Effects of the New Class III Antiarrhythmic Drug MS-551 and d-Sotalol on Canine Coronary Ligation-Reperfusion Ventricular Arrhythmias

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Abstract
The antiarrhythmic effects of a new class III antiarrhythmic agent, MS-551 [1, 3-dimethyl-6-{2-[N-(2-hydroxyethyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2, 4(1H, 3H)-pyrimidinedione hydrochloride], were investigated using canine coronary ligation-reperfusion arrhythmia models under slow and fast heart rate conditions and compared with those of d-sotalol. Slow and fast heart rate conditions were produced by using different anesthetics; i.e., halothane anesthesia for the slow heart rate condition and pentobarbital Na anesthesia for the fast heart rate condition. MS-551 prolonged QTc and suppressed the occurrence of fatal ventricular fibrillation (VF) on coronary reperfusion under either halothane or pentobarbital anesthesia. However, it also showed proarrhythmic effects, i.e., induction of torsades de pointes-like arrhythmia in 1 of 6 halothane anesthetized dogs before coronary ligation. d-Sotalol did not suppress the reperfusion VF in halothane anesthetized animals, nor did it show proarrhythmic effects. However, in the pentobarbital anesthetized animals, d-sotalol suppressed reperfusion VF accompanied by proarrhythmic effects in 1 of 7 dogs. d-Sotalol did not show reverse rate dependent QT prolongation. These results indicate that although both these class III drugs have similar electrophysiological properties, such as QTc prolongation, they have different antiarrhythmic effects. Also, antifibrillatory effects of class III drugs on coronary reperfusion apparently can not be explained solely by their QT prolonging effects.

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