Gallamine allosterically antagonizes muscarinic receptor-mediated inhibition of adenylate cyclase activity in the rat myocardium.

The ability of gallamine to modify muscarinic receptor binding properties and to antagonize muscarinic receptor-mediated inhibition of adenylate cyclase activity was investigated in the rat myocardium. Gallamine caused parallel shifts to the right in the dose-response curves for inhibition of adenylate cyclase activity by the highly efficacious muscarinic agonist oxotremorine-M and the partial agonist Bm 5 [N-methyl-N-(1-methyl-4-pyrrolidino)-2-butynyl acetamide]. The nature of this effect was inconsistent with competitive inhibition, but could be explained by allosteric antagonism. Similar dissociation constants of 0.52 and 0.83 microM were estimated for gallamine on the basis of its ability to antagonize responses to oxotremorine-M and Bm 5, respectively. The maximum shift in the dose-response curve of Bm 5 caused by gallamine was 90-fold, whereas that of oxotremorine-M was only 49-fold. When measured by inhibition of the binding of the specific muscarinic antagonist [3H]N-methylscopolamine, the dissociation constant of gallamine was estimated to be 1.1 microM. The present results illustrate good agreement between the ability of gallamine to modify muscarinic receptor binding properties and to antagonize muscarinic receptor-mediated inhibition of adenylate cyclase activity in the rat heart.