Abstract
In this review article we examine the main mechanisms leading to decreased nitric oxide (NO) bioavailability, and we present the current strategies available to increase NO levels, mainly by using antioxidants in patients with coronary artery disease. Decreased NO bioavailability in the vasculature is a key feature of all the classic risk factors for atherosclerosis, and it can be the result of NO's decreased synthesis and increased oxidative deactivation. Increased NO synthesis can be achieved by improving the intracellular redox state in endothelial cells, stabilizing endothelial NO synthase (eNOS) dimers, and maintaining sufficient intracellular levels of eNOS substrate L-arginine. Antioxidant treatment may have a dual role by increasing NO synthesis and decreasing its oxidative deactivation. However, in patients with coronary artery disease, although intracoronary infusions of vitamins or chronic vitamin treatment improve endothelial function, their effect on clinical outcome is questioned. In conclusion, in coronary artery disease, NO bioavailability can be increased mainly by reversing the causes of endothelial dysfunction via treatment of classic risk factors, while the use of antioxidant vitamins is controversial and the ideal antioxidant strategy is still unknown.
References
Furchgott RF, Zawadzki JV (1980) The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288:373–376
Rapoport RM, Murad F (1983) Agonist-induced endothelium-dependent relaxation in rat thoracic aorta may be mediated through cGMP. Circ Res 52:352–357
Berkenboom G, Unger P, Fang ZY, Degre S, Fontaine J (1989) Comparison of the responses to acetylcholine and serotonin on isolated canine and human coronary arteries. Cardiovasc Res 23:780–787
Crossman DC, Larkin SW, Fuller RW, Davies GJ, Maseri A (1989) Substance P dilates epicardial coronary arteries and increases coronary blood flow in humans. Circulation 80:475–484
Luscher TF, Boulanger CM, Yang Z, Noll G, Dohi Y (1993) Interactions between endothelium-derived relaxing and contracting factors in health and cardiovascular disease. Circulation 87(Suppl V):V36–V44
Toutouzas P, Tousoulis D, Davies GJ (1998) Nitric oxide synthesis in atherosclerosis. Eur Heart J 19:1504–1511
Ludmer PL, Selwyn AP, Shook TL, Wayne RR, Mudge GH, Alexander RW, Ganz P (1986) Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med 315:1046–1051
Collins P, Burman J, Chung HI, Fox K (1993) Hemoglobin inhibits endothelium-derived relaxation to acetylcholine in human coronary arteries in vivo. Circulation 87:80–86
Luscher TF, Boulanger CM, Dohi Y, Yang Z (1992) Endothelium-derived contracting factors. Hypertension 19:117–130
Vanhoutte PM, Shimokawa H (1989) Endothelium-derived relaxing factor and coronary vasospasm. Circulation 80:1–9
Goumas G, Tentolouris C, Tousoulis D, Stefanadis C, Toutouzas P (2001) Therapeutic modification of the L-arginine-eNOS pathway in cardiovascular diseases. Atherosclerosis 154:255–267
Vanhoutte PM (1988) The endothelium. Modulator of vascular smooth muscle tone. N Engl J Med 319:512–513
Palmer RMJ, Ashton DS, Moncada S (1988) Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature 333:664–666
Palmer RMJ, Ferrige AG, Moncada S (1987) Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327:524–526
Ignarro LJ (1989) Biological actions and properties of endothelium-derived nitric oxide formed and released from artery and vein. Circ Res 65:1–21
Chu A, Chambers DE, Lin C, Kuehl WD, Cobb FR (1990) Nitric oxide modulates epicardial coronary basal vasomotor tone in awake dogs. Am J Physiol 258:H1250–H1254
Ôousoulis D, Antoniades C, Tentolouris C, Goumas G, Stefanadis C, Toutouzas P (2002) L-arginine in cardiovascular disease: dream or reality? Vasc Med 3:203–211
Nunokawa Y, Ishida N, Tanaka S (1993) Cloning of inducible nitric oxide synthase in rat vascular smooth muscle cells. Biochem Biophys Res Commun 191:89–94
Rees DD, Palmer RMJ, Hodson HF, Moncada S (1989) A specific inhibitor of nitric oxide formation from L-arginine attenuates endothelium-dependent relaxation. Br J Pharmacol 96:418–424
Schulz R, Nava E, Moncada S (1992) Induction and potential biological relevance of a Ca2+-independent nitric oxide synthase in the myocardium. Br J Pharmacol 105:575–580
Waldman SA, Murad F (1988) Biochemical mechanisms underlying vascular smooth muscle relaxation: the guanylate cyclase-cyclic GMP system. J Cardiovasc Pharmacol 12(Suppl 5):S115–S118
Nava E, Palmer RMJ, Moncada S (1991) Inhibition of nitric oxide synthesis in septic shock: how much is beneficial? Lancet 338:1555–1557
Busse R, Mulsch A, Fleming I, Hecker M (1993) Mechanisms of nitric oxide release from the vascular endothelium. Circulation 87(Suppl V):V18–V25
Tentolouris C, Tousoulis D, Goumas G, Stefanadis C, Graham D, Toutouzas P (2000) L-arginine in coronary atherosclerosis. Int J Cardiol 75:123–128
Moncada S, Palmer RMJ, Higgs EA (1991) Nitric oxide: physiology, pathophysiology and pharmacology. Pharmacol Rev 43:109–142
Moncada S, Higgs A (1993) The L-arginine-nitric oxide pathway. N Engl J Med 329:2002–2012
Perrella MA, Hildebrand FL, Margulies KB, Burnett JC Jr (1991) Endothelium-derived relaxing factor in regulation of basal cardiopulmonary and renal function. Am J Physiol 261:R323–R328
Horio Y, Yasue H, Rokutanda M, Nakamura N, Ogawa H, Takaoka K, Matsuyama K, Kimura T (1986) Effects of intracoronary injection of acetylcholine in atherosclerotic coronary arteries. Am J Cardiol 57:984–989
Tousoulis D, Crake T, Kaski JC, Rosen S, Haider AW, Davies G (1995) Enhanced vasomotor responses of complex stenoses to acetylcholine in patients with chronic stable angina. Am J Cardiol 75:725–728
Hodgson JM, Marshall JJ (1989) Direct vasoconstriction and endothelium-dependent vasodilation. Mechanisms of acetylcholine effects on coronary flow and arterial diameter in patients with nonstenotic coronary arteries. Circulation 79:1043–1051
Newman CM, Maseri A, Hackett D, El-Tamimi HM, Davies GJ (1990) Response of angiographically normal and atherosclerotic left anterior descending coronary arteries to acetylcholine. Am J Cardiol 66:1070–1076
Zeiher AM, Drexler H, Wollschlager H, Just H (1991) Modulation of coronary vasomotor tone in humans: progressive endothelial dysfunction with different early stages of coronary atherosclerosis. Circulation 83:391–401
el-Tamimi H, Mansour M, Wargovich TJ, Hill JA, Kerensky RA, Conti CR, Pepine CJ (1994) Constrictor and dilator responses to intracoronary acetylcholine in adjacent segments of the same coronary artery in patients with coronary artery disease: endothelial function revisited. Circulation 89:45–51
Tousoulis D, Davies G, Tentolouris C, Crake T, Toutouzas P (1997) Inhibition of nitric oxide synthesis during the cold pressor test in patients with coronary artery disease. Am J Cardiol 79:1676–1679
Tousoulis D, Tentolouris C, Crake T, Toutouzas P, Davies G (1997) Basal and flow-mediated nitric oxide production by atheromatous coronary arteries. J Am Coll Cardiol 29:1256–1262
Tousoulis D, Davies GJ, Tentolouris C, Crake T, Lefroy DC, Toutouzas P (1997) Effects of inhibition of nitric oxide synthesis in patients with coronary artery disease and stable angina. Eur Heart J 18:608–613
Tousoulis D, Crake T, Kaski JC, Rosen SD, Haider AW, Davies GJ (1995) Enhanced vasomotor responses of complex coronary stenoses to acetylcholine in stable angina pectoris. Am J Cardiol 75:725–728
Droge W (2002) Free radicals in the physiological control of cell function. Physiol Rev 82:47–95
Tousoulis D, Tentolouris C, Crake T, Stefanadis C, Toutouzas P (1999) Effects of L- and D-arginine on the basal tone of human diseased coronary arteries and their responses to substance P. Heart 81:505–511
Egashira K, Hirooka Y, Kuga T, Mohri M, Takeshita A (1996) Effects of L-arginine supplementation on endothelium-dependent coronary vasodilation in patients with angina pectoris and normal coronary angiograms. Circulation 94:130–134
Tousoulis D, Davies G, Tentolouris C, Crake T, Toutouzas P (1997) Coronary stenosis dilation induced by L-arginine. Lancet 349:1812–1813
Tentolouris C, Tousoulis D, Crake T, Katsimaglis G, Stefanadis C, Davies G, Toutouzas P (1999) Inhibition of nitric oxide synthesis in human epicardial coronary arteries and stenosis in relation to serum lipid level. Atherosclerosis 147:285–292
Tentolouris C, Tousoulis D, Davies G, Toutouzas P (1999) Effects of acute administration of L-arginine in coronary atherosclerosis. Circulation 99:1646–1649
Tousoulis D, Davies GJ, Tentolouris C, Crake T, Katsimaglis G, Stefanadis C, Toutouzas P (1998) Effects of changing the availability of the substrate for nitric oxide synthase L-arginine on coronary vasomotor tone in angina patients with angiographically normal coronary arteries. Am J Cardiol 82:1110–1113
Tousoulis D, Tentolouris C, Crake T, Goumas G, Stefanadis C, Toutouzas P, Davies GJ (1998) Complex stenosis morphology and vasomotor response to inhibition of nitric oxide synthesis. Heart 84:529–534
Taniyama Y, Griendling KK (2003) Reactive oxygen species in the vasculature. Molecular and cellular mechanisms. Hypertension 42:1075–1081
Mugge A, Elwell JH, Peterson TE, Hofmeyer TG, Heistad DD, Harrison DG (1991) Chronic treatment with polyethylene-glycolated superoxide dismutase partially restores endothelium-dependent vascular relaxations in cholesterol-fed rabbits. Circ Res 69:1293–1300
Li AE, Ito H, Rovira II, Kim KS, Takeda K, Yu ZY, Ferrans VJ, Finkel T (1999) A role for reactive oxygen species in endothelial cells anoikis. Circ Res 85:304–310
Marui N, Offmermann MK, Swerlick R, Kunsch C, Rosen CA, Ahmad M, Alexander RW, Medford RM (1993) Vascular cell adhesion molecule-1 (VCAM-1) gene transcription and expression are regulated through an antioxidant-sensitive mechanism in human vascular endothelial cells. J Clin Invest 92:1866–1874
Maulik N, Das DK (2002) Redox signaling in vascular angiogenesis. Free Radic Biol Med 33:1047–1060
Antoniades C, Tousoulis D, Tentolouris C, Toutouzas P, Stefanadis C (2003) Oxidative stress, antioxidant vitamins and atherosclerosis: from basic research to clinical practice. Çerz 28:628–638
Landmesser U, Cai H, Dikalov S, McCann L, Hwang J, Jo H, Holland SM, Harrison DG (2002) Role of p47(phox) in vascular oxidative stress and hypertension caused by angiotensin II. Hypertension 40:511–515
Radi R, Beckman JW, Bush KM, Freeman BA (1991) Peroxynitrite induced membrane lipid peroxidation: the cytotoxic potential of superoxide and nitric oxide. Arch Biochem Biophys 288:481–487
Zeiher AM, Schachinger V, Minners J (1995) Long term cigarette smoking impairs endothelium-dependent coronary arterial vasodilator function. Circulation 92:1094–1100
Reznick AZ, Cross CE, Hu ML, Suzuki YJ, Khwaja S, Safadi A, Motchnik PA, Packer L, Halliwell B (1992) Modification of plasma proteins by cigarette smoke as measured by protein carbonyl formation. Biochem J 286:607–611
Galle J, Bengen J, Schollmeyer P, Wanner C (1995) Impairment of endothelium-dependent dilation in rabbit renal arteries by oxidized lipoprotein (a): role of oxygen derived radicals. Circulation 92:1582–1589
Noguchi N (2002) Novel insights into the molecular mechanisms of antiatherosclerotic properties of antioxidants: the alternatives to radical scavenging. Free Radic Biol Med 33:1480–1489
Tousoulis D, Antoniades C, Tentolouris C, Tsioufis C, Toutouza M, Toutouzas P, Stefanadis C (2003) Antioxidant vitamins C and E administration in smokers: effects on endothelial function and adhesion molecules. Atherosclerosis 170:263–269
Tousoulis D, Antoniades C, Tountas C, Bosinakou E, Kotsopoulou M, Toutouzas P, Stefanadis C (2003) Vitamin C affects thrombosis/fibrinolysis system and reactive hyperemia in patients with non-insulin dependent diabetes mellitus and coronary artery disease. Diabetes Care 26:2749–2753
Widlansky ME, Gokce N, Keaney JF Jr, Vita JA (2003) The clinical implications of endothelial dysfunction. J Am Coll Cardiol 42:1149–1160
Tousoulis D, Davies G, Crake T, Lerman A, Hasdai D, Holmes D (1998) Acetylcholine and endothelial function. Circulation 98:1587A–1590A
Kugiyama K, Motoyama T, Hirashima O, Ohgushi M, Soejima H, Misumi K, Kawano H, Miyao Y, Yoshimura M, Ogawa H, Matsumura T, Sugiyama S, Yasue H (1998) Vitamin C attenuates abnormal vasomotor reactivity in spasm arteries in patients with coronary spastic angina. J Am Coll Cardiol 32:103–109
Solzbach U, Hornig B, Jeserich M, Just H (1997) Vitamin C improves endothelial dysfunction of epicardial coronary arteries in hypertensive patients. Circulation 96:1513–1519
Richartz BM, Werner G, Ferrari M, Figulla HR (2001) Reversibility of coronary endothelial vasomotor dysfunction in idiopathic dilated cardiomyopathy: acute effects of vitamin C. Am J Cardiol 88:1001–1005
Channon KM, Qian HS, George SE (2000) Nitric oxide synthase in atherosclerosis and vascular injury. Arterioscler Thromb Vasc Biol 20:1873–1881
Nunes GL, Sgoutas DS, Redden RA, Sigman SR, Gravanis MB, King SB III, Berk BC (1995) Combination of vitamins C and E alters the response to coronary balloon injury in the pig. Arterioscler Thromb Vasc Biol 15:156–165
Rodes J, Cote G, Lesperance J, Bourassa MG, Doucet S, Bilodeau L, Bertrand OF, Harel F, Gallo R, Tardif JC (1998) Prevention of restenosis after angioplasty in small coronary arteries with probucol. Circulation 97:429–436
Tardif JC, Cote G, Lesperance J, Bourassa M, Lambert J, Doucet S, Bilodeau L, Nattel S, de Guise P (1997) Probucol and multivitamins in the prevention of restenosis after coronary angioplasty. Multivitamins and Probucol Study Group. N Engl J Med 337:365–372
Schindler TH, Nitzsche EU, Munzel T, Olschewski M, Brink I, Jeserich M, Mix M, Buser PT, Pfisterer M, Solzbach U, Just H (2003) Coronary vasoregulation in patients with various risk factors in response to cold pressor testing: contrasting myocardial blood flow responses to short- and long-term vitamin C administration. J Am Coll Cardiol 42:814–822
Carr AC, Zhu BZ, Frei B (2000) Potential antiatherogenic mechanisms of ascorbate (vitamin C) and α-tocopherol (vitamin E). Circ Res 87:349–354
Keaney JF, Guo Y, Cunningham D, Shwaery GT, Xu A, Vita JA (1996) Vascular incorporation of α-tocopherol prevents endothelial dysfunction due to oxidized LDL by inhibiting protein kinase C stimulation. J Clin Invest 98:386–394
Tousoulis D, Xenakis C, Tentolouris C, Davies G, Pitsavos C, Antoniades C, Toutouzas P, Stefanadis C (2005) Effects of vitamin C and L-arginine co-administration on nitric oxide bioactivity in atherosclerotic coronary arteries. Heart [in press]
Kinlay S, Fang JC, Hikita H, Ho I, Delagrange DM, Frei B, Jung S, Gerhard M, Creager MA, Selwyn AP, Ganz P (1999) Plasma alpha-tocopherol and coronary endothelium-dependent vasodilator function. Circulation 100:219–221
Miwa K, Igawa A, Nakagawa K, Hirai T, Inoue H (1999) Consumption of vitamin E in coronary circulation in patients with variant angina. Cardiovasc Res 41:291–298
Jorge PA, Osaki MR, de Almeida E, Credidio Neto L, Metze K (1996) Effects of vitamin E on endothelium-dependent coronary flow in hypercholesterolemic dogs. Atherosclerosis 126:43–51
Andersson TL, Matz J, Ferns GA, Anggard EE (1994) Vitamin E reverses cholesterol-induced endothelial dysfunction in the rabbit coronary circulation. Atherosclerosis 111:39–45
DeMaio SJ, King SB III, Lembo NJ, Roubin GS, Hearn JA, Bhagavan HN, Sgoutas DS (1992) Vitamin E supplementation, plasma lipids and incidence of restenosis after percutaneous transluminal coronary angioplasty (PTCA). J Am Coll Nutr 11:68–73
Violi F, Cangemi R, Sabatino G, Pignatelli P (2004) Vitamin E for the treatment of cardiovascular disease: is there a future? Ann N Y Acad Sci 1031:292–304
Lee IM, Cook NR, Gaziano JM, Gordon D, Ridker PM, Manson JE, Hennekens CH, Buring JE (2005) Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial. JAMA 294:56–65
Miller ER III, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E (2005) Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 142:37–46
Hare JM, Stamler JS (2005) NO/redox disequilibrium in the failing heart and cardiovascular system. J Clin Invest 115:509–517
Williams KJ, Fisher EA (2005) Oxidation, lipoproteins, and atherosclerosis: which is wrong, the antioxidants or the theory? Curr Opin Clin Nutr Metab Care 8:139–146
Kabe Y, Ando K, Hirao S, Yoshida M, Handa H (2005) Redox regulation of NF-kappaB activation: distinct redox regulation between the cytoplasm and the nucleus. Antioxid Redox Signal 7:395–403
Shah AM, Channon KM (2004) Free radicals and redox signalling in cardiovascular disease. Heart 90:486–487
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Tousoulis, D., Antoniades, C. & Stefanadis, C. Nitric oxide in coronary artery disease: effects of antioxidants. Eur J Clin Pharmacol 62 (Suppl 1), 101–107 (2006). https://doi.org/10.1007/s00228-005-0019-5
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DOI: https://doi.org/10.1007/s00228-005-0019-5