Abstract 928: Gα11 - Mediated Signalling Contributes to the Formation of the Gradient in Action Potential Duration and Repolarizing K+ Currents in the Left Ventricular Free Wall of Mice
The endocardial to epicardial gradient in action potential duration (APD) is responsible for the normal pattern of repolarization in the left ventricle of many mammals including man. Differences in repolarizing K+ currents have been shown to underlie the gradient in APD. Recently, differences in local angiotensin II (AngII) action have been proposed to contribute to the formation of regional differences in the transient outward potassium current (Ito). In the heart, AngII exerts its action predominantly via AT1 receptors which couple to G-proteins of the Gαq/11 family. Moreover, other receptors that alter cardiac electrophysiology also activate these G-proteins, including α1-adrenoceptors and endothelin-A receptors. In the present study we investigate the role of Gα11-coupled receptors in the generation of regional differences in APD and repolarizing ionic currents. Single myocytes from endocardial and epicardial regions of the left ventricular free wall were isolated by enzymatic digestion from wild type (wt) controls and Gα11 - deficient (gna11−/−) mice and investigated using the whole cell patch clamp technique. In endocardial myocytes from gna11−/− mice APD90 was significantly shorter compared to wt (39.7±3.7 ms, n=25 vs. 80.7±7.7 ms, n=32, p<0.001) and indistinguishable from the APD90 in epicardial myocytes (31.1±2.8 ms, n=34, n.s.). No change was observed in epicardial myocytes. The fast component of Ito (Ito,f) measured at +40 mV was increased to relatively larger extent in endocardial (24.2±3.3pApF-1, n=22 vs. 14.1±1.3 pApF-1, n=17, p<0.05) than in epicardial myocytes (41.4±1.9 pApF-1, n=34 vs. 32.9±2 pApF-1,n=31, p<0.05) of gna11−/− mice. Moreover, the inwardly rectifying K+ current (IKir) measured at −120 mV was larger in endocardial myocytes of gna11−/− mice than in wt controls (−12.0±0.9 pApF-1, n=15 vs. −7.0±0.6 pApF-1, n=20, p<0.001). In 6-lead ECG recordings of gna11−/− mice the direction of the mean QRS-vector was unchanged, whereas the direction of the T-vector was significantly shifted leftwards, indicating an altered sequence of repolarization. These findings suggest, that Gα11-coupled receptors play a major role in the signalling cascade responsible for regional differences of Ito magnitude and hence APD.