title: Ranolazine-induced postrepolarization refractoriness suppresses induction of atrial flutter and fibrillation in anesthetized rabbits.
abstract: Ranolazine (Ran) is a novel anti-ischemic agent with electrophysiologic properties mainly attributed to the inhibition of late Na(+) current and atrial-selective early Na(+) current. However, there are only limited data regarding its efficacy and mechanism of action against atrial flutter (Afl) and atrial fibrillation (AF) in intact animals. Therefore, we aimed to investigate the electrophysiologic mechanism of Ran in a rabbit model of inducible atrial tachyarrhythmias elicited by acetylcholine (ACh). Arrhythmias were produced in 19 rabbits by rapid atrial burst pacing during control, after intravenous ACh and after Ran + ACh administration. Recording of right atrial monophasic action potentials (MAPs) and programmed stimulation were utilized to determine the duration of atrial repolarization at various cycle lengths and voltage levels of action potential, including 75% of total MAP duration (MAPD75), effective refractory period (ERP), and postrepolarization refractoriness (PRR = ERP - MAPD75) prior to and after Ran. Control stimulation yielded no arrhythmias or maximal nonsustained runs of Afl/AF. Upon ACh, 17 of 19 rabbits exhibited sustained Afl and AF as well as mixed forms of Afl/AF, while 2 animals revealed none or short runs of nonsustained arrhythmias and were excluded from the study. High-frequency burst pacing during the first 30 minutes after Ran + ACh failed to induce any arrhythmia in 13 of 17 rabbits (76%), while 2 animals displayed sustained Afl/AF and 2 other animals nonsustained Afl/AF. At basic stimulation cycle length of 250 milliseconds, Ran prolonged baseline atrial ERP (80 ± 8 vs 120 ± 9 milliseconds, P < .001) much more than MAPD75 (65 ± 7 vs 85 ± 7 milliseconds, P < .001), leading to atrial PRR which was more pronounced after Ran compared with control measurements (35 ± 11 vs 15 ± 10 milliseconds, P < .001). This in vivo study demonstrates that Ran exerts antiarrhythmic activity by suppressing inducibility of ACh-mediated Afl/AF in intact rabbits. Its action may predominantly be related to a significant increase in atrial PRR, resulting in depressed electrical excitability and impediment of arrhythmia initiation.
authors.affiliation: Department of Physiology, Medical School of Larissa & Thoracic and Cardiovascular Surgery of the University Hospital of Larissa, University of Thessaly, Larissa, Greece. iahd93@otenet.gr
authors.forename: Isaac
authors.initials: I
authors.lastname: Aidonidis
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Doulas
authors.forename: Apostolia
authors.initials: A
authors.lastname: Hatziefthimiou
authors.forename: Georgios
authors.initials: G
authors.lastname: Tagarakis
authors.forename: Vassilios
authors.initials: V
authors.lastname: Simopoulos
authors.forename: Ioannis
authors.initials: I
authors.lastname: Rizos
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Tsilimingas
authors.forename: Paschalis-Adam
authors.initials: PA
authors.lastname: Molyvdas
mesh_terms: D000083:Acetanilides / Q000494:pharmacology*; D000109:Acetylcholine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000758:Anesthesia; D000818:Animals; D001281:Atrial Fibrillation / Q000517:prevention & control*; D001282:Atrial Flutter / Q000517:prevention & control*; D005260:Female; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D011817:Rabbits; D000069458:Ranolazine; D012032:Refractory Period, Electrophysiological / Q000187:drug effects*; D026941:Sodium Channel Blockers / Q000494:pharmacology*
chemical_list: D000083:Acetanilides; D010879:Piperazines; D026941:Sodium Channel Blockers; D000069458:Ranolazine; D000109:Acetylcholine