Antiarrhythmic effects of HOE642, a novel Na(+)-H+ exchange inhibitor, on ventricular arrhythmias in animal hearts.
HOE642 (4-isopropyl-3-methylsulphonylbenzoyl-guanidine methanesulphonate), a novel Na(+)-H+ exchange subtype 1 inhibitor, was investigated for its possible antiarrhythmic effects on coronary artery ligation/reperfusion and ouabain-induced arrhythmias in the canine heart which may occur after intracellular Ca2+ overload. Also, the effects of HOE642 on coronary artery ligation/reperfusion of the left coronary artery were tested in rat hearts. HOE642 (1 mg/kg) significantly suppressed the occurrence of fatal ventricular fibrillation during coronary artery ligation and after reperfusion in dogs (2 out of 8 dogs in the treated group compared to 7 out of 8 dogs in the control group, P < 0.05), but did not suppress ventricular premature contractions and ventricular tachycardia during ischemia in the canine hearts. HOE642 at the same dose markedly reduced the total duration and the incidence of reperfusion-induced ventricular tachycardia, and the incidence and mortality of reperfusion-induced ventricular fibrillation in rats (ventricular tachycardia duration, 159 +/- 12 s to 21 +/- 8 s, P < 0.01; ventricular tachycardia, 100% to 69%; ventricular fibrillation, 89% to 0%, P < 0.01; mortality, 89% to 11%, P < 0.01). The heart rate, blood pressure, QT interval and ST segment did not change in the canine and rat hearts. HOE642 slightly decreased the arrhythmic ratio of the ouabain-induced arrhythmia only at two time points (28 and 35 min after injection) in the canine hearts. In conclusion, HOE642 has obvious antifibrillatory effects on ischemia/reperfusion arrhythmias and, in addition, has a weak suppressing effect on the ouabain-induced arrhythmia.
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Department of Pharmacology, Yamanashi Medical University, Japan.
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Hashimoto
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D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000097:blood / Q000494:pharmacology*; D002316:Cardiotonic Agents; D003331:Coronary Vessels / Q000502:physiology; D004071:Digitalis Glycosides; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006146:Guanidines / Q000097:blood / Q000494:pharmacology*; D007275:Injections, Intravenous; D008297:Male; D017202:Myocardial Ischemia / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013450:Sulfones / Q000097:blood / Q000494:pharmacology*; D014693:Ventricular Fibrillation / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*
D000889:Anti-Arrhythmia Agents; D002316:Cardiotonic Agents; D004071:Digitalis Glycosides; D006146:Guanidines; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C093373:cariporide