beta-adrenergic receptor blockers restore cardiac calcium release channel (ryanodine receptor) structure and function in heart failure.
BACKGROUND
beta-Adrenergic receptor blockade is one of the most effective treatments for heart failure, a leading cause of mortality worldwide. The use of beta-adrenergic receptor blockers in patients with heart failure is counterintuitive, however, because they are known to decrease contractility in normal hearts. The ryanodine receptor (RyR2) on cardiac sarcoplasmic reticulum is the key calcium release channel required for excitation-contraction coupling. In failing hearts, the stoichiometry and function of the RyR2 macromolecular complex is altered. Decreased levels of phosphatases (PP1 and PP2A) and hyperphosphorylation by protein kinase A result in dissociation of the regulatory protein FKBP12.6 and channels with increased open probability.


RESULTS
Here, we show that systemic oral administration of a beta-adrenergic receptor blocker reverses protein kinase A hyperphosphorylation of RyR2, restores the stoichiometry of the RyR2 macromolecular complex, and normalizes single-channel function in a canine model of heart failure.


CONCLUSIONS
These results may, in part, explain the improved cardiac function observed in heart failure patients treated with beta-adrenergic receptor blockers.
Reiken
S
S
Center for Molecular Cardiology, Department of Pharmacology, Circulatory Physiology Division, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA.
Gaburjakova
M
M
Gaburjakova
J
J
He Kl
K L
KL
Prieto
A
A
Becker
E
E
Yi Gh
G H
GH
Wang
J
J
Burkhoff
D
D
Marks
A R
AR
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism; D002304:Cardiac Pacing, Artificial / Q000009:adverse effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004285:Dogs; D006333:Heart Failure / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D015151:Immunoblotting; D008790:Metoprolol / Q000494:pharmacology* / Q000627:therapeutic use; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011233:Precipitin Tests; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology
D000319:Adrenergic beta-Antagonists; D019837:Ryanodine Receptor Calcium Release Channel; D017868:Cyclic AMP-Dependent Protein Kinases; D008790:Metoprolol; D002118:Calcium