Zeneca ZD7114 acts as an antagonist at β3‐adrenoceptors in rat isolated ileum

The relaxant effects of Zeneca ZD7114, BRL37344 (putative β3‐adrenoceptor agonists) and various phenylethylamine‐based agonists were studied in isolated ileum of the rat where tone was increased with carbachol (0.5 μm). Agonist‐induced relaxation was measured under equilibrium conditions with α‐, β1‐ and β2‐adrenoceptors inhibited. 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 μm) and ZD7114 was without significant relaxant effect even at high concentrations (10 μm). Relaxant responses to isoprenaline and BRL37344 were weakly antagonized by high concentrations of (±)‐propranolol (10 and 100 μm) yielding pKB values of 5.7 with isoprenaline as the agonist and 5.5 with BRL37344 as the agonist. The non‐selective β‐adrenoceptor antagonist, (±)‐alprenolol (1–100 μm) caused competitive antagonism of the relaxant responses to isoprenaline (pA2 value = 6.5). A similar pKB value was obtained when BRL37344 was used as the agonist (6.4). Relaxant effects of isoprenaline and BRL37344 were also antagonized by ZD7114 (1–100 μm) yielding pA2 and pKB values of 6.3 and 6.7 respectively. 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 β3‐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 β3‐adrenoceptor in rat ileum.