Effects of sodium channel blockade on ibutilide induced prolongation of repolarization in the isolated rabbit ventricle

Ibutilide fumarate is indicated for the termination of atrial fibrillation and atrial flutter. It's mechanism of action is unclear but may involve activation of a late inward Na(+) current.

Twenty seven experiments were performed using an isolated perfused rabbit right ventricle preparation. In each experiment effective refractory periods (ERP) and transmembrane 90% action potential durations (APD) were measured. In 8 experiments ERP and APD were measured at baseline, in the presence of ibutilide (0. 1[emsp4 ]uM), and in the presence of both ibutilide and tetrodotoxin (TTX, 2[emsp4 ]uM). In 8 experiments lidocaine (10[emsp4 ]uM) was used in place of TTX. Measures were made at 200, 400, and 800[emsp4 ]msec paced cycle lengths under each condition. The baseline values for APD at 200, 400 and 800[emsp4 ]msec cycle lengths for the experiments treated with ibutilide and TTX were 111+/-8, 140+/-14 and 159+/-22[emsp4 ]msec, respectively. In the presence of ibutilide, APD increased to 130+/-19, 192+/-26 and 217+/-35[emsp4 ]msec at 200, 400 and 800[emsp4 ]msec cycle lengths, respectively (all p< or =0.03). After the addition of TTX there was no shortening of APD or ERP compared to treatment with ibutilide alone at any cycle length (all p> or =0.062). Similarly, in the presence of ibutilide and lidocaine there were no changes in APD or ERP compared to treatment with ibutilide alone (all p > or =0.41). In 11 control experiments, there were no changes in APD or ERP on serial measures after placebo and TTX or lidocaine.

Ibutilide induced prolongation of ventricular repolarization is not affected by Na(+) channel blockade with lidocaine or TTX in the isolated rabbit heart. These findings suggest that the effects of ibutilide are not mediated by a Na(+) channel dependent late current or that this mechanism contributes minimally to its action in this model.