CHRONIC USE OF PROTON PUMP INHIBITORS AND THE QUANTITY OF G, D, AND ECL CELLS IN THE STOMACH.

BACKGROUND: Acid inhibition from chronic proton pump inhibitor use and a possible increase in gastrin can lead to changes in the regulation of hydrochloric acid production. However, it has not known whether such chronic use changes the presence of gastrin, delta, and enterochromaffin-like cells in the stomach or the relationship between gastrin and delta cells. AIM: To analyze the number of gastrin-producing gastrin cells, somatostatin-producing cells, and histamine-producing cells in patients who were chronic users of proton pump inhibitor, with or without related Helicobacter pylori infection. METHODS: Biopsies from 105 patients, including 81 chronic proton pump inhibitor users (experimental group) and 24 controls, were processed immunohistochemically and subjected to counting of gastrin, delta, and enterochromaffin-like cells in high-magnification microscopic fields and in 10 glands. RESULTS: Gastrin cell, delta cell, and enterochromaffin-like cells counts were similar across the groups and appeared to be unaffected by Helicobacter pylori infection. The ratio between gastrin cells and delta cells was higher in the chronic users of proton pump inhibitor group than in controls. CONCLUSION: Chronic users of proton pump inhibitor does not affect gastrin cell, delta cell, and enterochromaffin-like cell counts significantly, but may alter the ratio between gastrin cells and delta cells.

Chronic use of proton pump inhibitors and the quantity of g, d, and ecl cells in the stomach / Uso crônico de inibidores de bomba de prótons e a quantidade de células g, d e ecl no estômago

ABSTRACT Background: Acid inhibition from chronic proton pump inhibitor use and a possible increase in gastrin can lead to changes in the regulation of hydrochloric acid production. However, it has not known whether such chronic use changes the presence of gastrin, delta, and enterochromaffin-like cells in the stomach or the relationship between gastrin and delta cells. Aim: To analyze the number of gastrin-producing gastrin cells, somatostatin-producing cells, and histamine-producing cells in patients who were chronic users of proton pump inhibitor, with or without related Helicobacter pylori infection. Methods: Biopsies from 105 patients, including 81 chronic proton pump inhibitor users (experimental group) and 24 controls, were processed immunohistochemically and subjected to counting of gastrin, delta, and enterochromaffin-like cells in high-magnification microscopic fields and in 10 glands. Results: Gastrin cell, delta cell, and enterochromaffin-like cells counts were similar across the groups and appeared to be unaffected by Helicobacter pylori infection. The ratio between gastrin cells and delta cells was higher in the chronic users of proton pump inhibitor group than in controls. Conclusion: Chronic users of proton pump inhibitor does not affect gastrin cell, delta cell, and enterochromaffin-like cell counts significantly, but may alter the ratio between gastrin cells and delta cells.

RESUMO Racional: A inibição ácida pelo uso crônico de inibidores de bomba de prótons e o possível aumento da gastrina podem ser seguidos de alterações na regulação da produção do ácido clorídrico. Ainda não está definido se o uso crônico altera a quantidade de células G, D e ECL no estômago ou a razão células G/D. Objetivo: Avaliar o número de células G - produtoras de gastrina -, células D - produtoras de somatostatina - e células ECL - produtoras de histamina -, em pacientes com uso crônico de inibidores de bomba de prótons, com ou sem infecção pelo Helicobacter pylori. Método: Trata-se de estudo retrospectivo avaliando 105 pacientes, 81 usadores crônicos de inibidores de bomba de prótons e 24 controles, através de biópsias com contagem das células G, D e ECL por estudo imunoistoquímico, de forma quantitativa onde havia maior número de células positivas por campo microscópico de grande aumento e em 10 glândulas. Resultados: Não houve diferença estatística comparando-se o número de células G, D e ECL. A razão entre as células G e D foi maior nos pacientes usadores crônicos de inibidores de bomba de prótons. Conclusão: O uso crônico de inibidores de prótons parece não interferir na contagem das células G, D e ECL, porém, interfere na razão entre as células G e D.

Gastric carcinoids after long-term use of a proton pump inhibitor.

BACKGROUND: Proton pump inhibitors (PPIs) are potent inhibitors of gastric acid secretion and give hypergastrinemia secondary to gastric hypoacidity. PPI treatment therefore induces enterochromaffin-like (ECL) cell hyperplasia. Long-term hypergastrinemia in rodents and man also leads to ECL cell neoplasia. Whether long-term PPI treatment will induce ECL cell neoplasia in man has been disputed. AIM: To describe gastric carcinoids in two patients with a history of long-term PPI use. RESULTS: Two patients had been taking PPI for 12-13 years due to gastro-oesophageal reflux disease. At routine upper gastrointestinal endoscopy a solitary tumour was found in the oxyntic mucosa of both patients. Histology from the tumours showed in both cases a well-differentiated neuroendocrine tumour. Biopsies from flat oxyntic mucosa showed no signs of atrophic gastritis and a normal presence of parietal cells in both cases, but hyperplasia of ECL cells. The tumour in patient 1 was resected endoscopically. After cessation of PPI treatment the tumour regressed in patient 2 and the ECL cell hyperplasia regressed in both patients. In patient 2 serum gastrin and chromogranin A were elevated during PPI treatment, and normalised after cessation of treatment. In patient 1, unfortunately, we had serum only after treatment, and at that time both parameters were normal. CONCLUSION: These cases show that hypergastrinemia secondary to proton pump inhibitors treatment, like other causes of hypergastrinemia, may induce enterochromaffin-like cell carcinoids in man.

Immunotherapy for gastric premalignant lesions and cancer.

Chronic atrophic gastritis, a precancerous change for gastric cancer, shows a loss of appropriate glands, Helicobacter pylori infection and autoimmune gastritis being the two main etiologic factors. While H. pylori eradication is the mandatory treatment for the former, no etiologic treatment is available for the latter, in which a Th1-type response, modulated by Tregs and Th17 cells, is involved. H. pylori-related atrophic gastritis is a risk factor for gastric adenocarcinoma, while autoimmune atrophic gastritis is also linked to a substantial risk of gastric type I carcinoid, related to the chronic stimulus exerted by hypergastrinemia on enterochromaffin-like cells. Several studies have been published on gastric cancer treatment through an active specific immunotherapy, aimed at improving the immunoregulatory response and increasing the circulating tumor-specific T cells. No study on immunotherapy of carcinoids is available but, in our experience, the administration of an antigastrin 17 vaccine induced carcinoid regression in two out of three patients treated.

Toxicology and toxicokinetics of oral pantoprazole in neonatal and juvenile dogs.

BACKGROUND: Pantoprazole is an irreversible inhibitor of H(+) /K(+) adenosine triphosphatase proton pump. This study encompassed the period of postnatal stomach development to determine whether immature animals are uniquely sensitive to progression of PPI-induced enterochromaffin-like cell hyperplasia. METHODS: Pantoprazole was administered to beagle dogs at 3, 10, or 30 mg/kg/day (10/sex/group) from PND 1 for 13 weeks, subsets of animals had a 13-week recovery period. Clinical signs, body weights, growth, clinical chemistry, and neurobehavioral endpoints were assessed. Selected organs were weighed and histologically examined. RESULTS: There were no effects on body weights, growth, landmarks of physical and reproductive development, or sensory and neurobehavioral function. Cholesterol and triglyceride levels were increased at 10 and 30 mg/kg/day, but resolved during the recovery period. Stomach weight was increased at all doses, but after recovery the differences in stomach weights resolved for females although male stomach weights remained slightly increased. Pantoprazole-related microscopic findings in the stomach consisted of increased mucosal height, glandular necrosis, and glandular dilation at all doses; and ECL cell hyperplasia, parietal cell vacuolation, and atrophy of chief cells are noted at 10 and/or 30 mg/kg/day. There was a partial recovery of these microscopic changes indicated by a decreased incidence and/or severity of increased mucosal height, glandular necrosis, ECL cell hyperplasia, and chief cell atrophy, and complete resolution of other microscopic observations. CONCLUSION: Pantoprazole administered to beagles from PND 1 for 13 weeks resulted in findings similar to those in adult dogs and juvenile dogs, which showed no increase in severity or progression of ECL hyperplasia.

Five-year follow-up of patients treated for 1 year with octreotide long-acting release for enterochromaffin-like cell carcinoids.

BACKGROUND: Gastric carcinoids type 1 (GC1) are neuroendocrine tumors (NETs) arising from the enterochromaffin-like (ECL) cells in patients with chronic atrophic gastritis (CAG). The treatment of GC1 has been endoscopic polypectomy or surgical tumor excision and antrectomy. One year treatment with somatostatin analogs (SSAs) diminished tumor load and ECL cell density. The effect persisted 1 year after treatment was discontinued. However, the optimal SSA dose and treatment duration are unknown. OBJECTIVES: The aim of the present work was to study macroscopic and histopathological changes in the stomach and serum markers gastrin and chromogranin A (CgA) in GC1 patients 5 years after 1 year of octreotide long-acting release (LAR) treatment. MATERIAL AND METHODS: Five patients with GC1 were included 5 years after the initial year of octreotide LAR treatment. All patients underwent upper gastrointestinal endoscopy including tumor and mucosal biopsies from oxyntic mucosa, chest and abdominal computer tomography and octreotide scintigraphy. Fasting serum gastrin and CgA were also measured. RESULTS: At 5 years, one patient had a highly malignant gastric tumor, one patient had an increased number of GCs, regional and distant metastases and three patients had an increased number of GCs. Serum gastrin and CgA increased to pre-treatment levels after 1 year of follow-up and were unchanged at the 5-year follow-up. CONCLUSIONS: The disease had progressed in all five GCs patients treated with octreotide for 12 months at 5 years of follow-up. This suggests that, if started, octreotide treatment should not be discontinued in these patients.

Tachyphylaxis of the ECL-cell response to PACAP: receptor desensitization and/or depletion of secretory products.

BACKGROUND AND PURPOSE: Rat stomach ECL cells secrete histamine and pancreastatin in response to gastrin and pituitary adenylate cyclase-activating peptide-27 (PACAP). This study applies microdialysis to explore how ECL cells in situ respond to PACAP and gastrin. EXPERIMENTAL APPROACH: Both peptides were administered by microinfusion into the gastric submucosa. The microdialysate was analysed for histamine and pancreastatin (ECL-cell markers) and for somatostatin (D-cell marker). KEY RESULTS: Microinfusion of PACAP (0.01-0.3 nmol microl(-1)) raised microdialysate histamine and pancreastatin dose-dependently. The response was powerful but short-lived. The response to gastrin was sustained at all doses tested. It is unlikely that the transient nature of the histamine response to PACAP reflects inadequate histamine synthesis, since the pancreastatin response to PACAP was short-lived too, and both gastrin and PACAP activated ECL-cell histidine decarboxylase. Unlike gastrin, PACAP mobilized somatostatin. Co-infusion of somatostatin abolished the histamine-mobilizing effect of PACAP. However, pretreatment with the somatostatin receptor type-2 antagonist (PRL-2903) did not prolong the histamine response to PACAP, suggesting that mobilization of somatostatin does not explain the transient nature of the response. Repeated administration of 0.1 nmol microl(-1) of PACAP (1 h infusions, 1 h intervals) failed to induce a second histamine response. Pretreatment with a low dose of PACAP (0.03 nmol microl(-1)) abolished the response to a subsequent near-maximal PACAP challenge (0.3 nmol microl(-1)). CONCLUSION: The transient nature of the histamine response to PACAP reflects desensitization of the PACAP receptor and/or exhaustion of a specific storage compartment that responds to PACAP but not to gastrin.

A comparison of the effects of gastrin, somatostatin and dopamine receptor ligands on rat gastric enterochromaffin-like cell secretion and proliferation.

Gastrin regulates ECL cell histamine release and is a critical determinant of acid secretion. ECL cell secretion and proliferation is inhibited by gastrin antagonists and somatostatin but little is known about the role of dopamine agonists in this process. Since the ECL cell exhibits all three classes of receptor we evaluated and compared the effects of the gastrin receptor antagonist, (YF476), lanreotide (SST agonist) and novel dopaminergic agents (BIM53061 and BIM27A760) on ECL cell histamine secretion and proliferation. Highly enriched (>98%) ECL cell preparations prepared from rat gastric mucosa using a FACS approach were studied. Real-time PCR confirmed presence of the CCK2, SS2 and SS5 and D1 receptors on ECL cells. YF476 inhibited histamine secretion and proliferation with IC(50)s of 1.25 nM and 1.3 x 10(-11) M respectively, values 10-1000x more potent than L365,260. Lanreotide inhibited secretion and proliferation (2.2 nM, 1.9 x 10(-10) M) and increased YF476-inhibited proliferation a further 5-fold. The dopamine agonist, BIM53061, inhibited gastrin-mediated ECL cell secretion and proliferation (17 nM, 6 x 10(-10) M) as did the novel dopamine/somatostatin chimera BIM23A760 (22 nM, 4.9 x 10(-10) M). Our studies demonstrate that the gastrin receptor antagonist, YF476, is the most potent inhibitor of ECL cell histamine secretion and proliferation. Lanreotide, a dopamine agonist and a dopamine/somatostatin chimera inhibited ECL cell function but were 10-1000x less potent than YF476. Agents that selectively target the CCK2 receptor may provide alternative therapeutic strategies for gastrin-mediated gastrointestinal cell secretion and proliferation such as evident in the hypergastrinemic gastric carcinoids associated with low acid states.

Increased gastric expression of MMP-7 in hypergastrinemia and significance for epithelial-mesenchymal signaling.

Chronic hypergastrinemia is associated with enterochromaffin-like (ECL) cell hyperplasia, which may progress to gastric carcinoid tumors. The latter consists of epithelial cells and stroma, and both compartments usually regress after normalization of hypergastrinemia. We previously showed that matrix metalloproteinase (MMP)-7 in gastric epithelial cells was upregulated by Helicobacter pylori and described MMP-7-dependent reciprocal signaling between the epithelium and a key stromal cell type, the myofibroblast. Here, we describe the regulation of gastric MMP-7 by gastrin and the potential significance for recruiting and maintaining myofibroblast populations. Biopsies of the gastric corpus and ECL cell carcinoid tumors were obtained from hypergastrinemic patients. Western blot analysis, ELISA, immunohistochemistry, and promoter-luciferase (luc) reporter assays were used to study MMP-7 expression. Gastric myofibroblasts were identified by alpha-smooth muscle actin (alpha-SMA) expression, and the effects of MMP-7 on myofibroblast proliferation were investigated. In hypergastrinemic patients, there was an increased abundance of MMP-7 and alpha-SMA in gastric corpus biopsies and ECL cell carcinoid tumors. In the latter, MMP-7 was localized to ECL cells but not stromal cells, which were nevertheless well represented. Gastrin stimulated MMP-7-luc expression in both AGS-G(R) and primary human gastric epithelial cells. Conditioned medium from gastrin-treated human gastric glands stimulated myofibroblast proliferation, which was inhibited by neutralizing antibodies to MMP-7. MMP-7 increased the proliferation of myofibroblasts via the MAPK and phosphatidylinositol 3-kinase (PI3K) pathways. In conclusion, stimulation of gastric MMP-7 by elevated plasma gastrin may activate epithelial-mesenchymal signaling pathways regulating myofibroblast function via MAPK and PI3K pathways and contribute to stromal deposition in ECL cell carcinoid tumors.

Direct effects of nitric oxide on histamine release from rat enterochromaffin-like cells.

The direct effects of nitric oxide (NO) on enterochromaffin-like (ECL) cells have not yet been demonstrated. In this study we investigated the direct effects of NO donors on rat ECL cells. The NO donor, NOR3 (10 and 100 microM), decreased gastrin-induced histamine release. 100 microM NOR3 increased cGMP levels and reduced gastrin-induced calcium influx. ODQ, an inhibitor of guanylate cyclase, completely blocked NOR3-induced inhibition of histamine release. These results suggest that NO inhibits gastric acid secretion via suppression of gastrin-induced histamine release through a pathway in which NO activates guanylate cyclase, in addition to increasing cGMP levels and reducing gastrin-induced calcium influx. The use of NO as a new type of gastric acid inhibitor that decreases histamine levels in the stomach would be beneficial as increased histamine levels resulting from use of a histamine H2 receptor antagonist or proton pump inhibitor have various effects on tumors and immunological functions.

Consequences of long-term proton pump blockade: insights from studies of patients with gastrinomas.

Proton pump inhibitors are being increasingly used and for longer periods of time, especially in patients with gastroesophageal reflux disease. Each of these trends has led to numerous studies and reviews of the potential risk-benefit ratio of the long-term use of proton pump inhibitors. Both long-term effects of hypergastrinaemia due to the profound acid suppression caused by proton pump inhibitors as well as the effects of hypo-/achlorhydria per se have been raised and studied. Potential areas of concern that have been raised in the long-term use of proton pump inhibitors, which could alter this risk-benefit ratio include: gastric carcinoid formation; the development of rebound acid hypersecretion when proton pump inhibitor treatment is stopped; the development of tolerance; increased oxyntic gastritis in H. pylori patients and the possibility of increasing the risk of gastric cancer; the possible stimulation of growth of non-gastric tumours due to hypergastrinaemia; and the possible effect of the hypo/achlorhydria on nutrient absorption, particularly iron and vitamin B12. Because few patients with idiopathic gastro-oesophageal reflux disease/peptic ulcer disease have been treated long-term (i.e., >10 years), there is little known to address the above areas of potential concern. Most patients with gastrinomas with Zollinger-Ellison syndrome have life-long hypergastrinaemia, require continuous proton pump inhibitors treatment and a number of studies report results of >5-10 years of tratment and follow-up. Therefore, an analysis of Zollinger-Ellison syndrome patients can provide important insights into some of the safety concerns raised above. In this paper, results from studies of Zollinger-Ellison syndrome patients and other recent studies dealing with the safety concerns above, are briefly reviewed.

Treatment of ECL cell carcinoids with octreotide LAR.

BACKGROUND: Patients with chronic atrophic gastritis (CAG) and hypergastrinaemia are at risk of developing hyperplasia of the enterochromaffin-like (ECL) cells and ECL-cell-derived tumours. The effect of the somatostatin analogue octreotide on ECL cell carcinoids is examined. METHODS: Five patients with hypergastrinaemia and ECL cell carcinoids were enrolled in a 1-year study of octreotide LAR (long-acting release) 20 mg given at monthly intervals. Biopsies from tumours and from flat oxyntic mucosa were done at the start and 3, 6 and 12 months thereafter. Sections were stained with haematoxylin-erythrosin, immunostained with chromogranin A (CgA) and doublestained with CgA and Ki-67. Serum gastrin and CgA were measured. RESULTS: The number of visible tumours was reduced by more than 50 %. Sections from both tumours and flat mucosa showed a reduced number of CgA immunoreactive cells. Mean serum gastrin decreased from 421 to 186 pM (normal <40 pM); P > 0.05, and serum CgA from 73 to 25 ng/ml (normal < 30 ng/ml); P < 0.001. CONCLUSIONS: During treatment the patients were still markedly hypergastrinaemic, whereas the serum CgA showed normalization. A diminished tumour load and reduced ECL cell density were found, indicating an antiproliferative effect of octreotide directly on the ECL cells.

ECL-cell derived gastric cancer in male cotton rats dosed with the H2-blocker loxtidine.

Spontaneously hypergastrinemic cotton rats (Sigmodon hispidus) develop tumors that have the phenotype of an adenocarcinoma but most likely originate from the enterochromaffin-like (ECL) cells. Among inbred animals approximately 50% of the females, but <1% of males develop spontaneous gastric carcinomas. Gastrin is the principle carcinogen in this model, as >4 months of hypergastrinemia results in carcinoma, but a gastrin receptor antagonist prevents carcinomas. Carcinomas can also be induced by partial corpectomy. In the present study, the insurmountable H2-receptor antagonist loxtidine (200 mg/kg/day) was given to male cotton rats for 6 months. The loxtidine-dosed animals developed hypergastrinemia, whereas control animals remained normogastrinemic. At termination, 4 of 5 cotton rats had cancer located to the oxyntic mucosa, whereas 1 animal had dysplasia. The gastric mucosa of all of the control animals was normal. In the dysplastic mucosa of loxtidine-dosed animals there was a marked increase in chromogranin A-positive cells, where numerous groups of cells also stained positive with the Sevier-Munger technique. In areas of high proliferation and cancer there were also histidine decarboxylase, chromogranin A, and Sevier-Munger-positive cells, altogether indicating an ECL cell origin of the tumors. This represents an interesting animal model where ECL cell-derived gastric cancer can be induced by pharmacological acid inhibition in 6 months.

Direct effects of proton pump inhibitors on histamine release from rat enterochromaffin-like cells.

Enterochromaffin-like (ECL) cells play a central role in the regulation of gastric acid secretion. Previous studies have shown that proton pump inhibitors accelerate histamine release from ECL cells through the effects of gastrin. However, direct effects of proton pump inhibitors on ECL cells have not been demonstrated to date because the indirect effects of gastrin are difficult to suppress. We investigated the direct effects of proton pump inhibitors medication on ECL cells using an elutriation system. ECL cells were stimulated with gastrin or rabeprazole, and histamine release from ECL cells was measured. Rabeprazole increased histamine release through a pathway that differed from that of gastrin. The histamine increase was likely due to an acceleration of vesicular monoamine transporter 2 (VMAT2). Rabeprazole increased histamine release from ECL cells directly via VMAT2, but did not affect the total amount of histamine in the cells. The results suggest that patients receiving proton pump inhibitors for extended periods must be monitored extensively because gastric tumor proliferation may be promoted by increased histamine release from ECL cells.

Tumor necrosis factor-alpha effects on rat gastric enterochromaffin-like cells.

Gastric enterochromaffin-like (ECL) cells are histamine-producing cells in the gastric epithelium which are responsible for the peripheral regulation of acid secretion. The gastric mucosa is frequently infected with Helicobacter pylori, leading to increased levels of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). The aim of our current study was to identify the effect of TNF-alpha on programmed cell death. ECL cells were isolated from the rat corpus mucosa to a purity >90%. TNF receptor and adapter protein presence were determined using RT-PCR, Western blot and immunocytochemistry. Apoptosis was measured by Tdt-mediated dUTP nick end labeling reaction and by DNA fragmentation based ELISA. Isolated ECL cells were found to express the TNF receptor p55 and IFN-gamma receptor, but not the TNF receptor p75 or CD95. TNF-alpha (25 ng/ml) increased apoptosis in ECL cells approximately 4-fold, IFN-gamma had no effect. Western blot analysis revealed that TNF-alpha caused degradation of I kappa B alpha within 10 min. EMSA demonstrated that TNF-alpha led to increased DNA-binding activity of NF kappa B and that proteasome inhibitors counteracted NF kappa B activation. Proteasome inhibitors, specific antisense oligodeoxynucleotides against the p65 subunit of the NF kappa B complex and the NO synthase inhibitor N(G)-monomethyl-L-arginine completely prevented TNF-alpha-induced apoptosis. Our data suggest that TNF-alpha induces apoptosis of isolated gastric ECL cells via activation of NF kappa B and the generation of NO.

Long-term safety of proton pump inhibitors: risks of gastric neoplasia and infections.

After Helicobacter pylori eradication was introduced and largely eliminated the need for maintenance therapy for peptic ulcer disease, gastroesophageal reflux disease (GERD) became the main indication for prolonged gastric acid inhibition. The drug effect on GERD depends on the degree of acid inhibition, thus the efficacious proton pump inhibitors are preferred. The proton pump inhibitors have few immediate side effects, the main concern being the profound hypoacidity and hypergastrinaemia they induce. In short-term, hypergastrinaemia causes rebound hyperacidity, possibly worsening GERD and reducing the efficacy of histamine H(2) blockers. In the long-term, hypergastrinaemia causes enterochromaffin-like cell hyperplasia and carcinoids. Since enterochromaffin-like cells may be important in gastric carcinogenesis, iatrogenic hypergastrinaemia may predispose to carcinoma. Gastric hypoacidity also increases gut bacterial infections, and the barrier function of acid against viral and prion infections requires further assessment.

Control of secretion from rat stomach ECL cells in situ and in primary culture.

The acid-producing part of the stomach is rich in peptide-hormone-producing endocrine/paracrine cells of different types. In birds and all mammals studied, ECL cells constitute the quantitatively predominant endocrine cell population in this location. They produce histamine and an as yet unidentified peptide hormone. The paracrine action of the ECL cells is to provide histamine to mediate the stimulating effect of gastrin on the acid-secreting parietal cells: the gastrin-ECL cell-parietal cell axis. Secretion of histamine from the ECL cells was studied in intact conscious rats subjected to gastric submucosal microdialysis and using isolated cells in primary culture. The microdialysis experiments revealed that ECL-cell histamine can be mobilized by the local infusion of gastrin, pituitary adenylate cyclase-activating peptide (PACAP), vasoactive intestinal peptide (VIP), peptide YY (PYY), met-enkephalin, endothelin and noradrenaline/adrenaline. While gastrin and met-enkephalin induced a sustained elevation of the submucosal histamine concentration, endothelin, PYY, PACAP, VIP, and noradrenaline/adrenaline induced a transient elevation. Somatostatin, galanin and the prostanoid, misoprostol, inhibited gastrin-stimulated histamine mobilization. Studies of isolated ECL cells (80-90% purity) showed gastrin, PACAP and VIP to stimulate histamine secretion and somatostatin, galanin and misoprostol to inhibit gastrin-stimulated secretion. At present, it seems unlikely that metenkephalin, endothelin, adrenaline and PYY act directly on the ECL cells in situ since the effects could not be reproduced with isolated ECL cells. Clearly, the ECL cells operate under the multifactorial control of circulating hormones, local hormones, catecholamines, neuropeptides and inflammatory mediators.

Long-term omeprazole treatment suppresses body weight gain and bone mineralization in young male rats.

BACKGROUND: The stomach is rich in endocrine cells, including those producing ghrelin, which is thought to play a role in the control of body growth. Omeprazole treatment is associated with hypergastrinaemia, resulting in growth of the oxyntic mucosa in general and the enterochromaffin-like (ECL) cells in particular. In the present study, we examined the effects of long-term omeprazole treatment on young male rats with respect to body growth and stomach. METHODS: Male rats (24 days old) were treated with omeprazole (400 micromol/kg/day) or vehicle for 77 days. The body weight was recorded twice per week. At sacrifice, dual-energy X-ray absorptiometry (DXA) was used to assess total bone area, bone mineral content (BMC), bone mineral density (BMD) and body composition (fat and lean body mass). The lengths of the spine and the femur were recorded. The plasma concentrations of gastrin and histamine were determined by radioimmunoassays. The endocrine cells of the stomach were examined by immunocytochemistry. RESULTS: The body weight gain was suppressed by omeprazole treatment. The bone area, BMC and BMD were reduced, while the lengths of the spine and the femur and the body composition were unchanged. Omeprazole-induced hypergastrinaemia was associated with enlargement of the oxyntic area and with hyperplasia of ECL cells but not of A-like cells and D cells. In contrast, the enterchromaffin (EC) cell density in the antrum was reduced. CONCLUSIONS: Omeprazole treatment of young male rats reduces body weight and bone mass gain. The densities of ECL cells in the oxyntic mucosa was increased and of the EC cells in the antral mucosa reduced.