molecular mechanisms of vascular thrombosis

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We have recently shown that chronic inhibition of nitric oxide (NO) synthesis by Nomega-nitro-L-arginine methyl ester (L-NAME) activates local angiotensin-converting enzyme (ACE) activity as well as induces vascular fibrosis and inflammatory changes in rats. Angiotensin II is known to activate coagulation cascade and inhibit fibrinolytic activity in the vessel wall.In the present study, we hypothesized that cyclic flow variations (CFV) , resulting from recurrent arterial thrombosis and its dislodgement, is induced in stenosed carotid arteries in a rat model of chronic inhibition of NO synthesis. Four groups of rats were studies : control group, L group received L-NAME,L+Hyd group received L-NAME and hydralazine, and L+A group received L-NAME and ACE inhibitor imidapril for 4 weeks. After anesthesia, stenosis was induced by constricting an exposed carotid artery, and CFV was determined using a ultrasonic flow prove. CFV provocation rate was 0% in the control group, 94% in the L group, 80% in the L+Hyd group, and 0% in the L+ACE inhibitor group. The carotid artery ACE activity was increased in the L and L+Hyd groups, and was suppressed in the L=ACE inhibitor group. In separate studies, treatment with thrombin antagonist argatroban, but not with vehicle or aspirin, nearly abolished CFV.There was no significant difference among groups in blood platelet count, platelet aggregation in response to collagen and indices of coagulation cascade (PT and APTT) .In conclusion, these findings suggest that CFV could be provoked by producing stenosis possibly via local thrombin generation in this animal model and that local ACE is likely to contribute to such changes.