THE INTERACTION OF MCN-A-343 WITH MUSCARINE RECEPTORS IN CARDIAC AND SMOOTH-MUSCLE

The interaction of the muscarine receptor partial agonist lorophenylca rbamoyloxy)-2-butynyltrimethylammonium chloride (McN-A-343) was invest igated at muscarine receptors in the atria and taenia caeci of the gui nea-pig to compare its interaction at the muscarine M2 receptor in the two tissues. In the smooth muscle, the muscarine M3 receptor subtype is responsible for the contractile response but the major subtype dete cted in binding or antibody experiments is the M2 subtype. In guinea p ig atria the dissociation constant of McN-A-343 at muscarine receptors was 15.2 muM determined in functional experiments on left atria in Mc Ewen's solution or 14.8 muM in binding experiments with [H-3](-)-quinu clidinol benzilate ([H-3]QNB) in the same medium containing 5'-guanyly limidodiphosphate (50 muM). In the taenia caeci, the dissociation cons tant estimated for McN-A-343 at the M3 receptor from functional experi ments based on the contractile response to the agonist in McEwen's sol ution was 4.6 muM. This value was similar to the dissociation constant (6.2 muM) estimated from binding studies versus [H-3]QNB conducted in the same medium although studies with ]-5,11-dihydro-6H-pyrido[2,3-b] [1,4]benzodiazepine 6-one (AF-DX 116) versus [H-3](-)-N-methylscopolam ine suggested that 70% of the receptors were the M2 subtype. The prese nce of the M2 subtype in the taenia caeci was also confirmed by the ab ility of oxotremorine to inhibit the increase in cAMP produced by isop renaline (10 muM) since apparent pK(B) values for AF-DX 116 and hexahy drosiladiphenidol were 6.95 and 6.75, respectively. McN-A-343 (100 muM ) failed to inhibit the response to isoprenaline and did not antagoniz e the inhibitory response to oxotremorine. It is concluded that the ap parent affinity of McN-A-343 for muscarine M2 receptors in the atria a nd the taenia caeci differs and a number of explanations are discussed .