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 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.

• Authors: Moon-Doo Kim, Su-Yong Eun, Su-Hyun Jo
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 544 Issue 1-3 Pg. 82-90 (Aug 21 2006) ISSN: 0014-2999 [Print] Netherlands
• PMID: 16860311 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antipsychotic Agents
• Delayed Rectifier Potassium Channels
• Ether-A-Go-Go Potassium Channels
• KCNH1 protein, human
• Potassium
• Prochlorperazine

Topics

• Animals
• Antipsychotic Agents (pharmacology)
• Arrhythmias, Cardiac (etiology)
• Delayed Rectifier Potassium Channels (antagonists & inhibitors, physiology)
• Dose-Response Relationship, Drug
• Ether-A-Go-Go Potassium Channels (antagonists & inhibitors, physiology)
• Guinea Pigs
• Inhibitory Concentration 50
• Long QT Syndrome
• Myocytes, Cardiac (drug effects, metabolism)
• Oocytes (metabolism)
• Potassium (metabolism)
• Prochlorperazine (pharmacology)
• Time Factors
• Xenopus