Effects of Ivabradine on the Pulmonary Vein Electrical Activity and Modulation of Pacemaker Currents and Calcium Homeostasis

Introduction: Ivabradine is a novel heart rate decreasing agent with selective and specific antagonist effects on the pacemaker current (If). The aim of this study was to investigate the pharmacological effects of ivabradine on the pulmonary vein (PV) cardiomyocytes. Methods: Whole-cell patch clamp techniques and the indo-1 fluorimetric ratio technique were used to investigate the characteristics of the If and intracellular calcium (Ca²⁺i) in single isolated rabbit PV cardiomyocytes with pacemaker activity before and after an ivabradine administration (0.3, 3, 10, and 30 μM). Results: Ivabradine concentration-dependently decreased the spontaneous activity and the If in PV cardiomyocytes. The decreased extent of the PV beating rate or If by the different concentrations of ivabradine correlated well with the baseline PV beating rates. The IC50 of the spontaneous activity and If induced by ivabradine were 9.5μM and 3.5μM, respectively. Moreover, ivabradine (30uM, but not 3uM) decreased the Ca²+i transient in the PV cardiomyocytes and ivabradine (30 uM) decreased the L-type calcium current in the PV cardiomyocytes. Conclusion: Ivabradine decreased the pacemaker currents and Ca²+i transient in the PV cardiomyocytes, which may contribute to its inhibitory effects on the PV spontaneous activity.