Burn injury alters beta-adrenergic receptor and second messenger function in rat ventricular muscle.

Abstract

OBJECTIVES:

The molecular pharmacologic bases for the attenuated cardiovascular and metabolic responses to catecholamines, after burn injury, have not been elucidated. In the present study, myocardial tissues were used as a model of beta-adrenergic receptors to study burn injury-induced alterations in receptors and in signal transduction.

DESIGN:

Prospective study, randomized to treatment and control groups.

SETTING:

University-hospital research laboratory.

SUBJECTS:

Male Sprague-Dawley rats (180 to 210 g).

INTERVENTIONS:

A 50% body surface area burn or sham-burn was administered to the rats.

MEASUREMENTS AND MAIN RESULTS:

Myocardial membranes were isolated at 24 hrs, 7 days and 14 days after 50% body surface area scald or sham injury. (-)125I-iodocyanopindolol was used to assess maximal binding capacity and affinity of the beta-adrenergic receptor. Basal and stimulated concentrations of second messenger, cyclic adenosine monophosphate (cAMP), were also assessed. Production of cAMP during isoproterenol stimulation tested the integrity of the beta-adrenergic receptor-mediated signal transduction. Forskolin, which stimulates adenylate cyclase enzyme directly (bypassing the receptor and G protein) to produce cAMP, tested the efficacy of the enzyme itself. Maximal binding capacity was unaltered between the experimental and control groups, but the affinity (mean +/- SEM) was significantly decreased in burned animals at 7 days (125.4 +/- 15.5 picomoles [pmol]; p = .01) and at 14 days (216.7 +/- 50.7 pmol; p = .001) compared with controls (75.5 +/- 8.4 pmol). In different set experimental and control groups, basal concentrations of cAMP in myocardial membranes were significantly decreased in burned animals at 7 days (control 38.6 +/- 4.2 vs. 5.8 +/- 0.9 pmol/mg of protein/min; p = .003) and at 14 days (control 47.4 +/- 3.2 vs 28.3 +/- 6.6 pmol/mg of protein/min; p = .002). The forskolin (direct)-stimulated synthesis of cAMP was decreased in burned animals at 24 hrs (control 339.0 +/- 40.5 vs. 214.4 +/- 16.6 pmol/mg of protein/min; p = .01), at 7 days (control 289.0 +/- 34.4 vs. 32 +/- 13.0 pmol/mg of protein/min; p = .01), and at 14 days (control 322.9 +/- 28.6 vs. 137.0 +/- 46.1 pmol/mg of protein/min; p = .01). The isoproterenol or receptor-mediated stimulation of cAMP production was also significantly (p < .001) impaired in burned animals compared with controls at 24 hrs (control 134.7 +/- 11.9 vs. 83.1 +/- 13.3 pmol/mg of protein/min), and at 14 days (control 128.2 +/- 7.2 vs. 92.8 +/- 17.7 pmol/mg of protein/min).

CONCLUSION:

The etiology of the decreased responses in the myocardium to exogenous and endogenous beta-adrenergic receptor agonists after burn injury may be attributed to decreased affinity for ligands, and also to impaired receptor-mediated signal transduction and to decreased adenylate cyclase enzyme activity, resulting in decreased basal and stimulated second messenger (cAMP) production.

• Authors: C Wang, J A Martyn
• Journal: Critical care medicine (Crit Care Med) Vol. 24 Issue 1 Pg. 118-24 (Jan 1996) ISSN: 0090-3493 [Print] United States
• PMID: 8565516 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Adrenergic beta-Agonists
• Receptors, Adrenergic, beta
• Colforsin
• Iodocyanopindolol
• Pindolol
• Cyclic AMP
• Isoproterenol

Topics

• Adrenergic beta-Agonists (pharmacology)
• Animals
• Burns (metabolism)
• Cell Membrane (metabolism)
• Colforsin (pharmacology)
• Cyclic AMP (metabolism)
• Heart Ventricles
• In Vitro Techniques
• Iodocyanopindolol
• Isoproterenol (pharmacology)
• Male
• Myocardium (metabolism, ultrastructure)
• Pindolol (analogs & derivatives, metabolism)
• Rats
• Rats, Sprague-Dawley
• Receptors, Adrenergic, beta (metabolism)
• Second Messenger Systems
• Signal Transduction