Nitric oxide in coronary artery disease: roles in atherosclerosis, myocardial reperfusion and heart failure.
Nitric oxide (NO), derived from the vascular endothelium or other cells of the cardiovascular system, has an important role in physiological regulation of blood flow and has pathophysiological functions in cardiovascular disease. The mechanisms and enzymes involved in the biosynthesis of NO and biological actions of NO, including vasodilatation, cytotoxicity and inflammation, are briefly reviewed. These reactions involving NO cause pathological disturbances of arterial function, coronary blood flow regulation, and may contribute to cardiac myocyte dysfunction. NO and prostacyclin (PGI2), which is also released from the endothelium, act synergistically to inhibit platelet aggregation and adhesion, and in some arteries these mediators also synergise in terms of vasodilatation. In addition, NO is capable of hyperpolarizing vascular smooth muscle, but activation of the endothelium may cause hyperpolarization and may thus promote vasodilatation by an additional mechanism. After myocardial ischemia and reperfusion, production of NO and superoxide radicals represent important mechanisms of cytotoxicity, causing injury to the coronary endothelium and myocytes and compromising ventricular contractile function. Moreover, upon reperfusion endothelium-dependent vasodilatation is impaired and the coronary arteries constrict, leading to irregular myocardial perfusion. This is a consequence of the accumulation of activated leucocytes that we found to generate endogenous inhibitors of NO. These factors have yet to be fully characterised, but clearly they may have a role in irregularities of myocardial reperfusion and cellular injury. Chronic heart failure is associated both with impairment of endothelium-dependent vasodilatation and with excess production of NO via the inducible NO synthase (iNOS), although it is unclear whether the latter assists or compromises ventricular contractile performance under these conditions. Disturbances in the activity of isoforms of NO synthase in the artery wall also accompany the development of atherosclerosis, providing conditions propitious for vasospasm and thrombosis, and perhaps contributing to cell proliferation. Reversing these NO defects with therapeutic agents including angiotensin converting enzyme (ACE) inhibitors offers promise in protecting against some manifestations of vascular disease.
Dusting
G J
GJ
Department of Physiology, University of Melbourne, Parkville, Victoria, Australia.
D017130:Angioplasty / Q000009:adverse effects; D000818:Animals; D001161:Arteriosclerosis / Q000209:etiology* / Q000503:physiopathology; D001794:Blood Pressure / Q000502:physiology; D003326:Coronary Circulation / Q000502:physiology; D003327:Coronary Disease / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control; D004730:Endothelium, Vascular / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic; D006333:Heart Failure / Q000209:etiology* / Q000503:physiopathology; D006801:Humans; D006937:Hypercholesterolemia / Q000209:etiology / Q000503:physiopathology; D007249:Inflammation / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000209:etiology* / Q000503:physiopathology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000502:physiology; D014664:Vasodilation / Q000502:physiology
D009569:Nitric Oxide; D019001:Nitric Oxide Synthase