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 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, PD134,308 and JB93190) in the absence and presence of a high concentration of the histamine H2-receptor antagonist, famotidine (30 microM). 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 (pKB approximately 9.1, approximately 8.9, in the absence and presence of famotidine, respectively) was approximately 30 fold more potent than either L-365,260 (pKB approximately 7.4, approximately 7.1) or PD134,308 (pKB approximately 7.6, approximately 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.

Characterization of the receptors and mechanisms involved in the cardiovascular actions of sCCK-8 in the pithed rat.

1. The cardiovascular actions of cholecystokinin and related peptides were investigated in the pithed rat. The receptors and the mechanisms involved in these experiments were characterized. 2. Sulphated cholecystokinin octapeptide (sCCK-8, 0.1-100 nmol kg-1, i.v.) elicited a dose-dependent bradycardia and increase in mean arterial blood pressure. Neither gastrin-17 nor pentagastrin had any effect at concentrations up to 100 nmol kg-1. 3. Both the pressor response and bradycardia elicited by sCCK-8 were reduced by the selective CCKA receptor antagonists, devazepide (0.5-50 nmol kg-1) and lorglumide (1-7 mumol kg-1). The selective CCKB receptor antagonists, CI-988 (1 mumol kg-1) and L-365,260 (15 mumol kg-1) did not inhibit the effects of sCCK-8. 4. The pressor response induced with sCCK-8 was reduced by treatment with either phentolamine (3 mumol kg-1) or guanethidine (2 mumol kg-1) and was unaffected by treatment with propranolol, atropine or hexamethonium. The pressor response also persisted following bilateral adrenalectomy. 5. The bradycardia induced with sCCK-8 was unaffected by treatment with phentolamine, propranolol, guanethidine, atropine, hexamethonium or bilateral adrenalectomy. 6. The tetrapeptide of cholecystokinin (CCK-4) elicited a dose-dependent pressor response but did not induce bradycardia. The pressor response was unaffected by devazepide (50 nmol kg-1), L-365260 (15 mumol kg-1) or phentolamine (3 mumol kg-1). 7. In the pithed rat, sCCK-8 acted via CCKA receptors to increase arterial blood pressure indirectly, at least in part, through activation of alpha-adrenoceptors. The observed bradycardia was also mediated byCCKA receptors but possibly through a direct action on the heart.