BETA(1)-ADRENOCEPTOR AND BETA(2)-ADRENOCEPTOR ANTAGONIST ACTIVITIES OF ICI-215001, A PUTATIVE BETA(3)-ADRENOCEPTOR AGONIST

1 The present study was undertaken to characterize the beta(3)-adrenoc eptor agonist activity of ICI-215001 and to determine whether it exhib its additional activities on beta(1)- and beta(2)-adrenoceptors in iso lated spontaneously beating atrium, trachea and ileum of guinea-pig. 2 In guinea-pig atrium, isoprenaline, a non-selective beta-adrenoceptor agonist, caused concentration-dependent, positive chronotropic effect s that were inhibited by atenolol, a selective beta(1)-antagonist. ICI -215001 also competitively antagonized the increase in heart rate caus ed by isoprenaline. 3 ICI-215001 exhibited low intrinsic activity at i ncreasing the beating rate of atrium and no activity on resting or ind uced tone of tracheal strips. 4 In strips of guinea-pig trachea, contr acted submaximally with carbachol, isoprenaline, caused concentration- dependent relaxations. Both ICI-118551, a selective beta(2)-adrenocept or antagonist, and ICI-215001 competitively inhibited the relaxations caused by isoprenaline. 5 In isolated strips of guinea-pig ileum longi tudinal smooth muscle contracted with histamine, isoprenaline and ICI- 215001 caused relaxations which were inhibited by alprenolol, a beta-a drenoceptor antagonist with modest affinity for beta(3)-adrenoceptors, but were resistant to ICI-118551 and atenolol. 6 These results indica te that ICI-215001 exhibits beta(3)-adrenoceptor agonist activity as d emonstrated by relaxations mediated via atypical beta-adrenoceptors in the longitudinal smooth muscle of guinea-pig ileum. Further, the stud ies demonstrate that ICI-215001 can act as an antagonist at beta(1)- a nd beta(2)-adrenoceptors in situations where its intrinsic agonist act ivity is low.