Ranolazine, an antianginal agent, markedly reduces ventricular arrhythmias induced by ischemia and ischemia-reperfusion

Am J Physiol Heart Circ Physiol. 2009 Nov;297(5):H1923-9. doi: 10.1152/ajpheart.00173.2009. Epub 2009 Sep 18.

Abstract

We tested the effect of the antianginal agent ranolazine on ventricular arrhythmias in an ischemic model using two protocols. In protocol 1, anesthetized rats received either vehicle or ranolazine (10 mg/kg, iv bolus) and were subjected to 5 min of left coronary artery (LCA) occlusion and 5 min of reperfusion with electrocardiogram and blood pressure monitoring. In protocol 2, rats received either vehicle or three doses of ranolazine (iv bolus followed by infusion) and 20 min of LCA occlusion. With protocol 1, ventricular tachycardia (VT) occurred in 9/12 (75%) vehicle-treated rats and 1/11 (9%) ranolazine-treated rats during reperfusion (P = 0.003). Sustained VT occurred in 5/12 (42%) vehicle-treated but 0/11 in ranolazine-treated rats (P = 0.037). The median number of episodes of VT during reperfusion in vehicle and ranolazine groups was 5.5 and 0, respectively (P = 0.0006); median duration of VT was 22.2 and 0 s in vehicle and ranolazine rats, respectively (P = 0.0006). With protocol 2, mortality in the vehicle group was 42 vs. 17% (P = 0.371), 10% (P = 0.162) and 0% (P = 0.0373) with ranolazine at plasma concentrations of 2, 4, and 8 microM, respectively. Ranolazine significantly reduced the incidence of ventricular fibrillation [67% in controls vs. 42% (P = 0.414), 30% (P = 0.198) and 8% (P = 0.0094) in ranolazine at 2, 4, and 8 microM, respectively]. Median number (2.5 vs. 0; P = 0.0431) of sustained VT episodes, incidence of sustained VT (83 vs. 33%, P = 0.0361), and the duration of VT per animal (159 vs. 19 s; P = 0.0410) were also significantly reduced by ranolazine at 8 microM. Ranolazine markedly reduced ischemia-reperfusion induced ventricular arrhythmias. Ranolazine demonstrated promising anti-arrhythmic properties that warrant further investigation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetanilides / administration & dosage
  • Acetanilides / blood
  • Acetanilides / pharmacology*
  • Angina Pectoris / drug therapy
  • Animals
  • Anti-Arrhythmia Agents / administration & dosage
  • Anti-Arrhythmia Agents / blood
  • Anti-Arrhythmia Agents / pharmacology*
  • Blood Pressure / drug effects
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Electrocardiography
  • Female
  • Heart Rate / drug effects
  • Infusions, Intravenous
  • Injections, Intravenous
  • Male
  • Myocardial Ischemia / complications
  • Myocardial Ischemia / drug therapy*
  • Myocardial Ischemia / physiopathology
  • Myocardial Reperfusion Injury / complications
  • Myocardial Reperfusion Injury / drug therapy*
  • Myocardial Reperfusion Injury / physiopathology
  • Piperazines / administration & dosage
  • Piperazines / blood
  • Piperazines / pharmacology*
  • Ranolazine
  • Rats
  • Rats, Sprague-Dawley
  • Tachycardia, Ventricular / etiology
  • Tachycardia, Ventricular / physiopathology
  • Tachycardia, Ventricular / prevention & control*
  • Time Factors
  • Ventricular Fibrillation / etiology
  • Ventricular Fibrillation / physiopathology
  • Ventricular Fibrillation / prevention & control*

Substances

  • Acetanilides
  • Anti-Arrhythmia Agents
  • Piperazines
  • Ranolazine