Abstract 2515: A Selective IKur Blocker, BMS-394136 Selectively Prolongs Atrial APD and Refractoriness in Beagles and Rabbits
Introduction: IKur is a repolarizing K+ current encoded by the KCNA5 gene and is expressed predominantly in atrium of rabbit, dog and human. IKur is a potential atrial-selective target for treatment of atrial fibrillation. A novel selective IKur inhibitor, BMS-394136, was evaluated in anesthetized rabbits and dogs both in vivo and in vitro for electrophysiologic and hemodynamic effects.
Methods: Beagle dogs (male, 7–14 kg, n=5) and rabbits (male, 3– 4kg, n=6) were anesthetized with α-chloralose and propofol and fentanyl, respectively. Multi-electrode catheters were inserted into right atrium and left ventricle for measuring of AERP and VERP at baseline and after each dose. BMS-394136 was infused at incremental doses of 0.3, 1, 3 and 10 mg/kg in both species. ECG, and mean blood pressure (MAP) were recorded continuously. Standard microelectrode technique was used for in vitro action potential duration (APD) measurements.
Results: (*p<0.05). BMS-394136 dose-dependently prolonged AERP by 1±1, 9±4*, 14±3*, and 25±6* ms in dogs, and by 5±3*, 17±2*, 20±2* and 34±2* ms in rabbits at 0.3, 1.0, 3.0 and 10 mg/kg, respectively, without VERP, PR and QRS intervals changes. QTcf interval was prolonged only in rabbits at 10 mg/kg (220±4 to 231±3* ms), but not in dogs (289±3 to 292±2). BMS-394136 produced similar, mild BP decrease and HR increase in dogs and rabbits. APD at 30, 50 and 90 percent of repolarization in rabbits and dogs was dose-dependently increased by 0.3, 1.0, 3.0 and 10 μM of BMS-394136. APD50 showed the most significantly change in both rabbits and beagles compared with APD30 and APD90 (atrial APD50 13±4 to 36±5 ms in rabbits, and 98±41 to 109±38 in beagles).
Conclusions: The selective IKur inhibitor, BMS-394136 increased atrial APD and prolonged AERP but not VERP in both rabbits and beagles, suggesting potential for safer, effective treatment of AF.