Abstract
Background and Aims: Carvedilol ((+/-)-1-(carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol), a β-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<sup>+</sup>/Ca<sup>2+</sup> exchanger (NCX1) has not been investigated. Methods and Results: We examined the effects of carvedilol and metoprolol, 2 β-blockers, on Na<sup>+</sup>/Ca<sup>2+</sup> exchange current (I<sub>NCX</sub>) in guinea-pig cardiac ventricular cells and fibroblasts expressing dog cardiac NCX1. Carvedilol suppressed I<sub>NCX</sub> in a concentration-dependent manner but metoprolol did not. IC<sub>50</sub> values for the Ca<sup>2+</sup> influx (outward) and efflux (inward) components of I<sub>NCX</sub> were 69.7 and 61.5 µmol/l, respectively. Carvedilol at 100 μmol/l inhibited I<sub>NCX</sub> in CCL39 cells expressing wild type NCX1 similar to mutant NCX1 without the intracellular regulatory loop. Carvedilol at 30 µmol/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.
Published Version
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