title: Antifibrillatory effect of ranolazine during severe coronary stenosis in the intact porcine model.
abstract: BACKGROUND
  Clinical evidence suggests that the antianginal agent ranolazine has antiarrhythmic properties, but its effects on vulnerability to ventricular fibrillation (VF) and T-wave alternans (TWA) during coronary artery stenosis have not been measured.
  
  
  OBJECTIVE
  We investigated whether the antiarrhythmic effect of ranolazine during acute coronary stenosis could be quantified by measuring VF threshold and TWA magnitude.
  
  
  METHODS
  Electrode catheters placed in the left ventricular apex were used to determine VF threshold during ventricular pacing at 130 beats/min, and TWA was quantified from epicardial electrograms using modified moving average method (N = 18). Left anterior descending coronary flow was reduced with a balloon occluder by 75% for 10 minutes. The I(Kr) blocker E-4031 was used to distinguish effects of late I(Na) and I(Kr) inhibition by ranolazine.
  
  
  RESULTS
  Before stenosis, ranolazine and E-4031 increased VF threshold from 32 ± 4 mA to 46 ± 4 mA (mean ± SEM), P = .02, and from 33 ± 5 mA to 40 ± 9 mA, P = .02, respectively. During stenosis, ranolazine increased VF threshold from 19 ± 2 mA to 33 ± 3 mA (P = .02), whereas E-4031 decreased VF threshold from 21 ± 3 mA to 15 ± 3 mA (P = .02). The ischemia-induced increase in TWA was suppressed by ranolazine but not by E-4031, consistent with effects of these agents on VF threshold.
  
  
  CONCLUSIONS
  Ranolazine exerts significant antifibrillatory effects during coronary stenosis through direct effects on cardiac electrical properties independent of coronary flow. Ranolazine's antifibrillatory action during myocardial ischemia does not appear to be mediated by blockade of I(Kr) but rather by inhibition of late I(Na). TWA changes paralleled vulnerability to VF as indicated by VF threshold testing.
authors.affiliation: Department of Pharmacological Sciences, Medical School, University of Tampere, Finland.
authors.forename: Tuomo
authors.initials: T
authors.lastname: Nieminen
authors.forename: Danilo Y
authors.initials: DY
authors.lastname: Nanbu
authors.forename: Ibere P
authors.initials: IP
authors.lastname: Datti
authors.forename: Gabriel R
authors.initials: GR
authors.lastname: Vaz
authors.forename: Caio A M
authors.initials: CA
authors.lastname: Tavares
authors.forename: José R M
authors.initials: JR
authors.lastname: Pegler
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Nearing
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
authors.forename: Richard L
authors.initials: RL
authors.lastname: Verrier
mesh_terms: D000083:Acetanilides / Q000494:pharmacology*; D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D023921:Coronary Stenosis; D004195:Disease Models, Animal; D022062:Electrophysiologic Techniques, Cardiac; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D000069458:Ranolazine; D012720:Severity of Illness Index; D016896:Treatment Outcome; D014693:Ventricular Fibrillation / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D000083:Acetanilides; D004791:Enzyme Inhibitors; D010879:Piperazines; D000069458:Ranolazine