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Role of atherosclerosis on myocardial infarction -cross talk of renine-angiotensis system and nitric oxide-

动脉粥样硬化对心肌梗死的作用-肾素-血管紧张系统和一氧化氮的串扰-

基本信息

批准号：
08670792
负责人：
NISHIDA Masashi
金额：
$ 1.41万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

项目摘要

Drugs which effectively reduce myocardial infarction size in animal exprerimental models could not always be effective in clinical myocardial infarction, partly because coronary atherosclerosis is existing in background of clinical myocardial infarction. Angiotensin converting enzyme inhibitors (ACEI) inhibit the extent of myocardial infarction, together with reduction of atherosclerotic lesion. Because ACEI also inhibit kininase, increase bradykinin concentration and augment NO production, ACEI is assumed to reduce myocardial infarct size when given to atherosclerotic model through regression of atherosclerosis and maintaining NO production. In this study, we applied 1% cholesterol diet to Japanese while rabbit. Myocardial infarct size was markedly enlarged in cholesterol fed rabbits. In these rabbits, myeloperoxidase activity and LTB4 production in ischemic region were increased, suggesting that activation of leukocytes in coronary microcirculation is involved in the mechanism of myocardial injury in the hypercholesterolemic model. Endothelium dependent relaxation was attenuated in hypercholesterolemic rabbits and exogenous NO donnor reduced the extent of myocardial infarction. Therefore, reduction of NO production in atherosclerotic vessel might be responsible for the activation of leukocytes in cholesterol fed animals. In hypercholesterol diet group, ACE activity in vascular wall and angiotensin II level in serum were also increased. ACEI could reduced both the ACE activity and the angiotensin II level, together with reduction of atherosclerotic lesion. These results suggest that (1) activation of renin-angiotensin inhibits NO production in coronary circulation, (2) reduction of NO production activates leukocytes in myocardial tissue and augment myocardial infarct size and (3) ACEI can improve these pathophysiology in atherosclerotic lesion.

在动物实验模型中有效缩小心肌梗死大小的药物，在临床心肌梗死中不一定有效，部分原因是临床心肌梗死背景下存在冠状动脉粥样硬化。血管紧张素转换酶抑制剂（ACEI）抑制心肌梗死的程度，同时减少动脉粥样硬化病变。由于ACEI还能抑制激肽酶，增加缓激肽浓度，增加NO的产生，因此假设ACEI通过回归动脉粥样硬化和维持NO的产生来减少动脉粥样硬化模型的心肌梗死面积。本研究采用1%胆固醇日粮饲喂日本白兔。饲喂胆固醇的家兔心肌梗死面积明显增大。缺血区髓过氧化物酶活性和LTB4生成增加，提示冠状动脉微循环白细胞活化参与了高胆固醇血症模型心肌损伤的机制。高胆固醇血症家兔内皮依赖性松弛减轻，外源性一氧化氮能降低心肌梗死程度。因此，动脉粥样硬化血管中NO生成的减少可能是胆固醇喂养动物白细胞活化的原因。高胆固醇饮食组大鼠血管壁ACE活性升高，血清血管紧张素II水平升高。ACEI可降低ACE活性和血管紧张素II水平，减少动脉粥样硬化病变。这些结果表明：(1)肾素-血管紧张素的激活抑制冠状动脉循环中NO的产生；(2)NO产生的减少激活心肌组织中的白细胞并增加心肌梗死面积；(3)ACEI可以改善动脉粥样硬化病变的这些病理生理。