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The vascular endothelium is a monolayer of cells between the vessel lumen and the vascular smooth muscle cells. Far from being inert, it is metabolically active and produces a variety of vasoactive mediators. Among these mediators, endothelial derived nitric oxide is essential in the maintenance of vascular homeostasis, and defects in the L-arginine: nitric oxide pathway have been implicated in a variety of cardiovascular diseases.
From EDRF to nitric oxide
In 1980, Furchgott and Zawadzki showed that the presence of vascular endothelial cells is essential for acetylcholine to induce relaxation of isolated rabbit aorta.1 If the vascular endothelium was removed, the blood vessel failed to relax in response to acetylcholine but still responded to glyceryl trinitrate. This endothelium dependent relaxation of vascular smooth muscle to acetylcholine is mediated by an endogenous mediator initially named endothelium derived relaxing factor (EDRF),1 which was subsequently identified as nitric oxide.2 3
L-arginine: nitric oxide pathway
Endothelium derived nitric oxide is synthesised from the amino acid L-arginine by the endothelial isoform of nitric oxide synthase, yielding L-citrulline as a byproduct.4 Nitric oxide is labile with a short half life (< 4 seconds in biological solutions). It is rapidly oxidised to nitrite and then nitrate by oxygenated haemoglobin before being excreted into the urine.4 Several co-factors are required for nitric oxide biosynthesis. These include nicotinamide adenine dinucleotide phosphate (NADPH), flavin mononucleotide, flavin adenine dinucleotide, tetrahydrobiopterin (BH4), and calmodulin. Once synthesised, the nitric oxide diffuses across the endothelial cell membrane and enters the vascular smooth muscle cells where it activates guanylate cyclase, leading to an increase in intracellular cyclic guanosine-3',5-monophosphate (cGMP) concentrations4 (fig 1). As a second messenger, cGMP mediates many of the biological effects of nitric oxide including the control of vascular tone and platelet function. In addition, nitric oxide has other molecular targets which include haem or other …
- Additional references for "Endothelial function and nitric oxide: clinical relevance" by Vallance and Chan. Heart 2001;85:342-350
- Anastasiou E, Lekakis JP, Alevizaki M, et al. Impaired endothelial-dependent vasodilatation in women with previous gestational diabetes. Diabetes Care 1998;21:111-15.
- Anderson TJ, Uehata A, Gerhard MD, et al. Endothelial function in the human coronary and peripheral circulation. J Am Coll Cardiol 1995;26:1235-41.
- Angus JA, Cocks TM, McPherson GA, et al. The acetylcholine paradox:a constrictor of human small coronary arteries even in the presence of endothelium. Clin Exp Pharmacol Physiol 1991;18:33-6.
- Baylis C, Vallance P. Measurement of nitric oxide and nitrate levels in plasma and urine - what does this measure tell us about the activity of the endogenous nitric oxide system? Curr Opin Nephrol Hypertens 1998;7:50-62.
- Bellamy MF, McDowell IFW, Ramsey MW, et al. Hyperhomocysteinemia after an oral methionine load acutely impairs endothelial function in healthy adults. Circulation 1998;98:1848-52.
- Bhagat K, Vallance P. Inflammatory cytokines impair endothelium-dependent dilatation in humans, in vivo. Circulation 1997;96:3042-7.
- Boger RH, Bode-Boger SM, Szuba A, et al. Asymmetric dimethylarginine (ADMA): a noval risk factor for endothelial dysfunction. Its role in hypercholesterolemia. Circulation 1998;98:1842-7.
- Bucala R, Tracey KL, Cerami A. Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilation in experimental diabetes. J Clin Invest 1991;87:432-8.
- Busse R, Mulsch A, Fleming I, Hecker M. Mechanisms of nitric oxide release from the vascular endothelium. Circulation 1993;87:V18-25.
- 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.
- 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.
- Celermajer DS. Endothelial dysfunction: Does it matter? Is it reversible? J Am Coll Cardiol 1997;30:325-33.
- Chataigneau T, Feletou M, Huang PL, et al. Acetylcholine-induced relaxation in blood vessels from endothelial nitric oxide synthase knockout mice. Br J Pharmacol 1999;126:219-26.
- Clancy RM, Leszczynska-Piziak J, Abramson SB. Nitric oxide, an endothelial cell relaxation factor, inhibits neutrophil superoxide anion production via a direct action on the NADPH oxidase. J Clin Invest 1992;90:1116-21.
- Clarkson P, Celermajer DS, Powe AJ, et al. Endothelium-dependent dilatation is impaired in young healthy subjects with a family history of premature coronary disease. Circulation 1997;96:3378-83.
- Cockcroft JR, Chowienczyk PJ, Benjamin N, et al. Preserved endothelium-dependent vasodilatation in patients with essential hypertension. N Engl J Med 1994;330:1036-40.
- Collier J, Vallance P. Biphasic response to acetylcholine in human hand veins in vivo: the role of the endothelium. Clin Sci 1990;78:101-4.
- Cooke JP, Andon NA, Girerd WJ, et al. Arginine restores cholinergic relaxation of hypercholesterolemic rabbit thoracic aorta. Circulation 1991;83:1057-62.
- Corson MA, James NL, Latta SE, et al. Phosphorylation of endothelial nitric oxide synthase in response to fluid shear stress. Cir Res 1996;79:984-91.
- Creager MA, Cooke JP, Mendelsohn ME, et al. Impaired vasodilation of forearm resistance vessels in hypercholesterolaemic humans. J Clin Invest 1990;86:228-34.
- Farquharson CA, Struthers AD. Spironolactone increases nitric oxide bioavailability, improves endothelial vasodilator dysfunction, and suppresses vascular angiotensin I/ angiotensin II conversion in patients with chronic failure. Circulation 2000;101:594-7.
- Fleming I, Bauersachs J, Fisslthaler B, et al. Calcium-independent activation of the endothelial nitric oxide synthase in response to tyrosine phosphatase inhibitors and fluid shear stress. Circ Res 1998;82:686-95.
- Forte P, Copland M, Smith LM, et al. Basal nitric oxide synthesis in essential hypertension. Lancet 1997;349:837-42.
- Garg UC, Hassid A. Nitric oxide-generating vasodilators and 8-bromo-cyclic gaunosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest 1989;83:1774-7.
- Janssens S, Flaherty D, Nong Z, et al. Human endothelial nitric oxide gene transfer inhibits vascular vascular smooth muscle cell proliferation and neointima formation after balloon injury in rats. Circulation 1998;97:1274-81.
- 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;91:1314-19.
- Kawagishi T, Matsuyoshi M, Emoto M, et al. Impaired endothelial-dependent vascular responses of retinal and intrarenal arteries in patients with type 2 diabetes. Arterioscler Thromb Vasc Biol 1999;19:2509-16.
- Lansman JB, Hallam TJ, Rink TJ. Single stretch-activated ion channels in vascular endothelial cells as mechanotransducers? Nature 1987;325:811-13.
- Levine GN, Frei B, Koulouris SN, et al. Ascorbic acid reverses endothelial vasomotor dysfunction in patients with coronary artery disease. Circulation 1996;93:1107-13.
- Lewis TV, Dart AM, Chin-Dusting JP. Endothelium-dependent relaxation by acetylcholine is impaired in hypertriglyceridemic humans with normal levels of plasma LDL cholesterol. J Am Coll Cardiol 1999;33:805-12.
- MacAllister RJ, Calver AL, Collier J, et al. Vascular and hormonal responses to arginine: provision of substrate for nitric oxide or non-specific effects? Clin Sci (Colch) 1995;89:183-90.
- Makimattila S, Mantysaari M, Groop P-H, et al. Hyperreactivity to nitrovasodilators in forearm vasculature is related to autonomic dysfunction in insulin-dependent diabetes mellitus. Circulation 1997;95:618-25.
- Naruse K, Shimizu K, Muramatsu M, et al. Long-term inhibition of NO synthesis promotes atherosclerosis in the hyperchoolesrterolemic rabbit thoracic aorta. Arterioscler Thromb 1994;14:746-52.
- Nava E, Palmer RMJ, Moncada S. Inhibition of nitric oxide synthesis in septic shock: how much is beneficial? Lancet 1991;338:1555-7.
- Neunteufl T, Katzenschlager R, Hassan A, et al. Systemic endothelial dysfunction is related to the extent and severity of coronary artery disease. Atherosclerosis 1997;129:111-18.
- Panza JA, Casino PR, Kilcoyne CM, et al. Role of endothelium-derived nitric oxide in the abnormal endothelium-dependent vascular relaxation of patients with essential hypertension. Circulation 1993;87:1468-74.
- Pepke-Zaba J, Higenbottam TW, Dinh-Xuan AT, et al. Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension. Lancet 1991;338:1173-4.
- Petros A, Lamb G, Leone A, et al. Effects of a nitric oxide synthase inhibitor in humans with septic shock. Cardiovasc Res 1994;28:34-9.
- Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone evaluation study investigators. N Engl J Med 1999;341:709-17.
- 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.
- Rees DD, Palmer RM, Moncada S. Role of endothelium-derived nitric oxide in the regulation of blood pressure. Proc Natl Acad Sci USA 1989;86:3375-8.
- Rossaint R, Falke KJ, Lopez F, et al. Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl J Med 1993;328:399-405.
- Schachinger Schachinger, Halle M, et al. Lipoprotein(a) selectively impairs receptor-mediated endothelial vasodilator function of the human coronary circulation. J Am Coll Cardiol 1998;30:927-34.
- Schoeffter P, Dion R, Godfraind T. Modulatory role of the vascular endothelium in the contractility of human isolated internal mammary artery. Br J Pharmacol 1988;95:531-43.
- Stroes E, deBruin T, deValk H, et al. NO activity in familial combined hyperlipidaemia: potential role of cholesterol remants. Cardiovasc Res 1997;36:445-52.
- Ting HH, Timimi FK, Boles KS, et al. Vitamin C improves endothelium-dependent vasodilatation in patients with non-insulin dependent diabetes mellitus. J Clin Invest 1996;97:22-8.
- Werns SW, Walton JA, Hsia HH, et al. Evidence of endothelial dysfunction in angiographically normal coronary arteries of patients with coronary artery disease. Circulation 1989;79:287-91.
- Yasue H, Matsuyama K, Okumura K, et al. Responses of angiographically normal human coronary arteries to intracoronary injection of acetylcholine by age and segment. Posible role of early coronary atherosclerosis. Circulation 1990;81:482-90.
- Hingorani AD, Cross J, Kharbanda RK, et al. Acute systemic inflammation impairs endothelium-dependent dilatation in humans. Circulation 2000;102:994-9.
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