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

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 beta 3-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 x 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 beta-adrenoceptor antagonist. An alpha2-adrenoceptor antagonist, yohimbine, did not influence the inhibitory effects of any of the beta-adrenoceptor agonists tested.5. Concentration-response curves to acetylcholine (10-8 to 10-3 M), [Nle10]NKA(4-10) (10-10 to10-6 M) and substance P (10- to 3 x 10-6 M) were also significantly shifted to the right by salbutamol(10-6 M), whereas SR58611A and BRL37344 (10-6 M) had no effect.6. These results suggest that the stimulation of putative beta 3-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 beta2-adrenoceptor agonistic component may be involved in the effects of BRL 37344.