CONTRACTION OF GUINEA-PIG GALLBLADDER - MUSCARINIC M-3 OR M-4 RECEPTORS

The muscarinic receptor mediating contraction of the guinea-pig isolat ed gallbladder, currently being disputed to belong either to the M-3 o r M-4 subtype, was characterized by subtype-preferring agonists and di scriminating antagonists. Highly significant correlations of agonist p otencies to contract the gallbladder, e.g., arecaidine propargyl ester , oxotremorine, 5-methylfurtrethonium > arecoline, arecaidine 2-butyne -1,4-diyl bisester > (R)-nipecotic acid ethyl ester > orophenyl)carbam yl]oxy]-2-butynyltrimethylammonium iodide (4-Cl-McN-A-343), (S)-nipeco tic acid ethyl ester > rophenyl)carbamoyl]oxy]-2-butynyltrimethylammon ium chloride (McN-A-343) were found with muscarinic M-3 receptors medi ating contraction of the guinea-pig ileum and vasodilation in rat perf used kidney. Functional affinities at guinea-pig gallbladder muscarini c receptors of antagonists known to distinguish between native or clon ed muscarinic M-3/m3 and M-4/m4 receptors, e.g., himbacine, methoctram ine, mefurtramine, tripitramine, idaverine, zamifenacin and 1-dihydro- 6H-pyrido(2,3-b)(1,4)benzodiazepin-6-one (AQ-RA 741), were consistent with those at guinea-pig ileal muscarinic M-3 receptors but not with p ublished data at recently defined muscarinic M-4 receptors in rabbit a nococcygeus muscle or at muscarinic M-1 and M-2 receptors in rabbit va s deferens. Antagonist affinities at guinea-pig gallbladder correlated also best with published binding data on native or cloned muscarinic M-3/m3 receptors but not with those for muscarinic M-4/m4 receptors. T he agonist potencies and antagonist affinities suggest that smooth mus cle contraction elicited by muscarinic stimuli in guinea-pig gallbladd er is mediated by functional muscarinic M-3 receptors. (C) 1997 Elsevi er Science B.V.