Blockade of HERG human K + channel and IKr of guinea pig cardiomyocytes by prochlorperazine

Abstract

Prochlorperazine, a drug for the symptomatic control of nausea, vomiting and psychiatric disorders, can induce prolonged QT, torsades de pointes and sudden death. We studied the effects of prochlorperazine on human ether- a- go- go-related gene ( HERG) channels expressed in Xenopus oocytes and also in the delayed rectifier K + current of guinea pig cardiomyocytes. Prochlorperazine induced a concentration-dependent decrease in current amplitudes at the end of the voltage steps and tail currents of HERG. The IC 50 for a prochlorperazine block of HERG current in Xenopus oocytes progressively decreased relative to the degree of depolarization, from 42.1 μM at − 40 mV to 37.4 μM at 0 mV to 22.6 μM at + 40 mV. The block of HERG by prochlorperazine was use-dependent, exhibiting a more rapid onset and a greater steady-state block at higher frequencies of activation, while there was partial relief of the block with reduced frequencies. In guinea pig ventricular myocytes, bath applications of 0.5 and 1 μM prochlorperazine at 36 °C blocked rapidly activating delayed rectifier K + current by 38.9% and 76.5%, respectively, but did not significantly block slowly activating delayed rectifier K + current. Our findings suggest that the arrhythmogenic side effects of prochlorperazine are caused by a blockade of HERG and the rapid component of the delayed rectifier K + current rather than by a blockade of the slow component.