Acute beta-blockade prevents myocardial beta-adrenergic receptor desensitization and preserves early ventricular function after brain death.

Abstract

OBJECTIVE:

Beta-adrenergic receptor desensitization through activation of the G protein-coupled receptor kinase 2 is an important mechanism of early cardiac dysfunction after brain death. We hypothesized that acute beta-blockade can prevent myocardial beta-adrenergic receptor desensitization after brain death through attenuation of G protein-coupled receptor kinase 2 activity, resulting in improved cardiac function.

METHODS:

Adult pigs underwent either sham operation, induction of brain death, or treatment with esmolol (beta-blockade) for 30 minutes before and 45 minutes after brain death (n = 8 per group). Cardiac function was assessed at baseline and for 6 hours after the operation. Myocardial beta-adrenergic receptor signaling was assessed 6 hours after operation by measuring sarcolemmal membrane adenylate cyclase activity, beta-adrenergic receptor density, and G protein-coupled receptor kinase 2 expression and activity.

RESULTS:

Baseline left ventricular preload recruitable stroke work was similar among sham, brain death, and beta-blockade groups. Preload recruitable stroke work was significantly decreased 6 hours after brain death versus sham, and beta-blockade resulted in maintenance of baseline preload recruitable stroke work relative to brain death and not different from sham. Basal and isoproterenol-stimulated adenylate cyclase activities were preserved in the beta-blockade group relative to the brain death group and were not different from the sham group. Left ventricular G protein-coupled receptor kinase 2 expression and activity in the beta-blockade group were markedly decreased relative to the brain death group and similar to the sham group. Beta-adrenergic receptor density was not different among groups.

CONCLUSION:

Acute beta-blockade before brain death attenuates beta-adrenergic receptor desensitization mediated by G protein-coupled receptor kinase 2 and preserves early cardiac function after brain death. These data support the hypothesis that acute beta-adrenergic receptor desensitization is an important mechanism in early ventricular dysfunction after brain death. Future studies with beta-blocker therapy immediately after brain death appear warranted.

• Authors: Prakash K Pandalai, Kelly M McLean, Christian F Bulcao, Jodie Y Duffy, Karen M D'Souza, Walter H Merrill, Jeffrey M Pearl, Shahab A Akhter
• Journal: The Journal of thoracic and cardiovascular surgery (J Thorac Cardiovasc Surg) Vol. 135 Issue 4 Pg. 792-8 (Apr 2008) ISSN: 1097-685X [Electronic] United States
• PMID: 18374758 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenergic beta-Antagonists
• Propanolamines
• Receptors, Adrenergic, beta
• esmolol

Topics

• Adrenergic beta-Antagonists (pharmacology)
• Animals
• Brain Death
• Disease Models, Animal
• Heart (drug effects, physiopathology)
• Myocardium (metabolism)
• Propanolamines (pharmacology)
• Receptors, Adrenergic, beta (drug effects)
• Swine
• Ventricular Function (drug effects)