An Antiarrhythmic Effect of a Chymase Inhibitor after Myocardial Infarction

• Published in: The Journal of pharmacology and experimental therapeutics 2004-05, Vol.309 (2), p.490-497
• Main Authors: Jin, Denan, Takai, Shinji, Sakaguchi, Masato, Okamoto, Yukiko, Muramatsu, Michiko, Miyazaki, Mizuo
• Format: Article
• Language: English
• Subjects: Animals; Anti-Arrhythmia Agents - pharmacology; Anti-Arrhythmia Agents - therapeutic use; Chymases; Dogs; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Humans; Myocardial Infarction - drug therapy; Oxazoles - chemistry; Oxazoles - pharmacology; Oxazoles - therapeutic use; Serine Endopeptidases - metabolism; Sulfonamides - chemistry; Sulfonamides - pharmacology; Sulfonamides - therapeutic use
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.103.061465

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.