Clemastine, a conventional antihistamine, is a high potency inhibitor of the HERG K+ channel.
Human ether-à-go-go-related gene (HERG) encodes the alpha-subunit of channels carrying the cardiac rapid delayed K+ current (Ikr), which is a major determinant of the duration of ventricular action potentials (APs) and of the QT interval. This study investigated the effects on HERG channel current (IHERG) of clemastine, a "conventional" antihistamine that has been associated with delayed ventricular repolarization in vitro, but for which no adverse effects on the human QT interval have been reported. Whole-cell patch-clamp measurements of IHERG were made at 37 degrees C from human embryonic kidney (HEK 293) cells stably expressing HERG channels. IHERG tails at -40 mV following depolarizing pulses to +20 mV were inhibited by clemastine with an IC50 value of 12 nM; this drug concentration also produced a marked inhibition of peak IHERG elicited during an AP voltage-clamp command. Clemastine produced a reversible approximately -5 mV shift in the IHERG steady-state voltage-dependent activation curve, but voltage-dependence of inactivation was unaffected. Development of IHERG inhibition by clemastine showed strong time-dependence. The S6 point mutations Y652A and F656A greatly attenuated the inhibitory effect of clemastine. We conclude that clemastine is a high potency inhibitor of IHERG, that this action is contingent upon channel gating and that clemastine interacts with a high affinity drug-binding site in the HERG channel pore cavity. The disparity between clemastine's potent IHERG inhibition and a lack of QT-prolongation in normal clinical use underscores the need to interpret HERG IC50 data for novel compounds in the context of information from other safety assays.
Ridley
John M
JM
Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, University Walk, Bristol BS8 1TD, UK.
Milnes
James T
JT
Hancox
Jules C
JC
Witchel
Harry J
HJ
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002974:Clemastine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000187:drug effects; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D006801:Humans; D008297:Male; D009154:Mutation; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D013997:Time Factors; D016276:Ventricular Function
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006634:Histamine H1 Antagonists; C000606913:KCNH2 protein, human; D026902:Potassium Channel Blockers; D002974:Clemastine; D002118:Calcium