Impact of chymase inhibitor on cardiac function and survival after myocardial infarction.
OBJECTIVE
Recent studies have demonstrated that hamsters, like humans, possess both angiotensin converting enzyme (ACE)- and chymase-dependent angiotensin (Ang) II-forming pathways in cardiovascular tissues. We recently found that, after myocardial infarction (MI) in hamsters, cardiac chymase was significantly activated. In order to determine whether suppression of cardiac chymase activity could provide prognostic benefit after MI, we examined the effects of NK3201, a novel, orally active and specific chymase inhibitor, on cardiac function and survival during the acute phase of MI in hamsters.


METHODS
Two hundred and ten male Syrian hamsters were used in the present study. The left coronary artery of each hamster was ligated to induce MI. NK3201 at a dose of 30 mg/kg per day was administered orally by gastric gavage, starting either 3 days before or 1 day after MI.


RESULTS
ACE and chymase activities were significantly increased in the infarcted left ventricle 3 days after MI. NK3201 treatment starting 3 days before MI significantly inhibited the increase in cardiac chymase activity, while it did not affect ACE activity either in plasma or in heart 3 days after MI. A significant improvement in cardiac function was observed 3 and 14 days after MI in the group receiving NK3201. Compared with vehicle treatment, NK3201 treatment initiated either 3 days before or 1 day after MI significantly reduced the mortality rate during the 14 days of observation following MI.


CONCLUSIONS
These findings indicate that cardiac chymase plays an important role after MI and this finding may provide a novel therapeutic target in post-MI treatment.
Jin
Denan
D
Department of Pharmacology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki City, Osaka 569-8686, Japan. pha012@art.osaka-med.ac.jp
Takai
Shinji
S
Yamada
Mayumi
M
Sakaguchi
Masato
M
Kamoshita
Keiichi
K
Ishida
Koichi
K
Sukenaga
Yoshikazu
Y
Miyazaki
Mizuo
M
D000081:Acetamides / Q000627:therapeutic use*; D000818:Animals; D006224:Cricetinae; D015150:Echocardiography, Doppler; D008297:Male; D009203:Myocardial Infarction / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy*; D009206:Myocardium / Q000201:enzymology*; D007703:Peptidyl-Dipeptidase A / Q000097:blood; D011743:Pyrimidines / Q000627:therapeutic use*; D012083:Renin / Q000097:blood; D015842:Serine Proteinase Inhibitors / Q000627:therapeutic use*; D015996:Survival Rate
D000081:Acetamides; C437945:NK3201; D011743:Pyrimidines; D015842:Serine Proteinase Inhibitors; D007703:Peptidyl-Dipeptidase A; D012083:Renin