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


METHODS
Prospective study, randomized to treatment and control groups.


METHODS
University-hospital research laboratory.


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


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


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).


CONCLUSIONS
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.
Wang
C
C
Department of Anesthesiology, Harvard Medical School, Boston, MA, USA.
Martyn
J A
JA
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002056:Burns / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D006352:Heart Ventricles; D066298:In Vitro Techniques; D020120:Iodocyanopindolol; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000378:metabolism* / Q000648:ultrastructure; D010869:Pindolol / Q000031:analogs & derivatives / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015290:Second Messenger Systems; D015398:Signal Transduction
D000318:Adrenergic beta-Agonists; D011943:Receptors, Adrenergic, beta; D005576:Colforsin; D020120:Iodocyanopindolol; D010869:Pindolol; D000242:Cyclic AMP; D007545:Isoproterenol