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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   KCNH 2 ‐encoded human Ether‐à‐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 (I h   ERG  ) were made from  hERG  expressing cells at 37°C. I h   ERG   was inhibited with an  IC  50  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 I h   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  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 h   ERG   with similar potency to that reported for native I f  and  HCN  channels, with S6 binding determinants resembling those observed for  HCN 4. These findings may have important implications both clinically and for future bradycardic drug design.

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