Interaction of some muscarinic agonists and antagonists at the prejunctional muscarinic receptor in the rabbit ear artery preparation.

The inhibitory effect of several muscarinic agonists on responses to sympathetic nerve stimulation of the isolated perfused ear artery of the rabbit was compared to that of acetylcholine in preparations pretreated with dyflos, cocaine and yohimbine. In general the potency of the agonists was similar to that observed at peripheral muscarinic sites except for arecaidine propargyl ester and 4-(m-chlorophenylcarbamoyloxy)-2-butynyl trimethylammonium chloride (McN-A-343). The inhibitory effect observed with N-benzyl-3-pyrrolidyl acetate methobromide (AHR-602) was not exerted via muscarinic receptors. With carbachol (CCh) as an agonist, the antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) was found to have a pKB value of 7.74 and thus was 19 fold less active as an antagonist of responses to the agonist, than previously reported for guinea-pig ileum. When McN-A-343 was used as the agonist, the slope of the Schild plot with the antagonist was significantly less than unity. It is suggested that an allosteric interaction of 4-DAMP may be involved with this agonist. By use of an allosteric model, a pKB of 8.56 for 4-DAMP was obtained. Secoverine produced similar pKB values with either CCh (8.19) or McN-A-343 (8.13) as the agonist.