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β-Adrenergic stimulation increases the intra-sarcoplasmic reticulum Ca2+ threshold for Ca2+ wave generation
Timothy L Domeier1, Joshua T Maxwell, Lothar A Blatter
1Department of Molecular Biophysics and Physiology, Rush University Medical Center, 1750 W. Harrison Street, Chicago, IL 60612, USA.
The Journal of Physiology
|September 19, 2012
Summary
Beta-adrenergic stimulation increases the threshold for spontaneous calcium waves in heart cells. This elevation in the sarcoplasmic reticulum calcium threshold, not just calcium levels, explains wave occurrence during stimulation.
Area of Science:
- Cardiology
- Molecular Biology
- Physiology
Background:
- Beta-adrenergic signaling enhances cardiac contractility but is linked to pro-arrhythmic spontaneous calcium (Ca2+) waves.
- A critical threshold of sarcoplasmic reticulum (SR) Ca2+ concentration ([Ca2+]SR) is required to trigger these Ca2+ waves.
- It remains debated whether elevated beta-adrenergic activity increases Ca2+ waves by altering this threshold or simply by raising [Ca2+]SR.
Purpose of the Study:
- To investigate the direct effect of beta-adrenergic stimulation on the [Ca2+]SR threshold for spontaneous Ca2+ waves.
- To clarify the relationship between [Ca2+]SR, beta-adrenergic stimulation, and the incidence of pro-arrhythmic Ca2+ waves.
Main Methods:
- Utilized low-affinity Ca2+ indicator fluo-5N within the SR of rabbit ventricular myocytes to directly monitor [Ca2+]SR.
- Applied electrical pacing and manipulated extracellular Ca2+ ([Ca2+]o) and sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) activity (using cyclopiazonic acid or thapsigargin).
- Administered the beta-adrenergic agonist isoproterenol (ISO) to assess its impact on [Ca2+]SR and Ca2+ wave generation.
Main Results:
- Isoproterenol (ISO) increased [Ca2+]SR above the control threshold, consistently triggering Ca2+ waves.
- In the presence of ISO, Ca2+ waves ceased at a [Ca2+]SR level higher than the control threshold, indicating an elevated threshold.
- Wave latency increased with ISO and was dependent on how much [Ca2+]SR exceeded the threshold.
Conclusions:
- Acute beta-adrenergic stimulation elevates the [Ca2+]SR threshold required for spontaneous Ca2+ wave initiation.
- The primary driver of Ca2+ waves during beta-adrenergic stimulation is the robust increase in [Ca2+]SR above this newly elevated threshold.
- The increased [Ca2+]SR threshold and prolonged wave latency may serve as protective mechanisms against pro-arrhythmic Ca2+ release.
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