PHARMACOLOGICAL CHARACTERIZATION OF THE MUSCARINIC RECEPTOR SUBTYPE MEDIATING CONTRACTION OF HUMAN PERIPHERAL AIRWAYS

The postjunctional muscarinic receptors mediating contraction of human bronchial smooth muscle have been characterized using four nonselecti ve muscarinic receptor agonists and eight subtype selective and nonsel ective muscarinic antagonists. Carbachol, methacholine, oxotremorine M and (+)-cis-dioxolane all caused concentration-related contractions o f human bronchial smooth muscle with a rank order of potency (pD(2)) o f (+)-cis-dioxolane (7.3 +/- 0.2) > oxotremorine M (6.7 +/- 0.2) > car bachol (6.4 +/- 0.1) > methacholine (5.8 +/- 0.2, n = 5 for all). Maxi mum contractions were not significantly different between agonists, wh ether expressed as absolute mg tension changes or as a percentage of t he maximum response to 0.3 mM histamine. Antagonist apparent affinitie s (pK(B)) were determined against carbachol-induced contractions and t he following rank order was obtained; 4-DAMP (9.4 +/- 0.3) greater tha n or equal to atropine (9.1 +/- 0.1) > zamifenacin (7.6 +/- 0.1)> hexa hydrosiladifenidol (HMSiD; 7.1 +/- 0.1) greater than or equal to himba cine (7.0 +/- 0.3) greater than or equal to pirenzepine (6.8 +/- 0.2) > para-fluoro-hexahydrosiladifenidol (p-F-HHSiD; 6.7 +/- 0.1) > methoc tramine (5.3 +/- 0.2). This rank order of antagonist affinities is con sistent with activation of M(3) receptors. The affinities of HHSiD, p- F-HHSiD and zamifenacin were, however, lower than those reported in gu inea pig trachea.