Promiscuous or heterogeneous muscarinic receptors in rat atria? I. Schild analysis with simple competitive antagonists.

Carbachol has been shown to produce a biphasic response in rat left atria. At low concentrations, carbachol depresses basal inotropy, while at high doses a positive inotropic effect is observed. The negative inotropic response can be selectively eliminated by pretreatment of rats with pertussis toxin. The aim of these studies was to determine whether or not evidence could be obtained to show that different muscarinic receptors produced these different biochemical responses to the agonist carbachol. Schild analysis was used to measure the equilibrium dissociation constant of the antagonist-receptor complex for antagonism of the negative inotropy to carbachol by atropine, scopolamine 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) and AF-DX 116. The antagonism of the positive inotropic response to carbachol by these antagonists was studied in atria from rats pretreated with pertussis toxin where the negative inotropy was nearly completely abolished. In general, it was found that the antagonists did not produce simple competitive blockade of the positive inotropy but rather a nominal shift to the right of the dose-response curves followed by a depression of maximal responses. However, it was found that when pA2 or pKb values could be calculated, they coincided with those determined for the antagonism of the negative inotropy to carbachol. The conclusion drawn from these experiments was that no evidence was obtained to disprove the null hypothesis that a common receptor, interacting with two G-proteins, mediates these two effects of carbachol in rat left atria. The implications of these data for the classification of drug receptors with agonists is discussed.