Pharmacological Profile of the Bradycardic Agent Ivabradine on Human Cardiac Ion Channels.

Background/aims: Ivabradine lowers the heart rate by inhibition of hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels mediating the 'funny' pacemaker current If in the sinoatrial node. It is clinically approved for the treatment of heart failure and angina pectoris. Due to its proposed high selectivity for If administration of ivabradine is not associated with the side effects commonly observed following the application of other heart rate lowering agents. Recent evidence, however, has shown significant affinity of ivabradine towards K11.1 (ether-a-go-go related gene, ERG) potassium channels. Despite the inhibition of K11.1 channels by ivabradine, cardiac action potential (AP) duration and heart rate corrected QT interval (QT) of the human electrocardiogram (ECG) were not prolonged. We thus surmised that compensatory mechanisms might counteract the drug's inhibitory action on K11.1.

Methods: The effects of ivabradine on human K11.1 and K7.1 potassium, Ca1.2 calcium, and Na1.5 sodium channels, heterologously expressed in tsA-201 cells, were studied in the voltage-clamp mode of the whole cell patch clamp technique. In addition, changes in action potential parameters of human induced pluripotent stem cell (iPSC) derived cardiomyocytes upon application of ivabradine were studied with current-clamp experiments.

Results: Here we show that ivabradine exhibits significant affinity towards cardiac ion channels other than HCN. We demonstrate for the first time inhibition of human voltage-gated Na1.5 sodium channels at therapeutically relevant concentrations. Within this study we also confirm recent findings of human K11.1 inhibition by low µM concentrations of ivabradine and observed no prolongation of ventricular-like APs in cardiomyocytes derived from iPSCs.

Conclusion: Our results provide an explanation why ivabradine, despite its affinity for K11.1 channels, does not prolong the cardiac AP and QT interval. Furthermore, our results suggest the inhibition of voltage-gated Na1.5 sodium channels to underlie the recent observations of slowed atrioventricular conduction by increased atrial-His bundle intervals upon administration of ivabradine.