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The 5-HT2 antagonist ketanserin is an open channel blocker of human cardiac ether-à-go-go-related gene (hERG) potassium channels.
Br J Pharmacol. 2008 Oct; 155(3):365-73.BJ

Abstract

BACKGROUND AND PURPOSE

Ketanserin, a selective 5-HT receptor antagonist, prolongs the QT interval of ECG in patients. The purpose of the present study was to determine whether ketanserin would block human cardiac ether-à-go-go-related gene (hERG) potassium channels.

EXPERIMENTAL APPROACH

Whole-cell patch voltage-clamp technique was used to record membrane currents in HEK 293 cells expressing wild type or mutant hERG channel genes.

KEY RESULTS

Ketanserin blocked hERG current (I(hERG)) in a concentration-dependent manner (IC50=0.11 microM). The drug showed an open channel blocking property, the block increasing significantly at depolarizing voltages between +10 to +60 mV. Voltage-dependence for inactivation of hERG channels was negatively shifted by 0.3 microM ketanserin. A 2.8 fold attenuation of inhibition by elevation of external K+ concentration (from 5.0 to 20 mM) was observed, whereas the inactivation-deficient mutants S620T and S631A had the IC50s of 0.84 +/- 0.2 and 1.7 +/-0.4 microM (7.6 and 15.4 fold attenuation of block). In addition, the hERG mutants in pore helix and S6 also significantly reduced the channel block (2-59 fold) by ketanserin.

CONCLUSIONS AND IMPLICATIONS

These results suggest that ketanserin binds to and blocks the open hERG channels in the pore helix and the S6 domain; channel inactivation is also involved in the blockade of hERG channels. Blockade of hERG channels most likely contributes to the prolongation of QT intervals in ECG observed clinically at therapeutic concentrations of ketanserin.

Authors+Show Affiliations

Department of Medicine, and Research Centre of Heart, Brain, Hormone and Healthy Aging, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo 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

18574455

Citation

Tang, Q, et al. "The 5-HT2 Antagonist Ketanserin Is an Open Channel Blocker of Human Cardiac Ether-à-go-go-related Gene (hERG) Potassium Channels." British Journal of Pharmacology, vol. 155, no. 3, 2008, pp. 365-73.
Tang Q, Li ZQ, Li W, et al. The 5-HT2 antagonist ketanserin is an open channel blocker of human cardiac ether-à-go-go-related gene (hERG) potassium channels. Br J Pharmacol. 2008;155(3):365-73.
Tang, Q., Li, Z. Q., Li, W., Guo, J., Sun, H. Y., Zhang, X. H., Lau, C. P., Tse, H. F., Zhang, S., & Li, G. R. (2008). The 5-HT2 antagonist ketanserin is an open channel blocker of human cardiac ether-à-go-go-related gene (hERG) potassium channels. British Journal of Pharmacology, 155(3), 365-73. https://doi.org/10.1038/bjp.2008.261
Tang Q, et al. The 5-HT2 Antagonist Ketanserin Is an Open Channel Blocker of Human Cardiac Ether-à-go-go-related Gene (hERG) Potassium Channels. Br J Pharmacol. 2008;155(3):365-73. PubMed PMID: 18574455.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The 5-HT2 antagonist ketanserin is an open channel blocker of human cardiac ether-à-go-go-related gene (hERG) potassium channels. AU - Tang,Q, AU - Li,Z-Q, AU - Li,W, AU - Guo,J, AU - Sun,H-Y, AU - Zhang,X-H, AU - Lau,C-P, AU - Tse,H-F, AU - Zhang,S, AU - Li,G-R, Y1 - 2008/06/23/ PY - 2008/6/25/pubmed PY - 2008/11/13/medline PY - 2008/6/25/entrez SP - 365 EP - 73 JF - British journal of pharmacology JO - Br. J. Pharmacol. VL - 155 IS - 3 N2 - BACKGROUND AND PURPOSE: Ketanserin, a selective 5-HT receptor antagonist, prolongs the QT interval of ECG in patients. The purpose of the present study was to determine whether ketanserin would block human cardiac ether-à-go-go-related gene (hERG) potassium channels. EXPERIMENTAL APPROACH: Whole-cell patch voltage-clamp technique was used to record membrane currents in HEK 293 cells expressing wild type or mutant hERG channel genes. KEY RESULTS: Ketanserin blocked hERG current (I(hERG)) in a concentration-dependent manner (IC50=0.11 microM). The drug showed an open channel blocking property, the block increasing significantly at depolarizing voltages between +10 to +60 mV. Voltage-dependence for inactivation of hERG channels was negatively shifted by 0.3 microM ketanserin. A 2.8 fold attenuation of inhibition by elevation of external K+ concentration (from 5.0 to 20 mM) was observed, whereas the inactivation-deficient mutants S620T and S631A had the IC50s of 0.84 +/- 0.2 and 1.7 +/-0.4 microM (7.6 and 15.4 fold attenuation of block). In addition, the hERG mutants in pore helix and S6 also significantly reduced the channel block (2-59 fold) by ketanserin. CONCLUSIONS AND IMPLICATIONS: These results suggest that ketanserin binds to and blocks the open hERG channels in the pore helix and the S6 domain; channel inactivation is also involved in the blockade of hERG channels. Blockade of hERG channels most likely contributes to the prolongation of QT intervals in ECG observed clinically at therapeutic concentrations of ketanserin. SN - 0007-1188 UR - https://www.unboundmedicine.com/medline/citation/18574455/The_5_HT2_antagonist_ketanserin_is_an_open_channel_blocker_of_human_cardiac_ether_à_go_go_related_gene__hERG__potassium_channels_ L2 - https://doi.org/10.1038/bjp.2008.261 DB - PRIME DP - Unbound Medicine ER -