Blockade of HERG human K+ channel and IKr of guinea pig cardiomyocytes by prochlorperazine.
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 IC50 for a prochlorperazine block of HERG current in Xenopus oocytes progressively decreased relative to the degree of depolarization, from 42.1 microM at -40 mV to 37.4 microM at 0 mV to 22.6 microM 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 muM prochlorperazine at 36 degrees 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.
Kim
Moon-Doo
MD
Department of Psychiatry, Cheju National University College of Medicine, Jeju, Korea.
Eun
Su-Yong
SY
Jo
Su-Hyun
SH
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000209:etiology; D051668:Delayed Rectifier Potassium Channels / Q000037:antagonists & inhibitors* / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000502:physiology*; D006168:Guinea Pigs; D020128:Inhibitory Concentration 50; D008133:Long QT Syndrome; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism; D011188:Potassium / Q000378:metabolism; D011346:Prochlorperazine / Q000494:pharmacology*; D013997:Time Factors; D014981:Xenopus
D014150:Antipsychotic Agents; D051668:Delayed Rectifier Potassium Channels; D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; D011188:Potassium; D011346:Prochlorperazine