Antiarrhythmic and Proarrhythmic Effects of Sematilide in Canine Ventricular Arrhythmia Models

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Abstract
Using canine ventricular arrhythmia models induced by two-stage coronary ligation, digitalis, adrenaline, coronary ligation and reperfusion, and programmed electrical stimulation (PES), we examined the antiarrhythmic or proarrhythmic effects of sematilide, N-[2(diethylamino)ethyl]-4-[(methylsulfonyl)amino]-benzamide hydrochloride. Sematilide in an intravenous (i.v.) dose range of 0.3 to 6.0 mg/kg prolonged the QTc interval, but had an antiarrhythmic effect only on the arrhythmias induced by PES (7 out of 10 dogs with old myocardial infarction). Sematilide was not effective on coronary ligation and reperfusion arrhythmia or the spontaneously occurring automaticity arrhythmias induced by two-stage coronary ligation, digitalis and adrenaline, respectively, and even aggravated digitalis and adrenaline-induced arrhythmias. These results indicate that the class III agent sematilide is similar to other new class III agents, such as d-sotalol, E-4031 and MS-551, in that it was not effective on the automaticity arrhythmias, but different from these new class III agents, in that sematilide prevented only the induction of ventricular arrhythmias induced by PES and did not suppress the coronary ligation-reperfusion arrhythmias. The PES induced arrhythmias are thought to be induced exclusively by a reentrant mechanism, but the reperfusion arrhythmias may involve not only re-entry, but also automaticity, and we reported the effectiveness of MS-551, E-4031 and d-sotalol on the latter arrhythmia. Sematilide is different in that it even aggravated some automaticity arrhythmias.

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