Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 151, Issue 7, Pages 941-951Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.bjp.0707297
Keywords
torsades de pointes; beat-to-beat short-term variability; QT interval; dofetilide; HMR 1556; repolarization reserve
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Background and purpose: Assessing the proarrhythmic potential of compounds during drug development is essential. However, reliable prediction of drug-induced torsades de pointes arrhythmia (TdP) remains elusive. Along with QT interval prolongation, assessment of the short-term variability of the QT interval (STV(QT)) may be a good predictor of TdP. We investigated the relative importance of I-Ks and I-Kr block in development of TdP together with correlations between QTc interval, QT interval variability and incidence of TdP. Experimental approach: ECGs were recorded from conscious dogs and from anaesthetized rabbits given the IKr blocker dofetilide (DOF), the IKs blocker HMR-1556 (HMR) and their combination, intravenously. PQ, RR and QT intervals were measured and QTc and short-term variability of RR and QT intervals calculated. Key results: DOF increased QTc interval by 20% in dogs and 8% in rabbits. HMR increased QTc in dogs by 12 and 1.9% in rabbits. Combination of DOF+HMR prolonged QTc by 33% in dogs, by 16% in rabbits. DOF or HMR given alone in dogs or HMR given alone in rabbits induced no TdP. Incidence of TdP increased after DOF+HMR combinations in dogs (63%) and following HMR+DOF (82%) and DOF+HMR combinations (71%) in rabbits. STV(QT) markedly increased only after administration of DOF+HMR combinations in both dogs and rabbits. Conclusion and implications: STV(QT) was markedly increased by combined pharmacological block of IKr and IKs and may be a better predictor of subsequent TdP development than the measurement of QTc interval prolongation.
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