Biphasic dose-response curves to arecoline in rat atria-mediation by a single promiscuous receptor or two receptor subtypes?

Arecoline produces a biphasic response in rat left atria, i.e., a depression of basal inotropy at low doses and a positive inotropic effect at higher doses. These present studies were designed to determine whether it can be shown that the two separate responses to arecoline are mediated by two distinct cell surface muscarinic receptors. The antagonists scopolamine, 4-DAMP and AF-DX 116 produced apparent simple competitive antagonism of the negative responses to arecoline. Schild analysis was used to measure the equilibrium dissociation constant of the antagonist-receptor complex for antagonism of this response to arecoline by these antagonists. In atria from rats treated with pertussis toxin, the negative inotropy to arecoline was abolished and only the positive inotropic effects were observed. The antagonism of the positive inotropic response to arecoline by these antagonists was studied separately in atria from rats treated with pertussis toxin by the Schild technique. The pKB estimates made from the Schild regressions indicated no evidence to suggest that the two responses to arecoline (negative and positive inotropy) were mediated by two separate receptors in rat left atria. These data are discussed in terms of a single muscarinic receptor in this tissue mediating these two responses by interaction with two G-proteins in the same cell membrane. These data also are discussed in terms of the use of agonist potency ratios for the classification of receptors.