Tags

Type your tag names separated by a space and hit enter

Inhibition of HERG potassium channels by the antimalarial agent halofantrine.
Br J Pharmacol. 2000 Aug; 130(8):1967-75.BJ

Abstract

Halofantrine is a widely used antimalarial agent which has been associated with prolongation of the 'QT interval' of the electrocardiogram (ECG), torsades de pointes and sudden death. Whilst QT prolongation is consistent with halofantrine-induced increases in cardiac ventricular action potential duration, the cellular mechanism for these observations has not been previously reported. The delayed rectifier potassium channel, I(Kr), is a primary site of action of drugs causing QT prolongation and is encoded by the human-ether-a-go-go-related gene (HERG). We examined the effects of halofantrine on HERG potassium channels stably expressed in Chinese hamster ovary (CHO-K1) cells. Halofantrine blocked HERG tail currents elicited on repolarization to -60 mV from +30 mV with an IC(50) of 196.9 nM. The therapeutic plasma concentration range for halofantrine is 1.67-2.98 microM. Channel inhibition by halofantrine exhibited time-, voltage- and use-dependence. Halofantrine did not alter the time course of channel activation or deactivation, but inactivation was accelerated and there was a 20 mV hyperpolarizing shift in the mid-activation potential of steady-state inactivation. Block was enhanced by pulses that render channels inactivated, and channel blockade increased with increasing duration of depolarizing pulses. We conclude that HERG channel inhibition by halofantrine is the likely underlying cellular mechanism for QT prolongation. Our data suggest preferential binding of halofantrine to the open and inactivated channel states.

Authors+Show Affiliations

Department of Medicine, University of New South Wales, Victor Chang Cardiac Research Institute, Sydney, NSW, Australia. h.tie@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

10952689

Citation

Tie, H, et al. "Inhibition of HERG Potassium Channels By the Antimalarial Agent Halofantrine." British Journal of Pharmacology, vol. 130, no. 8, 2000, pp. 1967-75.
Tie H, Walker BD, Singleton CB, et al. Inhibition of HERG potassium channels by the antimalarial agent halofantrine. Br J Pharmacol. 2000;130(8):1967-75.
Tie, H., Walker, B. D., Singleton, C. B., Valenzuela, S. M., Bursill, J. A., Wyse, K. R., Breit, S. N., & Campbell, T. J. (2000). Inhibition of HERG potassium channels by the antimalarial agent halofantrine. British Journal of Pharmacology, 130(8), 1967-75.
Tie H, et al. Inhibition of HERG Potassium Channels By the Antimalarial Agent Halofantrine. Br J Pharmacol. 2000;130(8):1967-75. PubMed PMID: 10952689.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of HERG potassium channels by the antimalarial agent halofantrine. AU - Tie,H, AU - Walker,B D, AU - Singleton,C B, AU - Valenzuela,S M, AU - Bursill,J A, AU - Wyse,K R, AU - Breit,S N, AU - Campbell,T J, PY - 2000/8/22/pubmed PY - 2001/3/3/medline PY - 2000/8/22/entrez SP - 1967 EP - 75 JF - British journal of pharmacology JO - Br J Pharmacol VL - 130 IS - 8 N2 - Halofantrine is a widely used antimalarial agent which has been associated with prolongation of the 'QT interval' of the electrocardiogram (ECG), torsades de pointes and sudden death. Whilst QT prolongation is consistent with halofantrine-induced increases in cardiac ventricular action potential duration, the cellular mechanism for these observations has not been previously reported. The delayed rectifier potassium channel, I(Kr), is a primary site of action of drugs causing QT prolongation and is encoded by the human-ether-a-go-go-related gene (HERG). We examined the effects of halofantrine on HERG potassium channels stably expressed in Chinese hamster ovary (CHO-K1) cells. Halofantrine blocked HERG tail currents elicited on repolarization to -60 mV from +30 mV with an IC(50) of 196.9 nM. The therapeutic plasma concentration range for halofantrine is 1.67-2.98 microM. Channel inhibition by halofantrine exhibited time-, voltage- and use-dependence. Halofantrine did not alter the time course of channel activation or deactivation, but inactivation was accelerated and there was a 20 mV hyperpolarizing shift in the mid-activation potential of steady-state inactivation. Block was enhanced by pulses that render channels inactivated, and channel blockade increased with increasing duration of depolarizing pulses. We conclude that HERG channel inhibition by halofantrine is the likely underlying cellular mechanism for QT prolongation. Our data suggest preferential binding of halofantrine to the open and inactivated channel states. SN - 0007-1188 UR - https://www.unboundmedicine.com/medline/citation/10952689/Inhibition_of_HERG_potassium_channels_by_the_antimalarial_agent_halofantrine_ L2 - https://doi.org/10.1038/sj.bjp.0703470 DB - PRIME DP - Unbound Medicine ER -