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

1.金黄地鼠心肌梗死后心脏糜酶的变化及血管紧张素转换酶(ACE)抑制剂和血管紧张素受体(A)II受体拮抗剂对心肌梗死后心功能和存活的影响我们最近发现，在这种模型中，心脏糜酶的激活比ACE更持久，AT1受体拮抗剂的治疗而不是ACE抑制剂的单独治疗对心功能和存活有显著的有利作用。这些结果表明，通过激活的心脏糜酶过度产生AII可能在判断MI后的预后中起重要作用(Jpn J Pharmacol)。86：203-214(2001))糜酶抑制剂对仓鼠心肌梗死后的抑制作用与抑制激活的心脏糜酶有关，…可显著改善心功能，提高存活率在相同的模型中，AT1受体阻滞剂观察到的预后有益效应的更多和更多的程度与观察到的结果相似。这些结果表明，通过激活的心脏糜酶过度产生AII在判断MI(Life Sci，生命科学)后的预后中起重要作用。14：437-446(2002))。在MIChymase抑制剂和AT1受体拮抗剂治疗后，Chymase抑制剂的抗心律失常作用对MI后的心肌梗死面积无明显影响，因此这些预后有利作用可能与MI急性期对致死性心律失常的抑制密切相关。因此，我们观察了凝乳酶抑制剂和AT1受体拮抗剂对犬永久性左冠状动脉结扎致心肌梗死模型的抗心律失常作用。心肌梗死后给予糜酶抑制剂治疗后，心脏总AII形成活性和血浆AII浓度明显降低。心室率也受到明显抑制。AT1拮抗剂治疗也观察到类似的结果。这些结果提示，激活AT1受体激活的心脏糜酶产生过多的AII可能直接参与了犬MI模型心律失常的发生，而糜酶抑制剂的抗心律失常作用可能是MI后存活改善的主要原因。心肌糜酶在金黄地鼠冠状动脉缺血再灌流后心脏重构中的作用心肌梗死后的心脏重构在心梗后慢性心力衰竭的发生发展中起重要作用。因此，我们正在研究心肌梗死(MI)慢性期(6个月)时心脏糜酶的变化及血管紧张素转换酶抑制剂、血管紧张素转换酶抑制剂AT1受体拮抗剂和血管紧张素转换酶抑制剂联合应用的影响。在该模型心肌梗死后，我们发现心肌糜乳酶的激活与心肌I、III型胶原和转化生长因子-β基因表达水平的升高有关，关于这些药物在心肌梗死慢性期的作用的研究正在进行中。较少

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