title: The antianginal agent ranolazine is a potent antiarrhythmic agent that reduces ventricular arrhythmias: through a mechanism favoring inhibition of late sodium channel.
abstract: BACKGROUND
  The antianginal agent ranolazine (R) has shown some promise as an antiarrhythmic agent but its mechanism of action is not known. Previously, we have shown that R suppresses ventricular arrhythmias at a concentration >10 μM that may affect multiple ion currents including IKr.
  
  
  OBJECTIVE
  The present study was carried out to determine the effects of low dose (4 μM) of R that primarily inhibits late I(Na) on ischemia/reperfusion induced ventricular arrhythmias.
  
  
  METHODS
  We subjected 20 anesthetized rats to 5 min of proximal left coronary artery occlusion followed by 5 min of reperfusion. Rats were randomized to vehicle control (C; n = 10) versus low dose R (n = 10; 3.33 mg/kg i.v. bolus plus 3.2 mg/kg/h R started 20 min prior to occlusion, which yields a concentration of 4 μM, within the known level that blocks late Na channels but well below the level that has effect on IKr or peak I(Na)). Reperfusion-induced arrhythmias were quantitated by electrocardiographic monitoring.
  
  
  RESULTS
  In the C group 9/10 rats developed any arrhythmias versus 3/10 in the R group (P = 0.02); 6/10 developed ventricular tachycardia (VT) in the C group versus 0/10 in the R group (P = 0.01). The median number of episodes of VT were 1.5 in the C group versus 0 in the R group (P = 0.005). Sustained VT (>10 sec) occurred in 3/10 C and 0/10 in R (P = 0.21). The median duration of VT was 1.8 seconds in C versus 0 in R (P = 0.005). Ventricular fibrillation occurred in 1/10 in C and 0 in R. Ventricular premature beats (VPBs) occurred in 9/10 C and 3/10 R rats (P = 0.02). The median number of VPBs was 5.5 in the C group versus 0 in R group (P = 0.01). The ischemic risk zones were equivalent in the C and R groups (35 ± 3% and 32 ± 3% of the left ventricle, respectively).
  
  
  CONCLUSIONS
  In conclusion, data show that the marked antiarrhythmic effect of R in the setting of acute ischemia/reperfusion occurs at low doses consistent with inhibition of late I(Na) .
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 / Q000494:pharmacology*; D000787:Angina Pectoris / Q000188:drug therapy*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D005260:Female; D010879:Piperazines / Q000494:pharmacology*; D000069458:Ranolazine; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D017180:Tachycardia, Ventricular / Q000188:drug therapy*
chemical_list: D000083:Acetanilides; D000889:Anti-Arrhythmia Agents; D010879:Piperazines; D026941:Sodium Channel Blockers; D000069458:Ranolazine