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The antipsychotic drug chlorpromazine inhibits HERG potassium channels.
Br J Pharmacol. 2003 Jun; 139(3):567-74.BJ

Abstract

(1) Acquired long QT syndrome (aLQTS) is caused by prolongation of the cardiac action potential because of blockade of cardiac ion channels and delayed repolarization of the heart. Patients with aLQTS carry an increased risk for torsade de pointes arrhythmias and sudden cardiac death. Several antipsychotic drugs may cause aLQTS. Recently, cases of QTc prolongation and torsade de pointes associated with chlorpromazine treatment have been reported. Blockade of human ether-a-go-go-related gene (HERG) potassium channels, which plays a central role in arrhythmogenesis, has previously been reported to occur with chlorpromazine, but information on the mechanism of block is currently not available. We investigated the effects of chlorpromazine on cloned HERG potassium channels to determine the biophysical mechanism of block. (2) HERG channels were heterologously expressed in Xenopus laevis oocytes, and ion currents were measured using the two-microelectrode voltage-clamp technique. (3) Chlorpromazine blocked HERG potassium channels with an IC(50) value of 21.6 micro M and a Hill coefficient of 1.11. (4) Analysis of the voltage dependence of block revealed a reduction of inhibition at positive membrane potentials. (5) Inhibition of HERG channels by chlorpromazine displayed reverse frequency dependence, that is, the amount of block was lower at higher stimulation rates. No marked changes in electrophysiological parameters such as voltage dependence of activation or inactivation, or changes of the inactivation time constant were observed. (6) In conclusion, HERG channels were blocked in the closed and activated states, and unblocking occurred very slowly.

Authors+Show Affiliations

Department of Cardiology, Medical University Hospital Heidelberg, Bergheimerstrasse 58, D-69115 Heidelberg, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

12788816

Citation

Thomas, Dierk, et al. "The Antipsychotic Drug Chlorpromazine Inhibits HERG Potassium Channels." British Journal of Pharmacology, vol. 139, no. 3, 2003, pp. 567-74.
Thomas D, Wu K, Kathöfer S, et al. The antipsychotic drug chlorpromazine inhibits HERG potassium channels. Br J Pharmacol. 2003;139(3):567-74.
Thomas, D., Wu, K., Kathöfer, S., Katus, H. A., Schoels, W., Kiehn, J., & Karle, C. A. (2003). The antipsychotic drug chlorpromazine inhibits HERG potassium channels. British Journal of Pharmacology, 139(3), 567-74.
Thomas D, et al. The Antipsychotic Drug Chlorpromazine Inhibits HERG Potassium Channels. Br J Pharmacol. 2003;139(3):567-74. PubMed PMID: 12788816.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The antipsychotic drug chlorpromazine inhibits HERG potassium channels. AU - Thomas,Dierk, AU - Wu,Kezhong, AU - Kathöfer,Sven, AU - Katus,Hugo A, AU - Schoels,Wolfgang, AU - Kiehn,Johann, AU - Karle,Christoph A, PY - 2003/6/6/pubmed PY - 2004/2/28/medline PY - 2003/6/6/entrez SP - 567 EP - 74 JF - British journal of pharmacology JO - Br J Pharmacol VL - 139 IS - 3 N2 - (1) Acquired long QT syndrome (aLQTS) is caused by prolongation of the cardiac action potential because of blockade of cardiac ion channels and delayed repolarization of the heart. Patients with aLQTS carry an increased risk for torsade de pointes arrhythmias and sudden cardiac death. Several antipsychotic drugs may cause aLQTS. Recently, cases of QTc prolongation and torsade de pointes associated with chlorpromazine treatment have been reported. Blockade of human ether-a-go-go-related gene (HERG) potassium channels, which plays a central role in arrhythmogenesis, has previously been reported to occur with chlorpromazine, but information on the mechanism of block is currently not available. We investigated the effects of chlorpromazine on cloned HERG potassium channels to determine the biophysical mechanism of block. (2) HERG channels were heterologously expressed in Xenopus laevis oocytes, and ion currents were measured using the two-microelectrode voltage-clamp technique. (3) Chlorpromazine blocked HERG potassium channels with an IC(50) value of 21.6 micro M and a Hill coefficient of 1.11. (4) Analysis of the voltage dependence of block revealed a reduction of inhibition at positive membrane potentials. (5) Inhibition of HERG channels by chlorpromazine displayed reverse frequency dependence, that is, the amount of block was lower at higher stimulation rates. No marked changes in electrophysiological parameters such as voltage dependence of activation or inactivation, or changes of the inactivation time constant were observed. (6) In conclusion, HERG channels were blocked in the closed and activated states, and unblocking occurred very slowly. SN - 0007-1188 UR - https://www.unboundmedicine.com/medline/citation/12788816/The_antipsychotic_drug_chlorpromazine_inhibits_HERG_potassium_channels_ L2 - https://doi.org/10.1038/sj.bjp.0705283 DB - PRIME DP - Unbound Medicine ER -