Effect of carvedilol on atrial excitation-contraction coupling, Ca release, and arrhythmogenicity.

Carvedilol is an FDA-approved β-blocker commonly used for treatment of high blood pressure, congestive heart failure, and cardiac tachyarrhythmias, including atrial fibrillation. We investigated at the cellular level the mechanisms through which carvedilol interferes with sarcoplasmic reticulum (SR) Ca release during excitation-contraction coupling (ECC) in single rabbit atrial myocytes. Carvedilol caused concentration-dependent (1-10 µM) failure of SR Ca release. Failure of ECC and Ca release was the result of dose-dependent inhibition of voltage-gated Na () and L-type Ca () currents that are responsible for the rapid depolarization phase of the cardiac action potential (AP) and the initiation of Ca-induced Ca release from the SR, respectively. Carvedilol (1 µM) led to AP duration shortening, AP failures, and peak inhibition by ~80%, whereas was not markedly affected. Carvedilol (10 µM) blocked almost completely and reduced by ~40%. No effect on Ca-transient amplitude, , and was observed in control experiments with the β-blocker metoprolol, suggesting that the carvedilol effect on ECC is unlikely the result of its β-blocking property. The effects of carvedilol (1 µM) on subcellular SR Ca release was spatially inhomogeneous, where a selective inhibition of peripheral subsarcolemmal Ca release from the junctional SR accounted for the cell-averaged reduction in Ca-transient amplitude. Furthermore, carvedilol significantly reduced the probability of spontaneous arrhythmogenic Ca waves without changes of SR Ca load. The data suggest a profound antiarrhythmic action of carvedilol in atrial myocytes resulting from an inhibitory effect on the SR Ca release channel. Here we show that the clinically widely used β-blocker carvedilol has profound effects on Ca signaling and ion currents, but also antiarrhythmic effects in adult atrial myocytes. Carvedilol inhibits sodium and calcium currents and leads to failure of ECC but also prevents spontaneous Ca release from cellular sarcoplasmic reticulum (SR) Ca stores in form of arrhythmogenic Ca waves. The antiarrhythmic effect occurs by carvedilol acting directly on the SR ryanodine receptor Ca release channel.