Effects of selective IKr channel blockade by E-4031 on ventricular electro-mechanical relationship in the halothane-anesthetized dogs

An inversion of electro-mechanical coupling: namely, mechanical relaxation which precedes electrical repolarization, has been proposed as a surrogate marker to predict the occurrence of drug-induced arrhythmias. The present study was designed to qualitatively and quantitatively clarify the effects of rapidly activating delayed rectifier K+ current (IKr)-selective blockade by E-4031 on the electro-mechanical relationship in vivo. We adopted the halothane-anesthetized canine model (n=4). E-4031 in doses of 0.01 and 0.1 mg/kg that can provide the plasma concentrations effectively to inhibit IKrin vitro significantly delayed the repolarization beyond the initiation of diastole, resulting in the inversion of electro-mechanical coupling, which provides an ideal proarrhythmic substrate, while the durations of left ventricular systole and diastole remained the same. Since these observed changes were solely caused by the repolarization delay, the inversion of electro-mechanical coupling may have a similar extent of sensitivity to QT-interval prolongation as a surrogate marker in predicting the onset of IKr inhibitor-induced arrhythmias.