The vascular endothelium produces NO, which is basally released at concentrations of about 2 to 20 nmol/L. 1 2 This NO diffuses to the subjacent vascular smooth muscle, where it regulates vascular tone. 3 4 However, the endothelially derived NO also diffuses to the luminal surface of the endothelium, where it exerts a number of important physiological effects, including (1) scavenging of superoxide radicals, 5 6 (2) inhibition of platelet adherence and aggregation, 7 8 (3) modulation of endothelial layer permeability, 9 and (4) attenuation of leukocyte function. 10 11 This antileukocyte effect of NO has several components. First, NO markedly attenuates leukocyte rolling along the endothelium by inhibiting the expression of P-selectin on the vascular endothelium. 11 12 Second, NO inhibits the firm adherence of leukocytes to the endothelium, 11 12 13 partially by inhibition of ICAM-1 and VCAM-1 expression. 14 Downregulation of these cell adhesion molecules by NO occurs through inhibition of protein kinase C activation 15 and via prevention of the transcription factor nuclear factor-κB, which usually induces expression of the mRNA for these adhesion molecules. 14 Third, NO inhibits leukocyte action by inhibiting the cytoassembly of NADPH oxidase, 16 thereby attenuating the release of superoxide radicals by activated leukocytes, particularly granulocytes. 17 These effects of NO pertain to both neutrophils and monocytes and appear to be relevant to atherosclerosis.

Against this backdrop of important effects of physiological concentrations of NO, effective NO levels are decreased in a variety of circulatory disorders, including myocardial ischemia-reperfusion, 18 19 20 circulatory shock and trauma, 21 22 and hypercholesterolemia and atherosclerosis. 23 24 The decrease in NO levels occurs in the early stages of hypercholesterolemia before the development of atherosclerotic plaques 23 24 25 26 and is clearly due to reduced basal release of NO 27 in addition to diminished agonist-mediated NO release. 24 25 26 This reduction in basal NO release leads to an increased leukocyte adherence to the coronary vascular endothelium in hypercholesterolemic rabbits. 27 It is therefore not surprising that replacement therapy to restore the NO deficit has been considered in several of these disease states.