Late Sodium Current in Atrial Cardiomyocytes Contributes to the Induced and Spontaneous Atrial Fibrillation in Rabbit Hearts

摘要

Increased late sodium current (I-Na) induces long QT syndrome 3 with increased risk of atrial fibrillation (AF). The role of atrial late I-Na in the induction of AF and in the treatment of AF was determined in this study. AF parameters were measured in isolated rabbit hearts exposed to late I-Na enhancer and inhibitors. Late I-Na from isolated atrial and ventricular myocytes were measured using whole-cell patch-clamp techniques. We found that induced-AF by programmed S1S2 stimulation and spontaneous episodes of AF were recorded in hearts exposed to either low (0.1-3 nM) or high (3-10 nM) concentrations of ATX-II (n = 10). Prolongations in atrial monophasic action potential duration at 90% completion of repolarization and effective refractory period by ATX-II (0.1-15 nM) were greater in hearts paced at slow than at fast rates (n = 5-10, P < 0.05). Both endogenous and ATX-II-enhanced late I-Na density were greater in atrial than that in ventricular myocytes (n = 9 and 8, P < 0.05). Eleclazine and ranolazine reduced AF window and AF burden in association with the inhibition of both endogenous and enhanced atrial late I-Na with half maximal inhibitory concentrations (IC50) of 1.14 and 9.78, and 0.94 and 8.31 mu M, respectively. The IC(50)s for eleclazine and ranolazine to inhibit peak I-Na were 20.67 and 101.79 mu M, respectively, in atrial myocytes. In conclusion, enhanced late I-Na in atrial myocytes increases the susceptibility for AF. Inhibition of either endogenous or enhanced late I-Na,I- with increased atrial potency of drugs is feasible for the treatment of AF.