Impairment and restoration of nitric oxide-dependent vasodilation in cardiovascular disease

Abstract

The generation of nitric oxide by the vascular endothelium maintains a continuous vasodilator tone that is essential for the regulation of blood flow and blood pressure. Nitric oxide also contributes to the control of platelet aggregation and has important antiatherogenic effects. These properties are mediated by the action of constitutive nitric oxide synthase and subsequent activation by nitric oxide of soluble guanylate cyclase. Impaired release of nitric oxide occurs in most animal and human models of hypertension, contributing to the increased peripheral resistance and most likely to the development of cardiovascular complications. Antihypertensive medications (angiotensin-converting enzyme [ACE] inhibitors and calcium channel blockers) appear to prevent the impairment of nitric oxide-mediated vasodilation in experimental hypertension, though in humans the data are not as clear. Reduced nitric oxide release appears therefore to be a consequence rather than a cause of high blood pressure, and the reduction in blood pressure per se is most important. In hyperlipidaemia, endothelium-dependent relaxations are reduced probably due to the inhibitory action of oxidized low-density lipoproteins on endothelium-dependent relaxations. Lipid-lowering strategies and, more recently, ACE inhibition have been demonstrated to improve nitric oxide dependent coronary vasodilation in hypercholesterolaemic patients with and without atheromatous coronary disease. Nitric oxide dependent vasodilation is also impaired in insulin- and non-insulin-dependent diabetes as well as in healthy aging. Endothelial dysfunction may be improved in non-insulin-dependent diabetes by administration of the antioxidants, supporting the hypothesis that nitric oxide inactivation by oxygen-derived free radicals contributes to abnormal vascular reactivity in diabetes.