Effect of carvedilol on atrial excitation-contraction coupling, Ca²⁺ 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) Ca²⁺ release during excitation-contraction coupling (ECC) in single rabbit atrial myocytes. Carvedilol caused concentration-dependent (1-10 µM) failure of SR Ca²⁺ release. Failure of ECC and Ca²⁺ release was the result of dose-dependent inhibition of voltage-gated Na⁺ (I_Na) and L-type Ca²⁺ (I_Ca) currents that are responsible for the rapid depolarization phase of the cardiac action potential (AP) and the initiation of Ca²⁺-induced Ca²⁺ release from the SR, respectively. Carvedilol (1 µM) led to AP duration shortening, AP failures, and peak I_Na inhibition by ~80%, whereas I_Ca was not markedly affected. Carvedilol (10 µM) blocked I_Na almost completely and reduced I_Ca by ~40%. No effect on Ca²⁺-transient amplitude, I_Ca, and I_Na 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 Ca²⁺ release was spatially inhomogeneous, where a selective inhibition of peripheral subsarcolemmal Ca²⁺ release from the junctional SR accounted for the cell-averaged reduction in Ca²⁺-transient amplitude. Furthermore, carvedilol significantly reduced the probability of spontaneous arrhythmogenic Ca²⁺ waves without changes of SR Ca²⁺ load. The data suggest a profound antiarrhythmic action of carvedilol in atrial myocytes resulting from an inhibitory effect on the SR Ca²⁺ release channel.NEW & NOTEWORTHY Here we show that the clinically widely used β-blocker carvedilol has profound effects on Ca²⁺ 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 Ca²⁺ release from cellular sarcoplasmic reticulum (SR) Ca²⁺ stores in form of arrhythmogenic Ca²⁺ waves. The antiarrhythmic effect occurs by carvedilol acting directly on the SR ryanodine receptor Ca²⁺ release channel.