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Am J Physiol Endocrinol Metab 260: E226-E231, 1991;
0193-1849/91 $5.00
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AJP - Endocrinology and Metabolism, Vol 260, Issue 2 E226-E231, Copyright © 1991 by American Physiological Society

ARTICLES

Adenylate cyclase agonist properties of CGP-12177A in brown fat: evidence for atypical beta-adrenergic receptors

P. J. Scarpace and M. Matheny
Geriatric Research, Education and Clinical Center, Department of Veterans Affairs Medical Center, Gainesville, Florida 32608.

Thermogenesis in brown adipose tissue (BAT) is stimulated by catecholamine activation of adenylate cyclase through the beta-adrenergic receptor. Recently it was reported that the beta-adrenergic antagonist CGP-12177A stimulates oxygen consumption in BAT. To investigate the mechanism of action of CGP-12177A in BAT, we assessed the inhibitory and stimulatory affects of CGP-12177A on the adenylate cyclase system in myocardial and BAT membranes from rats. CGP-1277A inhibited isoproterenol-stimulated adenylate cyclase activity in a dose-dependent manner, with an inhibitory constant (Ki) of 1.94 +/- 0.18 microM in BAT and 0.49 +/- 0.11 microM in the heart. However, in the absence of isoproterenol, CGP-12177A stimulated adenylate cyclase in BAT with two components of activation, and half-maximal stimulation occurred at 1 microM and 1.5 mM. In contrast, CGP-12177A did not stimulate adenylate cyclase activity in heart membranes. Propranolol inhibited the isoproterenol-stimulated activity with a potency that was one log less in BAT compared with heart. Propranolol fully blocked the high-affinity component but only weakly blocked the low-affinity component of CGP-12177A-stimulated activity in BAT. Pindolol was also less potent in BAT but inhibited the CGP-12177A-stimulated activity in a manner similar to the inhibition of the isoproterenol-stimulated activity, suggesting the CGP-12177A activation was beta-receptor mediated. Binding curves of [125I]iodocyanopindolol ([125I]ICYP) in competition with CGP-12177A demonstrated a shift to lower affinity in the presence of beta,gamma-imidoguanosine 5'-triphosphate, indicating that CGP-12177A has agonist properties with respect to the [125I]ICYP binding site.(ABSTRACT TRUNCATED AT 250 WORDS)


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