title: First direct comparison of the late sodium current blocker ranolazine to established antiarrhythmic agents in an ischemia/reperfusion model.
abstract: BACKGROUND
  There are few safe antiarrhythmics for ischemic heart disease. Whereas ranolazine is a promising late INa blocker with antiarrhythmic effects, and devoid of pro-arrhythmic properties, there are no direct comparisons between ranolazine and other antiarrhythmic agents in an ischemia/reperfusion setting. HYPOTHESIS AND METHODS: To determine whether ranolazine was as effective as sotalol and lidocaine to reduce ischemia/reperfusion-induced arrhythmias, anesthetized rats were subjected to 5 minutes of proximal left coronary artery occlusion plus 5 minutes of reperfusion, which causes severe ventricular arrhythmias. At 21 minutes prior to coronary occlusion, rats (n = 20 per group) were randomized to receive either sotalol (intravenous [IV] bolus 5 mg/kg, 10 mg/kg per hour infusion), lidocaine (IV bolus 2.5 mg/kg, 2.5 mg/kg/hr infusion), ranolazine (IV bolus 3.3 mg/kg, 3.2 mg/kg per hour infusion), or saline (control).
  
  
  RESULTS
  The incidence of ventricular arrhythmias in the sotalol (S), lidocaine (L), ranolazine (R), and control (C) groups was 7/20, 10/20, 9/20, and 16/20, respectively (P = .01 S vs C, P = .10 L vs C, and P = .048 R vs C). Duration of ventricular tachycardia (VT) episodes was reduced from 15.5 seconds (mean) in C to 1.3 seconds in S, 1.4 sec in L and 0.09 sec in R (P < .05 for S vs C and R vs C by Wilcoxon test). The number of rats with any (≥ 10 seconds) sustained VT was 3 in C versus 1, 0, and 0 in the S, L, and R groups, respectively. Two rats in C had reversible ventricular fibrillation versus 0 in the S, L, and R groups. The number of ventricular premature beats (VPBs) per rat was 10.9 in C, 2.3 in S, 4.9 in L, and 5.7 in R (P < .05 for S, L, or R vs C). P = NS for R versus L or S for all analyses.
  
  
  CONCLUSIONS
  In this first head-to-head comparison of R vs other antiarrhythmic agents at therapeutic doses in an ischemia/reperfusion model, ranolazine (which lacks pro-arrhythmic effects) was as effective as either sotalol or lidocaine to reduce reperfusion-induced ventricular arrhythmias.
authors.affiliation: The Heart Institute, Good Samaritan Hospital, Los Angeles, CA 90017, USA. rkloner@goodsam.org
authors.forename: Robert A
authors.initials: RA
authors.lastname: Kloner
authors.forename: Joan S
authors.initials: JS
authors.lastname: Dow
authors.forename: Anil
authors.initials: A
authors.lastname: Bhandari
mesh_terms: D000083:Acetanilides / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008012:Lidocaine / Q000008:administration & dosage / Q000494:pharmacology; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D011897:Random Allocation; D000069458:Ranolazine; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D013015:Sotalol / Q000008:administration & dosage / Q000494:pharmacology; D018709:Statistics, Nonparametric; D017180:Tachycardia, Ventricular / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D014693:Ventricular Fibrillation / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control
chemical_list: D000083:Acetanilides; D000889:Anti-Arrhythmia Agents; D004791:Enzyme Inhibitors; D010879:Piperazines; D008012:Lidocaine; D013015:Sotalol; D000069458:Ranolazine