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Inhibition of the human ether-a-go-go-related gene (HERG) potassium channel by cisapride: affinity for open and inactivated states.
Br J Pharmacol. 1999 Sep; 128(2):444-50.BJ

Abstract

1 Cisapride is a prokinetic agent which has been associated with QT prolongation, torsades de pointes and cardiac arrest. The cellular mechanism for these observations is high affinity blockade of IKr (encoded by HERG). 2 In a chronic transfection model using CHO-K1 cells, cisapride inhibited HERG tail currents after a step to +25 mV with similar potency at room and physiological temperatures (IC50 16. 4 nM at 20-22 degrees C and 23.6 nM at 37 degrees C). 3 Channel inhibition exhibited time-, voltage- and frequency-dependence. In an envelope of tails test, channel blockade increased from 27+/-8% after a 120 ms depolarizing step to 50+/-4% after a 1.0 s step. These findings suggested affinity for open and/or inactivated channel states. 4 Inactivation was significantly accelerated by cisapride in a concentration-dependent manner and there was a small (-7 mV) shift in the voltage dependence of steady state inactivation. 5 Channel blockade by cisapride was modulated by [K+]o, with a 26% reduction in the potency of channel blockade when [K+]o was increased from 1 to 10 mM. 6 In conclusion, HERG channel inhibition by cisapride exhibits features consistent with open and inactivated state binding and is sensitive to external potassium concentration. These features may have significant clinical implications with regard to the mechanism and treatment of cisapride-induced proarrhythmia.

Authors+Show Affiliations

Department of Medicine, University of New South Wales, Victor Chang Cardiac Research Institute, St Vincent's Hospital, Sydney, Australia. B.Walker@Garvan.unsw.edu.auNo 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

10510456

Citation

Walker, B D., et al. "Inhibition of the Human Ether-a-go-go-related Gene (HERG) Potassium Channel By Cisapride: Affinity for Open and Inactivated States." British Journal of Pharmacology, vol. 128, no. 2, 1999, pp. 444-50.
Walker BD, Singleton CB, Bursill JA, et al. Inhibition of the human ether-a-go-go-related gene (HERG) potassium channel by cisapride: affinity for open and inactivated states. Br J Pharmacol. 1999;128(2):444-50.
Walker, B. D., Singleton, C. B., Bursill, J. A., Wyse, K. R., Valenzuela, S. M., Qiu, M. R., Breit, S. N., & Campbell, T. J. (1999). Inhibition of the human ether-a-go-go-related gene (HERG) potassium channel by cisapride: affinity for open and inactivated states. British Journal of Pharmacology, 128(2), 444-50.
Walker BD, et al. Inhibition of the Human Ether-a-go-go-related Gene (HERG) Potassium Channel By Cisapride: Affinity for Open and Inactivated States. Br J Pharmacol. 1999;128(2):444-50. PubMed PMID: 10510456.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of the human ether-a-go-go-related gene (HERG) potassium channel by cisapride: affinity for open and inactivated states. AU - Walker,B D, AU - Singleton,C B, AU - Bursill,J A, AU - Wyse,K R, AU - Valenzuela,S M, AU - Qiu,M R, AU - Breit,S N, AU - Campbell,T J, PY - 1999/10/8/pubmed PY - 1999/10/8/medline PY - 1999/10/8/entrez SP - 444 EP - 50 JF - British journal of pharmacology JO - Br. J. Pharmacol. VL - 128 IS - 2 N2 - 1 Cisapride is a prokinetic agent which has been associated with QT prolongation, torsades de pointes and cardiac arrest. The cellular mechanism for these observations is high affinity blockade of IKr (encoded by HERG). 2 In a chronic transfection model using CHO-K1 cells, cisapride inhibited HERG tail currents after a step to +25 mV with similar potency at room and physiological temperatures (IC50 16. 4 nM at 20-22 degrees C and 23.6 nM at 37 degrees C). 3 Channel inhibition exhibited time-, voltage- and frequency-dependence. In an envelope of tails test, channel blockade increased from 27+/-8% after a 120 ms depolarizing step to 50+/-4% after a 1.0 s step. These findings suggested affinity for open and/or inactivated channel states. 4 Inactivation was significantly accelerated by cisapride in a concentration-dependent manner and there was a small (-7 mV) shift in the voltage dependence of steady state inactivation. 5 Channel blockade by cisapride was modulated by [K+]o, with a 26% reduction in the potency of channel blockade when [K+]o was increased from 1 to 10 mM. 6 In conclusion, HERG channel inhibition by cisapride exhibits features consistent with open and inactivated state binding and is sensitive to external potassium concentration. These features may have significant clinical implications with regard to the mechanism and treatment of cisapride-induced proarrhythmia. SN - 0007-1188 UR - https://www.unboundmedicine.com/medline/citation/10510456/Inhibition_of_the_human_ether_a_go_go_related_gene__HERG__potassium_channel_by_cisapride:_affinity_for_open_and_inactivated_states_ L2 - https://doi.org/10.1038/sj.bjp.0702774 DB - PRIME DP - Unbound Medicine ER -