Acute β-adrenergic stimulation increases the sarcoplasmic reticulum Ca2+ threshold for Ca2+ waves, showing that the primary cause of Ca2+ waves is the robust increase in SR Ca2+ content.
Beta-adrenergic stimulation increases the sarcoplasmic reticulum Ca2+ threshold for Ca2+ wave generation, suggesting a protective mechanism against arrhythmogenic events.
Key points In the heart, Ca 2+ waves are arrhythmogenic spontaneous sarcoplasmic reticulum (SR) Ca 2+ release events that arise when the Ca 2+ content in the SR reaches a critical threshold level. β‐Adrenergic signalling induces Ca 2+ waves in cardiac myocytes, but it remains unclear if this is due to a decrease in the Ca 2+ wave threshold or more simply due to an increase in SR Ca 2+ content. We used direct, dynamic measurement of SR Ca 2+ levels to show that the Ca 2+ wave threshold is unexpectedly increased during β‐adrenergic stimulation. Our data show that the primary cause of Ca 2+ waves following acute β‐adrenergic stimulation is the increase in SR Ca 2+ content and not a decrease in the Ca 2+ wave threshold. We propose that the elevation of the Ca 2+ wave threshold represents a protective mechanism against arrhythmogenic events during periods of β‐adrenergic stimulation. Abstract β‐Adrenergic signalling induces positive inotropic effects on the heart that associate with pro‐arrhythmic spontaneous Ca 2+ waves. A threshold level of sarcoplasmic reticulum (SR) Ca 2+ (Ca 2+ SR ) is necessary to trigger Ca 2+ waves, and whether the increased incidence of Ca 2+ waves during β‐adrenergic stimulation is due to an alteration in this threshold remains controversial. Using the low‐affinity Ca 2+ indicator fluo‐5N entrapped within the SR of rabbit ventricular myocytes, we addressed this controversy by directly monitoring Ca 2+ SR and Ca 2+ waves during β‐adrenergic stimulation. Electrical pacing in elevated extracellular Ca 2+ (Ca 2+ o = 7 m m ) was used to increase Ca 2+ SR to the threshold where Ca 2+ waves were consistently observed. The β‐adrenergic agonist isoproterenol (ISO; 1 μ m ) increased Ca 2+ SR well above the control threshold and consistently triggered Ca 2+ waves. However, when Ca 2+ SR was subsequently lowered in the presence of ISO (by lowering Ca 2+ o to 1 m m and partially inhibiting sarcoplasmic/endoplasmic reticulum calcium ATPase with cyclopiazonic acid or thapsigargin), Ca 2+ waves ceased to occur at a Ca 2+ SR that was higher than the control threshold. Furthermore, for a set Ca 2+ SR level the refractoriness of wave occurrence (Ca 2+ wave latency) was prolonged during β‐adrenergic stimulation, and was highly dependent on the extent that Ca SR exceeded the wave threshold. These data show that acute β‐adrenergic stimulation increases the Ca 2+ SR threshold for Ca 2+ waves, and therefore the primary cause of Ca 2+ waves is the robust increase in Ca 2+ SR above this higher threshold level. Elevation of the Ca 2+ SR wave threshold and prolongation of wave latency represent potentially protective mechanisms against pro‐arrhythmogenic Ca 2+ release during β‐adrenergic stimulation.
Domeier et al. (Tue,) conducted a other in Arrhythmogenic spontaneous sarcoplasmic reticulum Ca2+ release events. Beta-adrenergic stimulation (isoproterenol) vs. Control threshold was evaluated on Sarcoplasmic reticulum Ca2+ threshold for Ca2+ waves. Acute β-adrenergic stimulation increases the sarcoplasmic reticulum Ca2+ threshold for Ca2+ waves, showing that the primary cause of Ca2+ waves is the robust increase in SR Ca2+ content.
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