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Comparison of the profiles of agonists as stimulants of the β 3 ‐adrenoceptor in vitro with their gastroprotective effects in the conscious rat
Author(s) -
Bahl A.K.,
Clayton N.M.,
Coates J.,
Martin D.P.,
Oakley I.G.,
Strong P.,
Trevethick M.A.
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15230.x
Subject(s) - agonist , atenolol , isoprenaline , propranolol , endocrinology , chemistry , salmeterol , medicine , partial agonist , pharmacology , intrinsic activity , stimulation , receptor , asthma , blood pressure
1 This paper compares the activity of a range of agonists as stimulants of the β 3 ‐adrenoceptor in rat isolated oesophagus with their ability to afford protection against indomethacin‐induced gastric damage in the conscious rat. 2 The β 3 ‐adrenoceptor agonists, CL 316243 and BRL 37344, the non‐selective β‐adrenoceptor agonist, isoprenaline and the selective β 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 β 1 ‐adrenoceptor agonist, denopamine, did not relax the preparation. 3 The relaxant responses to all agonists were resistant to blockade by atenolol (10 μ m ), and ICI 118551 (1 μ m ) thus suggesting that they were not mediated by either β 1 ‐ or β 2 ‐adrenoceptor stimulation. In contrast, cyanopindolol and propranolol did inhibit responses to BRL 37344, CL 316243 and isoprenaline, giving pA 2 values or pK B estimates which were consistent with an interaction at β 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 μ m ) concentrations of salmeterol used exerted non‐specific relaxant effects. 4 The agonist effects of CL 316243 and BRL 37344 on β 1 ‐ and β 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 (ED 50 values = 0.24 and 0.09 μmol 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 β 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 β 3 ‐adrenoceptor may confer mucosal protection in man.