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Inhibition of human ether-a-go-go-related gene K+ channel and IKr of guinea pig cardiomyocytes by antipsychotic drug trifluoperazine.
J Pharmacol Exp Ther. 2005 May; 313(2):888-95.JP

Abstract

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.

Authors+Show Affiliations

Department of Physiology, Seoul National University College of Dentistry, Yeongun-Dong. shjo@cheju.ac.krNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

15722405

Citation

Choi, Se-Young, et al. "Inhibition of Human Ether-a-go-go-related Gene K+ Channel and IKr of Guinea Pig Cardiomyocytes By Antipsychotic Drug Trifluoperazine." The Journal of Pharmacology and Experimental Therapeutics, vol. 313, no. 2, 2005, pp. 888-95.
Choi SY, Koh YS, Jo SH. Inhibition of human ether-a-go-go-related gene K+ channel and IKr of guinea pig cardiomyocytes by antipsychotic drug trifluoperazine. J Pharmacol Exp Ther. 2005;313(2):888-95.
Choi, S. Y., Koh, Y. S., & Jo, S. H. (2005). Inhibition of human ether-a-go-go-related gene K+ channel and IKr of guinea pig cardiomyocytes by antipsychotic drug trifluoperazine. The Journal of Pharmacology and Experimental Therapeutics, 313(2), 888-95.
Choi SY, Koh YS, Jo SH. Inhibition of Human Ether-a-go-go-related Gene K+ Channel and IKr of Guinea Pig Cardiomyocytes By Antipsychotic Drug Trifluoperazine. J Pharmacol Exp Ther. 2005;313(2):888-95. PubMed PMID: 15722405.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of human ether-a-go-go-related gene K+ channel and IKr of guinea pig cardiomyocytes by antipsychotic drug trifluoperazine. AU - Choi,Se-Young, AU - Koh,Young-Sang, AU - Jo,Su-Hyun, Y1 - 2005/02/18/ PY - 2005/2/22/pubmed PY - 2005/7/6/medline PY - 2005/2/22/entrez SP - 888 EP - 95 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 313 IS - 2 N2 - 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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/15722405/Inhibition_of_human_ether_a_go_go_related_gene_K+_channel_and_IKr_of_guinea_pig_cardiomyocytes_by_antipsychotic_drug_trifluoperazine_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=15722405 DB - PRIME DP - Unbound Medicine ER -