Abstract 2755: Ranolazine is a Potent Antiarrhythmic Agent That Reduces Ventricular Arrhythmias by Inhibition of the Late Sodium Channel
There is a lack of reliable and safe anti-arrhythmic agents for the treatment of ventricular arrhythmias. The anti-anginal agent ranolazine (R) has shown some promise but its mechanism of anti-arrhythmic 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. The present study was carried out to determine the effects of low dose (4 μM) of R that selectively inhibits late INa (INa, L) on ischemia/reperfusion induced ventricular arrhythmias. We first determined plasma levels of R in a rat model, 20 minutes following an IV bolus of 3.33 mg/kg followed by infusion of 3.2 mg/kg/hr; 10 mg/kg followed by 9.6 mg/kg/hr, and 30 mg/kg followed by 29 mg/kg/hr. Plasma levels at 20 minutes after the 3.33 mg/kg dosing regimen (low dose) averaged 4 μM, well within the known concentration that blocks INa, L, but well below the concentrations that inhibit IKr or peak INa. The 10 and 30 mg/kg doses resulted in plasma levels of 14 and 52 μM, respectively. We subjected 20 anesthetized rats to 5 minutes of proximal left coronary artery occlusion followed by 5 minutes of reperfusion. Rats were randomized to vehicle control (C; n = 10) versus low dose R (n = 10) groups. R or C was started 20 minutes prior to occlusion. Reperfusion induced arrhythmias were quantitated by ECG monitoring. 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 average number of episodes of VT were 8.2±1.4 in the C group versus 0 in the R group (p = 0.005). Sustained VT (> 10 sec) occurred in 3/10 C and 0 R (p = 0.07). The average duration of VT was 28±5 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). Average number of VPBs was 19±3 in the C group versus 1±0 in R group (p = 0.01). The ischemic risk zones were equivalent in the C and R groups (0.35 versus 0.31 of left ventricle, respectively). In conclusion, data show that the marked anti-arrhythmic effect of R in the setting of acute ischemia/reperfusion is likely due to inhibition of late INa.