Effect of gastrin receptor blockade on endocrine cells in rats during achlorhydria.

Hyperplasia of the oxyntic enterochromaffinlike cells in response to long-lasting blockade of acid secretion is closely related to hypergastrinemia. In the present study, the effect of a specific gastrin receptor antagonist on proton pump inhibitor-induced changes on serum gastrin levels, mucosal height, as well as gastrin- and enterochromaffin-like cells was investigated in rats. The proton pump inhibitor BY 308 or the vehicle methylcellulose [Methocel (controls)] was administered for 2 weeks in the presence and absence of the gastrin receptor antagonist PD 136450 (CAM 1189). BY 308 significantly increased serum gastrin levels, gastrin cell density, and antral gastrin concentration. Concomitant application of PD 136450 did not alter this response. In the oxyntic stomach, mucosal height, enterochromaffinlike cell density, labeling index of enterochromaffinlike cells, and histamine concentration were elevated after treatment with BY 308. These increases were almost completely abolished by PD 136450. Even in normogastrinemic control rats, PD 136450 significantly decreased mucosal height of the oxyntic part of the stomach and the labeling index of enterochromaffinlike cells. The results show that (a) trophic effects of drug-induced achlorhydria are mediated by gastrin; (b) even in control rats (normogastrinemic), gastrin is a trophic factor for the oxyntic mucosa; and (c) antral gastrin cell hyperplasia in states of chronic achlorhydria is not mediated by gastrin itself.     

Antral gastrin concentration in upper-gastrointestinal disease

Antral gastrin concentration (AGC) was measured in prepyloric mucosa specimens obtained by forceps biopsy during endoscopic examination of 174 clinic and hospital patients. AGC in 32 patients who had normal endoscopic findings, the control group, varied widely from 2 to 38.6 ng gastrin/mg tissue. The mean AGC of the control patients was 14.2±1.4 (mean ±1se) ng gastrin/mg tissue. AGC was similar to control values in 18 patients with duodenal ulcer, 14.7±2.1; 12 patients with a pyloric channel or antral ulcer, 16.4±3.5; and 48 patients with miscellaneous diagnoses, 14.3±1.5 AGC was significantly less than control values in 13 patients with a ulcer in the body or fundus of the stomach, 5.9±1.5, and 4 patients with the Zollinger-Ellison syndrome, 4.9±2.4. AGC was significantly greater than in control values in 16 patients with gastritis, 25.8±4.3; 22 patients with esophagitis, 23.2±3.0; and 9 patients with gastric atrophy and fasting serum hypergastrinemia 44.6±12.3. In a group of 77 of these patients with heterogeneous diagnoses, meal-stimulated 3-hr integrated gastrin output was directly related to AGC (r=0.47,P<0.001). In a group of 106 patients AGC was inversely related to histalogstimulated maximum acid output. The correlation was very weak (r=–0.20) but significant (P<0.05).Supported in part by Clinical Research Center grant RR-00073, U.S. Publich Health Service, Washington, D.C.This work was presented in part at the midwestern meeting of The American Federation of Clinical Research, October 31, 1974, and at the Annual Meeting of the American Federation for Clinical Research, Atlantic City, N.J., May 3, 1975.     

Antral gastrin cell proliferation after vagotomy in rats.

The total number of antral gastrin cells, the antral surface area and the serum gastrin concentration were determined in two groups of rats. The animals had been submitted at random either to vagotomy and pyloroplasty or to pyloroplasty alone 3 weeks before. The indirect immunoperoxidase reaction and a direct quantitative histological method were used to count the gastrin cells. Radioimmunoassay was used to estimate the serum gastrin concentration. The total number of gastrin cells in the stomach was 52% (p less than 0.01) more elevated in the vagotomized animals. Both antral mucosal surface and calculated concentration of gastrin cells per square millimeter of mucosa were significantly higher (0.01 less than p less than 0.05) in this group of animals. The serum gastrin values were significantly (p less than 0.01) more elevated after vagotomy. These observations indicate that vagotomy may induce an antral gastrin cell hyperplasia which could explain in part the hypergastrinemia observed after this surgical procedure.     

Antral gastrin concentration in gastric ulcer disease

Antral gastrin concentration (AGC) was measured in forceps biopsy specimens of prepyloric mucosa obtained at endoscopy in 65 patients with various kinds of gastric ulcer and in 31 nonulcer control patients. AGC in 32 patients with a lesser curvature gastric ulcer, 10.0±2.0 (mean ±1se) ng gastrin/mg tissue was significantly less (P<0.01) than AGC in 31 nonulcer control patients, 14.4±1.4. AGC was similar to the control values in 23 patients with a pyloric channel ulcer, 15.2±1.7; 5 patients with a greater curvature ulcer, 15.0±4.8; and 3 patients with both duodenal and gastric ulcers, 15.8±0.7. AGC was significantly greater (P<0.01) than the control values in 3 patients with a vagotomy and pyloroplasty and a gastric ulcer, 29.8±5.0. In contrast with most lesser curvature gastric ulcer patients who had low AGC, 3 gastric ulcer patients had antral gastrin values which were about three times the mean AGC of the controls. Two of these patients had fasting serum gastrin values which were more than twice the mean control fasting serum gastrin. Meal-stimulated integrated gastrin responses in these 3 patients ranged from three to nine times the mean control response. These findings suggest that a high AGC may account for a few instances of increased serum gastrin concentrations in gastric ulcer patients.This study was supported in part by Clinical Research Center Grant RR-00093 from the United States Public Health Service, Washington, D.C.     

Antral gastrin cell hyperfunction in children. A functional and immunocytochemical report.

Antral gastrin cell hyperfunction is a rare condition, often associated with severe duodenal ulcer disease. In children, clinical and functional characteristics of this syndrome are poorly known. Two cases are described here: one child had melena and the other had moderate abdominal pain, both without peptic ulceration. Basal and postprandial increase of gastrin levels showed a response over the upper normal range, indicating gastrin cell hyperfunction. Acid hypersecretion, both basal and after pentagastrin stimulation, was also found in the two children, confirming the biological effect of their sustained hypergastrinemia. Gastrin cell counts were within the normal range, while the number of somatostatin D cells was significantly reduced. This report stresses the importance of diagnosing antral gastrin cell hyperfunction in children because this unrecognized condition may manifest with serious complications (bleeding) or nonspecific abdominal symptoms.     

Molecular forms of gastrin in the circulation of patients with achlorhydria.

BACKGROUND/AIM: To study circulating gastrin profile, both fasting and postprandially, in patients with achlorhydria due to auto-immune atrophic gastritis, comparing these with normal healthy controls. METHODS: Circulating gastrins were measured using three region-specific radio-immunoassays: amidated gastrins (R98), N-terminal G34 (R526) and N-terminal G17 (GP168). Samples were analysed further using gel chromatography. RESULTS: Fasting gastrin concentrations were elevated in achlorhydria as measured using all three antisera: median 714 pmol/l (range 107-5176) in achlorhydria versus 12 pmol/l (2-33) in controls (R98), 343 pmol/l (45-4316) versus 10 pmol/l (5-41) (R526), and 720 pmol/l (14-6000) versus 2 pmol/l (1-10) (GP168). In patients, 47% of gastrin was amidated (95% in controls) and 30% was processed N-terminally only to G71 (4% in controls). Gastrin rose significantly postprandially: 1643 pmol/l (269-7142) in patients versus 24 pmol/l (5-142) in controls (R98), 432 pmol/l (113-4756) versus 15 pmol/l (7-45) (R526) and 2189 pmol/l (304-7150) versus 15 pmol/l (7-45) (GP168). Only 25% was amidated in the patient group (93.5% in controls) and 21% remained as component I (4% in controls). CONCLUSIONS: This abnormal gastrin profile associated with hypergastrinaemia secondary to achlorhydria is consistent with saturation of the enzymes involved in the processing of the pro-hormone, in particular amidation of the C-terminus.     

Antral release of gastrin and somatostatin in duodenal ulcer and control subjects.

Organ culture was used to compare gastrin and somatostatin release from cultured antral mucosa obtained from duodenal ulcer and non-ulcer (control) subjects. In response to dibutyryl cyclic AMP (DBCAMP) cultured antral mucosal explants from patients with a history of duodenal ulcer released a greater proportion of antral gastrin into the medium than did antral mucosal explants from non-ulcer subjects. Somatostatin release from antral mucosa from duodenal ulcer patients was substantially less than somatostatin released by antral explants from non-ulcer subjects. In the non-ulcer subjects there was a direct positive correlation between the amounts of antral somatostatin and gastrin released into the culture medium (r = 0.64, less than p 0.01). In the duodenal ulcer patients, however, there was no correlation between gastrin release and somatostatin release from antral mucosa ( r = 0.09; p greater than 0.2). Results of these studies identify enhanced gastrin release in response to stimulation and decreased release of somatostatin from antral mucosa of duodenal ulcer patients. These alterations in paracrine relationships of antral somatostatin and gastrin in duodenal ulcer subjects may contribute, at least in part, to the pathogenesis of duodenal ulcer disease.     

Biologic and immunologic gastrin activity in serum of patients with gastrinoma. Bioassay of gastrin activity in serum.

The biologic gastrin activity in serum from 14 patients with the Zollinger-Ellison syndrome was assessed by the stimulation of histamine release and acid secretion from the isolated vascularly perfused rat stomach and compared with the immunologic activity as determined by radioimmunoassay using an antibody directed towards the active site of the gastrin molecule. Biologic gastrin activity assessed by the stimulation of histamine release was more closely correlated to immunologic gastrin activity than biologic activity assessed by the stimulation of gastrin acid secretion. This study does not contradict the concept that gastrin stimulates acid secretion at least partly by releasing histamine and also shows that the immunologic gastrin activity determined with the help of an antibody directed towards the active site reflects biologic activity.     

Antral gastrin and somatostatin cell populations in rats after chronic administration of histamine

Variations in the size of the antral G and D cell populations under the effect of chronic stimulation of acid secretion with histamine were investigated in male Wistar rats. Osmotic minipumps delivering either 0.9% saline or histamine dihydrochloride (4.5 mg/kg/h) were implanted subcutaneously in gastric-fistula rats. Gastric secretion was collected prior to the implantation of the pump, after 7 days and after 14 days. Total antral G and D cell numbers and the G/D ratio were estimated at the end of the experiment. Administration of histamine during 14 days did not induce significant changes in the number of either G or D cells in the antrum despite a 3-fold increase in acid secretion.     

Gastric morphology and serum gastrin levels in pernicious anaemia.

Mucosal biopsies from multiple sites in the stomachs of 21 patients with pernicious anaemia have been examined. The histological changes almost always involved the entire gastric mucosa, including that of the pyloric antrum. Metaplastic changes were almost universal and consisted of intestinal metaplasia in the body and antrum and pyloric metaplasia in the body. The severity of the pyloric metaplasia was such as to make the distinction between body and antrum on biopsy impossible. No relationship was found between serum gastrin activity and the histological appearances of the gastric antrum or body.     

Mutual relationships between chromogranins A and B and gastrin in individual gastrin cells.

The chromogranins A and B (CgA and CgB, respectively), originally detected in the adrenal medulla, are present in various endocrine organs. Remarkably, their immunoreactivities vary among different endocrine cell types and also within a given endocrine cell population. With densitometric techniques at the cellular level, individual gastrin cells (n = 318) from guinea pig antral mucosa were studied to measure their content of immunoreactive CgA, CgB, and gastrin. The composition of these secretory proteins in individual gastrin cells varied considerably but with predictable components. Statistical evaluation of the data showed that immunoreactivities for gastrin and CgA correlated negatively in these cells; CgA and CgB immunoreactivities also correlated inversely. On the other hand, immunoreactivities for gastrin and CgB exhibited a high positive correlation. The mutual relationships between gastrin, CgA, and CgB suggest that under physiological conditions biosynthetic pathways of these secretory constituents are linked to each other in individual gastrin cells.     

Fasting serum gastrin and basal gastric acid secretion.

The gastric secretion of acid was examined 30 minutes basally (BAO) and in response to stepwise increasing doses of pentagastrin in subjects with (n = 51) and without (n = 40) peptic ulcer disease. None of them showed basal anacidity. Before insertion of the gastric tube, blood was taken for radioimmunological determination of the serum gastrin concentration (SG). A significant positive correlation was found between SG and BAO in the subjects without ulcer. This was mainly due to a close correlation in 20 healthy young volunteers. When BAO and SG was expressed as proportions of calculated maximal acid response (Vmax) and half maximal dose of pentagastrin (Km), respectively, the positive correlation between SG and BAO was improved and reached significance also in the individuals with peptic ulcer disease. The findings suggest that the serum concentration of gastrin plays a role in the basal gastric secretion.     

Alterations in serum and antral gastrin levels in genetically diabetic mice.

Many gastrointestinal structural and functional properties are known to be altered in diabetes. In this study, we investigated whether serum and tissue gastrin levels are abnormally altered in a strain of genetically diabetic mice (C57BL/KSJ). Both serum and antral gastrin concentration were found to be significantly increased 3.4- and 2-fold above normal values in diabetic mice fed ad libitum. The increase in tissue gastrin concentration is most probably due to an increase in both cellular gastrin content and G-cell number, since the latter property is increased 130% in diabetic animals. Pair feeding studies demonstrated that diabetes associated hyperphagia is not a major factor in inducing these endocrine changes, since antral and serum gastrin are still significantly elevated above normal in diabetic animals fed a restricted diet. G-cell number, however, is not significantly increased above normal values in pair fed diabetic mice. The peak serum gastrin concentration after a meal and the duration of postprandial hypergastrinemia are also significantly increased above normal in diabetic animals. Gel filtration chromatography studies indicate that the antral nucosae of normal and diabetic mice have identical molecular forms of the hormone. It is therefore concluded that antral and serum gastrin concentration are increased in genetically diabetic mice due to both dietary alterations and other, as yet undefined, factors specific for the disease, and that the resultant hypergastrinemia may contribute to some of the gastrointestinal alterations seen in diabetes.