EXPRESSION OF INDUCIBLE NITRIC-OXIDE SYNTHASE INHIBITS PLATELET-ADHESION AND RESTORES BLOOD-FLOW IN THE INJURED ARTERY

NO generated by endothelial cells is vasoprotective by antagonizing pl atelet adhesion and smooth muscle contraction. Since vascular smooth m uscle tells (VSMCs) produce NO in response to cytokine stimulation and after arterial injury, we speculated that NO produced by VSMCs could compensate for the loss of endothelium. Using balloon catheter denudat ion of the rat carotid artery as a model for arterial injury and reste nosis. we have evaluated the timecourse of expression of inducible NO synthase (iNOS) by in situ hybridization and immunohistochemistry and studied the effect of iNOS on platelet adhesion and blood flow of the injured vessel. iNOS mRNA and protein were expressed in the innermost layer of the media from day 1 and were subsequently detected in the ne ointima, whereas no expression was detectable in the uninjured artery. Systemic administration of N-omega-nitro-L-arginine methyl ester (L-N AME) resulted in a twofold to threefold increase in the adhesion of In -111-labeled platelets to the injured vessel wall. Platelet adhesion w as also enhanced threefold by local delivery of L-NAME from a gel surr ounding the injured vessel, whereas the stereoisomer, D-NAME, had no e ffect. Finally, inhibition of NO synthase led to a 24% reduction of th e blood flow in the injured carotid artery. These results demonstrate that arterial injury triggers the expression of iNOS in the lesion and that NO produced by iNOS inhibits platelet adhesion and restores bloo d flow. This could explain the disappearance of platelet thrombi from deendothelialized arterial surfaces within a few days after injury and indicates the importance of NO generated by iNOS for the maintenance of vascular tone. Thus, expression of iNOS in lesions may represent a protective mechanism that compensates for the loss of endothelium.