title: Sodium channel block by ranolazine in an experimental model of stretch-related atrial fibrillation: prolongation of interatrial conduction time and increase in post-repolarization refractoriness.
abstract: OBJECTIVE
  In several clinical and pre-clinical studies, application of ranolazine (RAN) led to suppression of atrial fibrillation (AF). The aim of the present study was to investigate whether RAN can suppress AF in an experimental rabbit whole heart model, in which acute haemodynamic changes trigger AF. Ranolazine was compared with flecainide and sotalol as established antiarrhythmic agents.
  
  
  RESULTS
  In 60 Langendorff-perfused, isolated rabbit hearts, AF episodes were evoked by burst pacing with a fixed number of stimuli at baseline and following acute atrial stretch. Data were obtained in the absence and presence of acute dilatation of the left atrium (20 mmHg) at baseline and after drug application (RAN 10 µM, n = 10; flecainide 2 µM, n = 10; sotalol 50 µM, n = 10). Application of sotalol, but not RAN or flecainide increased the atrial action potential duration at 90% repolarization (aAPD90); however, both RAN (+8 ms) and flecainide (+13 ms) increased interatrial conduction time. All three drugs caused a significant increase in atrial effective refractory period (aERP) and, thus, an increase in atrial post-repolarization refractoriness (aPRR: +11 ms each, P < 0.05). Acute dilatation of the left atrium reduced aAPD90 and aERP. The described drug effects were preserved in the setting of acute atrial dilatation. Acute atrial dilatation significantly increased the incidence of AF. Ranolazine and flecainide, but not sotalol, decreased the number of responses.
  
  
  CONCLUSIONS
  Ranolazine-related sodium channel block is preserved upon acute atrial stretch. Ranolazine suppresses stretch-induced AF by increasing interatrial conduction time and aPRR. These results shed further evidence on the potential role of RAN in the prevention of AF. This might also apply to clinical conditions that are associated with haemodynamic or mechanical disorders, leading to acute dilatation of the atria.
authors: Division of Electrophysiology, Department of Cardiovascular Medicine, University Hospital of Münster, Albert-Schweitzer Campus 1, Münster, Germany. milbergp@uni-muenster.de
authors: Peter
authors: P
authors: Milberg
authors: Gerrit
authors: G
authors: Frommeyer
authors: Shokoufeh
authors: S
authors: Ghezelbash
authors: Sridharan
authors: S
authors: Rajamani
authors: Nani
authors: N
authors: Osada
authors: Radu
authors: R
authors: Razvan
authors: Luiz
authors: L
authors: Belardinelli
authors: Günter
authors: G
authors: Breithardt
authors: Lars
authors: L
authors: Eckardt
mesh_terms: D000083:Acetanilides / Q000008:administration & dosage*; D000284:Administration, Oral; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage; D001281:Atrial Fibrillation / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology*; D005260:Female; D005424:Flecainide / Q000008:administration & dosage; D006329:Heart Conduction System / Q000187:drug effects / Q000503:physiopathology*; D006339:Heart Rate / Q000187:drug effects*; D066298:In Vitro Techniques; D009431:Neural Conduction / Q000187:drug effects*; D010879:Piperazines / Q000008:administration & dosage*; D011817:Rabbits; D000069458:Ranolazine; D012032:Refractory Period, Electrophysiological / Q000187:drug effects*; D026941:Sodium Channel Blockers / Q000008:administration & dosage; D013015:Sotalol / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D000083:Acetanilides; D000889:Anti-Arrhythmia Agents; D010879:Piperazines; D026941:Sodium Channel Blockers; D013015:Sotalol; D000069458:Ranolazine; D005424:Flecainide