title: Class I/B antiarrhythmic property of ranolazine, a novel antianginal agent, in dog and human cardiac preparations.
abstract: The aim of this study was to investigate the cellular electrophysiological effects of ranolazine on action potential characteristics. The experiments were carried out in dog and human cardiac preparations using the conventional microelectrode technique. In dog Purkinje fibres ranolazine produced a concentration- and frequency-dependent depression of the maximum rate of depolarization (V(max)) while action potential duration (APD) was shortened. In dog and human right ventricular papillary muscle ranolazine exerted no significant effect on APD, while it produced, like mexiletine, use-dependent depression of V(max) with relatively fast onset and offset kinetics. In dog midmyocardial preparations the drug did not exert statistically significant effect on repolarization at 10 μM, although a tendency toward prolongation was observed at 20 μM. A moderate lengthening of APD(90) by ranolazine was noticed in canine atrial preparations obtained from dogs in sinus rhythm and in tachypacing induced remodelled preparations. Use-dependent depression of V(max) was more pronounced in atria from dogs in sinus rhythm than those in remodelled atria or in the ventricle. These findings indicate that ranolazine, in addition to its known late sodium current blocking effect, also depresses peak I(Na) with class I/B antiarrhythmic characteristics. Although peak I(Na) inhibition by ranolazine is stronger in the atria, it is also substantial (at fast stimulation frequencies) in ventricular preparations. Ranolazine also decreased the dispersion of ventricular repolarization (the difference in APD(90) values between Purkinje fibres and papillary muscles), which can contribute to the antiarrhythmic property of the drug.
authors.affiliation: Department of Pharmacology & Pharmacotherapy, University of Szeged, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Szél
authors.forename: István
authors.initials: I
authors.lastname: Koncz
authors.forename: Norbert
authors.initials: N
authors.lastname: Jost
authors.forename: István
authors.initials: I
authors.lastname: Baczkó
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Husti
authors.forename: László
authors.initials: L
authors.lastname: Virág
authors.forename: Alexandra
authors.initials: A
authors.lastname: Bussek
authors.forename: Erich
authors.initials: E
authors.lastname: Wettwer
authors.forename: Ursula
authors.initials: U
authors.lastname: Ravens
authors.forename: Julius Gy
authors.initials: JG
authors.lastname: Papp
authors.forename: András
authors.initials: A
authors.lastname: Varró
mesh_terms: D000083:Acetanilides / Q000494:pharmacology* / Q000627:therapeutic use; D000787:Angina Pectoris / Q000188:drug therapy*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016275:Atrial Function / Q000187:drug effects; D004285:Dogs; D055724:Electrophysiological Phenomena / Q000187:drug effects; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006325:Heart Atria / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D011690:Purkinje Fibers / Q000187:drug effects / Q000502:physiology; D000069458:Ranolazine
chemical_list: D000083:Acetanilides; D000889:Anti-Arrhythmia Agents; D010879:Piperazines; D000069458:Ranolazine