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

Abstract

Introduction: Ivabradine is a novel heart rate decreasing agent with selective and specific antagonist effects on the pacemaker current (I_f). 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 I_f 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 I_f in PV cardiomyocytes. The decreased extent of the PV beating rate or I_f by the different concentrations of ivabradine correlated well with the baseline PV beating rates. The IC₅₀ of the spontaneous activity and I_f induced by ivabradine were 9.5 µM and 3.5 µM, respectively. Moreover, ivabradine (30 µM, but not 3 µM) decreased the Ca²⁺_i transient in the PV cardiomyocytes and ivabradine (30 µM) 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.