Abstract
Beta-adrenergic signaling induces positive inotropic effects on the heart that frequently associate with spontaneous arrhythmogenic Ca release events including Ca waves. It remains unclear if the greater incidence of Ca waves is due to increased sarcoplasmic reticulum (SR) Ca content ([Ca]SR) or a change in the function of ryanodine receptors. To address this controversy we utilized dynamic [Ca]SR measurements (fluo-5N) to test if beta-adrenergic stimulation alters the [Ca]SR level where Ca waves initiate (wave threshold) during rest after action potential stimulation. Under control conditions [Ca]SR was progressively increased to the wave threshold via incremental increases in pacing frequency in a high extracellular Ca (7 mM) environment. In the presence of the beta-adrenergic agonist isoproterenol (ISO, 1 microM) [Ca]SR increased and Ca waves were observed. When [Ca]SR was subsequently lowered using low extracellular Ca (1 mM) and SERCA inhibition (3 microM cyclopiazonic acid), Ca waves were no longer observed, even at [Ca]SR levels above the control wave threshold. In parallel experiments we found that resting cytosolic [Ca] (indo-1) was similar between the respective experimental conditions. Indirect assessment of [Ca]SR using the amplitude of the cytosolic Ca transient induced by 10 mM caffeine confirmed our observation that in the presence of ISO Ca waves only occur when [Ca]SR is above the control wave threshold. Furthermore, spontaneous Ca spark measurements (fluo-4) showed a tendency towards spark inhibition in the presence of ISO at experimentally matched [Ca]SR. Together, these data show that acute beta-adrenergic stimulation increases the [Ca]SR threshold for Ca waves, and therefore the primary cause of Ca waves is the robust increase in [Ca]SR above this higher threshold level. Elevation of the [Ca]SR wave threshold may be interpreted as a protective mechanism against pro-arrhythmogenic Ca release during beta-adrenergic stimulation.
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