Abstract 21061: Mild IKr inhibition Significantly Enhances IKur-induced Selective Prolongation of Atrial Refractoriness
Introduction: The ultrarapid delayed rectifier K+ current (IKur) has been proposed as an atrial-selective target for antiarrhythmic treatment of AF. We previously demonstrated that the IKur inhibitor, BMS-394136, selectively prolonged atrial refractoriness in rabbits. It has been suggested that under normal conditions, IKur inhibition prolongs APD mostly during the early repolarization phase, an effect which could augment IKr activation and facilitate the terminal phase of repolarization, ultimately limiting the effectiveness of IKur inhibition to prolong AERP. This study evaluated the effects of the selective IKur inhibitor, BMS-394136, on AERP and VERP in rabbits, in the absence and presence of low dose sotalol to mildly inhibit IKr.
Methods: Adult male rabbits (3–3.5 kg) were anesthetized and a decapolar electrode catheter was inserted and positioned so that the distal electrodes were located in right ventricle and proximal electrodes were located in right atrium to measure AERP and VERP. Rabbits were divided into three groups (n=5/each) and were intravenously infused over 30 min with either sotalol alone (0.5 mg/kg), BMS-394136 alone (3 mg/kg), or sotalol + BMS-394136 together at the same doses. The sub-efficacious dose of sotalol was selected because it mildly prolonged AERP with no effect on VERP in pilot studies. AERP and VERP were measured at baseline and at the end of infusion and the ECG and BP were recorded continuously.
Results: Sotalol alone did not significantly affect VERP and QT interval (QTcf +9.7 ms and VERP +1.3% at 30 min, P>0.05). BMS-394136 alone had no effect on QT interval or VERP. Both sotalol alone and BMS-394136 alone increased AERP during the infusion period with maximal AERP prolongation of 8.1±0.8% and 27.6±1.9% (Mean±SEM, P<0.05), respectively, at 30 min. Simultaneous infusion of sotalol + BMS-394136 significantly prolonged AERP by 46.7±6.7% (P<0.05), a level well beyond the additive effects of sotalol and BMS-394136 alone. Sotalol + BMS-394136 had no effect on VERP and QT interval (QTcf +2.2 ms and VERP −0.1% at 30 min, P>0.05).
Conclusions: Mild IKr inhibition by a sub-efficacious dose of sotalol enhances the effects of an IKur inhibitor on prolongation of AERP, without compromising atrial selectivity.
- © 2010 by American Heart Association, Inc.