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 presence of histamine H2-receptor blockade, to 5-methylfurmethide (5-MeF) and McN-A 343, high efficacy and low efficacy acetylcholine (ACh) M-receptor agonists, respectively, in isolated stomach preparations from the 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 histamine H2-receptor blockade suggesting that the responses were totally dependent upon gastric mucosal histamine. However, in the mouse and immature rat assays, although the histamine H2-receptor antagonists produced small but significant rightward shifts and, in some cases, depression of the maximum of the agonist concentration-effect curves, a significant secretory response remained, presumed to be due to direct stimulation of oxyntic cells. 3. Previously, by assuming that the histamine H2-receptor blockade alters the mode of agonist-stimulated acid secretion from mainly an indirect action mediated by histamine release to direct 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 in the operational model of agonism, at ACh M-receptors on the histamine-releasing cells than on the oxyntic cells. In this study it was possible to account for the variation in the behaviour of the agonists both between and within assays by simply varying the efficacy expressed by the agonists at each of the cells in the model. The efficacy variation could be due to receptor concentration variation.4. The data and analysis are discussed in terms of contemporary models for the role of histamine in the regulation of gastric acid secretion.
Welsh
N J
NJ
Department of Analytical Pharmacology, King's College School of Medicine & Dentistry, Rayne Institute, London.
Shankley
N P
NP
Black
J W
JW
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005744:Gastric Acid / Q000378:metabolism*; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000494:pharmacology; D008297:Male; D008954:Models, Biological; D009116:Muscarine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010277:Parasympathomimetics / Q000494:pharmacology*; D051381:Rats; D011976:Receptors, Muscarinic / Q000187:drug effects*; D013270:Stomach / Q000187:drug effects*
D006633:Histamine Antagonists; D010277:Parasympathomimetics; D011976:Receptors, Muscarinic; C008446:5-methylfurtrethonium; D009116:Muscarine