Abstract 9642: Prolongation of AERP and APD with the Selective IKur inhibitor, BMS-394136, is Increased in the Zucker Diabetic Fatty Rat
Introduction: Diabeties mellitus is a risk factor for atrial fibrillation (AF). We previously reported that atrial ischemia increases activity of a selective IKur inhibitor, BMS-394136, on atrial effective refractory period (AERP) and action potential duration (APD) without effecting ventricular effective refractory period (VERP) in dog heart. This study evaluated the efficacy of BMS-394136 on AERP and APD in Zucker Diabetic Fatty (ZDF) rats.
Methods: Male ZDF370 (obese and diabetic) and ZDF371 (lean control) rats on normal diet, averaging 7 months of age, were entered into the study. After induction of anesthesia, a 2F multielectrode was placed into right ventricle to measure VERP. BMS-394136 (10 mg/kg) was infused over 5 min through the jugular vein. After VERP assessment, hearts were removed and perfused in a Langendorff apparatus with Tyrode’s buffer for assessment of AERP and APD at BMS-394136 concentrations of 1.0, 3.0 and 10.0 µM, respectively. After Langendorff perfusion, atrial strips were removed and studied with standard microelectrode techniques in perfusion.
Results: (*p<0.05). The average weight and blood glucose was 367g and >600mg/dl in the ZDF370 rats and 465g* and 253* mg/dl in the ZDF371 rats. VERP was prolonged by BMS-394136 in vivo by 21±1.7 ms (39%) in ZDF370 rats (n=10), and by 24±1.7 ms (50%) in ZDF371 rats. No differences in APD100 (64±4ms vs 64±3 ms) or AERP (29±2ms vs 25±2ms) were observed at baseline in Langendorff mode from ZDF370 and ZDF371 hearts (n=4/each). However, BMS-394136 dose-dependently prolonged APD100 and AERP to a greater extent in ZDF370 rats at 1.0µM (11%* and 36%*), 3.0µM (27%* and 44%*) and 10.0µM (33%* and 64%*) than in ZDF371 rats at 1.0µM (-2%* and 3%), 3.0µM (3% and 3%) and 10.0 µM (8% and 14%). In atrial strips (n=4), BMS-394136 increased APD30 by (%) 0±2, 22±3, 33±2*, APD50 by(%) 14±4, 36±5, 32±7, 50±4* and APD90 by (%)3±4, 14±9, 23±5* at concentrations of 1.0µM, 3.0µM and 10.0 μ M in ZDF370 rats, no effect was observed on APD prolongation in ZDF371 rats.
Conclusions: Diabeties mellitus may increase the efficacy of the selective IKur inhibitor, BMS-394136, on prolongation of AERP and APD. The absence of effect with BMS-394136 on VERP confirms the atrial selective activity of this compound or ion channel remodeling.
- © 2012 by American Heart Association, Inc.