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

在动物实验模型中有效缩小心肌梗死范围的药物在临床心肌梗死中并不总是有效的，部分原因是冠状动脉粥样硬化存在于临床心肌梗死的背景中。血管紧张素转换酶抑制剂（ACEI）可抑制心肌梗死的范围，同时减少动脉粥样硬化病变。由于ACEI也抑制激肽酶，增加缓激肽浓度和增加NO的产生，ACEI被认为是通过逆转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%胆固醇饲料饲养日本白兔。胆固醇喂养的家兔心肌梗死面积明显扩大。在这些家兔中，缺血区髓过氧化物酶活性和LTB 4产生增加，表明冠状动脉微循环中白细胞的激活参与了高胆固醇血症模型中心肌损伤的机制。高胆固醇血症兔的内皮依赖性舒张功能减弱，外源性NO供体可减轻心肌梗死范围。因此，动脉粥样硬化血管中NO产生的减少可能是胆固醇喂养动物中白细胞活化的原因。高胆固醇饮食组血管壁ACE活性和血清血管紧张素II水平也明显升高。ACEI可降低ACE活性和血管紧张素II水平，减轻动脉粥样硬化病变。提示：（1）激活肾素-血管紧张素抑制冠脉循环NO生成;（2）减少NO生成可激活心肌组织白细胞，增加心肌梗死面积;（3）ACEI可改善动脉粥样硬化病变的上述病理生理过程。

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.