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.
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.
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DOI：
10.1161/circep.111.968305
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发表时间：
2012-04
期刊：
影响因子：
--
通讯作者：
Antzelevitch C
中科院分区：
文献类型：
--
作者：
Burashnikov A;Pourrier M;Gibson JK;Lynch JJ;Antzelevitch C
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. 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 (APD50,75,90), effective refractory period (ERP), post-repolarization refractoriness (PRR), maximum rate of rise of the action potential (AP) upstroke (Vmax), diastolic threshold of excitation (DTE), conduction time (CT), and the shortest S1-S1 permitting 1:1 activation (S1-S1) 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 APD90 (p=n.s.), but significant prolongation of APD50 at 30 µM and rapid rates. In contrast, ranolazine and dl-sotalol produced consistent concentration- and reverse rate-dependent prolongation of APD90. 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 INa-mediated parameters (i.e., Vmax, CT, DTE, and S1-S1) were also significantly depressed by vernakalant and ranolazine, but not by dl-sotalol. Only vernakalant elevated AP plateau voltage, consistent with blockade of IKur and Ito. 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 APD90 and ERP. This suggests that during the rapid activation rates of AF, the INa blocking action of the mixed ion channel blocker vernakalant takes prominence. This mechanism may explain vernakalant’s anti AF efficacy.
