Effects of Bepridil Versus E-4031 on Transmural Ventricular Repolarization and Inducibility of Ventricular Tachyarrhythmias in the Dog

Abstract

Bepridil (a multiple channel blocker) may markedly prolong the QT interval and induce polymorphic ventricular tachyarrhythmias (VTA). We compared the transmural ventricular repolarization characteristics and inducibility of polymorphic VTA after administration of bepridil versus the pure I(Kr) blocker, E-4031, each administered to five open-chest dogs. We used plunge needle electrode to record transmural left ventricular (LV) repolarization and activation-recovery interval (ARI) to estimate local repolarization. The correlation between paced cycle length and ARI was separately examined in the LV endocardium, mid-myocardium (Mid), and epicardium. Attempts to induce VTA were made during bradycardia and sympathetic stimulation. Bepridil and E-4031 prolonged QT interval and ARI in all LV layers, though the magnitude of prolongation was greatest in Mid, increasing the transmural ARI dispersion, particularly during bradycardia. Compared with E-4031, bepridil caused mild, reverse use-dependent changes in ventricular repolarization, and less ARI dispersion than E-4031 during slow ventricular pacing. Both drugs increased ARI(max) and cycle length at 50% of ARI(max), though the changes were smaller after bepridil than after E-4031 administration. Bradycardia after the administration of each drug induced no VTA; however, sympathetic stimulation induced sustained polymorphic VTA in two of five dogs treated with E-4031 versus no dog treated with bepridil. Unlike the pure I(kr) blocker, E-4031, bepridil exhibited weak properties of reverse use-dependency and protected against sympathetic stimulation-induced VTA. It may be an effective supplemental treatment for recipients of implantable cardioverter defibrillator.