title: Evaluation of ICI D7114, a putative stimulant of brown adipocytes, on histamine-contracted guinea-pig ileum.
abstract: 1. Experiments were performed to characterize the effects of the novel brown adipocyte stimulant, ICI D7114, in the guinea-pig isolated ileum, right atrium and tracheal chain. In the ileum, agonist-induced inhibition of the contractile response to either histamine or prostaglandin E2 (PGE2) was assessed, along with effects on resting rate in the atrium and resting tone in the tracheal chain. In the latter two preparations, antagonism of isoprenaline-induced responses by ICI D7114 was also assessed. 2. Inhibitory responses were obtained in the ileum to ICI D7114, isoprenaline, BRL37344, and noradrenaline. The responses to ICI D7114, isoprenaline and BRL37344 were resistant to blockade with propranolol (5 microM), naloxone (1 microM), methysergide (0.1 microM), cimetidine, indomethacin and 8-phenyltheophylline (all 10 microM). These responses to isoprenaline, in the presence of propranolol (5 microM), were competitively antagonized by alprenolol (1-100 microM) with a pA2 value of 6.44. The responses to ICI D7114 and BRL37344 were antagonized by single concentrations of alprenolol (1 microM) with apparent pKB values of 6.53 and 6.57 respectively. These data indicate an effect of ICI D7114 at the atypical beta-adrenoceptor in the guinea-pig ileum. 3. The order and relative potency of agonists at the atypical beta-adrenoceptor was BRL37344 (4) < isoprenaline (1) = ICI D7114 (1.1) > noradrenaline (0.5). 4. ICI D7114 (1 nM - 10 microM) caused no significant change in the rate of beating or the resting tone of the guinea-pig right atrium or tracheal chain respectively. It did, however, cause selective blockade of the responses to isoprenaline in these tissues (apparent pKB values 7.63 and 5.85 in atrium and tracheal chain respectively). Responses to histamine (atrium) and aminophylline (tracheal chain) were not significantly affected by 10 microM ICI D7114.5. These results demonstrate that ICI D7114 possesses selective agonist activity at atypical beta-adrenoceptors in the guinea-pig ileum and its use as a tool may help to establish a role for the atypical beta-adrenoceptor in the control of gastrointestinal motility.
authors.affiliation: VIM Research Department, Zeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire.
authors.forename: J W
authors.initials: JW
authors.lastname: Growcott
authors.forename: C
authors.initials: C
authors.lastname: Wilson
authors.forename: B
authors.initials: B
authors.lastname: Holloway
authors.forename: S
authors.initials: S
authors.lastname: Mainwaring
mesh_terms: D002001:Adipose Tissue, Brown / Q000166:cytology / Q000187:drug effects*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D015232:Dinoprostone / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006632:Histamine / Q000494:pharmacology; D006633:Histamine Antagonists / Q000494:pharmacology*; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D009200:Myocardial Contraction / Q000187:drug effects; D010642:Phenoxyacetates / Q000494:pharmacology*; D050198:Phenoxypropanolamines; D011943:Receptors, Adrenergic, beta / Q000187:drug effects; D014132:Trachea / Q000187:drug effects
chemical_list: D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D006633:Histamine Antagonists; D010642:Phenoxyacetates; D050198:Phenoxypropanolamines; D011943:Receptors, Adrenergic, beta; C071909:ICI D7114; D006632:Histamine; D015232:Dinoprostone