Inhibition of HERG human K+ channel and IKr of guinea pig cardiomyocytes by antipsychotic drug trifluoperazine.

Abstract

Trifluoperazine, 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 trifluoperazine on the human ether-a-go-go-related gene (HERG) channel expressed in Xenopus oocytes and on the delayed rectifier K+ current of guinea pig cardiomyocytes. The application of trifluoperazine showed a dose-dependent decrease in current amplitudes at the end of voltage steps and tail currents of HERG. The IC50 for a trifluoperazine block of HERG current progressively decreased according to depolarization: IC50 values at –40, 0, and +40 mV were 21.6, 16.6, and 9.29 μM, respectively. The voltage dependence of the block could be fitted with a monoexponential function, and the fractional electrical distance was estimated to be δ = 0.65. The block of HERG by trifluoperazine was use-dependent, exhibiting more rapid onset and greater steady-state block at higher frequencies of activation; there was partial relief of the block with decreasing frequency. In guinea pig ventricular myocytes, bath applications of 0.5 and 2 μM trifluoperazine at 36°C blocked the rapidly activating delayed rectifier K+ current by 32.4 and 72.9%, respectively; however, the same concentrations of trifluoperazine failed to significantly block the slowly activating delayed rectifier K+ current. Our findings suggest the arrhythmogenic side effect of trifluoperazine is caused by a blockade of HERG and the rapid component of the delayed rectifier K+ current rather than by the blockade of the slow component.