title: Electrophysiological effects of ivabradine in dog and human cardiac preparations: potential antiarrhythmic actions.
abstract: Ivabradine is a novel antianginal agent which inhibits the pacemaker current. The effects of ivabradine on maximum rate of depolarization (V(max)), repolarization and spontaneous depolarization have not yet been reported in human isolated cardiac preparations. The same applies to large animals close to human in heart size and spontaneous frequency. Using microelectrode technique action potential characteristics and by applying patch-clamp technique ionic currents were studied. Ivabradine exerted concentration-dependent (0.1-10 μM) decrease in the amplitude of spontaneous diastolic depolarization and reduction in spontaneous rate of firing of action potentials and produced a concentration- and frequency-dependent V(max) block in dog Purkinje fibers while action potential duration measured at 50% of repolarization was shortened. In the presence of ivabradine, at 400 ms cycle length, V(max) block developed with an onset kinetic rate constant of 13.9 ± 3.2 beat(-1) in dog ventricular muscle. In addition to a fast recovery of V(max) from inactivation (τ=41-46 ms) observed in control, a second slow component for recovery of V(max) was expressed (offset kinetics of V(max) block) having a time constant of 8.76 ± 1.34 s. In dog after attenuation of the repolarization reserve ivabradine moderately but significantly lengthened the repolarization. In human, significant prolongation of repolarization was only observed at 10 μM ivabradine. Ivabradine in addition to the Class V antiarrhythmic effect also has Class I/C and Class III antiarrhythmic properties, which can be advantageous in the treatment of patients with ischemic heart disease liable to disturbances of cardiac rhythm.
authors.affiliation: Department of Pharmacology & Pharmacotherapy, University of Szeged, Szeged, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Koncz
authors.forename: Tamás
authors.initials: T
authors.lastname: Szél
authors.forename: Miklós
authors.initials: M
authors.lastname: Bitay
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Cerbai
authors.forename: Kristian
authors.initials: K
authors.lastname: Jaeger
authors.forename: Ferenc
authors.initials: F
authors.lastname: Fülöp
authors.forename: Norbert
authors.initials: N
authors.lastname: Jost
authors.forename: László
authors.initials: L
authors.lastname: Virág
authors.forename: Péter
authors.initials: P
authors.lastname: Orvos
authors.forename: László
authors.initials: L
authors.lastname: Tálosi
authors.forename: Attila
authors.initials: A
authors.lastname: Kristóf
authors.forename: István
authors.initials: I
authors.lastname: Baczkó
authors.forename: Julius Gy
authors.initials: JG
authors.lastname: Papp
authors.forename: András
authors.initials: A
authors.lastname: Varró
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001145:Arrhythmias, Cardiac / Q000188:drug therapy*; D001552:Benzazepines / Q000494:pharmacology* / Q000627:therapeutic use; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D055724:Electrophysiological Phenomena / Q000187:drug effects*; D006321:Heart / Q000187:drug effects* / Q000502:physiology* / Q000503:physiopathology; D006801:Humans; D000077550:Ivabradine; D007700:Kinetics; D011188:Potassium / Q000378:metabolism; D011817:Rabbits; D026941:Sodium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000889:Anti-Arrhythmia Agents; D001552:Benzazepines; D026941:Sodium Channel Blockers; D000077550:Ivabradine; D011188:Potassium