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

Abstract

BackgroundIvabradine 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.Methods and ResultsPatch clamp recordings of hERG current (IhERG) were made from hERG expressing cells at 37°C. IhERG 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 IhERG 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.ConclusionsIvabradine 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 IhERG 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.

hERG potassium channel inhibition by ivabradine requires channel gating

“…These findings complement those in a recently published report from our laboratories, also reporting hERG K + channel inhibition and delayed ventricular repolarization with ivabradine, the latter observed in adult guinea-pig perfused intact hearts [2]. We also observed changes to refractory period and steepening of the left ventricular basal action potential restitution curve with the drug [2], effects that are associated with increased risk of ventricular fibrillation. Ivabradine has been thought to have a good cardiac safety profile [3], but within the last year the drug has been added to the "CredibleMeds" database of drugs associated with QT prolongation and Torsades de Pointes (TdP) as carrying a conditional risk of TdP [4], and case reports of TdP in patients receiving ivabradine together with other medications have begun to appear [5,6].…”

“…They further demonstrated inhibition by the drug of the native rapid delayed rectifier K + current, I Kr , from murine fetal ventricular myocytes and that it delayed ventricular repolarization in those cells [1]. These findings complement those in a recently published report from our laboratories, also reporting hERG K + channel inhibition and delayed ventricular repolarization with ivabradine, the latter observed in adult guinea-pig perfused intact hearts [2]. We also observed changes to refractory period and steepening of the left ventricular basal action potential restitution curve with the drug [2], effects that are associated with increased risk of ventricular fibrillation.…”

“…We favor the second interpretation. In our study, we applied an 'envelope of tails' protocol to investigate gated versus resting/closed state channel block [2], using a drug concentration for I hERG ; this is consistent with activation-dependence of inhibition [2]. Some voltagedependence of inhibition is also evident in Figure 2C of the study of Lees-Miller and colleagues as the current-voltage relations for peak tail current in control and ivabradine only diverge substantially at 0mV and more positive voltages [1].…”

“…In the Discussion of their paper, Lees-Miller and colleagues highlight some similarities and differences between their findings [1] and our own recent report [2]: both studies provide These results are intriguing, and the notion that the drug may accumulate in lipid is attractive, because at clinically relevant plasma levels of the drug [7] comparatively little inhibition of either HCN4 or hERG channels might be anticipated and yet the drug is clearly clinically effective at slowing heart rate. Interesting questions arise, however, as to the likely contribution of the second novel potential interaction site and regarding the gating dependence of the drug's inhibitory effect on hERG.…”

Neuro-cardiac interaction in malignant ventricular arrhythmia and sudden cardiac death

“…Reducing heart rate using the I f blocker ivabradine increases VFT (Vaillant et al 2008) suggesting that the effect of VNS may be due to heart rate. This should however be regarded with caution as there is recent evidence that ivabradine can have effects on ventricular repolarisation (Melgari et al 2015) and may have other 'antiarrhythmic' effects (Koncz et al 2011) as opposed to a pure effect on heart rate alone.…”