hERG Potassium Channel Blockade by the HCN Channel Inhibitor Bradycardic Agent Ivabradine

作者：Melgari Dario; Brack Kieran E; Zhang Chuan; Zhang Yihong; El Harchi Aziza; Mitcheson John S; Dempsey Christopher E; Ng G Andre^*; Hancox Jules C

来源：Journal of the American Heart Association, 2015, 4(4): e001813.

DOI：10.1161/JAHA.115.001813

• bradycardic agent
• HCN
• HCN4
• hERG
• ivabradine
• QT interval
• repolarization

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-a-go-go-Related Gene (hERG) potassium channels, which strongly influence ventricular repolarization and susceptibility to torsades de pointes arrhythmia.
Methods and Results-Patch clamp recordings of hERG current (IhERG) were made from hERG expressing cells at 37 degrees C. IhERG was inhibited with an IC50 of 2.07 mu mol/L for the hERG 1a isoform and 3.31 mu mol/L for coexpressed hERG 1a/1b. The voltage and time-dependent characteristics of I-hERG 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 pi-pi 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 MAPD(90) 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 I-hERG 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.

• 出版日期2015-4