PHARMACOLOGICAL ANALYSIS OF THE CCKB GASTRIN RECEPTORS MEDIATING PENTAGASTRIN-STIMULATED GASTRIC-ACID SECRETION IN THE ISOLATED STOMACH OF THE IMMATURE RAT/

1 The CCKB/gastrin receptors mediating pentagastrin stimulation of gas tric acid secretion by histamine release and by direct stimulation of oxyntic cells have been characterized in the immature rat isolated sto mach assay. This was achieved by estimating antagonist affinity values for competitive antagonists from three distinct chemical classes (L-3 65,260, PD134,308 and JB93190) in the absence and presence of a high c oncentration of the histamine H-2-receptor antagonist, famotidine (30 mu M). 2 Pentagastrin produced concentration-dependent stimulation of gastric acid secretion in the absence and presence of famotidine. Famo tidine depressed the maximum secretory response to pentagastrin althou gh 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 maxi mum responses obtained in the presence, but not absence, of famotidine . 3 All three CCKB/gastrin receptor antagonists behaved as surmountabl e antagonists in the absence and presence of famotidine. JB93190 (pK(B ) similar to 9.1, similar to 8.9, in the absence and presence of famot idine, respectively) was approximately 30 fold more potent than either L-365,260 (pK(B) similar to 7.4, similar to 7.1) or PD134,308 (pK(B) similar to 7.6, similar to 7.4). 4 It was assumed that the famotidine converted pentagastrin-stimulated acid secretion from a combination of an indirect action due to the release of histamine and a direct actio n 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 was assumed to sum to produce the t otal response to pentagastrin obtained in the absence of famotidine. I t was found that this model could account quantitatively for the behav iour of the three antagonists without invoking a difference in antagon ist affinity for the CCKB/gastrin receptors mediating the direct and i ndirect actions of pentagastrin. However, a conclusion of receptor hom ogeneity has to be qualified because the model was also used to genera te simulations which indicated that the analysis could only detect ant agonist affinity differences of greater than one log-unit between ente rochromaffin-like (ECL) and oxyntic cell CCKB/gastrin receptor populat ions.