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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 IKr and IKs blockade could induce TdP in anaesthetized guinea pigs and whether short-term variability (STV) or triangulation of action potentials could predict TdP.
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 IKr blocker E-4031 (3, 10 and 30 nmol kg−1 min−1), the IKs 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.
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 IK 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 IKr and IKs 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.
British Journal of Pharmacology (2008) 154, 1414–1426; doi:10.1038/bjp.2008.169; published online 19 May 2008