beta-adrenergic stimulation increases the intra-SR Ca termination threshold for spontaneous Ca waves in cardiac myocytes

摘要

beta-adrenergic stimulation of cardiac myocytes enhances intracellular calcium cycling, which frequently associates with pro-arrhythmic Ca waves. The threshold level of free calcium in the sarcoplasmic reticulum ([Ca](SR)) where waves initiate is increased during beta-adrenergic stimulation.(1) Here, we measured [Ca](SR) directly to monitor the [Ca](SR) level at which spontaneous Ca waves terminated (termination threshold) during beta-adrenergic stimulation. Compared with control conditions, application of the beta-adrenergic receptor agonist isoproterenol (ISO; 1 mu M) resulted in an increase in basal [Ca](SR) and an increase in the [Ca](SR) at which spontaneous Ca waves terminated. When [Ca](SR) was experimentally matched, ISO stimulation resulted in a decrease in the depletion amplitude of the waves. Sensitization of ryanodine receptor SR Ca release channels to Ca with a low dose of caffeine in the presence of ISO was able to decrease the termination threshold compared with control conditions. Therefore, the Ca wave termination level may represent an important mode of altering Ca depletion from the SR and reducing the arrhythmogenic potential during beta-adrenergic stimulation.