EVALUATION OF ICI-D7114, A PUTATIVE STIMULANT OF BROWN ADIPOCYTES, ONHISTAMINE-CONTRACTED GUINEA-PIG ILEUM

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 inhib ition of the contractile response to either histamine or prostaglandin E2 (PGE2) was assessed, along with effects on resting rate in the atr ium and resting tone in the tracheal chain. In the latter two preparat ions, antagonism of isoprenaline-induced responses by ICI D7114 was al so 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 prop ranolol (5 mum), naloxone (I mum), methysergide (0.1 mum), cimetidine, indomethacin and 8-phenyltheophylline (all 10 mum). These responses t o isoprenaline, in the presence of propranolol (5 muM), were competiti vely antagonized by alprenolol (I - 100 muM) with a pA2 value of 6.44. The responses to ICI D7114 and BRL37344 were antagonised by single co ncentrations of alprenolol (1 muM) with apparent pK(B) values of 6.53 and 6.57 respectively. These data indicate an effect of ICI D7114 at t he atypical beta-adrenoceptor in the guinea-pig ileum. 3 The order and relative potency of agonists at the atypical beta-adrenoceptor was BR L37344 (4) > isoprenaline (1) = ICI D7114 (1.1) > noradrenaline (0.5). 4 ICI D7114 (I nm - 10 muM) caused no significant change in the rate of beating or the resting tone of the guinea-pig right atrium or trach eal chain respectively. It did, however, cause selective blockade of t he responses to isoprenaline in these tissues (apparent pK(B) values 7 .63 and 5.85 in atrium and tracheal chain respectively). Responses to histamine (atrium) and aminophylline (tracheal chain) were not signifi cantly affected by 10 muM ICI D7114. 5 These results demonstrate that ICI D7114 possesses selective agonist activity at atypical beta-adreno ceptors in the guinea-pig ileum and its use as a tool may help to esta blish a role for the atypical beta-adrenoceptor in the control of gast rointestinal motility.