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Lipolytic effects of conventional β 3 ‐adrenoceptor agonists and of CGP 12,177 in rat and human fat cells: preliminary pharmacological evidence for a putative β 4 ‐adrenoceptor
Author(s) -
Galitzky Jean,
Langin Dominique,
Verwaerde Patrick,
Montastruc JeanLouis,
Lafontan Max,
Berlan Michel
Publication year - 1997
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0701523
Subject(s) - agonist , isoprenaline , partial agonist , lipolysis , endocrinology , medicine , antagonist , chemistry , schild regression , intrinsic activity , potency , receptor , in vitro , biology , stimulation , biochemistry , adipose tissue
1 The nature of rat and human fat cell β 3 ‐adrenoceptors was investigated by studying the effects of the new β 3 ‐adrenoceptor selective antagonist, SR 59,230A, on lipolysis induced by the conventional β 3 ‐adrenoceptor agonists, CL 316,243 and SR 58,611A, and by the non‐conventional partial β 3 ‐adrenoceptor agonist CGP 12,177 (a potent β 1 ‐ and β 2 ‐adrenoceptor antagonist with partial β 3 ‐adrenoceptor agonist property). 2 In rat fat cells, the rank order of potency of agonists was: CL 316,243>isoprenaline>SR 58,611A>CGP 12,177. The three former agents were full agonists whereas CGP 12,177 was a partial agonist (intrinsic activity of 0.70). In human fat cells, the lipolytic effect of CGP 12,177 reached 25 % of isoprenaline effect. CL 316,243 was a poor inducer of lipolysis and SR 58,611A was ineffective. 3 In rat fat cells, lipolysis induced by CL 316,243 and SR 58,611A was competitively antagonized by SR 59,230A. Schild plots were linear with pA 2 values of 6.89 and 6.37, respectively. Conversely, 0.1, 0.5 and 1 μ M SR 59,230A did not modify the concentration‐response curve of CGP 12,177. A rightward shift of the curve was however observed with 10 and 100 μ M of SR 59,230A. The apparent pA 2 value was 5.65. The non‐selective β‐adrenergic antagonist, bupranolol, competitively displaced the concentration‐response curve of CGP 12,177 and CL 316,243. Schild plots were linear with pA 2 values of 6.70 and 7.59, respectively. CL316,243‐mediated lipolytic effect was not antagonized by CGP 20,712A. In human fat cells, CGP 12,177‐mediated lipolytic effect was antagonized by bupranolol and CGP 20,712A. SR 59,230A (0.1, 1 and 10 μ M ) did not modify the concentration‐response curve of CGP 12,177. A rightward shift was however observed at 100 μ M leading to an apparent pA 2 value of 4.32. 4 The results suggest that the non‐conventional partial agonist CGP 12,177 can activate lipolysis in fat cells through the interaction with a β‐adrenoceptor pharmacologically distinct from the β 3 ‐adrenoceptor, i.e. through a putative β 4 ‐adrenoceptor. They suggest that the two subtypes coexist in rat fat cells whereas only the putative β 4 ‐adrenoceptor mediates lipolytic effect of CGP12,177 in human fat cells.British Journal of Pharmacology (1997) 122 , 1244–1250; doi: 10.1038/sj.bjp.0701523