|Budget Amount *help
¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2002: ¥1,600,000 (Direct Cost: ¥1,600,000)
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 MI
In 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
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 MI
Chymase 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 hamsters
The 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