M A Wood1, I Fuller, A Hong. 1. Virginia Commonwealth University/Medical College of Virginia, Richmond, VA 23298-0053, USA.
Abstract
INTRODUCTION: 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. METHODS AND RESULTS: 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. CONCLUSION: 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.
INTRODUCTION: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. METHODS AND RESULTS: 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. CONCLUSION: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.