Characterization of postjunctional muscarinic receptors mediating contraction in rat anococcygeus muscle.
The present study was designed to characterize the postjunctional muscarinic receptors mediating contraction in rat anococcygeus muscle by means of a series of muscarinic agonists and subtype-preferring key muscarinic antagonists. Cumulative addition of muscarinic agonists elicited concentration-dependent contractions with the following rank order of potency (pD2 values): (+)-muscarine (6.36) > or = oxotremorine M (6.21) > or = arecaidine propargyl ester (APE) (6.18) > carbachol (5.68) = (+/-)-methacholine (5.65) > 4-(4-chlorophenyl-carbamoyloxy)-2-butynyltrimethylammonium chloride (4-Cl-McN-A-343) (4.28) > 4-(3-chlorophenylcarbamoyloxy)-2-butynyltrimethylammonium chloride (McN-A-343) (3.89). (+)-Muscarine, oxotremorine M, carbachol and (+/-)-methacholine behaved as full agonists, whereas APE, 4-Cl-McN-A-343 and McN-A-343 displayed partial agonism. The contractile responses of the rat anococcygeus muscle to (+/-)-methacholine were competitively antagonized by pirenzepine (pA2 = 6.92), 11-[[4-[4-(diethylamino)butyl]-1-piperidinyl]acetyl] 5,11-dihydro-6H-pyrido(2,3-b) (1,4)-benzodiazepine-6-one (AQ-RA 741; pA2 = 6.75), himbacine (pA2 = 7.11), (+/-)-p-fluoro-hexahydro-sila-difenidol (p-F-HHSiD; pA2 = 7.68) and the (R)- and (S)-enantiomers of hexahydro-difenidol [(R)-HHD: pA2 = 8.52; (S)-HHD: pA2 = 6.06]. A comparison of the pA2 values derived from studies of contraction in rat anococcygeus muscle with literature binding (pKi values) and functional affinities (pA2 values) obtained at native M1-M4 receptors strongly suggests that the postjunctional muscarinic receptors mediating contraction in rat anococcygeus muscle are of the M3 subtype.
Weiser
M
M
Pharmakologisches Institut für Naturwissenschaftler, Biozentrum Niederursel, Universität Frankfurt, M., Germany.
Mutschler
E
E
Lambrecht
G
G
D000818:Animals; D004347:Drug Interactions; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology*; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects*; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011976:Receptors, Muscarinic / Q000145:classification / Q000187:drug effects* / Q000502:physiology; D013237:Stereoisomerism
D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D010880:Piperidines; D011976:Receptors, Muscarinic; C060685:hexahydrodifenidol