Comparison of the profiles of agonists as stimulants of the beta 3-adrenoceptor in vitro with their gastroprotective effects in the conscious rat.

1. This paper compares the activity of a range of agonists as stimulants of the beta 3-adrenoceptor in rat isolated oesophagus with their ability to afford protection against indomethacin-induced gastric damage in the conscious rat. 2. The beta 3-adrenoceptor agonists, CL 316243 and BRL 37344, the non-selective beta-adrenoceptor agonist, isoprenaline and the selective beta 2-adrenoceptor agonist, salmeterol, all evoked concentration-dependent relaxation of precontracted muscularis mucosa from rat oesophagus. The rank order of agonist potency was BRL 37344 > CL 316243 > isoprenaline >> salmeterol. The selective beta 1-adrenoceptor agonist, denopamine, did not relax the preparation. 3. The relaxant responses to all agonists were resistant to blockade by atenolol (10 microM), and ICI 118551 (1 microM) thus suggesting that they were not mediated by either beta 1- or beta 2-adrenoceptor stimulation. In contrast, cyanopindolol and propranolol did inhibit responses to BRL 37344, CL 316243 and isoprenaline, giving pA2 values or pKB estimates which were consistent with an interaction at beta 3-adrenoceptors (i.e. approximately 8.0 and 6.5 respectively). However, responses to salmeterol were resistant to blockade by all the antagonists tested, which suggests that the high (> 1 microM) concentrations of salmeterol used exerted non-specific relaxant effects. 4. The agonist effects of CL 316243 and BRL 37344 on beta 1- and beta 2-adrenoceptors were assessed on guinea-pig right atrium and precontracted trachea respectively. Both agonists had minimal activity as stimulants of heart rate, but did relax trachea, being 380 (CL 316243) and 21 (BRL 37344) fold less potent than isoprenaline. 5. CL 316243 and BRL 37344 were potent inhibitors of indomethacin-induced gastric antral ulceration in the conscious rat (ED50 values = 0.24 and 0.09 mumol kg-1, p.o.) Salmeterol was approximately 100 times less potent than BRL 37344 as a gastroprotective agent and denopamine was without effect. 6. The gastroprotective effects of CL 316243 and BRL 37344 were resistant to blockade by ICI 118551 (10 mg kg-1, p.o.) and propranolol (10 mg kg-1, p.o.). In contrast, both antagonists caused dose-related inhibition of the protective action of salmeterol (10 mg kg-1, p.o.). Cyanopindolol was not assessed as an antagonist in vivo because preliminary experiments revealed that it exacerbated indomethacin-induced gastric damage in its own right. 7. In conclusion, the beta 3-adrenoceptor agonists CL 316243 and BRL 37344 were potent inhibitors of indomethacin-induced gastric antral ulceration in the rat. These data suggest that an agonist which is potent and selective for the human beta 3-adrenoceptor may confer mucosal protection in man.