Abstract 1515: Regional Effects of Katp Channel Openers Reflect Distinct Atrial and Ventricular Katp Channel Structure in the Murine Heart

Abstract

Classically, cardiac sarcolemmal KATP channels are thought to be composed of Kir6.2 (inward-rectifier potassium channel 6.2, KCNJ11) and SUR2A (sulfonylurea receptor type 2A, ABCC9) subunits. However, the evidence is strong that SUR1 (sulfonylurea receptor type 1, ABCC8) subunits are also expressed in the heart and that they play a significant functional role in the atria. To examine this further, we have estimated the effects of potassium channel-opening drugs diazoxide (specific to SUR1 > SUR2A) and pinacidil (SUR2A > SUR1) in intact hearts from wild type (WT, n=6) and SUR1−/− mice (KO, n=3) that lack SUR1 subunits. Action potential duration (APD) in both atria and ventricles were estimated by optical mapping of posterior surface of Langendorff-perfused hearts using the voltage sensitive dye RH237 and high spatiotemporal resolution CMOS camera (100x100 pixels; 3,000 frames/sec). In WT hearts, diazoxide (300 μM) decreased APD in atria (from 33.6±2.1 ms to 25.5±1.0 ms, p<0.001) and did not change it in ventricles (60.0±8.5 ms vs 61.2±8.3 ms, NS). The absence of SUR1 in KO mice resulted in loss of efficacy of diazoxide in atria (37.5±0.7 ms vs 36.5±0.7 ms, NS). In contrast, pinacidil (300 μM) significantly decreased ventricular APD in both type of mice (from 60.0±8.5 ms to 30.5±4.2 ms in WT, p<0.001; and from 62.0±1.4 ms to 30.5±6.4 ms in KO, p<0.001) and did not change atrial APD in either WT or KO hearts. Glass microelectrode recordings from isolated superfused atria confirmed the optical data. In both WT and KO hearts, the APD in left ventricle was significantly longer and the effect of pinacidil was significantly greater than in right ventricle (APD decreasing by 56.3±4.2% and 62.3±12.0% in left ventricle vs 49.4±3.4% and 50.9±4.1% in right ventricle for WT and KO mice respectively, p<0.05). Similar differences between APDs in right and left atria were not observed. Collectively, these results indicate that in the intact mouse heart, significant differential KATP pharmacology in atria and ventricles results from SUR1 predominance in forming the atrial channel, highlighting an unappreciated heterogeneity of KATP function in the heart.