Tags

Type your tag names separated by a space and hit enter

The antidepressant drug fluoxetine is an inhibitor of human ether-a-go-go-related gene (HERG) potassium channels.
J Pharmacol Exp Ther. 2002 Feb; 300(2):543-8.JP

Abstract

Fluoxetine is a commonly prescribed antidepressant compound. Its action is primarily attributed to selective inhibition of the reuptake of serotonin (5-hydroxytryptamine) in the central nervous system. Although this group of antidepressant drugs is generally believed to cause fewer proarrhythmic side effects compared with tricyclic antidepressants, serious concerns have been raised by case reports of tachycardia and syncopes associated with fluoxetine treatment. To determine the electrophysiological basis for the arrhythmogenic potential of fluoxetine, we investigated the effects of this drug on cloned human ether-a-go-go-related gene (HERG) potassium channels heterologously expressed in Xenopus oocytes using the two-microelectrode voltage-clamp technique. We found that fluoxetine blocked HERG channels with an IC(50) value of 3.1 microM. Inhibition occurred fast to open channels with very slow unbinding kinetics. Analysis of the voltage dependence of block revealed loss of inhibition at membrane potentials greater than 40 mV, indicating that channel inactivation prevented block by fluoxetine. No pronounced changes in electrophysiological parameters such as voltage dependence of activation or inactivation, or inactivation time constant could be observed, and block was not frequency-dependent. This is the first study demonstrating that HERG potassium channels are blocked by the selective serotonin reuptake inhibitor fluoxetine. We conclude that HERG current inhibition might be an explanation for the arrhythmogenic side effects of this drug.

Authors+Show Affiliations

Department of Cardiology, Medical University Hospital Heidelberg, Heidelberg, Germany.No 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

11805215

Citation

Thomas, Dierk, et al. "The Antidepressant Drug Fluoxetine Is an Inhibitor of Human Ether-a-go-go-related Gene (HERG) Potassium Channels." The Journal of Pharmacology and Experimental Therapeutics, vol. 300, no. 2, 2002, pp. 543-8.
Thomas D, Gut B, Wendt-Nordahl G, et al. The antidepressant drug fluoxetine is an inhibitor of human ether-a-go-go-related gene (HERG) potassium channels. J Pharmacol Exp Ther. 2002;300(2):543-8.
Thomas, D., Gut, B., Wendt-Nordahl, G., & Kiehn, J. (2002). The antidepressant drug fluoxetine is an inhibitor of human ether-a-go-go-related gene (HERG) potassium channels. The Journal of Pharmacology and Experimental Therapeutics, 300(2), 543-8.
Thomas D, et al. The Antidepressant Drug Fluoxetine Is an Inhibitor of Human Ether-a-go-go-related Gene (HERG) Potassium Channels. J Pharmacol Exp Ther. 2002;300(2):543-8. PubMed PMID: 11805215.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The antidepressant drug fluoxetine is an inhibitor of human ether-a-go-go-related gene (HERG) potassium channels. AU - Thomas,Dierk, AU - Gut,Bernd, AU - Wendt-Nordahl,Gunnar, AU - Kiehn,Johann, PY - 2002/1/24/pubmed PY - 2002/2/28/medline PY - 2002/1/24/entrez SP - 543 EP - 8 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 300 IS - 2 N2 - Fluoxetine is a commonly prescribed antidepressant compound. Its action is primarily attributed to selective inhibition of the reuptake of serotonin (5-hydroxytryptamine) in the central nervous system. Although this group of antidepressant drugs is generally believed to cause fewer proarrhythmic side effects compared with tricyclic antidepressants, serious concerns have been raised by case reports of tachycardia and syncopes associated with fluoxetine treatment. To determine the electrophysiological basis for the arrhythmogenic potential of fluoxetine, we investigated the effects of this drug on cloned human ether-a-go-go-related gene (HERG) potassium channels heterologously expressed in Xenopus oocytes using the two-microelectrode voltage-clamp technique. We found that fluoxetine blocked HERG channels with an IC(50) value of 3.1 microM. Inhibition occurred fast to open channels with very slow unbinding kinetics. Analysis of the voltage dependence of block revealed loss of inhibition at membrane potentials greater than 40 mV, indicating that channel inactivation prevented block by fluoxetine. No pronounced changes in electrophysiological parameters such as voltage dependence of activation or inactivation, or inactivation time constant could be observed, and block was not frequency-dependent. This is the first study demonstrating that HERG potassium channels are blocked by the selective serotonin reuptake inhibitor fluoxetine. We conclude that HERG current inhibition might be an explanation for the arrhythmogenic side effects of this drug. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/11805215/The_antidepressant_drug_fluoxetine_is_an_inhibitor_of_human_ether_a_go_go_related_gene__HERG__potassium_channels_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=11805215 DB - PRIME DP - Unbound Medicine ER -