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


OBJECTIVE
The present study was carried out to determine the effects of low dose (4 μM) of R that primarily inhibits late I(Na) 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 3.2 mg/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 I(Na)). 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 I(Na) .
Kloner
Robert A
RA
The Heart Institute, Good Samaritan Hospital, Los Angeles, CA 90017, USA. rkloner@goodsam.org
Dow
Joan S
JS
Bhandari
Anil
A
D000083:Acetanilides / Q000494:pharmacology*; D000787:Angina Pectoris / Q000188:drug therapy*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D005260:Female; D010879:Piperazines / Q000494:pharmacology*; D000069458:Ranolazine; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D017180:Tachycardia, Ventricular / Q000188:drug therapy*
D000083:Acetanilides; D000889:Anti-Arrhythmia Agents; D010879:Piperazines; D026941:Sodium Channel Blockers; D000069458:Ranolazine