Beneficial effects of cardiac chymase inhibition during the acute phase of myocardial infarction.
Recently, the presence of the chymase-dependent angiotensin (Ang) II-generating system in hamsters, dogs, monkeys, as well as human cardiovascular tissues has been identified. We have reported that the activation of cardiac chymase was more prominent than that of angiotensin converting enzyme (ACE) and that AT1 receptor antagonist treatment rather than ACE inhibitor treatment alone provided significant beneficial effects on cardiac function and survival after MI in hamsters. The aim of the present study was to determine whether this different effects between AT1 receptor antagonist and ACE inhibitor were due to the activation of cardiac chymase after MI in hamsters by using 4-[1-[[bis-(4-methyl-pheny)-methyl]-carbamoyl]-3-(2-ethoxy-benzyl)-4-oxo-azetidine-2-yloxy]-benzoic acid (BCEAB), a novel, orally active and specific chymase inhibitor. The ACE and chymase activities in the infarcted left ventricle were significantly increased 3 days after MI. BCEAB (100 mg/kg/day, p.o.) treatment starting 3 days before MI significantly suppressed the cardiac chymase activity, while it did not affect the plasma and cardiac ACE activities 3 days after MI. A significant improvement in hemodynamics (maximal negative and positive rates of pressure development; left ventricular systolic pressure) was observed for the treatment with BCEAB 3 days after MI. BCEAB (100 mg/kg/day, p.o.) treatment starting 3 days before MI significantly reduced the mortality rate during 14 days of observation following MI (vehicle, 61.1%, n = 18; BCEAB, 27.8%, n = 18; P < 0.05). These findings demonstrated for the first time that cardiac chymase participates directly in the pathophysiologic state after MI in hamsters.
Jin
Denan
D
Department of Pharmacology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki City, Osaka 569-8686, Japan.
Takai
Shinji
S
Yamada
Mayumi
M
Sakaguchi
Masato
M
Miyazaki
Mizuo
M
D000208:Acute Disease; D000704:Analysis of Variance; D000818:Animals; D001384:Azetidines / Q000627:therapeutic use*; D001565:Benzoates / Q000627:therapeutic use*; D053818:Chymases; D006224:Cricetinae; D004195:Disease Models, Animal; D009203:Myocardial Infarction / Q000201:enzymology / Q000401:mortality / Q000517:prevention & control*; D011480:Protease Inhibitors / Q000627:therapeutic use*; D012697:Serine Endopeptidases / Q000378:metabolism*
C439760:4-(1-((bis(4-methylphenyl)methyl)carbamoyl)-3-(2-ethoxybenzyl)-4-oxoazetidine-2-yloxy)benzoic acid; D001384:Azetidines; D001565:Benzoates; D011480:Protease Inhibitors; D012697:Serine Endopeptidases; D053818:Chymases