Mechanism of carvedilol induced action potential and calcium alternans

Carvedilol is a nonspecific β-blocker clinically used for the treatment of cardiovascular diseases but has also been shown to have profound effects on excitation-contraction coupling and Ca signaling at the cellular level. We investigate the mechanism by which carvedilol facilitates Ca transient (CaT) and action potential duration (APD) alternans in rabbit atrial myocytes. Carvedilol lowered the frequency threshold for pacing-induced CaT alternans and facilitated alternans in a concentration-dependent manner. Carvedilol prolonged the sarcoplasmic reticulum (SR) Ca release refractoriness by significantly increasing the time constant τ of recovery of SR Ca release; however, no changes in L-type calcium current recovery from inactivation or SR Ca load were found after carvedilol treatment. Carvedilol enhanced the degree of APD alternans nearly two-fold. Carvedilol slowed the APD restitution kinetics and steepened the APD restitution curve at the pacing frequency (2 Hz) where alternans were elicited. No effect on the CaT or APD alternans ratios was observed in experiments with a different β-blocker (metoprolol), excluding the possibility that the carvedilol effect on CaT and APD alternans was determined by its β-blocking properties. These data suggest that carvedilol contributes to the generation of CaT and APD alternans in atrial myocytes by modulating the restitution of CaT and APD.