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.

A Novel, Potent, and Selective Inhibitor of Cardiac Late Sodium Current Suppresses Experimental Arrhythmias

“…However, it is possible that improved efficacy could be demonstrated using different dosing regimens. Although ranolazine (4 mM) did not reduce the arrhythmic activity induced by ischemia in the present study, it was reported to do so in a study of anesthetized rats (Dhalla et al, 2009). The different results may reflect either a species or a methodological (i.e., 5 versus 30 minutes duration of ischemia) difference between the studies.…”

Impact of ranolazine on ventricular arrhythmias – A systematic review

“…In ischemia and ischemia‐reperfusion models, ranolazine showed to reduce the incidence, frequency, and duration of VT during reperfusion subsequent to 5 min of ischemia, while it reduced the incidence and duration of VT and VF during 20 minutes of ischemia 39. Additionally, in another model, during 5 minutes of reperfusion, ranolazine showed to reduce except the incidence and duration of VT, the number of ventricular premature beats 40.…”

Ranolazine: safe and effective in a patient with hypertensive cardiomyopathy and multiple episodes of electrical storm

“…Experimental evidence emphasizes the increase in VF threshold and the suppression of ischemia‐induced arrhythmias by ranolazine 17, 18. According to MERLIN‐TIMI 36 trial, ranolazine suppresses VA during the first week after admission for non‐ST elevation acute coronary syndrome 14.…”