hERG potassium channel blockade by the HCN channel inhibitor bradycardic agent ivabradine.
BACKGROUND
Ivabradine is a specific bradycardic agent used in coronary artery disease and heart failure, lowering heart rate through inhibition of sinoatrial nodal HCN-channels. This study investigated the propensity of ivabradine to interact with KCNH2-encoded human Ether-à-go-go-Related Gene (hERG) potassium channels, which strongly influence ventricular repolarization and susceptibility to torsades de pointes arrhythmia.


RESULTS
Patch clamp recordings of hERG current (IhERG) were made from hERG expressing cells at 37°C. Ih ERG was inhibited with an IC50 of 2.07 μmol/L for the hERG 1a isoform and 3.31 μmol/L for coexpressed hERG 1a/1b. The voltage and time-dependent characteristics of Ih ERG block were consistent with preferential gated-state-dependent channel block. Inhibition was partially attenuated by the N588K inactivation-mutant and the S624A pore-helix mutant and was strongly reduced by the Y652A and F656A S6 helix mutants. In docking simulations to a MthK-based homology model of hERG, the 2 aromatic rings of the drug could form multiple π-π interactions with the aromatic side chains of both Y652 and F656. In monophasic action potential (MAP) recordings from guinea-pig Langendorff-perfused hearts, ivabradine delayed ventricular repolarization and produced a steepening of the MAPD90 restitution curve.


CONCLUSIONS
Ivabradine prolongs ventricular repolarization and alters electrical restitution properties at concentrations relevant to the upper therapeutic range. In absolute terms ivabradine does not discriminate between hERG and HCN channels: it inhibits Ih ERG with similar potency to that reported for native If and HCN channels, with S6 binding determinants resembling those observed for HCN4. These findings may have important implications both clinically and for future bradycardic drug design.
School of Physiology & Pharmacology, Medical Sciences Building, Bristol, United Kingdom (D.M., Y.Z., A.E.H., J.C.H.).
Dario
D
Melgari
Department of Cardiovascular Sciences, Cardiology Group, Glenfield Hospital, University of Leicester, United Kingdom (K.E.B., C.Z., A.N.).
Kieran E
KE
Brack
Department of Cardiovascular Sciences, Cardiology Group, Glenfield Hospital, University of Leicester, United Kingdom (K.E.B., C.Z., A.N.).
Chuan
C
Zhang
School of Physiology & Pharmacology, Medical Sciences Building, Bristol, United Kingdom (D.M., Y.Z., A.E.H., J.C.H.).
Yihong
Y
Zhang
School of Physiology & Pharmacology, Medical Sciences Building, Bristol, United Kingdom (D.M., Y.Z., A.E.H., J.C.H.).
Aziza
A
El Harchi
Department of Cell Physiology and Pharmacology, Maurice Shock Medical Sciences Building, Leicester, United Kingdom (J.S.M.).
John S
JS
Mitcheson
School of Biochemistry, Medical Sciences Building, Bristol, United Kingdom (C.E.D.).
Christopher E
CE
Dempsey
Department of Cardiovascular Sciences, Cardiology Group, Glenfield Hospital, University of Leicester, United Kingdom (K.E.B., C.Z., A.N.) NIHR Leicester Cardiovascular Biomedical Research Unit, Leicester, United Kingdom (A.N.).
G André
GA
Ng
School of Physiology & Pharmacology, Medical Sciences Building, Bristol, United Kingdom (D.M., Y.Z., A.E.H., J.C.H.).
Jules C
JC
Hancox
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D001919:Bradycardia / Q000188:drug therapy; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000187:drug effects; D006168:Guinea Pigs; D057809:HEK293 Cells; D006321:Heart / Q000187:drug effects; D006801:Humans; D000077550:Ivabradine; D008297:Male; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology*
D001552:Benzazepines; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D026902:Potassium Channel Blockers; D000077550:Ivabradine
HCN; HCN4; QT interval; bradycardic agent; hERG; ivabradine; repolarization