Effects of two β3‐adrenoceptor agonists, SR 58611A and BRL 37344, and of salbutamol on cholinergic and NANC neural contraction in guinea‐pig main bronchi in vitro

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Abstract
1 The aim of the present study was to investigate the type of adrenoceptor which modulates constriction of the guinea-pig isolated main bronchus in response to electrical field stimulation (EFS). Drugs used were salbutamol and two agonists reportedly selective for the putative β3-adrenoceptor: BRL 37344 and SR 58611A. 2 At basal tone, all three drugs induced relaxation, however, SR 58611A and BRL 37344 (10−9 to 10−6 m) relaxed guinea-pig isolated main bronchus more weakly than salbutamol (10−9 to 10−6 m). The effects observed at 10−6 m were 43% ± 9%, 63% ± 4% and 98% ± 1% of the maximal effect induced by theophylline (3 × 10−3 m) for SR 58611A, BRL 37344 and salbutamol, respectively. 3 SR 58611A and BRL 37344 (10−8 to 10−6 m) did not significantly modify the cholinergic component of the response to EFS, but caused a concentration-dependent reduction of the nonadrenergic non-cholinergic (NANC) excitatory component (41.8% ± 10.1% and 56.8% ± 7.4% respectively at 10−6 m, n = 6–7). Salbutamol (10−9 to 10−7 m) strongly inhibited both components, with 91.1% ± 4.2% of inhibition for the NANC contraction and 62.0% ± 5.2% of inhibition for the cholinergic contraction (10−7 m, n = 7). 4 Whereas the inhibitory effects of salbutamol were strongly inhibited by both propranolol (10−6 m) and ICI 118,551 (10−6 m), those of BRL 37344 were only slightly, albeit significantly reduced by both propranolol and ICI 118,551, and those of SR 58611A were unaffected by treatment with either β-adrenoceptor antagonist. An α2-adrenoceptor antagonist, yohimbine, did not influence the inhibitory effects of any of the β-adrenoceptor agonists tested. 5 Concentration-response curves to acetylcholine (10−8 to 10−3 m), [Nle10]NKA(4–10) (10−10 to 10−6 m) and substance P (10−10 to 3 × 10−6 m) were also significantly shifted to the right by salbutamol (10−6 m), whereas SR 58611A and BRL 37344 (10−6 m) had no effect. 6 These results suggest that the stimulation of putative β3-adrenoceptors exerts a specific prejunctional inhibitory action on NANC excitatory response induced by EFS of the isolated main bronchus of the guinea-pig. They also suggest that a β2-adrenoceptor agonistic component may be involved in the effects of BRL 37344.

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