Effects of a Typical I_Kr Channel Blocker Sematilide on the Relationship Between Ventricular Repolarization, Refractoriness and Onset of Torsades de Pointes

Abstract

The effects of a typical I_Kr channel blocker sematilide on the relationship between ventricular repolarization, refractoriness and onset of torsades de pointes (TdP) were studied using the canine isolated, blood-perfused ventricular septum preparation with monophasic action potential (MAP) recording. Intra-coronary infusion of sematilide (10 – 100 μg/min) prolonged the repolarization phase and effective refractory period, the extent of which was greater in the former than in the latter, resulting in prolongation of terminal repolarization process. Prolonging the basic pacing cycle length from 400 to 600 ms and/or increasing the drug doses enhanced each of these actions. Reverse use-dependence was obvious in the drug-induced prolongation of MAP duration, but it was less clear in the effective refractory period. More importantly, during sematilide infusion, in preparations paced at longer basic cycle length of 600 – 2000 ms, TdP-like polymorphic ventricular tachycardia was repeatedly induced by an extra-stimulus applied on the terminal repolarization phase, which indicates the appearance of electrically vulnerable period. Prolonging the basic pacing cycle length and/or increasing the drug doses prolonged this electrically vulnerable period in parallel with the terminal repolarization phase. These results suggest that prolongation of the terminal repolarization process by sematilide would enhance the chance of conduction slowing at less complete repolarization levels, which may be associated with a high incidence of TdP induction.