The antianginal agent ranolazine is a potent antiarrhythmic agent that reduces ventricular arrhythmias: Through a mechanism favoring inhibition of late sodium channel

Abstract

Background: The antianginal agent ranolazine (R) has shown some promise as an antiarrhythmic agent but its mechanism of action is not known. Previously, we have shown that R suppresses ventricular arrhythmias at a concentration >10 μM that may affect multiple ion currents including IKr. Purpose: The present study was carried out to determine the effects of low dose (4 μM) of R that primarily inhibits late INa on ischemia/reperfusion induced ventricular arrhythmias. Methods: We subjected 20 anesthetized rats to 5 min of proximal left coronary artery occlusion followed by 5 min of reperfusion. Rats were randomized to vehicle control (C; n = 10) versus low dose R (n = 10; 3.33 mg/kg i.v. bolus plus 3.2mg/kg/h R started 20 min prior to occlusion, which yields a concentration of 4 μM, within the known level that blocks late Na channels but well below the level that has effect on IKr or peak INa). Reperfusion-induced arrhythmias were quantitated by electrocardiographic monitoring. Results: In the C group 9/10 rats developed any arrhythmias versus 3/10 in the R group (P= 0.02); 6/10 developed ventricular tachycardia (VT) in the C group versus 0/10 in the R group (P= 0.01). The median number of episodes of VT were 1.5 in the C group versus 0 in the R group (P= 0.005). Sustained VT (>10 sec) occurred in 3/10 C and 0/10 in R (P= 0.21). The median duration of VT was 1.8 seconds in C versus 0 in R (P= 0.005). Ventricular fibrillation occurred in 1/10 in C and 0 in R. Ventricular premature beats (VPBs) occurred in 9/10 C and 3/10 R rats (P= 0.02). The median number of VPBs was 5.5 in the C group versus 0 in R group (P= 0.01). The ischemic risk zones were equivalent in the C and R groups (35 ± 3% and 32 ± 3% of the left ventricle, respectively). Conclusions: In conclusion, data show that the marked antiarrhythmic effect of R in the setting of acute ischemia/reperfusion occurs at low doses consistent with inhibition of late INa. © 2010 Blackwell Publishing Ltd.