Drug‐Induced Ventricular Tachyarrhythmia in Isolated Rabbit Hearts with Atrioventricular Block

Abstract: The aims of this study were to develop a suitable model to study proarrhythmic potential using isolated rabbit hearts with atrioventricular block and to examine the proarrhythmic potential of several drugs using this model. With a normal K/Mg solution (K + =5.7 mM and Mg 2+ =1 mM), d,l‐sotalol (10 and 30 μM), a class III antiarrhythmic drug, prolonged ventricular repolarization, such as QT intervals and monophasic action potential duration, and induced early after‐depolarization and polymorphic ventricular tachyarrhythmia. Cisapride (0.1 and 0.3 μM), a 5‐HT 4 receptor agonist, also prolonged the ventricular repolarization, and induced early after‐depolarization. With a low K/Mg solution (K + =1.5 mM and Mg 2+ =0.35 mM), d,l‐sotalol at 30 μM and cisapride at 0.3 μM more potently prolonged the ventricular repolarization than with a normal K/Mg solution. Furthermore, the incidence of polymorphic ventricular tachyarrhythmia caused by cisapride at 0.3 μM with a low K/Mg solution was higher than that with a normal K/Mg solution. Mosapride citrate, another 5‐HT 4 receptor agonist, at 10 μM prolonged the ventricular repolarization and induced early after‐depolarization with a low K/Mg solution, whereas the drug at 1 and 3 μM did not affect any of the parameters examined. Des‐4‐fluorobenzyl‐mosapride, a metabolite of mosapride citrate, at 10 μM slightly prolonged the ventricular repolarization without inducing early after‐depolarization or ventricular tachyarrhythmia. These results suggest that mosapride citrate and des‐4‐fluorobenzyl‐mosapride have much less proarrhythmic potential than cisapride and that isolated rabbit heart with atrioventricular block, perfused with a low K/Mg solution, is a suitable model for predicting the proarrhythmic potential of drugs.