EFFECT OF ATHEROSCLEROSIS ON ENDOTHELIUM-DEPENDENT INHIBITION OF PLATELET ACTIVATION IN HUMANS

Background-We investigated whether luminal release of nitric oxide (NO ) contributes to inhibition of platelet activation and whether these e ffects are reduced in patients with atherosclerosis. Methods and Resul ts-Femoral blood flow velocity and ex vivo whole blood platelet aggreg ation by impedance aggregometry were measured in femoral venous blood during femoral arterial infusion of acetylcholine (ACh; 30 mu g/min) i n 30 patients, 19 of whom had angiographic atherosclerosis. Measuremen ts were repeated with sodium nitroprusside (40 mu g/min), L-arginine ( 160 mu mol/min), and N-G-monomethyl-L-arginine (L-NMMA; 16 mu mol/min) . There was significant inhibition of collagen-induced platelet aggreg ation with ACh (45+/-9.5% lower, P<0.001), and this inhibition was gre ater in patients without atherosclerosis (68.7+/-10.4% reduction) than in those with atherosclerosis (32.5+/-8.1%, P=0.04). The magnitude of inhibition correlated with vasodilation with ACh, indicating an assoc iation between the smooth muscle and antiplatelet effects of endotheli um-dependent stimulation. Neither L-NMMA nor sodium nitroprusside alte red platelet aggregation. L-Arginine inhibited platelet aggregation eq ually in vitro (34+/-8% reduction, P<0.01) and in vivo (37+/-3% reduct ion, P<0.01). Conclusions Stimulation of NO release into the vascular lumen with ACh inhibits platelet aggregation, an effect that is attenu ated in patients with atherosclerosis and endothelial dysfunction. Bas al NO release does not appear to contribute to platelet passivation in vivo. L-Arginine inhibited platelet aggregation by its direct action on platelets. These findings provide a pathophysiological basis for th e observed increase in thrombotic events in atherosclerosis. Use of L- arginine and other strategies to improve endothelial NO activity may i mpact favorably on thrombotic events in atherosclerosis.