Suppressive Effect of Carvedilol on Na+/Ca2+ Exchange Current in Isolated Guinea-Pig Cardiac Ventricular Myocytes

摘要

Background and Aims: Carvedilol ((+/)-1-(carbazol4-yloxy)-34[2-(o-nnethoxyphenoxy)ethyliannino]-2-propa- nol), a beta-adrenoceptor-blocker, has multi-channel blocking and vasodilator properties. This agent dose-dependently improves left ventricular function and reduces mortality in patients with arrhythmia and chronic heart failure. However, the effect of carvedilol on the cardiac Na+/Ca2+ exchanger (NCX1) has not been investigated. Methods and Results: We examined the effects of carvedilol and metoprolol, 2 beta-blockers, on Na+/Ca2+ exchange current (I-NCX) in guineapig cardiac ventricular cells and fibroblasts expressing dog cardiac NCX1. Carvedilol suppressed INcx in a concentration dependent manner but metoprolol did not. IC50 values for the Ca2+ influx (outward) and efflux (inward) components of INcx were 69.7 and 61.5 mu mol/l, respectively. Carvedilol at 100 mu mol/l inhibited I-NCX in CCL39 cells expressing wild type NCX1 similar to mutant NCX1 without the intracellular regulatory loop. Carvedilol at 30 mu mol/l abolished ouabain-induced delayed afterdepolarizations. Conclusion: Carvedilol inhibited cardiac NCX in a concentration-dependent manner in isolated cardiac ventricles, but metoprolol did not. We conclude that carvedilol inhibits NCX1 at supratherapeutic concentrations. (C) 2016 S. Karger AG, Basel