Abstract 12964: Acute Atrial Ischemia Increases the Activity of BMS-394136, a Selective IKur Inhibitor, on Atrial Refractoriness and APD
Introduction: We previously reported that a selective IKur inhibitor, BMS-394136, dose-dependently prolonged atrial effective refractory period (AERP) and action potential duration (APD) without effecting ventricular effective refractory period (VERP). This study was designed to evaluate the atrial selective action of BMS-394136 in a canine model of acute right atrial ischemia.
Methods: Beagle dogs (9–14 kg, n=10) were anesthetized with α-chloralose. A median sternotomy was performed to access the coronary artery for ischemia. Multi-electrodes were sutured on the right atrial appendage for recording and stimulation. Atrial ischemia was created by double ligation of the right intermediate atrial artery. Vehicle and BMS-394136 (10 mg/kg) were infused 10 min before ligation and maintained for the first 20 min of ischemia. Right atrial tissues were removed after 3 hours ischemia for in vitro APD measurements with standard microelectrode techniques.
Results: (*p<0.05). In the vehicle group, AERP was shortened by −2±2, −3±4, −14±6* and −18±7* ms at 0.5, 1, 2 and 3 hours of ischemia. During ischemia, BMS-394136 prolonged AERP by 32±9*, 22±13, 3±7 and −11±9 ms at 0.5, 1, 2, and 3 hours of ischemia compared to baseline. In right atrium studied in a perfusion chamber, ischemia shortened atrial APD at 30, 50 and 90 percent by (%) −18, −8 and −13 compared to no ischemic tissues. In ischemic atrial tissues, BMS-394136 dose-dependently prolonged APD30 by (%) 13±5, 24±6, 25±10, 46±12*, and APD50 by 20±8*, 25±6*, 32±7*, 50±15* at concentrations of 0.3, 1.0, 3.0 and 10 μM. In the absence of ischemia, BMS-394136 had less effect, prolonging APD30 by (%) 14±9, 16±8, 37±21, 21±12, and APD50 by (%) 8±4, 12±3, 19±3, 26±4 at concentrations of 0.3, 1.0, 3.0 and 10μM. BMS-394136 did not affect APD90 in absence or presence of atrial ischemia.
Conclusions: Acute atrial ischemia appears to significantly improve the efficacy of the selective IKur inhibitor, BMS-394136 on prolongation of AERP and APD, which may be beneficial for the treatment of ischemic AF or AF resulting from cellular stress.
- © 2010 by American Heart Association, Inc.