1 The muscarinic receptor subtypes mediating contraction of the guinea-pig lung strip and inhibition of the release of acetylcholine from cholinergic vagus nerve endings in the guinea-pig trachea in vitro have previously been characterized as M 2 -like, i.e. having antagonist a nity pro®les that are qualitatively similar but quantitatively dissimilar compared to cardiac M 2 receptors. The present study sought to establish de®nitely the identity of these receptor subtypes by using the selective muscarinic receptor antagonist, tripitramine. Guinea-pig atria and guinea-pig trachea (postjunctional contractile response) were included for reference. 2 It was found that tripitramine antagonized methacholine-induced contractions of the guinea-pig lung strip with a pK B value of 8.76+0.05. Both the parallel shifts of the concentration-response curves and the slope of the Schild plot being not signi®cantly di erent from unity (when antagonist preincubation was for 2 h) indicated the involvement of a single population of receptors in the contractile response. From the pK B values obtained with tripitramine and a range of other selective muscarinic receptor antagonists (cf. Ro el et al., 1993), this single population of receptors can only be classi®ed as M 2 -like. 3 Tripitramine antagonized methacholine-induced negative chronotropic and inotropic responses in guinea-pig right and left atria with apparent pK B values of 9.4 ± 9.6. However, such values were only obtained when antagonist preincubation was relatively long and/or antagonist concentration relatively high (e.g. with 1 h at 100 or 300 nM but 3 h at 30 nM). It thus appears that low concentrations of tripitramine do not readily equilibrate with M 2 receptors in guinea-pig atria nor with M 2 -like receptors in the guinea-pig lung strip. 4 Tripitramine increased electrical ®eld stimulation-induced cholinergic twitch contractions in guineapig trachea in concentrations of 0.3 ± 100 nM, by blocking prejunctional muscarinic inhibitory autoreceptors; with higher concentrations, twitch contractions were progressively diminished, as a result of blocking postjunctional M 3 receptors (apparent pK B value 6.07+0.15). The pEC 20 value (7log concentration that increases twitch by 20% of maximum) was 8.29+0.08, which would suggest that M 4 receptors are involved in this response. 5 Oxotremorine-induced inhibition of the release of prelabelled [ 3 H]-acetylcholine from guinea-pig trachea, under conditions where there is no auto-feedback, was blocked by tripitramine (2 h preincubation) with a pK B value of 8.56+0.06. The slope of the corresponding Schild plot was not signi®cantly di erent from unity, which together with the parallel shifts of the concentration-response curves indicated the involvement of a single muscarinic receptor subtype. 6 Since the pK B value for tripitramine at prejunctional receptors in guinea-pig trachea is in between the a nities towards M 2 and M 4 receptors, correlation plots were constructed to compare the pK B values obtained with tripitramine and a ran...
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