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

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.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 (Ca(2+)(i)) in single isolated rabbit PV cardiomyocytes with pacemaker activity before and after an ivabradine administration (0.3, 3, 10, and 30 μM). Ivabradine (0.3, 3, 10, and 30 μM) concentration dependently decreased the spontaneous activity by 6 ± 3%, 32 ± 6%, 49 ± 5%, and 85 ± 4%, and decreased the I(f) by 35 ± 8%, 47 ± 9%, 62 ± 5%, and 65 ± 7%, respectively, 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 IC(50) of the spontaneous activity and I(f) induced by ivabradine were 9.5 and 3.5 μM, respectively. Moreover, ivabradine (30 μM, but not 3 μM) decreased the Ca(2+)(i) transient in the PV cardiomyocytes and ivabradine (30 μM) decreased the L-type calcium current in the PV cardiomyocytes.Ivabradine decreased the I(f)s and Ca(2+)(i) transient in the PV cardiomyocytes, which may contribute to its inhibitory effects on the PV spontaneous activity.