| Budget Amount *help |
¥13,500,000 (Direct Cost: ¥13,500,000)
Fiscal Year 2000: ¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 1999: ¥9,900,000 (Direct Cost: ¥9,900,000)
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| Research Abstract |
Our objectives are to clarify roles of chymase-dependent angiotensin II formation in cardiovascular pathophysiology and beneficial effect of chymase inhibitor to cardiovascular disease. After balloon injury in dog vessels, both ACE and chymase activities were increased in the injured arteries, and an angiotensin II receptor antagonist was effective in preventing the intimal formation, but an ACE inhibitor was ineffective (J.Hum.Hypertens. 13, S21-S25, 1999). In dog grafted veins, the activities of chymase was increased strongly, and the intimal formation was suppressed by either an angiotensin II receptor antagonist or a chymase inhibitor (FEBS Left. 467 : 141-144 ; 2000, Life Sci. 68 : 41-48 ; 2000). Recently, cilostazol, which is informed as a useful drug for suppression of restenosis after PICA in the Guideline of Japanese Circulation Association, suppressed intimal proliferation and chymase activity (Eur.J.Pharmacol. in press). This finding suggests that cilostazol may suppress the vascular proliferation via inhibition of chymase. Together, these data suggest that chymase plays a crucial role as an angiotensin II-generating enzyme in vascular remodeling in the injured vessels. On the other hand, to clarify the role of chymase in cardiac pathophysiology, we investigated myocardial infarction in hamster. In this model, 3 days after the myocardial infarction, cardiac chymase activity was strongly activated, and the mortality was suppressed by treatment of angiotensin II receptor antagonist, but not by angiotensin-converting enzyme inhibitor (reported in Japanese Pharmacological Meeting, 2000, submitted). These data suggest that chymase-dependent angiotensin II formation is associated with cardiac dysfunction after myocardial infarction and that chymase inhibitor is useful for improvement of cardiac function after myocardial infarction.
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