Ivabradine prolongs phase 3 of cardiac repolarization and blocks the hERG1 (KCNH2) current over a concentration-range overlapping with that required to block HCN4

hERG potassium channel inhibition by ivabradine requires channel gating

“…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].…”

“…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]. Preferential closed channel block would likely exhibit either neutral or inverse-voltage dependence (e.g.…”

“…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.…”

“…We read with great interest the recent paper in the journal by Lees-Miller and colleagues, who have demonstrated that the clinically used specific bradycardic agent ivabradine inhibits hERG potassium channels at concentrations overlapping those that inhibit HCN4, the major HCN isoform in the mammalian sinoatrial node [1]. 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].…”

“…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. Lees-Miller et al reported tonic block of I hERG using a protocol in which a gap was introduced between application of a large concentration of drug (20 µM) and voltage-protocol application, with maximal block then occurring on the first pulse in the presence of drug [1]. Two possible interpretations of this result are (i) that once the drug has accumulated at its binding site(s) it interacts with and inhibits channels in the closed/resting state; (ii) that once the drug has accumulated, it binds rapidly when the channel opens on membrane potential depolarization.…”