Rate-Dependent Effects of Vernakalant in the Isolated Non-Remodeled Canine Left Atria Are Primarily Due to Block of the Sodium Channel Comparison with Ranolazine and dl-Sotalol

Background —Several clinical trials have shown that vernakalant is effective in terminating recent-onset atrial fibrillation (AF). The electrophysiological actions of vernakalant are not fully understood. Methods and Results —Here we report the results of a blinded study comparing the in vitro canine atrial electrophysiological effects of vernakalant, ranolazine, and dl-sotalol. Action potential durations (APD 50,75,90 ), effective refractory period (ERP), post-repolarization refractoriness (PRR), maximum rate of rise of the action potential (AP) upstroke (V max ), diastolic threshold of excitation (DTE), conduction time (CT), and the shortest S 1 -S 1 permitting 1:1 activation (S 1 -S 1 ) were measured using standard stimulation and microelectrode recording techniques in isolated normal, non-remodeled canine arterially-perfused left atrial preparations. Vernakalant caused variable but slight prolongation of APD 90 (p=n.s.), but significant prolongation of APD 50 at 30 μM and rapid rates. In contrast, ranolazine and dl-sotalol produced consistent concentration- and reverse rate-dependent prolongation of APD 90 . Vernakalant and ranolazine caused rate-dependent, whereas dl-sotalol caused reverse rate-dependent, prolongation of ERP. Significant rate-dependent PRR developed with vernakalant and ranolazine, but not with dl-sotalol. Other I Na -mediated parameters (i.e., V max , CT, DTE, and S 1 -S 1 ) were also significantly depressed by vernakalant and ranolazine, but not by dl-sotalol. Only vernakalant elevated AP plateau voltage, consistent with blockade of I Kur and I to . Conclusions —In isolated canine left atria, the effects of vernakalant and ranolazine were characterized by use-dependent inhibition of sodium channel-mediated parameters and those of dl-sotalol by reverse rate-dependent prolongation of APD 90 and ERP. This suggests that during the rapid activation rates of AF, the I Na blocking action of the mixed ion channel blocker vernakalant takes prominence. This mechanism may explain vernakalant9s anti AF efficacy.