Block of HERG Human K+ Channel and IKr of Guinea Pig Cardiomyocytes by Chlorpromazine

Abstract

Chlorpromazine, a commonly used antipsychotic drug, has been known to induce QT prolongation and torsades de pointes, which can cause sudden death. We studied the effects of chlorpromazine on the human ether-a-go-go-related gene (HERG) channel expressed in Xenopus oocytes and on delayed rectifier K+ current of guinea pig ventricular myocytes. Application of chlorpromazine showed a dose-dependent decrease in the amplitudes of steady-state currents and tail currents of HERG. The decrease became more pronounced at increasingly positive potential, suggesting that the blockade of HERG by chlorpromazine is voltage dependent. IC50 for chlorpromazine block of HERG current was progressively decreased according to depolarization: IC50 values at -30, 0, and +30 mV were 10.5, 8.8, and 4.9 μM, respectively. The block of HERG current during the voltage step increased with time starting from a level 89% of the control current. In guinea pig ventricular myocytes, bath application of 2 and 5 μM chlorpromazine at 36°C blocked rapidly activating delayed rectifier K+ current (IKr) by 31 and 83%, respectively. How-ever, the same concentrations of chlorpromazine failed to significantly block slowly activating delayed rectifier K+ current (IKs). Our findings suggest that the arrhythmogenic side effect of chlorpromazine is caused by blockade of HERG and rapid component of delayed rectifier K+ current rather than by blockade of the slow component.