β1‐ and β2‐adrenoceptor antagonist activities of ICI‐215001, a putative β3‐adrenoceptor agonist

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Abstract
1 The present study was undertaken to characterize the β3-adrenoceptor agonist activity of ICI-215001 and to determine whether it exhibits additional activities on β1- and β2-adrenoceptors in isolated spontaneously beating atrium, trachea and ileum of guinea-pig. 2 In guinea-pig atrium, isoprenaline, a non-selective β-adrenoceptor agonist, caused concentration-dependent, positive chronotropic effects that were inhibited by atenolol, a selective β1-antagonist. ICI-215001 also competitively antagonized the increase in heart rate caused by isoprenaline. 3 ICI-215001 exhibited low intrinsic activity at increasing the beating rate of atrium and no activity on resting or induced tone of tracheal strips. 4 In strips of guinea-pig trachea, contracted submaximally with carbachol, isoprenaline, caused concentration-dependent relaxations. Both ICI-118551, a selective β2-adrenoceptor antagonist, and ICI-215001 competitively inhibited the relaxations caused by isoprenaline. 5 In isolated strips of guinea-pig ileum longitudinal smooth muscle contracted with histamine, isoprenaline and ICI-215001 caused relaxations which were inhibited by alprenolol, a β-adrenoceptor antagonist with modest affinity for β3-adrenoceptors, but were resistant to ICI-118551 and atenolol. 6 These results indicate that ICI-215001 exhibits β3-adrenoceptor agonist activity as demonstrated by relaxations mediated via atypical β-adrenoceptors in the longitudinal smooth muscle of guinea-pig ileum. Further, the studies demonstrate that ICI-215001 can act as an antagonist at β1- and β2-adrenoceptors in situations where its intrinsic agonist activity is low.