title: Inhibition of HERG potassium channels by the antimalarial agent halofantrine.
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.affiliation: Department of Medicine, University of New South Wales, Victor Chang Cardiac Research Institute, Sydney, NSW, Australia. h.tie@garvan.unsw.edu.au
authors.forename: H
authors.initials: H
authors.lastname: Tie
authors.forename: B D
authors.initials: BD
authors.lastname: Walker
authors.forename: C B
authors.initials: CB
authors.lastname: Singleton
authors.forename: S M
authors.initials: SM
authors.lastname: Valenzuela
authors.forename: J A
authors.initials: JA
authors.lastname: Bursill
authors.forename: K R
authors.initials: KR
authors.lastname: Wyse
authors.forename: S N
authors.initials: SN
authors.lastname: Breit
authors.forename: T J
authors.initials: TJ
authors.lastname: Campbell
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D016466:CHO Cells; D027682:Cation Transport Proteins; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D051638:Ether-A-Go-Go Potassium Channels; D015870:Gene Expression; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010616:Phenanthrenes / Q000494:pharmacology*; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000235:genetics; D024642:Potassium Channels, Voltage-Gated; D013997:Time Factors
chemical_list: D000962:Antimalarials; D027682:Cation Transport Proteins; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D010616:Phenanthrenes; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; C023768:halofantrine