Nitric oxide and atherosclerosis

Endothelial dysfunction has been shown in a wide range of vascular desorder s including atherosclerosis and related diseases. Here, we examine and addr ess the complex relationship among nitric oxide (NO)-mediated pathways and atherogenesis. In view of the numerous pathophysiological actions of NO, ab normalities could potentially occur at many sites: (a) impairment of membra ne receptors in the arterial wall that interact with agonists or physiologi cal stimuli capable of generating NO; (b) reduced concentrations or impaire d utilization of L-arginine; (c) reduction in concentration or activity bot h of inducible and endothelial NO synthase; (d) impaired release of NO from the atherosclerotic damaged endothelium; (e) impaired NO diffusion from en dothelium to vascular smooth muscle cells followed by decreased sensitivity to its vasodilator action; (f) local enhanced degradation of NO by increas ed generation of free radicals and/or oxidation-sensitive mechanisms; and ( g) impaired interaction of NO with guanylate cyclase and consequent limitat ion of cyclic GMP production. Therefore, one target for new drugs should be the preservation or restoration of NO-mediated signaling pathways in arter ies. Such novel therapeutic strategies may include administration of L-argi nine/antioxidants and gene-transfer approaches, (C) 2001 Academic Press.