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

• Published in: American journal of physiology. Heart and circulatory physiology 2009-11, Vol.297 (5), p.H1923-H1929
• Main Authors: Dhalla, Arvinder K, Wang, Wei-Qun, Dow, Joan, Shryock, John C, Belardinelli, Luiz, Bhandari, Anil, Kloner, Robert A
• Format: Article
• Language: English
• Subjects: 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; Blood Pressure - drug effects; Cardiac arrhythmia; Cardiology; Cardiovascular disease; Disease Models, Animal; Dose-Response Relationship, Drug; Drugs; Electrocardiography; Female; Heart Rate - drug effects; Infusions, Intravenous; Injections, Intravenous; Ischemia; Male; Myocardial Ischemia - complications; Myocardial Ischemia - drug therapy; Myocardial Ischemia - physiopathology; Myocardial Reperfusion Injury - complications; Myocardial Reperfusion Injury - drug therapy; Myocardial Reperfusion Injury - physiopathology; Pharmacology; 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
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00173.2009

2 Heart Institute, Good Samaritan Hospital, 3 Keck School of Medicine at University of Southern California, Los Angeles; and 1 CV Therapeutics, Palo Alto, California Submitted February 23, 2009 ; accepted in final form September 14, 2009 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 p rotocol 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 p rotocol 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 µM, 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 µM, 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 µM. Ranolazine markedly reduced ischemia-reperfusion induced ventricular arrhythmias. Ranolazine demonstrated promising anti-arrhythmic properties that warrant further investigation. arrhythmias; ranolazine; myocardial ischemia-reperfusion; ventricular tachycardia; ventricular fibrillation Address for reprint requests and other correspondence: A. K. Dhalla. Dept. of Pharmacology, CV Therapeutics, Inc., 3172 Porter Dr., Palo Alto, CA 94304 (e-mail: arvinder.dhalla{at}gilead.com ).