Block of HERG human K(+) channel and IKr of guinea pig cardiomyocytes by chlorpromazine.

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. IC 5 0 for chlorpromazine block of HERG current was progressively decreased according to depolarization: IC 5 0 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 (I K r ) by 31 and 83%, respectively. However, the same concentrations of chlorpromazine failed to significantly block slowly activating delayed rectifier K + current(I K s ). 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.