CHARACTERIZATION OF POSTJUNCTIONAL MUSCARINIC RECEPTORS MEDIATING CONTRACTION IN RAT ANOCOCCYGEUS MUSCLE

The present study was designed to characterize the postjunctional musc arinic receptors mediating contraction in rat anococcygeus muscle by m eans of a series of muscarinic agonists and subtype-preferring key mus carinic antagonists. Cumulative addition of muscarinic agonists elicit ed concentration-dependent contractions with the following rank order of potency (pD(2) values): (+)-muscarine (6.36) greater than or equal to oxotremorine M (6.21) greater than or equal to arecaidine propargyl ester (APE) (6.18) > carbachol (5.68) = (+/-)-methacholine (5.65) > l orophenylcarbamoyloxy)-2-butynyltrimethylammonium chloride (4-Cl-McN-A -343) (4.28) > lorophenylcarbamoyloxy)-2-butynyltrimethylammonium chlo ride (McN-A-343) (3.89). (+)-Muscarine, oxotremorine M, carbachol and (+/-)-methacholine behaved as full agonists, whereas APE, 4-Cl-McN-A-3 43 and McN-A-343 displayed partial agonism. The contractile responses of the rat anococcygeus muscle to (+/-)-methacholine were competitivel y antagonized by pirenzepine (pA(2) = 6.92), -[[4-[4-(diethylamino)but yl]-1-piperidinyl]acetyl] dihydro-6H-pyrido(2,3-b)(1,4)-benzodiazepine -6-one (AQ-RA 741; pA(2) = 6.75), himbacine (pA(2) = 7.11), (+/-)-p-fl uoro-hexahydro-sila-difenidol (p-F-HHSiD; pA(2) = 7.68) and the (R)- a nd (S)-enantiomers of hexahydro-difenidol [(R)-HHD: pA(2) = 8.52; (S)- HHD: pA(2) = 6.06]. A comparison of the pA(2) values derived from stud ies of contraction in rat anococcygeus muscle with literature binding (pK(i) values) and functional affinities (pA(2) values) obtained at na tive M-1-M-4 receptors strongly suggests that the postjunctional musca rinic receptors mediating contraction in rat anococcygeus muscle are o f the M-3 subtype.