Responses to BRL 37344 in the presence of phentolamine (1puM) and propranolol (1 pM) were antagonized by (±)-cyanopindolol (IpM), with an apparent pA2 value of 6.67. Responses to isoprenaline, under the same conditions, were antagonized in a competitive manner by (±)-cyanopindolol (0.1 to 10pM), with the slope of the Schild plot close to unity and a pA2 value of 7.12. 6 The resistance of the relaxant responses to antagonism by phentolamine and propranolol, along with the relatively high potency of the #3-adrenoceptor agonist BRL 37344 and the antagonism of 'resistant' responses by (±)-cyanopindolol would suggest that 'atypical' f6-adrenoceptors, similar to the fl3-adrenoceptors of rat adipocytes and other tissues, exist in the rat distal colon.

1 Experiments were carried out in order to characterize the receptors mediating relaxant responses to catecholamines in the rat gastric fundus. The effects of noradrenaline, isoprenaline and the 'atypical' or 13-adrenoceptor agonist, BRL 37344, on methacholine-induced tone were measured. Prazosin, propranolol and cyanopindolol were used as antagonists. 2 Relaxant responses to noradrenaline, in the presence of propranolol (1 M) were antagonized in a concentration-dependent manner by prazosin (0.01 to 1,pM), although this antagonism was weak and non-competitive in nature. Relaxant responses to isoprenaline, in the presence of prazosin (0.1 ,UM), were antagonized only by the highest concentration of propranolol (1 pM) giving a pKB of 6.3. BRL 37344 also relaxed the rat gastric fundus in the presence of prazosin (0.1 pM), and the responses to BRL 37344 were unaffected by propranolol (1 pM). 3 Tachyphylaxis to BRL 37344 was observed, a second concentration-response curve being significantly shifted to the right. Exposure of tissues to BRL 37344 (1 pM) between concentration-response curves also caused an 11 fold rightward shift in the response to isoprenaline. 4 In the presence of prazosin (0.1 uM) and propranolol (1,UM), the rank order of potency of the agonists was: (-)-isoprenaline (1.0) > (-)-noradrenaline (0.39) > BRL 37344 (0.10). 5 Responses to BRL 37344 in the presence of prazosin (0.1 pM) and propranolol (1 pM) were antagonized by (±)-cyanopindolol (1pM), with a pKB of 6.56. Responses to isoprenaline, under the same conditions, were antagonized in a competitive manner by (±)-cyanopindolol (0.1-1 uM), with the slope of a Schild plot close to unity and a pA2 value of 7.44. 6 The resistance to blockade by prazosin and propranolol and the antagonism by cyanopindolol of the responses mediated by isoprenaline and BRL 37344 suggest that atypical f-adrenoceptors similar to 'atypical',f-adrenoceptors in rat adipocytes and other tissues are present in the rat gastric fundus.

1 The presence of b 3 -adrenoceptors and the low a nity state of the b 1 -adrenoceptor (formerlỳ putative b 4 -adrenoceptor') was investigated in ring preparations of rat isolated aorta preconstricted with phenylephrine or prostaglandin F 2a (PGF 2a ). Relaxant responses to isoprenaline, selective b 3 -adrenoceptor agonists (BRL 37344, SR 58611A, CL 316243) and non-conventional partial agonists (CGP 12177A, cyanopindolol, pindolol) were obtained. 2 In phenylephrine-constricted, but not PGF 2a -constricted rings, relaxations to isoprenaline showed a propranolol-resistant component. 3 In phenylephrine-constricted rings, relaxations to BRL 37344 (pEC 50 , 4.64) and SR 58611A (pEC 50 , 4.94) were not antagonized by the selective b 3 -adrenoceptor antagonist SR 59230A (41 mM). CL 316243 (4100 mM) failed to produce relaxation. In PGF 2a -constricted rings only SR 58611A produced relaxation, which was not a ected by SR 59230A (43 mM). 4 Non-conventional partial agonists produced relaxation in phenylephrine-constricted but not PGF 2a -constricted rings. The relaxation to CGP 12177A was una ected by SR 59230A (41 mM) or by CGP 20712A (10 mM), reported to block the low a nity state of the b 1 -adrenoceptor. Abbreviations: DMSO, dimethyl sulphoxide; pEC 50 , negative logarithm of the concentration (M) of relaxant that produces 50% of its maximum response; PG, prostaglandin; R max , %, maximum % relaxation

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1 b-adrenoceptor-mediated relaxation was investigated in ring preparations of rat isolated thoracic aorta. Rings were pre-constricted with a sub-maximal concentration of noradrenaline (1 mM) and relaxant responses to cumulative concentrations of b-adrenoceptor agonists obtained. 2 The concentration-response curve (CRC) to isoprenaline was shifted to the right by propranolol (0.3 mM) with a steepening of the slope. Estimation of the magnitude of the shift from EC 50 values gave a pA 2 of 7.6. Selective b 1 -and b 2 -adrenoceptor antagonists, CGP 20712A (0.1 mM) and ICI 118551 (0.1 mM), respectively, produced 4 and 14 fold shifts of the isoprenaline CRC.