Combined pharmacological block of I(Kr) and I(Ks) increases short-term QT interval variability and provokes torsades de pointes.

Autor:	Lengyel, C, Varró, A, Tábori, K, Papp, J G, Baczkó, I
Předmět:	ANIMAL experimentation BENZOPYRANS BLOOD pressure COMPARATIVE studies DOGS DRUG synergism DOSE-effect relationship in pharmacology ELECTROCARDIOGRAPHY HEART beat HEART conduction system IMMUNITY INTRAVENOUS therapy RESEARCH methodology MEDICAL cooperation MEMBRANE proteins PHENETHYLAMINES POTASSIUM RABBITS RESEARCH SODIUM SULFONAMIDES VENTRICULAR tachycardia LONG QT syndrome EVALUATION research POTASSIUM antagonists CHEMICAL inhibitors
Zdroj:	British Journal of Pharmacology; Aug2007, Vol. 151 Issue 7, p941-951, 11p
Abstrakt:	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 I(Kr) blocker dofetilide (DOF), the I(Ks) 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 I(Kr) and I(Ks) and may be a better predictor of subsequent TdP development than the measurement of QTc interval prolongation. [ABSTRACT FROM AUTHOR]
Databáze:	Complementary Index
Externí odkaz:	Zobrazit plný text záznamu Plný text