Atrial-selective prolongation of refractory period with AVE0118 is due principally to inhibition of sodium channel activity.

The action of AVE0118 to prolong effective refractory period (ERP) in atria but not in ventricles is thought to be due to its inhibition of IKur. However, in nonremodeled atria, AVE0118 prolongs ERP but not action potential duration (APD70-90), which can be explained with the inhibition of sodium but not potassium channel current. ERP, APD, and the maximum rate of increase of the AP upstroke (Vmax) were measured in the canine-isolated coronary-perfused right atrial and in superfused ventricular tissue preparations. Whole-cell patch-clamp techniques were used to measure sodium channel current in HEK293 cells stably expressing SCN5A. AVE0118 (5-10 μM) prolonged ERP (P < 0.001) but not APD70 and decreased Vmax (by 15%, 10 μM, P < 0.05; n = 10 for each). Ventricular ERP, APD90, and Vmax were not changed significantly by 10 μM AVE0118 (all P = ns; n = 7). AVE0118 effectively suppressed acetylcholine-mediated persistent atrial fibrillation. AVE0118 (10 μM) reduced peak current amplitude of SCN5A-WT current by 36.5% ± 6.6% (P < 0.01; n = 7) and shifted half-inactivation voltage (V0.5) of the steady-state inactivation curve from -89.9 ± 0.5 to -96.0 ± 0.9 mV (P < 0.01; n = 7). Our data suggest that AVE0118-induced prolongation of atrial, but not ventricular ERP, is due largely to atrial-selective depression of sodium channel current, which likely contributes to the effectiveness of AVE0118 to suppress atrial fibrillation.