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molecular mechanisms of vascular thrombosis

血管血栓形成的分子机制

基本信息

批准号：
07557058
负责人：
TAKESHITA Akira
金额：
$ 8.58万
依托单位：
KYUSHU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1997
项目状态：
已结题

项目摘要

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.

我们最近发现，长期抑制一氧化氮（NO）合成的N-硝基-L-精氨酸甲酯（L-NAME）激活局部血管紧张素转换酶（ACE）的活性，以及诱导大鼠血管纤维化和炎症变化。血管紧张素II是已知的激活凝血级联反应和抑制纤溶活性在vessel wall.In目前的研究中，我们假设，循环流量的变化（CFV），导致反复动脉血栓形成和它的移位，在狭窄的大鼠模型的NO合成的慢性抑制颈动脉。实验分为4组：对照组、L组、L+Hyd组、L+A组，每组10只。麻醉后，通过缩窄暴露的颈动脉来诱导狭窄，并使用超声流量计测定CFV。CFV激发率在对照组为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抑制剂组则被抑制。在单独的研究中，凝血酶拮抗剂阿加曲班治疗几乎消除了CFV，而赋形剂或阿司匹林治疗则没有。血小板计数、血小板对胶原蛋白的反应性聚集和凝血级联反应指数在组间无显著差异（PT和APTT）。总之，这些发现表明，CFV可能是通过在该动物模型中产生局部凝血酶而产生狭窄引起的，可能会促成这种变化。