ANTIARRHYTHMIC EFFECTS OF HOE642, A NOVEL NA-H+ EXCHANGE INHIBITOR, ON VENTRICULAR ARRHYTHMIAS IN ANIMAL HEARTS()

HOE642 (4-isopropyl-3-methylsulphonylbenzoyl-guanidine methanesulphona te), a novel Na+-H+ exchange subtype 1 inhibitor, was investigated for its possible antiarrhythmic effects on coronary artery ligation/reper fusion and ouabain-induced arrhythmias in the canine heart which may o ccur 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 o ccurrence of fatal ventricular fibrillation during coronary artery lig ation and after reperfusion in dogs (2 out of 8 dogs in the treated gr oup compared to 7 out of 8 dogs in the control group, P < 0.05), but d id not suppress ventricular premature contractions and ventricular tac hycardia 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 re perfusion-induced ventricular fibrillation in rats (ventricular tachyc ardia duration, 159 +/- 12 s to 21 +/- 8 s, P < 0.01; ventricular tach ycardia, 100% to 69%; ventricular fibrillation, 89% to 0%, P < 0.01; m ortality, 89% to 11%, P < 0.01). The heart rate, blood pressure, QT in terval and ST segment did not change in the canine and rat hearts. HOE 642 slightly decreased the arrhythmic ratio of the ouabain-induced arr hythmia only at two time points (28 and 35 min after injection) in the canine hearts. In conclusion, HOE642 has obvious antifibrillatory eff ects on ischemia/reperfusion arrhythmias and, in addition, has a weak suppressing effect on the ouabain-induced arrhythmia.