Pharmacological analysis of the CCKB/gastrin receptors mediating pentagastrin‐stimulated gastric acid secretion in the isolated stomach of the immature rat

• Published in: British journal of pharmacology Vol. 119; no. 7; pp. 1401 - 1410
• Main Authors: Hills, David M., Gerskowitch, V. Paul, Roberts, Sonia P., Welsh, Nicola J., Shankley, Nigel P., Black, James W.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.12.1996; Nature Publishing
• Subjects: Animals; Binding, Competitive - drug effects; Biological and medical sciences; CCKB/gastrin receptors; Enterochromaffin Cells - drug effects; Enterochromaffin Cells - metabolism; Famotidine - pharmacology; Gastric Acid - metabolism; gastric acid secretion; Gastric Mucosa - drug effects; Gastric Mucosa - metabolism; Histamine; Histamine - pharmacology; Histamine H2 Antagonists - pharmacology; In Vitro Techniques; Kinetics; Medical sciences; Models, Biological; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pentagastrin; Pentagastrin - pharmacology; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Rats; Rats, Wistar; Receptors, Cholecystokinin - antagonists & inhibitors; Receptors, Cholecystokinin - drug effects; Stimulation, Chemical; Stomach; Agonist; Pentagastrin; Rat; Digestive system; Peptide hormone; Rodentia; Molecular interaction; Acidity; Neuropeptide; In vitro; Biological activity; Isolated organ; Vertebrata; Gastrointestinal hormone; Mammalia; Animal; Peptidergic receptor; Antagonist; Cholecystokinin; Mathematical model; Mechanism of action; Gastric juice; Pentapeptide
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1996.tb16052.x

1 The CCKB/gastrin receptors mediating pentagastrin stimulation of gastric acid secretion by histamine release and by direct stimulation of oxyntic cells have been characterized in the immature rat isolated stomach assay. This was achieved by estimating antagonist affinity values for competitive antagonists from three distinct chemical classes (L‐365,260, PD 134,308 and JB93190) in the absence and presence of a high concentration of the histamine H2‐receptor antagonist, famotidine (30 μm). 2 Pentagastrin produced concentration‐dependent stimulation of gastric acid secretion in the absence and presence of famotidine. Famotidine depressed the maximum secretory response to pentagastrin although the degree of depression varied between experimental replicates (25–60%). This variation was attributed to the histamine‐release mediated component of acid secretion, as judged by the consistency of the maximum responses obtained in the presence, but not absence, of famotidine. 3 All three CCKB/gastrin receptor antagonists behaved as surmountable antagonists in the absence and presence of famotidine. JB93190 (pK∼B∼9.1, ∼8.9, in the absence and presence of famotidine, respectively) was approximately 30 fold more potent than either L‐365,260 (pKB∼7.4, ∼7.1) or PD 134,308 (pKB∼7.6, ∼7.4). 4 It was assumed that the famotidine treatment converted pentagastrin‐stimulated acid secretion from a combination of an indirect action due to the release of histamine and a direct action on the oxyntic cell to solely a direct action on the oxyntic cell. A simple mathematical model of this two‐receptor system was developed. The direct and indirect components were assumed to sum to produce the total response to pentagastrin obtained in the absence of famotidine. It was found that this model could account quantitatively for the behaviour of the three antagonists without invoking a difference in antagonist affinity for the CCKB/gastrin receptors mediating the direct and indirect actions of pentagastrin. However, a conclusion of receptor homogeneity has to be qualified because the model was also used to generate simulations which indicated that the analysis could only detect antagonist affinity differences of greater than one log‐unit between enterochromaffin‐like (ECL) and oxyntic cell CCKB/gastrin receptor populations.