Effects of two beta 3-adrenoceptor agonists, SR 58611A and BRL 37344, and of salbutamol on cholinergic and NANC neural contraction in guinea-pig main bronchi in vitro.
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 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.
Martin
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Département de Pharmacologie, Faculté de Médecine Paris-Ouest, France.
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Manara
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Advenier
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D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000420:Albuterol / Q000494:pharmacology*; D000818:Animals; D001980:Bronchi / Q000294:innervation*; D016084:Bronchoconstriction / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004983:Ethanolamines / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D010275:Parasympathetic Nervous System / Q000502:physiology; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*; D018040:Receptors, Neurokinin-1 / Q000187:drug effects; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*
D000318:Adrenergic beta-Agonists; D004983:Ethanolamines; D011943:Receptors, Adrenergic, beta; D018040:Receptors, Neurokinin-1; D013764:Tetrahydronaphthalenes; C057368:BRL 37344; C076252:amibegron; D000420:Albuterol