title: Ranolazine, an antianginal agent, markedly reduces ventricular arrhythmias induced by ischemia and ischemia-reperfusion.
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.
authors.affiliation: CV Therapeutics, Inc., 3172 Porter Dr., Palo Alto, CA 94304, USA. arvinder.dhalla@gilead.com
authors.forename: Arvinder K
authors.initials: AK
authors.lastname: Dhalla
authors.forename: Wei-Qun
authors.initials: WQ
authors.lastname: Wang
authors.forename: Joan
authors.initials: J
authors.lastname: Dow
authors.forename: John C
authors.initials: JC
authors.lastname: Shryock
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
authors.forename: Anil
authors.initials: A
authors.lastname: Bhandari
authors.forename: Robert A
authors.initials: RA
authors.lastname: Kloner
mesh_terms: D000083:Acetanilides / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D000787:Angina Pectoris / Q000188:drug therapy; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D017202:Myocardial Ischemia / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D010879:Piperazines / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D000069458:Ranolazine; D051381:Rats; D017207:Rats, Sprague-Dawley; D017180:Tachycardia, Ventricular / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D013997:Time Factors; D014693:Ventricular Fibrillation / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: D000083:Acetanilides; D000889:Anti-Arrhythmia Agents; D010879:Piperazines; D000069458:Ranolazine