molecular mechanisms of vascular thrombosis

我们最近的研究表明，诺米加-硝基- l -精氨酸甲酯（L-NAME）对一氧化氮（NO）合成的慢性抑制可激活大鼠局部血管紧张素转换酶（ACE）活性，并诱导血管纤维化和炎症变化。已知血管紧张素II可激活凝血级联并抑制血管壁的纤溶活性。在本研究中，我们假设在慢性抑制NO合成的大鼠模型中，由复发性动脉血栓形成及其移位引起的循环血流变化（CFV）在狭窄的颈动脉中被诱导。研究四组大鼠：对照组，L组给予L- name治疗，L+Hyd组给予L- name和肼嗪治疗，L+ A组给予L- name和ACE抑制剂咪哌普利治疗，疗程4周。麻醉后，通过收缩暴露的颈动脉诱导狭窄，并使用超声血流仪测定CFV。对照组CFV激发率为0%，L组为94%，L+Hyd组为80%，L+ACE抑制剂组为0%。L和L+Hyd组颈动脉ACE活性升高，L=ACE抑制剂组颈动脉ACE活性降低。在单独的研究中，使用凝血酶拮抗剂阿加曲班治疗，而不使用载体或阿司匹林，几乎可以消除CFV。各组大鼠血小板计数、血小板对胶原蛋白的聚集反应及凝血级联指标（PT、APTT）差异无统计学意义。综上所述，这些发现表明，CFV可能是通过局部凝血酶产生狭窄引起的，而局部ACE可能促成了这种变化。

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.