modulate endothelium-dependent vasorelaxation in rabbits. Arterioscler Thromb 1993; 13: 852–6PubMedCrossRefGoogle Scholar
  171. 171.
    McAllister RM, Kimani JK, Webster JL, et al. Effects of exercise training on peripheral and visceral arteries in swine. J Appl Physiol 1996; 80: 216–5PubMedCrossRefGoogle Scholar
  172. 172.
    Kingwell B, Arnold P, Jennings G, et al. Spontaneous running increases aortic compliance in Wistar-Kyoto rats. Cardiovasc Res 1997; 35: 132–7PubMedCrossRefGoogle Scholar
  173. 173.
    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: 1102–10PubMedCrossRefGoogle Scholar
  174. 174.
    Johnson LR, Laughlin MH. Chronic exercise training does not alter pulmonary vasorelaxation in normal pigs. J Appl Physiol 2000; 88: 2008–16PubMedGoogle Scholar
  175. 175.
    Leon AS, Bloor CM. Effects of exercise and its cessation on the heart and its blood supply. J Appl Physiol 1968; 24: 485–90PubMedGoogle Scholar
  176. 176.
    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: 1483–9PubMedCrossRefGoogle Scholar
  177. 177.
    Wyatt HL, Mitchell J. Influences of physical conditioning and deconditioning on coronary vasculature of dogs. J Appl Physiol 1978; 45: 619–25PubMedGoogle Scholar
  178. 178.
    Lash J, Bohlen H. Functional adaptations of rat skeletal muscle arterioles to aerobic exercise training. J Appl Physiol 1992; 72: 2052–62PubMedGoogle Scholar
  179. 179.
    Kamiya A, Togawa T. Adaptive regulation of wall shear stress to flow change in the canine carotid artery. Am J Physiol 1980; 239: H14–21PubMedGoogle Scholar
  180. 180.
    Langille BL, O’Donnell F. Reductions in arterial diameter produced by chronic decreases in blood flow are endothelium-dependent. Nature 1986; 231: 405–7Google Scholar
  181. 181.
    Zarins CK, Zatina MA, Giddens DP, et al. Shear stress regulation of artery lumen diameter in experimental atherosclerosis. J Vasc Surg 1987; 5: 413–20PubMedGoogle Scholar
  182. 182.
    Gibbons G, Dzau V. The emerging concept of vascular remodelling. N Engl J Med 1994; 330: 1431–8PubMedCrossRefGoogle Scholar
  183. 183.
    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: 731–6PubMedCrossRefGoogle Scholar
  184. 184.
    Prior BM, Lloyd PG, Yang HT, et al. Exercise-induced vascular remodelling. Exerc Sports Sci Rev 2003; 31: 26–33CrossRefGoogle Scholar
  185. 185.
    DiCarlo SE, Blair RW, Bishop VS, et al. Daily exercise enhances coronary resistance vessel sensitivity to pharmacological activation. J Appl Physiol 1989; 66: 421–8PubMedGoogle Scholar
  186. 186.
    Laughlin M, Overholser K, Bhatte M. Exercise training increases coronary transport reserve in miniature swine. J Appl Physiol 1989; 67: 1140–9PubMedGoogle Scholar
  187. 187.
    Wang J, Wolin MS, Hintze TH. Chronic exercise enhances endothelium-mediated dilation of epicardial coronary artery in conscious dogs. Circ Res 1993; 73: 829–38PubMedCrossRefGoogle Scholar
  188. 188.
    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: 349–53PubMedCrossRefGoogle Scholar
  189. 189.
    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: H1–5Google Scholar
  190. 190.
    Muller JD, Myers PR, Laughlin MH. Vasodilator responses of coronary resistance arteries of exercise-trained pigs. Circulation 1994; 89: 2308–14PubMedCrossRefGoogle Scholar
  191. 191.
    Oltman C, Parker J, Adams H, et al. Effects of exercise training on vasomotor reactivity of porcine coronary arteries. Am J Physiol 1992; 263: H372–82PubMedGoogle Scholar
  192. 192.
    Maxwell AJ, Schauble E, Berstein D, et al. Limb blood flow during exercise is dependent on nitric oxide. Circulation 1998; 98: 369–74PubMedCrossRefGoogle Scholar
  193. 193.
    Niebauer J, Maxwell A, Lin P, et al. Impaired aerobic capacity in hypercholesterolemic mice: partial reversal by exercise training. Am J Physiol 1999; 276: H1346–54PubMedGoogle Scholar
  194. 194.
    Yen MH, Yang JH, Sheu JR, et al. Chronic exercise enhances endothelium-mediated dilation in spontaneously hypertensive rats. Life Sci 1995; 57: 2205–13PubMedCrossRefGoogle Scholar
  195. 195.
    Chen HI, Chiang IP. Chronic exercise decreases adrenergic agonist-induced vasoconstriction in spontaneously hypertensive rats. Am J Physiol 1996; 271: H977–83PubMedGoogle Scholar
  196. 196.
    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: 149–53PubMedCrossRefGoogle Scholar
  197. 197.
    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: 82–6PubMedCrossRefGoogle Scholar
  198. 198.
    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: 694–7PubMedCrossRefGoogle Scholar
  199. 199.
    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: 2683–92PubMedCrossRefGoogle Scholar
  200. 200.
    Silber DH, Sinoway LI. Reversible impairment of forearm vasodilation after forearm casting. J Appl Physiol 1990; 68: 1945–9PubMedGoogle Scholar
  201. 201.
    Haskell WL, Sims C, Myell J, et al. Coronary artery size and dilating capacity in ultradistance runners. Circulation 1993; 87: 1076–82PubMedCrossRefGoogle Scholar
  202. 202.
    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: 1005–16PubMedCrossRefGoogle Scholar
  203. 203.
    Green DJ, Cable NT, Fox C, et al. Modification of forearm resistance vessels by exercise training in young men. J Appl Physiol 1994; 77: 1829–33PubMedGoogle Scholar
  204. 204.
    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: 943–8PubMedGoogle Scholar
  205. 205.
    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: 1325–31PubMedCrossRefGoogle Scholar
  206. 206.
    Franke WD, Stephens GM, Schmid PG. Effects of intense exercise training on endothelium-dependent exercise induced vasodilatation. Clin Physiol 1998; 18: 521–8PubMedCrossRefGoogle Scholar
  207. 207.
    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: H1070–7PubMedGoogle Scholar
  208. 208.
    Clarkson P, Montgomery HE, Mullen MJ, et al. Exercise training enhances endothelial function in young men. J Am Coll Cardiol 1999; 33: 1379–85PubMedCrossRefGoogle Scholar
  209. 209.
    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: 860–6PubMedCrossRefGoogle Scholar
  210. 210.
    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: 20–5PubMedGoogle Scholar
  211. 211.
    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): 1681–9PubMedCrossRefGoogle Scholar
  212. 212.
    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: 2022–8PubMedCrossRefGoogle Scholar
  213. 213.
    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: H1999–2005Google Scholar
  214. 214.
    Taddei S, Galetta F, Virdis A, et al. Physical activity prevents age-related impairment in nitric oxide availability in elderly athletes. Circulation 2000; 101: 2896–901PubMedCrossRefGoogle Scholar
  215. 215.
    Bergholm R, Makimattila S, Valkonen N, et al. Intense physical training decreases circulating antioxidants and endothelium-dependent vasodilation in vivo. Atherosclerosis 1999; 145: 141–9CrossRefGoogle Scholar
  216. 216.
    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: 530–5PubMedCrossRefGoogle Scholar
  217. 217.
    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: 2782–7PubMedCrossRefGoogle Scholar
  218. 218.
    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: 83–9PubMedGoogle Scholar
  219. 219.
    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: H768–75Google Scholar
  220. 220.
    Griffin K, Woodman C, Price E, et al. Endothelium-mediated relaxation of porcine collateral-dependent arterioles is improved by exercise training. Circulation 2001; 103: 2839–44CrossRefGoogle Scholar
  221. 221.
    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: 429–37PubMedCrossRefGoogle Scholar
  222. 222.
    Powers S, Ji L, Leeuwenburgh C. Exercise training-induced alterations in skeletal muscle antioxidant capacity: a brief review. Med Sci Sports Exerc 1999; 31: 987–97PubMedCrossRefGoogle Scholar
  223. 223.
    Higashi Y, Sasaki S, Sasaki N, et al. Daily aerobic exercise improves reactive hyperaemia in patients with essential hypertension. Hypertension 1999; 33: 591–7PubMedCrossRefGoogle Scholar
  224. 224.
    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: 1194–202PubMedCrossRefGoogle Scholar
  225. 225.
    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: 1673–8PubMedCrossRefGoogle Scholar
  226. 226.
    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 pressGoogle Scholar
  227. 227.
    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: 1795–801PubMedCrossRefGoogle Scholar
  228. 228.
    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, 1996Google Scholar
  229. 229.
    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: 454–60PubMedCrossRefGoogle Scholar
  230. 230.
    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: e3PubMedGoogle Scholar
  231. 231.
    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: 124–7Google Scholar
  232. 232.
    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: 3152–8PubMedCrossRefGoogle Scholar
  233. 233.
    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: 1116–24PubMedCrossRefGoogle Scholar
  234. 234.
    Schuler G, Hambrecht R, Schlierf G. Regular physical exercise and low-fat diet: effects on progression of coronary artery disease. Circulation 1992; 86: 1–11PubMedCrossRefGoogle Scholar
  235. 235.
    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: 1079–87PubMedCrossRefGoogle Scholar
  236. 236.
    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: 641–8PubMedCrossRefGoogle Scholar
  237. 237.
    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: 778–86PubMedCrossRefGoogle Scholar
  238. 238.
    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: 286–93PubMedGoogle Scholar
  239. 239.
    Hornig B, Maier V, Drexler H. Physical training improves endothelial function in patients with chronic heart failure. Circulation 1996; 93: 210–4PubMedCrossRefGoogle Scholar
  240. 240.
    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: 706–13PubMedCrossRefGoogle Scholar
  241. 241.
    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: 1488–92PubMedCrossRefGoogle Scholar
  242. 242.
    Minotti JR, Johnson EC, Hudson TL, et al. Skeletal muscle response to exercise training in congestive heart failure. J Clin Invest 1990; 86: 751–8PubMedCrossRefGoogle Scholar
  243. 243.
    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: 193–201PubMedCrossRefGoogle Scholar
  244. 244.
    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: 597–603PubMedCrossRefGoogle Scholar
  245. 245.
    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: 2709–15PubMedCrossRefGoogle Scholar
  246. 246.
    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: 392–7PubMedCrossRefGoogle Scholar
  247. 247.
    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: 3095–101PubMedCrossRefGoogle Scholar
  248. 248.
    Patterson GC, Whelan RF. Reactive hyperaemia in the human forearm. Clin Sci 1955; 14: 197–211PubMedGoogle Scholar
  249. 249.
    Schmidt A, Pleiner J, Bayerle-Eder M, et al. Regular physical exercise improves endothelial function in heart transplant recipients. Clin Transplant 2002; 16: 137–43PubMedCrossRefGoogle Scholar
  250. 250.
    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: 1565–70PubMedGoogle Scholar
  251. 251.
    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: 2439–44PubMedGoogle Scholar

Copyright information

© Adis Data Information BV 2003

Authors and Affiliations

  • Andrew Maiorana
    • 1
    • 2
    • 3
  • Gerard O’Driscoll
    • 3
    • 4
  • Roger Taylor
    • 2
    • 4
  • Daniel Green
    • 1
    • 3
    • 4
  1. 1.Department of Human Movement and Exercise ScienceThe University of Western AustraliaCrawleyAustralia
  2. 2.Department of MedicineThe University of Western AustraliaCrawleyAustralia
  3. 3.Cardiac Transplant UnitRoyal Perth Hospital and West Australian Heart Research InstitutePerthAustralia
  4. 4.Department of CardiologyRoyal Perth Hospital and West Australian Heart Research InstitutePerthAustralia

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