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PubMed1976

Gastrin in the perinatal rat pancreas and gastric antrum: immunofluorescence localization of pancreatic gastrin cells and gastrin secretion in monolayer cell cultures.

The presence and development of immunoreactive gastrin (IRGa) in the fetal and neonatal pancreas and pyloric antrum of the rat were studied. IRGa appeared in both organs at least as early as the 16th day of fetal life. Antral IRGa increased rapidly and continuously in the neonatal period, while pancreatic IRGa concentration increased and was maintained at a relatively constant level from days 5 to 35. Monolayer cell cultures of the neonatal rat pancreas were used to evaluate the role of cyclic AMP mediated release of gastrin. The addition of N6,O2'-dibutyryl cyclic AMP (4 mM) or theophylline (4 mM) to the culture medium induced significant release of gastrin. The stimulation of adenylate cyclase with cholera toxin (10 ng/ml) also resulted in significant gastrin release. Long-term cultures (18-24 days) were shown to release gastrin continuously at a relatively constant rate. The cellular localization of pancreatic gastrin in 7-day-old cultures was performed by immunological techniques, using fluorescein-labeled antibodies to gastrin. The gastrin-containing cells were located at the periphery of most of the endocrine cell clusters. Immunofluorescence techniques for insulin and glucagon also showed that the alpha cells had a similar peripheral distribution, although they were more frequent in number. In contrast, insulin-containing cells were numerous and were present in all areas of the endocrine cell clusters. The studies support the following conclusions: a) Gastrin is present in the rat pancreas, even as early as late fetal life; b) Gastrin-producing cells are present and functionally competent in monolayer cell cultures of the neonatal rat pancreas for prolonged periods of time (24 days); c) Gastrin is released from these cells when intracellular levels of cyclic AMP are increased; d) By immunofluorescence methods, the gastrin-producing cells in pancreatic cell cultures are found to be located at the periphery of the endocrine cell clusters.

Animals↗

PubMed1985

Postprandial changes in serum concentrations of gastrin-17, gastrin-34, and total gastrin in patients with duodenal or gastric ulcers and in normal subjects.

The fasting concentrations of total gastrin and gastrin-17 (G-17) were similar in healthy volunteers and in asymptomatic patients with gastric ulcers or duodenal ulcers. However, the fasting serum concentration of gastrin-34 (G-34) was higher in patients with gastric ulcers than in normal subjects, in whom it was higher than in patients with duodenal ulcers. In response to food, the increases in G-17, G-34, and total gastrin were greater in ulcer patients than in healthy subjects. Cimetidine administration was associated with further increases in G-17, G-34, and total gastrin in normal subjects and gastric ulcer patients after meals. The ratio G-17/G-34 was similar in placebo-treated normal subjects and placebo-treated patients with gastric or duodenal ulcers. Cimetidine produced an increase in G-17/G-34 in placebo-treated normal subjects and placebo-treated patients with gastric or duodenal ulcers, but the ratio G-17/G-34 was greater in patients with gastric ulcers than in normal subjects. These results indicate that: differences in serum gastrin concentrations between patient groups, treatment regimens, and time of day are better detected by measuring G-17 and G-34 rather than total gastrin; there are differences in fasting and food-stimulated gastrin concentrations between normal subjects and patients with gastric or duodenal ulcers; the fasting concentration of G-34 is higher than G-17 in normal subjects and patients with gastric ulcers but not in patients with duodenal ulcers; food increases G-17 in all subjects but G-34 only in subjects with gastric ulcers; cimetidine increases the fasting concentration of total gastrin in normal subjects and patients with gastric ulcers and increases G-17 and G-34 in normal subjects; cimetidine increases the ratio G-17/G-34 in normal subjects and patients with gastric ulcers, but decreases G-17/G-34 in patients with duodenal ulcers. It is proposed: that measurements of total gastrin concentration should be replaced by measurements of G-17 and G-34 and that such measurements of G-17 and G-34 indicate differences in serum gastrin concentrations between normal subjects and those with peptic ulcers and between those with gastric versus duodenal ulcers. The role of altered gastrin metabolism in the pathogenesis of ulcers needs to be established.

Cimetidine↗

PubMed1976

Gastrin content and gastrin release. Studies on the antral content of gastrin and its release to serum during stimulation by food.

To examine the release of gastrin by food from antral mucosa eight patients were stimulated for 30 minutes by instillation of bovril during gastroscopy. Bovril caused a steady increase in serum concentrations of gastrin and an acute fall in the antral content of gastrin to 42+/-8.4 per cent after 10 minutes. After 10 minutes the antral content increased again towards the basal values. No change in gastrin components could be detected; component III (gastrin-17) constituted more than 95 per cent of the antral gastrins throughout the 30-minute period. The serum gastrin response to a steak meal was higher in 22 duodenal ulcer patients than in nine young normal subjects and it was higher postoperatively in eight patients studied before and after truncal vagotomy. In the duodenal ulcer patients whith the highest antral content of gastrin, the serum response to food was higher only during the early phase of the feeding response. It is concluded that the gastrin content of the antral mucosa represents an acute releasable pool of gastrin-17, which contributes only to the first 10-15 minutes of the feeding response. It does not reflect the total amount of gastrin released into the circulation during feeding.

Duodenal Ulcer↗

PubMed1995

Novel gastrin receptors mediate mitogenic effects of gastrin and processing intermediates of gastrin on Swiss 3T3 fibroblasts. Absence of detectable cholecystokinin (CCK)-A and CCK-B receptors.

We have reported previously mitogenic effects of gastrin on several immortalized and neoplastic cell lines, including Swiss 3T3 fibroblasts. Receptor subtypes, cholecystokinin (CCK)-A and CCK-B, for a closely related peptide, cholecystokinin, were recently cloned. These studies were undertaken to investigate if CCK-A- and CCK-B receptors were perhaps mediating the mitogenic effects of gastrin on Swiss 3T3 cells. Receptor antagonists that inhibit the biological effects and binding of peptides to the CCK-A (L-364,718 (L18)) and CCK-B (L-365,260 (L60)) receptors were ineffective toward inhibiting the binding and proliferative effects of gastrin on Swiss 3T3 cells. Radiolabeled L18 and L60 demonstrated no binding to the cells, indicating that CCK-A and CCK-B receptors may be absent on Swiss 3T3 cells. Radiolabeled CCK-8, gastrin, L18, and L60, on the other hand, demonstrated specific binding to a pancreatic cancer cell line (AR42J cells) (used as a positive control). In cross-linking studies the molecular mass of the major band of gastrin receptors (GR) on Swiss 3T3 cells was determined to be approximately 45 kDa. The mitogenic potency of 0.1-1.0 nM gastrin-like peptides on Swiss 3T3 cells was in the order of G1-17 > or = G1-17-Gly > G5-17 > or = G5-17-Gly > G2-17 > CCK-8-Gly > or = G1-17-Lys > or = CCK-8. The relative binding affinity of the peptides (based on the dose-dependent inhibition of binding of 125I-G1-17 to Swiss 3T3 cells) was similar to the relative mitogenic potency of the peptides as given above. Furthermore, G1-17-Gly was equally effective as G1-17 in displacing the binding of 125I-G1-17 to the 45-kDa GR from the Swiss 3T3 cells. Based on these studies it became evident that the novel gastrin preferring GR, expressed by Swiss 3T3 cells, binds and mediates the mitogenic effects of not only the mature (amidated) forms of gastrin-like peptides but also binds and mediates the mitogenic effects of glycine-extended forms of gastrin-like peptides. Possible mRNA expression of CCK-A and CCK-B receptor subtypes by gastrin-responsive rodent intestinal and fibroblast cell lines (Swiss 3T3, IEC-6, CA) was measured by the methods of Northern blot analysis and reverse transcriptase-polymerase chain reaction. mRNA from rat pancreas, AR42J cells, and rat antrum served as positive controls.(ABSTRACT TRUNCATED AT 400 WORDS)

3T3 Cells↗

PubMed1996

Gastrin and gastrin receptor antagonists bind to both N- and C-terminal halves of the 78 kDa gastrin-binding protein.

A 78 kDa gastrin-binding protein (GBP) has previously been identified as the target of the anti-proliferative effects of non-selective gastrin/cholecystokinin receptor antagonists on colorectal carcinoma cell lines. The GBP was related in sequence to a family of fatty acid oxidation enzymes possessing enoyl CoA hydratase and 3-hydroxyacyl CoA dehydrogenase activity. This study aims to define the binding site for gastrin and gastrin antagonists in greater detail. The N- and C-terminal halves of the porcine GBP were expressed independently as glutathione S-transferase fusion proteins in E. coli. Affinities of gastrin and gastrin antagonists for the fusion proteins were measured by competition for 125I-[Nle15]-gastrin binding in a covalent cross-linking assay. The N- and C-terminal fusion proteins bound gastrin with affinities of 9.9 +/- 6.1 and 71 +/- 48 microM, respectively (n = 3). These values were 40-fold and 300-fold lower than the affinity of the full-length GBP for gastrin (0.23 +/- 0.15 microM). In contrast, the affinities of the N- and C-terminal halves for the antagonists proglumide (22 +/- 13 and 10 +/- 4 mM, respectively) and benzotript (350 +/- 90 and 400 +/- 160 micro M, respectively) were similar to each other and to the affinities of proglumide and benzotript for the full-length GBP (5.1 +/- 3.6 mM and 200 +/- 120 microM, respectively). It is concluded that proglumide and benzotript bind independently to both the hydratase and dehydrogenase active sites of the GBP, while a single molecule of gastrin may bind simultaneously to both active sites. A model is proposed which is consistent with these data, and which will assist in the development of more potent and selective GBP antagonists.

Animals↗

PubMed2000

Glycine-extended gastrin synergizes with gastrin 17 to stimulate acid secretion in gastrin-deficient mice.

BACKGROUND & AIMS: Studies in gastrin-deficient mice have demonstrated critical roles for gastrin peptides in the regulation of gastric acid secretion, but the relative contributions of amidated (G-17) and glycine-extended (G17-Gly) gastrin remain unclear. We examined the effects of these 2 forms of gastrin on acid secretion in gastrin-deficient mice. METHODS: Sixty gastrin-deficient mice received infusions of saline, or 1, 6, or 14 days of amidated gastrin 17 (G-17), G17-Gly, or both G-17 and G17-Gly at 10 nmol. kg(-1). h(-1). Twenty-four gastrin-deficient mice were then infused for 14 days with 1, 2, or 5 nmol. kg(-1). h(-1) of G-17 or G-17 and G17-Gly. Acid secretion was determined 4 hours after pyloric ligation, and gastric tissue was processed for histology, immunohistochemistry, and electron microscopy. RESULTS: Infusion of G-17 increased acid secretion in a dose-dependent manner with a peak at 5 nmol. kg(-1). h(-1) and a subsequent decrease in acid secretion at higher doses. Infusion of G17-Gly alone had no effect on acid secretion, but coinfusion with G-17 resulted in significantly higher levels of acid secretion at all doses examined than infusion with G-17 alone. The potentiating effect of G17-Gly on G-17-induced acid secretion was associated with increased parietal cell activation but was independent of changes in parietal and enterochromaffin-like cell number, fundic proliferation rates, and H(+),K(+)-adenine triphosphatase expression. G17-Gly also prevented the formation of vacuolar canaliculi and lipofuscin bodies in the parietal cells induced by G-17. CONCLUSIONS: G17-Gly appears to synergize with G-17 to up-regulate acid secretion and prevent parietal cell degradation. These results suggest that G17-Gly plays an important role in parietal cell function.

Animals↗

PubMed1982

Vitamin-D-induced hypercalcaemia and its effect on serum gastrin, gastrin cells and antral gastrin in parathyroidectomized rats.

Nineteen rats were parathyroidectomized by electrocauterization, resulting in pronounced hypocalcaemia. Seven of these rats were then given vitamin D3 in a dose causing hypercalcaemia, while 7 received a dose which normalized serum calcium and 5 received no vitamin D. Ten further animals were sham-operated and were not given any extra vitamin D. The experimental period was 16 weeks. No significant differences in serum gastrin values were found between the different groups. Quantitative studies of the antral gastrin cells showed no difference in the number of gastrin cells per unit volume or unit segment between the different groups of vitamin-D-treated animals and sham-operated animals. However, the number of gastrin cells per unit segment was significantly higher in the hypocalcaemic animals than in the sham-operated animals, as a result of an increase in mucosal thickness. The amount of antral mucosal gastrin did not differ between the different groups. Thus the results of this study indicate that experimentally induced hypercalcaemia in parathyroidectomized rats does not influence the serum gastrin, the number of gastrin cells or antral gastrin.

Animals↗

PubMed1994

Urinary gastrin output and serum gastrin in patients with liver cirrhosis. Urinary gastrin output in cirrhosis.

The aim of the present study was to examine the diurnal urinary gastrin output in cirrhotics and to clarify whether in patients with hepatorenal syndrome urinary gastrin output is reduced. Thirty-two cirrhotics and 25 age- and sex-matched, controls were studied. Cirrhotics were divided into 3 groups: (I: without ascites and normal serum creatinine; II: ascites and normal creatinine; III: ascites and increased creatinine). Mean fasting serum gastrin concentration was lower in the control group than in Group I, II (p < 0.01) or III (p < 0.001). In this latter group mean serum gastrin concentration was significantly higher (p < 0.001) than in the other two groups of cirrhotics. The mean 24 h urinary gastrin output was lower (p < 0.001) in Group III patients than in the other groups of subjects studied. Also in the controls urinary gastrin output was lower (p < 0.01) than in Groups I and II. These findings suggest that: a) in cirrhotics with normal serum creatinine the average serum gastrin levels over the course of the day are indeed higher than in normals and b) In cirrhotics with hepatorenal syndrome, impaired urinary gastrin output appears to contribute significantly to their hypergastrinemia.

Adult↗

PubMed1982

Experimental hyperparathyroidism and its effect on serum gastrin, gastrin cells and antral gastrin in the rat.

Parathyroid glands from inbred rats were transplanted to rats of the same strain. The transplantation resulted in hyperparathyroidism and persistent hypercalcaemia. These hypercalcaemic animals were compared with the hypocalcaemic donors and with untreated controls. No significant differences in serum gastrin values were found between the different groups. In all three groups, one series of animals was killed 6 weeks after the transplantation (6w series) and another after 14 weeks (14w series). Quantitative studies of the antral gastrin cells showed an increase in the number of these cells per unit volume in the 6w series in the hyperparathyroid recipient animals. The number of gastrin cells per unit segment was also higher in the recipient animals than in the parathyroidectomized and untreated groups in both the 6w and 14w series. The amount of gastrin extracted from antral mucosa did not differ between the different groups. The findings show that an experimentally induced hyperparathyroidism in the rat gives a transient increase in the number of antral gastrin cells but no changes in the antral gastrin or serum gastrin levels.

Animals↗

PubMed1978

Gastrins in cat and dog: evidence for a biosynthetic relationship between the large molecular forms of gastrin and heptadecapeptide gastrin.

1. Extracts of antral, duodenal and jejunal mucosa contained the same concentrations and molecular forms of gastrin in cat and dog. In both species component III constituted 93%, component II 4% and components I and IV each 1% of the total immunoreactivity. 2. During electrical vagal stimulation or feeding in (a) anaesthetized cats with ligated kidney vessels and resected jejunum and ileum, (b) anaesthetized normal cats or (c) conscious normal cats, release of the large molecular forms of gastrin, components I and II, was not detectable. 3. Luminal perfusates of cat antrum contained only component III and occasionally less than 2% of component IV. 4. Intravenous injections into conscious cats of components I, II and III isolated from cat antrum revealed a significantly slower elimination of the large components (t1/2 approximately 4.2 and 4.0 min respectively) than of component III (t1/2 approximately 1.1 min). Thus the absence of components I and II in cat blood cannot be due to rapid degradation. 5. During feeding, components I and II constituted 20% of the total gastrin immunoreactivity in antral venous blood of dogs. This amount is sufficient to account for the predominance of large components in peripheral venous blood in dogs considering their slow metabolic clearance rates. 6. Luminal perfusates of dog antrum contained components I, II and III in proportions corresponding to those found in antrum. 7. The results indicate that components I and II are synthesized in the same proportions in gastrin cells of cat and dog. In the cat, components I and II are, however, never released from the cells. Since these components contain heptadecapeptide gastrin within their sequeaces, they probably represent biosynthetic precursors of the principal gastrin, the heptadecapeptide (component III). The predominance of component III in gastric juice suggests that the feline gastrin cell secretes only component III, which degrades to component IV in blood.

Animals↗

PubMed1983

Gastrin production following antrectomy. A study on the occurrence of gastrin-producing cells and the serum gastrin response to feeding.

Fifteen patients were studied 3 to 35 years after antrectomy, with a gastroduodenal (Billroth I (BI)) anastomosis in 8, and a gastrojejunal (Billroth II (BII)) anastomosis in 7. The investigations included gastric acid secretion, serum gastrin response to feeding and immunohistochemical search for gastrin-producing cells in gastric remnant mucosal biopsies. All of the patients had hypochlorhydria. The gastrin response to feeding was minimal. Apart from a significantly higher value of serum gastrin 3 hours post-prandial in BI operated as compared to BII operated patients, no greater differences were found in the gastrin production between the two groups of patients. No gastrin-producing cells could be identified in the gastric remnant, not even in areas of pseudopyloric metaplasia. It is concluded that the gastrin production following antrectomy is caused by extragastric G-cells; these cells are poorly stimulated by food, and do not respond to hypochlorhydria with hypergastrinaemia.

Aged↗

PubMed1984

The metabolism of gastrin-34, gastrin-17, and gastrin-14 in the isolated perfused pig liver.

The degradation of porcine and human gastrin-34, -17, and -14 in the isolated pig liver was investigated in 13 perfusion experiments. The concentrations of gastrins in the perfusate were measured by radioimmunoassay, and the molecular nature was determined by gel chromatography. Gastrin-34 was neither eliminated nor converted to other molecular forms, whereas gastrin-17 and -14 were both degraded in the liver, gastrin-17 being degraded to measurable smaller forms during the process. It is suggested that the liver plays an important part in the regulation of circulating gastrins.

Animals↗

PubMed1993

Eradication of Helicobacter pylori normalizes serum gastrin concentration and antral gastrin cell number in a patient with primary gastrin cell hyperplasia.

A 60-yr-old man with longstanding duodenal ulcer was found to have hyperchlorhydria, moderate fasting hypergastrinemia, and markedly exaggerated meal-stimulated gastrin release. Antral tissue specimens showed the proliferation of gastrin cells and increased gastrin content, and he was found to have Helicobacter pylori infection in the antral mucosa. His illness was diagnosed as primary gastrin cell hyperplasia with H. pylori infection. Eradication of H. pylori normalized not only gastrin hypersecretion but also gastrin cell hyperplasia. These results indicate that H. pylori infection could be one of the causes of this syndrome.

Bismuth↗

PubMed1976

Antral gastrin cells. A correlation between the number of gastrin cells and the total concentration of gastrin in serum and in antral mucosa. A pilot investigation.

Correlation between the gastrin cell number of delineated by immunohistological staining and the gastrin content in blood and antral mucosa has been studied in biopsies from the antral region of the human stomach. With a semiquantitative score system of the antral gastrin cells, we found correlation between the number of cells and the gastrin content in mucosa and serum and the grade of atrophic pyloric gastritis in 52 patients with different gastric diseases. It is concluded that further studies will be necessary before it is possible to estimate the total mass of gastrin cells and thereby compare different clinical groups.

Adult↗

PubMed1986

Comparison of the actions of bombesin, gastrin-releasing peptide-27, neuromedin B, and gastrin-releasing peptide-10 in causing release of gastrin and gastric inhibitory peptide in rats.

The objective of this study was to compare the gastrin- and gastric inhibitory peptide (GIP)-releasing actions of bombesin, gastrin-releasing peptide (GRP)-27, neuromedin B, and GRP-10 in rats. Both bombesin and GRP-27 are potent stimulants of gastrin and GIP release, whereas neuromedin B and GRP-10 are less effective, on a molar basis.

Animals↗

PubMed1982

Synthetic human gastrin I and gastrin-like pentapeptide in studies of intestinal absorption in man. Role of gastrin in human intestinal absorption.

The effects of synthetic human gastric I (SHG I) and gastrin-like pentapeptide (PG) on jejunal water, electrolyte, and glucose absorption were studied in 11 normal subjects. The i.v. administration of graded doses of SHG I increased plasma gastrin levels similar to those after food intake and in the Zollinger-Ellison syndrome. SHG I and PG caused no significant changes in the net movement of water and solute. The findings indicate that gastrin has no direct effect on intestinal absorption in normal man, and does not account for the mechanism of diarrhea in the Zollinger-Ellison syndrome.

Adult↗

PubMed1995

Gastrin sensitivity of primary human colorectal cancer: the effect of gastrin receptor antagonism.

The purpose of this study was to determine the effect of the gastrin receptor antagonist, CR2093, on basal and gastrin-stimulated growth of primary human colorectal adenocarcinomas and to relate this to gastrin receptor expression. Tumour cells, derived from surgical specimens by enzymatic disaggregation, were grown on matrices of type I collagen and irradiated fibroblasts. Gastrin receptor expression was measured by using a mouse monoclonal antibody directed against the gastrin receptor and an avidin-biotin immunocytochemical method. Increased growth in the presence of gastrin-17 (used at physiological concentrations and as assessed by [3H] thymidine uptake) was shown in 16/34 (47%) tumours. CR2093 significantly reversed this stimulated growth (P < 0.05, one way analysis of variance) in 9/16 (56.3%) of the tumours and inhibited the basal growth of 11/34 (32.4%). Basal growth inhibition was reversed by gastrin-17 in 82% (9/11) of tumours. Gastrin receptor expression was widespread, but was not related to the degree of growth response to gastrin, and there was no significant correlation between intensity of receptor expression and inhibition of basal growth by CR2093. In conclusion, both gastrin-stimulated and basal growth of primary human colorectal can be inhibited by gastrin receptor antagonism, but gastrin receptor expression does not predict the sensitivity of tumours to (i) the proliferative effects of gastrin or (ii) the inhibitory effects of a gastrin receptor antagonist on basal growth. Antigastrin agents may have clinical value in the treatment of gastrin-sensitive colorectal tumours, and gastrin receptor expression may be related to endogenous gastrin production by colorectal tumour cells.

Amino Acids↗

PubMedDate not supplied

Importance of sulfation of gastrin or cholecystokinin (CCK) on affinity for gastrin and CCK receptors.

We investigated the importance of sulfation of gastrin or cholecystokinin (CCK) on influencing their affinity for gastrin or CCK receptors by comparing the abilities of sulfated gastrin-17 (gastrin-17-II), desulfated gastrin-17 (gastrin-17-I), CCK-8 and desulfated CCK-8 [des(SO3)CCK-8] to interact with CCK or gastrin receptors on guinea pig pancreatic acini. For inhibiting binding of 125I-gastrin to gastrin receptors, gastrin-17-II (Kd 0.08 nM) greater than CCK-8 (Kd 0.4 nM) greater than gastrin-17-I (Kd 1.5 nM) greater than des(SO3)CCK-8 (Kd 28 nM). For inhibiting binding of 125I-Bolton Hunter-labeled CCK-8 to CCK receptors the relative potencies were: CCK-8 much greater than des(SO3)CCK-8 = gastrin-17-II greater than gastrin-17-I. Each peptide interacted with both high and low affinity CCK binding sites. The relative abilities of each peptide to interact with high affinity CCK receptors showed a close correlation with their abilities to cause half-maximal stimulation of enzyme secretion. These results demonstrate that, in contrast to older studies, sulfation of both CCK and gastrin increase their affinities for both gastrin and CCK receptors. Moreover, the gastrin receptor is relatively insensitive to the position of the sulfate moiety, whereas the CCK receptor is extremely sensitive to both the presence and exact position of the sulfate moiety.

Amylases↗