Potentiation of E‐4031‐induced torsade de pointes by HMR1556 or ATX‐II is not predicted by action potential short‐term variability or triangulation

Background and purpose: Torsade de pointes (TdP) can be induced by a reduction in cardiac repolarizing capacity. The aim of this study was to assess whether I Ks blockade or enhancement of I Na could potentiate TdP induced by I Kr blockade and to investigate whether short‐term variability (STV) or triangulation of action potentials preceded TdP. Experimental approach: Experiments were performed in open‐chest, pentobarbital‐anaesthetized, α1‐adrenoceptor‐stimulated, male New Zealand White rabbits, which received three consecutive i.v. infusions of either the I Kr blocker E‐4031 (1, 3 and 10 nmol kg−1 min−1), the I Ks blocker HMR1556 (25, 75 and 250 nmol kg−1 min−1) or E‐4031 and HMR1556 combined. In a second study rabbits received either the same doses of E‐4031, the I Na enhancer, ATX‐II (0.4, 1.2 and 4.0 nmol kg−1) or both of these drugs. ECGs and epicardial monophasic action potentials were recorded. Key results: HMR1556 alone did not cause TdP but increased E‐4031‐induced TdP from 25 to 80%. ATX‐II alone caused TdP in 38% of rabbits, as did E‐4031; 75% of rabbits receiving both drugs had TdP. QT intervals were prolonged by all drugs but the extent of QT prolongation was not related to the occurrence of TdP. No changes in STV were detected and triangulation was only increased after TdP occurred. Conclusions and implications: Giving modulators of ion channels in combination substantially increased TdP but, in this model, neither STV nor triangulation of action potentials could predict TdP. British Journal of Pharmacology (2007) 152, 1215–1227; doi:10.1038/sj.bjp.0707513; published online 29 October 2007