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Blockade of HERG human K+ channel and IKr of guinea pig cardiomyocytes by prochlorperazine.
Eur J Pharmacol. 2006 Aug 21; 544(1-3):82-90.EJ

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+Show Affiliations

Department of Psychiatry, Cheju National University College of Medicine, Jeju, Korea.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16860311

Citation

Kim, Moon-Doo, et al. "Blockade of HERG Human K+ Channel and IKr of Guinea Pig Cardiomyocytes By Prochlorperazine." European Journal of Pharmacology, vol. 544, no. 1-3, 2006, pp. 82-90.
Kim MD, Eun SY, Jo SH. Blockade of HERG human K+ channel and IKr of guinea pig cardiomyocytes by prochlorperazine. Eur J Pharmacol. 2006;544(1-3):82-90.
Kim, M. D., Eun, S. Y., & Jo, S. H. (2006). Blockade of HERG human K+ channel and IKr of guinea pig cardiomyocytes by prochlorperazine. European Journal of Pharmacology, 544(1-3), 82-90.
Kim MD, Eun SY, Jo SH. Blockade of HERG Human K+ Channel and IKr of Guinea Pig Cardiomyocytes By Prochlorperazine. Eur J Pharmacol. 2006 Aug 21;544(1-3):82-90. PubMed PMID: 16860311.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Blockade of HERG human K+ channel and IKr of guinea pig cardiomyocytes by prochlorperazine. AU - Kim,Moon-Doo, AU - Eun,Su-Yong, AU - Jo,Su-Hyun, Y1 - 2006/07/24/ PY - 2006/02/02/received PY - 2006/05/27/revised PY - 2006/06/02/accepted PY - 2006/7/25/pubmed PY - 2007/1/16/medline PY - 2006/7/25/entrez SP - 82 EP - 90 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 544 IS - 1-3 N2 - 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. SN - 0014-2999 UR - https://www.unboundmedicine.com/medline/citation/16860311/Blockade_of_HERG_human_K+_channel_and_IKr_of_guinea_pig_cardiomyocytes_by_prochlorperazine_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(06)00624-8 DB - PRIME DP - Unbound Medicine ER -