Effect of ranolazine on infarct size in a canine model of regional myocardial ischemia/reperfusion.
We assessed ranolazine's potential to reduce myocardial injury resulting from 90-min occlusion and 18-h reperfusion of left circumflex coronary artery (LCX) in anesthetized dogs. Ranolazine, a putative antianginal agent, has exhibited positive results in a variety of experimental models associated with the ischemic myocardium. Previous studies demonstrated that ranolazine possesses a mechanism of action involving increases in the amount of active pyruvate dehydrogenase during ischemia, suggesting that the compound may act to promote glucose utilization. Ranolazine was administered as a bolus of 3.3 mg/kg, followed by a constant infusion of 7.2 mg/kg/h for 20 h. The loading dose was administered 30 min before LCX occlusion. Control animals received appropriate volumes of vehicles (loading and infusion). Hemodynamics were unchanged between ranolazine and vehicle groups. Three animals in each group were excluded because of ventricular fibrillation (VF). There was no difference in degree of ST segment change between control and ranolazine-treated groups at any time during LCX occlusion. The area at risk (AAR) of infarct was 40.1 +/- 1.7 and 38.9 +/- 1.3% in control-treated (n = 13) and randolazine-treated (n = 8) animals, respectively (p = 0.631). Myocardial infarct size (IS) was 31.7 +/- 5.2 and 36.6 +/- 8.5% in control and ranolazine-treated animals, respectively (p = 0.603). No significant changes were observed in plasma content of enzymatic markers at 0.5, 2.0, and 18.0 h of reperfusion. The results of this in vivo study indicate that ranolazine did not provide protection from injury to regionally ischemic and reperfused myocardium despite its reported antiischemic activity.
Black
S C
SC
Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48109-0632.
Gralinski
M R
MR
McCormack
J G
JG
Driscoll
E M
EM
Lucchesi
B R
BR
D000083:Acetanilides; D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D003402:Creatine Kinase / Q000097:blood; D004285:Dogs; D006439:Hemodynamics / Q000187:drug effects; D007262:Infusions, Intravenous; D008297:Male; D008955:Models, Cardiovascular; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control*; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000378:metabolism; D010879:Piperazines / Q000097:blood / Q000627:therapeutic use*; D000069458:Ranolazine; D015427:Reperfusion Injury / Q000517:prevention & control*; D012307:Risk Factors
D000083:Acetanilides; D010879:Piperazines; D000069458:Ranolazine; D003402:Creatine Kinase