title: Muscarinic contraction in isolated guinea-pig trachea and antagonism by noradrenaline.
abstract: In contrast to other muscarinic agonists, WAL 2014 FU does not induce bronchospasm in laboratory animals. The present investigation was intended to test the hypothesis that this is due to a particular susceptibility of the drug's effect to antagonism by catecholamines, as a result of partial M3-agonism. The tonic activity of the muscarinic agonists, aceclidine, arecoline, carbachol, McN-A-343, RS 86, thiopilocarpine and WAL 2014 FU, was tested in groups of isolated tracheal muscle of the guinea-pig. Susceptibility to functional antagonism by beta-adrenoceptor stimulation was measured by the displacement of the concentration-force curves by 3 microM noradrenaline. Evaluation of the concentration-force relationship revealed differences in potency and intrinsic activity (carbachol-100%) ranging from 114% for arecoline to 36% for thiopilocarpine (WAL 2014 FU-63%). The catecholamine increased the concentration of agonist which induced 5% of the maximum effect achievable (EC05) values fivefold (carbachol) to more than 4,680 fold (thiopilocarpine) (WAL 2014 FU: 2,860 fold). Regression analysis between the intrinsic activity of the seven compounds and the antagonistic effect of noradrenaline revealed a significant correlation (Spearman correlation coefficient (r[s])=-0.79; p=0.036). Inhibition of the effects of endogenous catecholamines by beta-adrenolysis with 50 microM toliprolol increased the maximal contraction induced by 1 mM WAL 2014 FU, but did not affect maximal contraction induced by 30 microM arecoline. Pretreatment with 0.3-1.0 mM dibutyrylcyclic adenosine monophosphate (DBcAMP) shifted the concentration-response curves of arecoline, WAL 2014 FU and thiopilocarpine in a similar manner to noradrenaline. The results exclude an important contribution of adenylate cyclase-coupled M2-receptors to the susceptibility of tracheal contraction by muscarinic agonists to functional antagonism by noradrenaline, but emphasize the importance of intrinsic activity at the M3-receptors. The pronounced susceptibility of WAL 2014 FU-induced contraction to functional antagonism by beta-adrenoceptor activation provides an explanation for the failure of the drug to induce bronchospasm in vivo.
authors.affiliation: Dept of Research, Boehringer Ingelheim KG, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Walland
authors.forename: R
authors.initials: R
authors.lastname: Hammer
mesh_terms: D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology*; D011812:Quinuclidines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014132:Trachea / Q000187:drug effects* / Q000502:physiology
chemical_list: D018721:Muscarinic Agonists; D011812:Quinuclidines; D003994:Bucladesine; C079885:talsaclidine fumarate; D009638:Norepinephrine