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CARDIOVASCULAR

Inhibition of Human ether-a-go-go-Related Gene K⁺ Channel and I_Kr of Guinea Pig Cardiomyocytes by Antipsychotic Drug Trifluoperazine

Department of Physiology, Seoul National University College of Dentistry, Yeongun-Dong, Seoul, Korea (S.-Y.C.); and Departments of Microbiology (Y.-S.K.) and Physiology (S.-H.J.), Cheju National University College of Medicine, Jeju, Korea

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 = 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.

Address correspondence to: Su-Hyun Jo, Department of Physiology, Cheju National University College of Medicine, Ara 1-Dong, Jeju 690-756, Korea. E-mail: shjo{at}cheju.ac.kr

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