beta-adrenergic receptor blockers restore cardiac calcium release channel (ryanodine receptor) structure and function in heart failure.

Abstract

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.

METHODS AND 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.

• Authors: S Reiken, M Gaburjakova, J Gaburjakova, K L He Kl, A Prieto, E Becker, G H Yi Gh, J Wang, D Burkhoff, A R Marks
• Journal: Circulation (Circulation) Vol. 104 Issue 23 Pg. 2843-8 (Dec 04 2001) ISSN: 1524-4539 [Electronic] United States
• PMID: 11733405 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Adrenergic beta-Antagonists
• Ryanodine Receptor Calcium Release Channel
• Cyclic AMP-Dependent Protein Kinases
• Metoprolol
• Calcium

Topics

• Adrenergic beta-Antagonists (pharmacology, therapeutic use)
• Animals
• Binding, Competitive
• Calcium (metabolism)
• Cardiac Pacing, Artificial (adverse effects)
• Cyclic AMP-Dependent Protein Kinases (metabolism)
• Dogs
• Heart Failure (drug therapy, etiology, physiopathology)
• Immunoblotting
• Metoprolol (pharmacology, therapeutic use)
• Myocardium (metabolism, pathology)
• Phosphorylation (drug effects)
• Precipitin Tests
• Ryanodine Receptor Calcium Release Channel (drug effects, metabolism, physiology)