Pathophysiological roles of the cardic renin-angiotensin system after myocardial infarction-Chymase dependent angiotensin II-forming pathway and myocardial infarction-

1. 心肌梗死（MI）后仓鼠心肌酶的变化及血管紧张素转换酶（ACE）抑制剂和血管紧张素(A) II受体拮抗剂对心功能和生存的影响。我们最近发现，心脏酶的激活比ACE的激活更持久，并且在该模型中，AT1受体拮抗剂治疗比单独使用ACE抑制剂治疗对心功能和生存有显著的有益影响。这些发现表明，通过活化的心脏切酶过量产生AII可能在心肌梗死后的预后中起重要作用（中华医学杂志，86:203-214(2001)）。心肌梗死后乳糜酶抑制剂对心肌梗死的影响在仓鼠心肌梗死模型中，乳糜酶特异性治疗能抑制心肌活化的乳糜酶，显著改善心肌功能和生存率，其对预后的有利影响程度与AT1受体阻断在相同模型中所观察到的相似。这些发现表明，通过活化的心脏酶过量产生AII在心肌梗死后的预后中起重要作用（Life Sci. 14:437-446(2002)）。在MIChymase抑制剂和AT1受体拮抗剂治疗后，溶酶抑制剂的抗心律作用对心肌梗死后的梗死面积没有显著影响，因此这些预后有益作用可能与心肌梗死急性期致死性心律失常的抑制密切相关。因此，我们在永久性左冠状动脉结扎诱导的心肌梗死模型中检测了溶酶抑制剂和AT1受体拮抗剂的抗心律失常作用。心肌梗死后，chymase inhibitor可显著降低心肌总AII形成活性和血浆AII浓度，显著抑制心室速率。用AT1拮抗剂治疗也观察到类似的结果。这些发现表明，通过刺激AT1受体激活心脏溶酶产生过多的AII可能直接参与心肌梗死模型狗心律失常的出现，溶酶抑制剂的抗心律失常作用可能是心肌梗死后生存获益的主要原因。心肌酶在心肌缺血再灌注后心脏重构中的作用心肌重构在心肌梗死后慢性心力衰竭的发展中似乎很重要。因此，我们现在正在研究心肌酶的变化和ACE抑制剂的作用。chymase inhibitor AT1受体拮抗剂和ACE抑制剂联合chymase抑制剂在心肌梗死慢慢期（6个月）对仓鼠冠脉缺血再灌注模型的影响。在该模型中，心肌梗死后4周，我们发现心肌酶的激活与心肌I、III和TGF-β胶原mRNA水平的升高有关，我们正在研究这些药物在心肌梗死慢年期的作用。少

1. Changes of cardiac chymase and the variances of angiotensin converting enzyme (ACE) inhibitor and angiotensin (A) II receptor antagonist on cardiac function and survival after myocardial infarction (MI)After MI in hamsters, which possess both ACE- and chymase-dependent AII-generating pathways like in humans, we recently found that the activation of cardiac chymase was more permanent than that of ACE and that AT1 receptor antagonist treatment rather than ACE inhibitor treatment alone provided significant beneficial effects on cardiac function and survival in this model. These finding indicated that the excessive production of AII via activated cardiac chymase may play an important role in determination of prognosis after MI (Jpn J Pharmacol. 86:203-214 (2001)).2. Effects of chymase inhibitor after MIIn hamster MI model, in connection with suppression of the activated-cardiac chymase, cardiac function and survival rate were significantly improved by treatment with chymase specific inh … More ibitor and degree of the prognostic beneficial effects were similar to the finding observed by AT1 receptor blockade in same model. These finding demonstrated that the excessive production of AII via activated cardiac chymase plays an important role in determination of prognosis after MI (Life Sci. 14:437-446 (2002)).3. An antiarrythmic effect of chymase inhibitor after MIChymase inhibitors and AT1 receptor antagonists treatments did not affect infarct sizes significantly after MI, therefore these prognostic beneficial effects may closely relate to the suppression of lethal arrythmias during acute phase of MI. Therefore, we examined the antiarrythmic effects of chymase inhibitor and AT1 receptor antagonist in dog MI model induced by permanent left coronary ligation. The cardiac total AII-forming activity and plasma AII concentration were decreased significantly by the treatment with chymase inhibitor after MI. The rate of ventricular was also suppressed significantly. Similar results were also observed by treatment with AT1 antagonist treatment. These finding indicated that the excessive AII production via activated cardiac chymase by stimulating AT1 receptors may participate directly in the appearance of arrythmias in dog MI model and the antiarrythmic effect of chymase inhibitor may mainly responsible for the survival benefit after MI.4. Roles of cardiac chymase in the pathogenesis of cardiac remodeling after coronary ischemia-reperfusion in hamstersThe cardiac remodeling remote from infarction seems to be important in the development of chronic heart failure after MI. Therefore, we are now examining changes of cardiac chymase and the effects of ACE inhibitor, chymase inhibitor AT1 receptor antagonist and ACE inhibitor combined with chymase inhibitor during chronic phase of MI (6 months) in the coronary ischemia-reperfusion model of hamsters. After MI in this model, we found that activation of cardiac chymase was associated with increases of cardiac mRNA levels of collagen I, III and TGF-β 4 weeks after MI and the examination about the effects of these agents during chronic phase of MI are ongoing. Less