The heart rate-lowering agent ivabradine inhibits the pacemaker current If in human atrial myocytes

Introduction: It has been speculated that pacemaker current (I-f) in human atria could play a role in causing ectopic atrial automaticity. Ivabradine is a novel selective and specific I-f inhibitor in the sinus node that reduces heart rate without any negative inotropic effect. The aim of the study was to explore possible effects of ivabradine on I-f in atrial myocytes. Methods and Results: Using patch-clamp technique, we studied effects of ivabradine on I-f present in atrial myocytes isolated from human right appendages of patients undergoing cardiac surgery. The identification of HCN isoforms was obtained by means of multiplex single-cell RT-PCR. Ivabradine induced a marked concentration and use-dependent I-f inhibition with an IC50 at steady state of 2.9 mu M. Time constant of block development (Tau(on)) decreases with the increase in the ivabradine concentration. Use-dependent inhibition induced by ivabradine (3 mu M) was not modified in the presence of cAMP (10 mu M) in the pipette solution. Multiplex single-cell RT-PCR indicates that the major HCN gene subtype detected in atria was HCN2. HCN4 is detected weakly and HCN1 is not significantly detected. Conclusions: Ivabradine inhibits I-f current in the nonpacemaker cell with characteristics similar to those described previously in rabbit sinus node cells, but revealed a lesser sensitivity for I-f recorded in human atrial cell than hHCN4 subunits considered as the major contributors to native f-channels in human sinoatrial node. A potential protection of atrial arrhythmias by ivabradine is discussed.