Antiarrhythmic actions of tedisamil: Studies in rats and primates

Tedisamil is a new bradycardic agent, previously shown to block transient outward and delayed rectifier potassium currents in cardiac tissue [1,2]. In the present study tedisamil caused bradycardia and Q-Tc widening in rats and primates. Q-Tc widening is indicative of class III antiarrhythmic actions. In keeping with this, tedisamil had antiarrhythmic activity against electrical and ischemia-induced arrhythmias in rats. In rats, 0.5–4 mg/kg IV tedisamil caused parallel and dose-related increases in action-potential duration, “Q-Tc” interval, and refractory period; and decreases in maximum ventricular following frequency. In primates after 0.5–2.0 mg/kg IV, findings were similar for indices of Q-T widening and decreases in maximum ventricular following frequency. Tedisamil did not change QRS width, nor did it increase threshold currents for capture of ventricles, nor for fibrillo-flutter at doses below 4 mg/kg in rats. These findings were consistent with the lack of significant sodium-channel blockade. However, upon increasing the dose to 4 mg/kg, ventricular fibrillo-flutter could not be induced in rats by electrical stimulation; instead, only ventricular tachycardias with slow rates occurred. Ischemia-induced ventricular fibrillation was reduced in a dose-related manner by tedisamil in rats. The overall incidence of ischemia-induced ventricular tachycardia was not markedly reduced, but rates during tachycardic episodes were lower. When pacing was used to overcome tedisamil-induced bradycardia, antiarrhythmic actions during ischemia were more pronounced. These findings are consistent with the hypothesis that tedisamil increased refractoriness, which resulted in extended path lengths for reentry circuits and slower rates during episodes of ventricular tachycardia. High doses of tedisamil increased path lengths so much that the multiple reentry circuits of fibrillation could no longer occur. The limited study in primates suggests similar mechanisms could occur in humans.