title: Combined actions of ivabradine and ranolazine reduce ventricular rate during atrial fibrillation.
abstract: BACKGROUND
  Ventricular rate during atrial fibrillation (AF) can be reduced by slowing atrioventricular (AV) node conduction and/or by decreasing dominant frequency of AF. We investigated whether combined administration of ivabradine and ranolazine reduces ventricular rate during AF.
  
  
  RESULTS
  Ivabradine (maximum clinical dose, 0.25 mg/kg, and 0.10 mg/kg, i.v.) and ranolazine (2.4 mg/kg, i.v., bolus followed by 0.135 mg/kg/min) were studied in an anesthetized pig (N = 16) model of AF. Combined administration of 0.25 mg/kg ivabradine with ranolazine reduced ventricular rate during AF by 51.9 ± 9.7 beats/min (23%, P = 0.017) and dominant frequency of AF by 2.8 ± 0.5 Hz (32%, P = 0.005). It increased PR (P = 0.0002, P = 0.0007) and A-H intervals (P = 0.047, P = 0.002) during pacing at 130 and 180 beats/min, respectively, to a greater degree than additive effects of single agents. Combined administration of 0.1 mg/kg ivabradine with ranolazine exceeded additive effects of single agents on A-H intervals and dominant frequency of AF. Moreover, ranolazine potentiated low-dose ivabradine's reduction in ventricular rate, as combined administration more than doubled effects of the higher ivabradine dose alone and was similar to the combination with the higher dose. Neither drug nor their combination affected contractility (left ventricular [LV] dP/dt), QT or His-ventricular (H-V) intervals, or mean arterial pressure during sinus rhythm or AF.
  
  
  CONCLUSIONS
  Combined administration of ivabradine and ranolazine at clinically safe levels decreases ventricular rate during AF by reducing AV node conduction and AF dominant frequency without QT prolongation or depression in contractility. Targeting these actions offers intrinsic advantages over conventional nodal agents, which can reduce contractility.
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center; Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Verrier
authors.forename: Ana F G
authors.initials: AF
authors.lastname: Silva
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Bonatti
authors.forename: Julio A P
authors.initials: JA
authors.lastname: Batatinha
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Nearing
authors.forename: Gongxin
authors.initials: G
authors.lastname: Liu
authors.forename: Sridharan
authors.initials: S
authors.lastname: Rajamani
authors.forename: Dewan
authors.initials: D
authors.lastname: Zeng
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000503:physiopathology; D001552:Benzazepines / Q000008:administration & dosage*; D002317:Cardiovascular Agents / Q000008:administration & dosage*; D004359:Drug Therapy, Combination; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects* / Q000502:physiology; D000077550:Ivabradine; D008297:Male; D000069458:Ranolazine / Q000008:administration & dosage*; D013552:Swine
chemical_list: D001552:Benzazepines; D002317:Cardiovascular Agents; D000077550:Ivabradine; D000069458:Ranolazine
keywords: atrial fibrillation; atrioventricular node; dominant frequency; funny current; sodium current; ventricular rate