Adrenaline reveals the torsadogenic effect of combined blockade of potassium channels in anaesthetized guinea pigs

Abstract

Background and purpose: Torsade de pointes (TdP) can be induced in several species by a reduction in cardiac repolarizing capacity. The aim of this study was to assess whether combined I Kr and I Ks blockade could induce TdP in anaesthetized guinea pigs and whether short-term variability (STV) or triangulation of action potentials could predict TdP. Experimental approach: Experiments were performed in open-chest, pentobarbital-anaesthetized, adrenaline-stimulated male Dunkin Hartley guinea pigs, which received three consecutive i.v. infusions of either vehicle, the I Kr blocker E-4031 (3, 10 and 30 nmol kg -1 min -1), the I Ks blocker HMR1556 (75, 250, 750 nmol kg -1 min -1) or E-4031 and HMR1556 combined. Phenylephrine-stimulated guinea pigs were also treated with the K + channel blockers in combination. Arterial blood pressure, ECGs and epicardial monophasic action potential (MAP) were recorded. Key results: TdP was observed in 75% of adrenaline-stimulated guinea pigs given the K + channel blockers in combination, but was not observed in guinea pigs treated with either I K blocker alone, or in phenylephrine- stimulated guinea pigs. Salvos and ventricular tachycardia occurred with adrenaline but not with phenylephrine. No changes in STV or triangulation of the MAP signals were observed before TdP. Conclusions and implications: Combined blockade of both I Kr and I Ks plus the addition of adrenaline were required to induce TdP in anaesthetized guinea pigs. This suggests that there must be sufficient depletion of repolarization reserve and an appropriate trigger for TdP to occur. © 2008 Nature Publishing Group All rights reserved.