Lipolytic effects of conventional beta 3-adrenoceptor agonists and of CGP 12,177 in rat and human fat cells: preliminary pharmacological evidence for a putative beta 4-adrenoceptor.
1. The nature of rat and human fat cell beta 3-adrenoceptors was investigated by studying the effects of the new beta 3-adrenoceptor selective antagonist, SR 59,230A, on lipolysis induced by the conventional beta 3-adrenoceptor agonists, CL 316,243 and SR 58,611A, and by the non-conventional partial beta 3-adrenoceptor agonist CGP 12,177 (a potent beta 1- and beta 2-adrenoceptor antagonist with partial beta 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 pA2 value of 6.89 and 6.37, respectively. Conversely, 0.1, 0.5 and 1 microM 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 microM of SR 59,230A. The apparent pA2 value was 5.65. The non-selective beta-adrenergic antagonist, bupranolol, competitively displaced the concentration-response curve of CGP 12,177 and CL 316,243. Schild plots were linear with pA2 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 microM) did not modify the concentration-response curve of CGP 12,177. A rightward shift was however observed at 100 microM leading to an apparent pA2 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 beta-adrenoceptor pharmacologically distinct from the beta 3-adrenoceptor, i.e. through a putative beta 4-adrenoceptor. They suggest that the two subtypes coexist in rat fat cells whereas only the putative beta 4-adrenoceptor mediates lipolytic effect of CGP12,177 in human fat cells.
Galitzky
J
J
Laboratoire de Pharmacologie Médicale et Clinique, Unité 317 Institut National de la Santé et de la Recherche Médicale, Faculté de Médecine, Université Paul Sabatier, Toulouse, France.
Langin
D
D
Verwaerde
P
P
Montastruc
J L
JL
Lafontan
M
M
Berlan
M
M
D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D004149:Dioxoles / Q000494:pharmacology; D006801:Humans; D008066:Lipolysis / Q000187:drug effects*; D008297:Male; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*; D022702:Receptors, Adrenergic, beta-3; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
C097869:3-(2-ethylphenoxy)-1-(1,2,3,4-tetrahydronaphth-1-ylamino)-2-propanol oxalate; D000318:Adrenergic beta-Agonists; D004149:Dioxoles; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D022702:Receptors, Adrenergic, beta-3; D013764:Tetrahydronaphthalenes; C076126:disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate; C076252:amibegron; C033394:CGP 12177