Inhibition of human ether-a-go-go-related gene K+ channel and IKr of guinea pig cardiomyocytes by antipsychotic drug trifluoperazine.
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 IC(50) for a trifluoperazine block of HERG current progressively decreased according to depolarization: IC(50) values at -40, 0, and +40 mV were 21.6, 16.6, and 9.29 microM, respectively. The voltage dependence of the block could be fitted with a monoexponential function, and the fractional electrical distance was estimated to be delta = 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 microM trifluoperazine at 36 degrees 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.
Choi
Se-Young
SY
Department of Physiology, Seoul National University College of Dentistry, Yeongun-Dong. shjo@cheju.ac.kr
Koh
Young-Sang
YS
Jo
Su-Hyun
SH
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels / Q000235:genetics* / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors* / Q000502:physiology; D014268:Trifluoperazine / Q000494:pharmacology*; D014982:Xenopus laevis
D014150:Antipsychotic Agents; D027682:Cation Transport Proteins; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D014268:Trifluoperazine