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

Abstract

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=not significant), but significant prolongation of APD(50) at 30 μmol/L 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 sodium channel-mediated parameters (ie, V(max), CT, DTE, and S(1)-S(1)) also were depressed significantly by vernakalant and ranolazine, but not by dl-sotalol. Only vernakalant elevated AP plateau voltage, consistent with blockade of ultrarapid delayed rectified potassium current and transient outward potassium current.

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 vernakalant's anti-AF efficacy.

Figure 1

Effects of vernakalant, ranolazine, and dl-sotalol on action potential duration measured at 90 and 50% repolarization (APD₉₀ and APD₅₀) in coronary-perfused left atria. Upper panels: Superimposed action potentials recorded at a CL of 500 ms. Lower panels: Mean data for the effect of vernakalant, ranolazine, and dl-sotalol on APD₉₀ and APD₅₀. N=4–6. *- p<0.05 vs. respective control.

Figure 2

APD₉₀ and APD₇₅ data from individual experiments for the three drugs (n=5–6) recorded at a pacing CL of 1000 ms.

Figure 3

Rate- and concentration-dependent prolongation of effective refractory period (ERP) by vernakalant, ranolazine, and dl-sotalol in coronary-perfused left atria. N=4–6.*- p<0.05 vs. respective control.

Figure 4

Rate-dependent change in ERP relative to change in APD₇₅ in response to vernakalant, ranolazine, and dl-sotalol. The difference between ERP and APD₇₅ approximates post-repolarization refractoriness (PRR). In left atria, ERP is coincident with APD_75–80 under control conditions. n=4–6. *- p<0.05 vs. respective control. # p <0.05 vs. corresponding APD₇₅ value.

Figure 5

Effect of vernakalant, ranolazine, and dl-sotalol on the amplitude of phase 2 of atrial action potential recorded from coronary-perfused left atrial preparations. The changes in phase 2 were approximated by normalizing phase 2 amplitude to Phase 0 amplitude. Data were obtained at a CL of 500 ms. N=4–6 *- p<0.05 vs. control.

Figure 6

Effect of vernakalant, ranolazine, and dl-sotalol on in maximum rate of rise of the action potential upstroke (V_max). Upper panels: Typical examples of use-dependent reduction of V_max upon decrease of CL from 500 to 300 ms with vernakalant, ranolazine, and dl-sotalol. Bottom panels: Normalized changes at a CL of 500 ms (left plot) and upon abbreviation of CL from 500 to 300 ms (right plot) in the absence and presence of drugs. Right plot: V_max value at a CL of 500 ms was taken as 100% for each condition. N=3–5 *- p<0.05 vs. respective control.

Figure 7

Rate- and concentration-dependent effects of vernakalant, ranolazine, and dl-sotalol on diastolic threshold of excitation (DTE) and on the duration of P wave in coronary-perfused left atrial preparations. Ranolazine and vernakalant significantly increased DTE and P wave duration at rapid activation rates. N=4–6 *- p<0.05 vs. respective control.

Figure 8

Effect of vernakalant, ranolazine, and dl-sotalol to prolong the shortest cycle length permitting 1:1 activation. N=4–6. *- p<0.05 vs. respective control.