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.