ZENECA-ZD7114 ACTS AS AN ANTAGONIST AT BETA(3)-ADRENOCEPTORS IN RAT ISOLATED ILEUM

1 The relaxant effects of Zeneca ZD7114, BRL37344 (putative beta3-adrenoceptor agonists) and various phenylethylamine-based agonists were studied in isolated ileum of the rat where tone was increased with carbachol (0.5 mum). Agonist-induced relaxation was measured under equilibrium conditions with alpha-, beta1- and beta2-adrenoceptors inhibited. 2 Relaxant responses were obtained to isoprenaline, noradrenaline, and BRL37344, although, the efficacy of this latter agent was significantly lower than that of isoprenaline. Salbutamol caused weak relaxation (<20%) at high concentrations (10 mum) and ZD7114 was without significant relaxant effect even at high concentrations (10 mum). 3 Relaxant responses to isoprenaline and BRL37344 were weakly antagonized by high concentrations of (+/-)-propranolol (10 and 100 mum) yielding pK(B) values of 5.7 with isoprenaline as the agonist and 5.5 with BRL37344 as the agonist. 4 The non-selective beta-adrenoceptor antagonist, (+/-)-alprenolol (1 - 100 mum) caused competitive antagonism of the relaxant responses to isoprenaline (pA2 value = 6.5). A similar pK(B) value was obtained when BRL37344 was used as the agonist (6.4). 5 Relaxant effects of isoprenaline and BRL37344 were also antagonized by ZD7114 (1-100 mum) yielding pA2 and pK(B) values of 6.3 and 6.7 respectively. 6 The low potencies of (+/-)-propranolol and (+/-)-alprenolol as antagonists of the relaxant responses to isoprenaline and BRL37344 indicate that both the agonists and antagonists employed in the current study may interact with beta3-adrenoceptors in the rat isolated ileum. Contrary to the previous findings in guinea-pig ileum, where BRL37344 and ZD7114 were full agonists, in the current study, BRL37344 was a partial agonist and ZD7114 an antagonist at the beta3-adrenoceptor in rat ileum.