title: Effect of ranolazine on ventricular repolarization in class III antiarrhythmic drug-treated rabbits.
abstract: BACKGROUND
  Ranolazine exhibits a synergistic effect in combination with class III drugs to suppress atrial fibrillation.
  
  
  OBJECTIVE
  To investigate whether a combination therapy affects repolarization and provokes ventricular tachyarrhythmias (VT) in a sensitive model of proarrhythmia.
  
  
  METHODS
  Thirty-seven rabbits were assigned to 3 groups and fed with amiodarone (50 mg/kg/d; n = 10) or dronedarone (50 mg/kg/d; n = 10) over a period of 6 weeks. A third group was used as control (n = 17). After obtaining baseline data in Langendorff-perfused control hearts, sotalol (100 μM) was administered in this group. Thereafter, ranolazine (10 μM) was additionally infused on top of amiodarone, dronedarone, or sotalol.
  
  
  RESULTS
  Chronic treatment with amiodarone or dronedarone as well as sotalol significantly increased action potential duration at 90% repolarization (APD(90)). Additional treatment with ranolazine further increased APD(90) in amiodarone- and dronedarone-pretreated hearts but not in sotalol-treated hearts. Ranolazine increased postrepolarization refractoriness as compared with amiodarone or dronedarone alone owing to a marked effect on the refractory period. In contrast to amiodarone and dronedarone, acute application of sotalol increased dispersion of repolarization (P < .05). Additional treatment with ranolazine did not further increase spatial or temporal dispersion. After lowering extracellular [K(+)] in bradycardic hearts, no proarrhythmia occurred in amiodarone- or dronedarone-treated hearts whereas 11 of 17 sotalol-treated hearts showed early afterdepolarizations and subsequent polymorphic VT. Additional treatment with ranolazine reduced the number of VT episodes in sotalol-treated hearts and did not cause proarrhythmia in combination with amiodarone or dronedarone.
  
  
  CONCLUSIONS
  Application of ranolazine on top of class III drugs does not cause proarrhythmia despite a marked effect on ventricular repolarization. The effect of ranolazine on the repolarization reserve is associated with the lack of effect on early afterdepolarizations and dispersion of repolarization.
authors.affiliation: Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, Münster, Germany
authors.forename: Gerrit
authors.initials: G
authors.lastname: Frommeyer
authors.forename: Dennis
authors.initials: D
authors.lastname: Kaiser
authors.forename: Timo
authors.initials: T
authors.lastname: Uphaus
authors.forename: Sven
authors.initials: S
authors.lastname: Kaese
authors.forename: Nani
authors.initials: N
authors.lastname: Osada
authors.forename: Sridharan
authors.initials: S
authors.lastname: Rajamani
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
authors.forename: Günter
authors.initials: G
authors.lastname: Breithardt
authors.forename: Lars
authors.initials: L
authors.lastname: Eckardt
authors.forename: Peter
authors.initials: P
authors.lastname: Milberg
mesh_terms: D000083:Acetanilides; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents; D004195:Disease Models, Animal; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D006329:Heart Conduction System / Q000187:drug effects* / Q000503:physiopathology; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology*; D010879:Piperazines; D011817:Rabbits; D000069458:Ranolazine; D017180:Tachycardia, Ventricular / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D000083:Acetanilides; D000889:Anti-Arrhythmia Agents; D010879:Piperazines; D000069458:Ranolazine