APPLICATION OF A MODEL TO EXPLORE INTERSPECIES DIFFERENCES IN ACETYLCHOLINE M-RECEPTOR-STIMULATED GASTRIC-ACID SECRETION

1 Concentration-effect curves were obtained, in the absence and presen ce of histamine H-2-receptor blockade, to 5-methylfurmethide (5-MeF) a nd McN-A 343, high efficacy and low efficacy acetylcholine (ACh) M-rec eptor agonists, respectively, in isolated stomach preparations from th e mouse and immature rat and guinea-pig. 2 In the immature guinea-pig assay, the responses to 5-MeF and McN-A 343 were abolished by histamin e H-2-receptor blockade suggesting that the responses were totally dep endent upon gastric mucosal histamine. However, in the mouse and immat ure rat assays, although the histamine H-2-receptor antagonists produc ed small but significant rightward shifts and, in some cases, depressi on of the maximum of the agonist concentration-effect curves, a signif icant secretory response remained, presumed to be due to direct stimul ation of oxyntic cells. 3 Previously, by assuming that the histamine H -2-receptor blockade alters the mode of agonist-stimulated acid secret ion from mainly an indirect action mediated by histamine release to di rect stimulation of the oxyntic cell, we applied an operational model of agonism to similar data obtained in the mouse preparation. In that study we were able to account for the behaviour of 5-MeF and McN-A 343 by assuming that the agonists expressed 6 fold higher efficacy, tau i n the operational model of agonism, at ACh M-receptors on the histamin e-releasing cells than on the oxyntic cells. In this study it was poss ible to account for the variation in the behaviour of the agonists bot h between and within assays by simply varying the efficacy expressed b y the agonists at each of the cells in the model. The efficacy variati on could be due to receptor concentration variation. 4 The data and an alysis are discussed in terms of contemporary models for the role of h istamine in the regulation of gastric acid secretion.