Conditions affecting the interaction of cholinergic agents on the longitudinal muscle of the guinea-pig ileum—unexpected effects with hexamethonium

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Abstract
Affinity constants were determined for atropine and N-methyl atropine, using both acetylbetamethylcholine and carbaminoylcholine as agonists, on plexus-containing and plexus-free preparations of the guinea-pig ileum. Hexamethonium (1 times 10−4M) decreased the apparent affinity constant of atropine on the plexus-free preparation when carbaminoylcholine but not acetylbetamethylcholine was the agonist. With the latter agonist both antiacetylcholine drugs were equiactive. Hexamethonium’s selective action was associated with a significant shift to the left of the log dose-response curve to carbaminoylcholine on the plexus-free preparation. While others have observed that hexamethonium may be atropine-like, samples of hexamethonium have been reported as being contaminated with a “depolarizing compound”, which may account for the results presented in this study. Nevertheless, the present results are consistent with an allosteric rather than a direct binding mechanism in the blocking action of atropine. The observation that the agonist, acetylbetamethylcholine, was not similarly affected by hexamethonium (or any possible contaminant) suggests that agents with primarily muscarinic activity may not be so affected. This study is another example emphasizing the care needed in interpreting data obtained with the aid of “pharmacological tools”.