Chymase plays an important role in the regulation of local
angiotensin (Ang) II formation in the cardiac tissue. We recently found that cardiac
chymase was activated significantly and survival rate markedly improved by treatment with
chymase inhibitors after
myocardial infarction (MI) in hamsters. However, the mechanisms for this effect have not been established. Because lethal arrhythmias are generally believed to contribute to
sudden cardiac death, we assessed whether inhibition of cardiac
chymase would provide an antiarrhythmic effect during the 8-h ischemic period after 2-[4-(5-fluoro-3-methylbenzo-[b]thiophen-2-yl)
sulfonamide-3-methanesulfonylphenyl]
oxazole-4-carboxylicacid (
TY51184) (a specific
chymase inhibitor, 1 mg/kg i.v.) treatment by
ligation of left anterior descending coronary artery (LAD) in dogs. Effects of
candesartan (an Ang II type 1 receptor antagonist, 1 mg/kg i.v.) in this model were also assessed. Total Ang II-forming activity and
chymase activity in the infarcted heart were increased significantly 8 h after LAD
ligation. A time-dependent elevation of Ang II in plasma was also observed. A decrease in plasma Ang II levels after
TY51184 treatment occurred concomitantly with suppression of cardiac
chymase activity. LAD
ligation resulted in a large number of ventricular arrhythmias (VAs).
TY51184 and
candesartan treatments largely suppressed the appearance of VAs, and the efficacy of the two agents was similar. These findings demonstrate that
chymase inhibition can provide an antiarrhythmic effect after MI, and the reduction of Ang II by
TY51184 may be mainly responsible for this beneficial effect. An antiarrhythmic effect of
chymase inhibitors may contribute to reductions in the mortality rate during the acute phase after MI.