Gastrin Release Research Articles

The stomach and/or upper duodenum contain sites of action that control meal size and intermeal interval length by exogenous rat gastrin releasing peptide

The site(s) of action that control the reduction of food intake in response to the amphibian skin peptide bombesin (Bn) has been determined to be the area supplied by the celiac artery (CA), i.e., the stomach and the upper duodenum. Here, we investigated the gastrointestinal site(s) of action which controls meal size (MS) (normal rat chow) and intermeal interval length (IMI) by the mammalian homologues of Bn gastrin releasing peptides (GRP-10, GRP-27 and GRP-29, 0.01, 0.05, 0.1, 0.2 and 0.5nmol/kg) infused in the CA, the cranial mesenteric artery (CMA, supplying the small and large intestine), the femoral artery (FA, control) and the portal vein (PV, draining the gastrointestinal tract, control) in freely fed rats immediately prior to the onset of the dark cycle. We found that (1) GRP-29 (0.05, 0.1, 0.2 and 0.5nmol/kg) and GRP-27 (0.2 and 0.5nmol/kg) in the CA and GRP-29 (0.5nmol/kg) in the CMA reduced the MS relative to saline, (2) GRP-29 (0.1, 0.2 and 0.5nmol/kg) and GRP-27 (0.2 and 0.5nmol/kg) in the CA prolonged the IMI, (3) GRP-29 (0.1, 0.2 and 0.5nmol/kg) in the CA and GRP-29 (0.5nmol/kg) in the CMA increased the satiety ratio (SR, IMI/MS – the amount of food consumed per a given unit of time) and (4) neither peptide nor route showed any effect on the second MS. These results support an upper gastrointestinal site of action for MS and IMI length by GRP-27 and GRP-29, which is most likely the stomach and/or the duodenum.

Role of gastrin-releasing peptides in breast cancer metastasis

The gastrin-releasing peptide, which is an unfolded protein response regulator and functions as a Ca(2+)-binding molecular chaperone in the endoplasmic reticulum, is a regulatory human peptide that elicits gastrin release and regulates gastric acid secretion and enteric motor function. It has been shown to exhibit mitogenic activity in small cell lung cancer and plays a role in a lot of other human cancers including tumors in colon, stomach, pancreas, breast, and prostate. This study investigated the gastrin-releasing peptide expression in breast cancer to demonstrate the role of this biomarker in breast cancer metastasis. Gastrin-releasing peptide was analyzed in breast cancer tissue microarray specimens, including 200 primary breast cancer specimens and the corresponding lymph nodes from the same patients, through immunohistochemistry. The effect of gastrin-releasing peptide on the invasion ability of MCF-7 cells was evaluated using transwell assays. Gastrin-releasing peptide was highly expressed in breast cancer patients with lymph node metastasis. Besides, among the patients with lymph node metastasis, the ones with higher expression of gastrin-releasing peptide had shorter survival time. Overexpression of gastrin-releasing peptide significantly enhanced cell invasiveness. Conversely, a knockdown of gastrin-releasing peptide through the short hairpin RNA approach remarkably reduced MCF-7 cell invasion. Gastrin-releasing peptide expression may be associated with lymph node metastasis and may be used as an indicator of undesirable prognosis in patients with breast cancer.

Tu1833 Ingestion of a High Fat Diet Sensed by Primary Cilia Lowers Gastrin Secretion

Background:We have recently demonstrated that the presentation of primary cilia on gastric endocrine cells is regulated by food intake. A cilia-deficient mousemodel resulted in increased gastrin mRNA and hypergastrinemia, suggesting the presence of cilia is tightly linked to gastrin production. It has been shown in different organs that cilia dysfunction results in loss of sensory signaling, and obesity is characteristic of two ciliopathies, Bardet-Biedl syndrome and Alstrom. Therefore we tested the hypothesis that antral cilia can discriminate between standard and high fat diets. Methods: We analyzed C57BL/6J mice (wild type) fed with standard (Control, Lab Diet 5L0D) or High Fat (Research Diets Inc., D12492) chow. Mice were starved overnight and then allowed free access to food for 0.5, 1, 1.5, 2, 4 h and overnight (16 h). The amount of food ingested and emptied was determined by weighing the stomachs at time of euthanasia. Gastric acidity was measured by titration of gastric content and gastrin levels by ELISA. Cilia were visualized by immunohistochemistry for acetylated-tubulin then the number of cilia per gland (cpg) was quantified by morphometric analysis. Results: In mice fed Control chow (n=8), the maximum amount of food ingested was achieved by 1 h, gastric contents decreased by 4 h, and gastric acidity peaked at 2 h. The number of antral cilia decreased 45% over 1.5 h and then recovered by 4 h (Fig. 1A). Maximum circulating gastrin levels (3.5 fold increase) occurred by 2 h (Fig.1B). The stomach content, gastric acidity, gastrin levels, and cilia numbers did not change after 4 h of food intake. When mice were fed High Fat chow (n=6), the maximum amount of food ingested was achieved by 1 h and did not decrease for the entire 16 h of the experiment. Gastric acidity increased with High Fat intake, but in contrast with Control chow, remained elevated. The number of antral cilia varied slightly by 2 h then decreased only after 4 h (Fig.1A). Plasma gastrin levels increased 2 fold with High Fat during the first hour (Fig. 1B). However, gastrin levels did not increase further and did not reach the same level than with Control chow. Gastrin levels inversely correlated with antral cilia numbers with both chow diets. The number of cilia in the corpus was not different between the two diets. Conclusion: A high fat diet sensed by cilia on antral endocrine cells regulates gastrin release and thus the gastric response to food intake including acid secretion.

Tu1834 Orexins Exert a PRO-Apoptotic Effect on Digestive Human Neuroendocrine Tumors (NET) in an Ex-Vivo Culture Model of Tissue Slices

Background:We have recently demonstrated that the presentation of primary cilia on gastric endocrine cells is regulated by food intake. A cilia-deficient mousemodel resulted in increased gastrin mRNA and hypergastrinemia, suggesting the presence of cilia is tightly linked to gastrin production. It has been shown in different organs that cilia dysfunction results in loss of sensory signaling, and obesity is characteristic of two ciliopathies, Bardet-Biedl syndrome and Alstrom. Therefore we tested the hypothesis that antral cilia can discriminate between standard and high fat diets. Methods: We analyzed C57BL/6J mice (wild type) fed with standard (Control, Lab Diet 5L0D) or High Fat (Research Diets Inc., D12492) chow. Mice were starved overnight and then allowed free access to food for 0.5, 1, 1.5, 2, 4 h and overnight (16 h). The amount of food ingested and emptied was determined by weighing the stomachs at time of euthanasia. Gastric acidity was measured by titration of gastric content and gastrin levels by ELISA. Cilia were visualized by immunohistochemistry for acetylated-tubulin then the number of cilia per gland (cpg) was quantified by morphometric analysis. Results: In mice fed Control chow (n=8), the maximum amount of food ingested was achieved by 1 h, gastric contents decreased by 4 h, and gastric acidity peaked at 2 h. The number of antral cilia decreased 45% over 1.5 h and then recovered by 4 h (Fig. 1A). Maximum circulating gastrin levels (3.5 fold increase) occurred by 2 h (Fig.1B). The stomach content, gastric acidity, gastrin levels, and cilia numbers did not change after 4 h of food intake. When mice were fed High Fat chow (n=6), the maximum amount of food ingested was achieved by 1 h and did not decrease for the entire 16 h of the experiment. Gastric acidity increased with High Fat intake, but in contrast with Control chow, remained elevated. The number of antral cilia varied slightly by 2 h then decreased only after 4 h (Fig.1A). Plasma gastrin levels increased 2 fold with High Fat during the first hour (Fig. 1B). However, gastrin levels did not increase further and did not reach the same level than with Control chow. Gastrin levels inversely correlated with antral cilia numbers with both chow diets. The number of cilia in the corpus was not different between the two diets. Conclusion: A high fat diet sensed by cilia on antral endocrine cells regulates gastrin release and thus the gastric response to food intake including acid secretion.

Circadian Behaviour in Neuroglobin Deficient Mice

Neuroglobin (Ngb), a neuron-specific oxygen-binding globin with an unknown function, has been proposed to play a key role in neuronal survival. We have previously shown Ngb to be highly expressed in the rat suprachiasmatic nucleus (SCN). The present study addresses the effect of Ngb deficiency on circadian behavior. Ngb-deficient and wild-type (wt) mice were placed in running wheels and their activity rhythms, endogenous period and response to light stimuli were investigated. The effect of Ngb deficiency on the expression of Period1 (Per1) and the immediate early gene Fos was determined after light stimulation at night and the neurochemical phenotype of Ngb expressing neurons in wt mice was characterized. Loss of Ngb function had no effect on overall circadian entrainment, but resulted in a significantly larger phase delay of circadian rhythm upon light stimulation at early night. A light-induced increase in Per1, but not Fos, gene expression was observed in Ngb-deficient mice. Ngb expressing neurons which co-stored Gastrin Releasing Peptide (GRP) and were innervated from the eye and the geniculo-hypothalamic tract expressed FOS after light stimulation. No PER1 expression was observed in Ngb-positive neurons. The present study demonstrates for the first time that the genetic elimination of Ngb does not affect core clock function but evokes an increased behavioural response to light concomitant with increased Per1 gene expression in the SCN at early night.

Pathophysiology of duodenal ulcer disease

Before the discovery of Helicobacter pylori infection some 12 years ago, three major disturbances in gastric physiology had been identified in patients with duodenal ulcer disease. These abnormalities were: impaired acid inhibition of gastrin release from the antral mucosa, increased basal and stimulated acid secretion by the body of the stomach and increased acid load in the duodenum. Some of these abnormalities in gastric function can now be explained by the effects of H. pylori infection. The increased release of gastrin by the antral mucosa in duodenal ulcer patients, for example, can be entirely explained by the effects of this organism. Other abnormalities, however, appear to have a genetic basis or may be due to environmental factors. Much work has been conducted on the relationship between H. pylori and the development of duodenal ulcer disease and this paper aims to review recent studies in the field and to give an overview of the latest understanding of the pathophysiology of this disease.

Abdominal Pain and Liver Lesions in Zollinger‐Ellison Syndrome

van Os, Erim Schrama, Martijn Kamphuis, Karin de Herder, Wouter W Damen, Gerard M Case Reports United States J Pediatr Gastroenterol Nutr. 2012 Mar;54(3):435-7.

Gastrin releasing peptides increase Fos-like immunoreactivity in the enteric nervous system and the dorsal vagal complex

We and others have shown that gastrin-releasing peptide (GRP) reduces food intake. In this study, we determined the activation of the gastrointestinal and dorsal vagal complex (DVC) neurons by various forms of GRP to determine the pathway involved in this reduction. We found the following: (1) GRP-10, -27 and -29 (2.1nmol/kg, i.p.) increased the Fos-like immunoreactivity (Fos-LI, a marker for neuronal activation) in the myenteric neurons of the stomach and the area postrema (AP) of the DVC; (2) GRP-27 and GRP-29 increased the Fos-LI in the myenteric plexus of the duodenum; and (3) only GRP-29 increased the Fos-LI in the submucosal plexus of the duodenum. In conclusion, GRP may reduce food intake by activating the area postrema. The enteric neurons may have a potential role in this reduction through the direct activation of the AP or exerting local gut actions, such as the stimulation of gut motility or secretions.

Abstract 1112: Human rhomboid family-1 gene RHBDF1 assists trafficking of TGFa for GPCR-mediated transactivation of EGFR

Abstract Epidermal growth factor receptor (EGFR) can be transactivated by ligands of G protein-coupled receptors (GPCR). GPCR signaling pathways often involve the formation of clathrin-coated endosomes, which interact with endoplasmic reticulum/Golgi complex to form recycling endosome and secretion vesicles containing EGFR pro-ligands such as pro-TGFα, which is proteolytically processed and released on the cell surface to activate EGFR in an autocrine manner. We showed previously that human rhomboid family-1 gene RHBDF1 is essential for GPCR-EGFR transactivation by assisting the secretion of TGFα, a ligand of EGFR. We show here silencing the RHBDF1 with shRNA leads to inhibition of EGFR ligand-dependent transactivation induced by GPCR ligands such as gastrin release peptide (GRP) and sphingosine-1-phosphate. However, RHBDF1 is not involved in EGFR ligand-independent GPCR-EGFR transactivation induced by isoproterenol. Inhibitors of endosome formation and membrane trafficking such as chlorpromazine, nocodazole, and cytochalasin-D also inhibit GRP-induced EGFR phosphorylation. Inhibitors of endosome acidification such as chloroquine and BFA lessen the inhibitory effect of RHBDF1 shRNA on GRP-induced EGFR phosphorylation. The RHBDF1 protein localizes mainly to the endoplasmic reticulum with pro-TGFα and GRASP55 in starved, quiescent cancer cells, but is phosphorylated and translocated to the cell surface upon GPCR ligands stimulation. GPCR ligands also activate the intracellular signaling molecule Src which then co-translocates with RHBDF1 and clathrin to the plasma membrane. Src-clathrin interaction and co-localization to the cell surface are RHBDF1-dependent. These findings are consistent with the view that, in response to GPCR activation, RHBDF1 assists pro-TGFα trafficking to the cell surface through clathrin coated trafficking. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1112. doi:10.1158/1538-7445.AM2011-1112

Incretin physiology beyond glucagon‐like peptide 1 and glucose‐dependent insulinotropic polypeptide: cholecystokinin and gastrin peptides

Gastrin and cholecystokinin (CCK) are homologous hormone systems known to regulate gastric acid secretion, gallbladder emptying, and cell growth in the pancreas and stomach. They are, however, also involved in the development and secretory functions of pancreatic islet cells. For instance, foetal and neonatal islets express significant amounts of gastrin, and human as well as porcine islet cells express the gastrin/CCK-B receptor abundantly. Therefore, exogenous gastrin and CCK peptides stimulate insulin and glucagon secretion in man. Accordingly, endogenous hypergastrinaemia is accompanied by islet cell hyperplasia and increased insulin secretion. Conventionally, the effect of gastrointestinal hormones on insulin secretion (the incretin effect) has been defined and quantified in relation to oral versus intravenous glucose loadings. Under these unphysiological conditions, the release of gastrin and CCK and, hence, their effect on insulin secretion are modest in comparison with the effects of glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 (GLP-1). Consequently, the interest of CCK and gastrin in incretin research has for decades been limited. A few years ago, however, it was suggested that gastrin together with epidermal growth factor or later GLP-1 might stimulate beta cell growth and secretion. Recent studies have shown that the combination of gastrin and GLP-1 actually restores normoglycaemia in diabetic mice. Therefore, a short review of the incretin system in a broader functional context that includes gastrin and CCK peptides may be timely.

The role of ghrelin in the organism

Ghrelin was discovered in 1999 as an endogenous ligand of the growth hormone secretagogue receptor (GHS-R). About 60-70% of ghrelin in the blood is released from oxyntic cells (X/A-like cells) of the stomach body and fundus. Ghrelin acts via interactions with specific receptors located, for example, in the hypothalamus, pituitary gland, pancreas, kidneys, myocardium, blood vessels, adipose tissue, ovaries and placenta. Ghrelin is directly related to the control of energy balance through appetite stimulation, food intake increase and meal initiation as well as reduction of adipose tissue utilization. Moreover, ghrelin increases hydrochloric acid secretion and gastrin release, controls gastric motility, and also protects the mucous membrane of the stomach and intestine. Besides its effects on the gastrointestinal tract, ghrelin influences the cardiovascular system, bone metabolism, insulin secretion, gonad function and the immune system. It exerts anti-inflammatory effects and inhibits apoptosis of cardiomyocytes and endothelium. The plasma ghrelin level depends on the nutrition level and lifestyle factors. This article describes the most important functions of ghrelin in the organism.

Immunohistochemical study of gastrin in colorectal carcinoma tissues and adjacent mucosa.

To study gastrin expression in colorectal carcinoma tissues and adjacent mucosa and discuss the function of gastrin in colorectal carcinoma. Gastrin expression in colorectal carcinoma tissues and adjacent mucosa was examined in 58 cases using immunohistochemical and immunoelectron microscopy. A total of 35.1% of colorectal carcinoma transitional mucosa (TM), 48.3% of nontypical dysplasia mucosa and 60.3% of carcinoma tissue were positive for gastrin expression (P < 0.05). Immunoelectron microscopy revealed that protein A gold (PAG) granules localized to different electron-dense secretory granules in carcinoma cells, the intercellular spaces, and the microvillar membrane surface. Gastrin expression in colorectal carcinoma tissue and adjacent mucosa, and the release of gastrin by carcinoma may be an initiating factor in carcinoma occurrence and development. Positive gastrin expression in colorectal carcinoma tissues can serve as a differentiation marker.

Glutamate Acts as a Neurotransmitter for Gastrin Releasing Peptide-Sensitive and Insensitive Itch-Related Synaptic Transmission in Mammalian Spinal Cord

Itch sensation is one of the major sensory experiences of human and animals. Recent studies have proposed that gastrin releasing peptide (GRP) is a key neurotransmitter for itch in spinal cord. However, no direct evidence is available to indicate that GRP actually mediate responses between primary afferent fibers and dorsal horn neurons. Here we performed integrative neurobiological experiments to test this question. We found that a small population of rat dorsal horn neurons responded to GRP application with increases in calcium signaling. Whole-cell patch-clamp recordings revealed that a part of superficial dorsal horn neurons responded to GRP application with the increase of action potential firing in adult rats and mice, and these dorsal horn neurons received exclusively primary afferent C-fiber inputs. On the other hands, few Aδ inputs receiving cells were found to be GRP positive. Finally, we found that evoked sensory responses between primary afferent C fibers and GRP positive superficial dorsal horn neurons are mediated by glutamate but not GRP. CNQX, a blocker of AMPA and kainate (KA) receptors, completely inhibited evoked EPSCs, including in those Fos-GFP positive dorsal horn cells activated by itching. Our findings provide the direct evidence that glutamate is the principal excitatory transmitter between C fibers and GRP positive dorsal horn neurons. Our results will help to understand the neuronal mechanism of itch and aid future treatment for patients with pruritic disease.

The von economo neurons in apes and humans

The von Economo neurons (VENs) are large bipolar neurons located in frontoinsular (FI) and anterior cingulate cortex (ACC) in great apes and humans but not other primates. We stereologically counted the VENs in FI and the limbic anterior (LA) area of ACC and found them to be more numerous in humans than in apes. In humans, VENs first appear in small numbers in the 36th week postconception are rare at birth and increase in number during the first 8 months after birth. There are significantly more VENs in the right hemisphere than the left in FI and LA in postnatal brains; this may be related to asymmetries in the autonomic nervous system. The activity of the inferior anterior insula, containing FI, is related to physiological changes in the body, decision-making, error recognition, and awareness. In a preliminary diffusion tensor imaging study of the connections of FI, we found that the VEN-containing regions connect with the frontal pole as well as with other parts of frontal and insular cortex, the septum, and the amygdala. The VENs and a related cell population, the fork cells, selectively express the bombesin peptides neuromedin B (NMB) and gastrin releasing pepide, which signal satiety. The loss of VENs and fork cells may be related to the loss of satiety signaling in patients with frontotemporal dementia who have damage to FI. These cells may be morphological specializations of an ancient population of neurons involved in the control of appetite present in the insular cortex in all mammals.

Mechanisms of Intragastric pH Sensing

Luminal amino acids and lack of luminal acidity as a result of acid neutralization by intragastric foodstuffs are powerful signals for acid secretion. Although the hormonal and neural pathways underlying this regulatory mechanism are well understood, the nature of the gastric luminal pH sensor has been enigmatic. In clinical studies, high pH, tryptic peptides, and luminal divalent metals (Ca2+ and Mg2+) increase gastrin release and acid production. The calcium-sensing receptor (CaSR), first described in the parathyroid gland but expressed on gastric G cells, is a logical candidate for the gastric acid sensor. Because CaSR ligands include amino acids and divalent metals, and because extracellular pH affects ligand binding in the pH range of the gastric content, its pH, metal, and nutrient-sensing functions are consistent with physiologic observations. The CaSR is thus an attractive candidate for the gastric luminal sensor that is part of the neuroendocrine negative regulatory loop for acid secretion.

Identification of endocrine cells of the stomach that express acid-sensitive background potassium (K2P9.1/TASK3) channels

The family of two-pore domain potassium (K(₂P)) channels is important in setting and controlling the background potassium current of excitable cells. This study examines the localisation of the acid-sensitive channel, K(₂P)9.1 (TASK3), in cells of the gastric mucosa. We observed K(₂P)9.1 immunoreactivity in endocrine cells of the mucosal glands of the guinea-pig, rat and mouse but the channels were not detected in parietal, chief, or mucous cells. K(₂P)9.1 channel immunoreactivity was consistently co-localised with histidine decarboxylase immunopositive enterochromaffin-like (ECL) cells, and with the majority of ghrelin immunoreactive X/A cells. Localisation in somatostatin immunoreactive D cells was rare in the guinea-pig, and did not occur in the stomach of rat, but, in the mouse, K(₂P)9.1 channels were observed in the majority of somatostatin-immunoreactive D cells. Conversely, sections taken from the guinea-pig and mouse stomachs, but not rat stomach, revealed K(₂P)9.1 in gastrin-containing G cells. These results demonstrate the presence of K(₂P)9.1 channels in the entero-endocrine ECL, G and D cell populations of the stomach that regulate acid secretion through the release of histamine, gastrin and somatostatin. K(₂P)9.1 channels were located in the ghrelin X/A cells that regulate food intake.

Gastrin response to candidate messengers in intact conscious rats monitored by antrum microdialysis

We monitored gastrin release in response to locally applied candidate messengers in intact conscious rats. Earlier studies have been performed on anaesthetized animals, isolated pieces of antrum, or purified preparations of gastrin cells. In this study we created an experimental situation to resemble physiological conditions, using reverse microdialysis to administer regulatory peptides and amines that might affect gastrin secretion. Microdialysis probes were implanted in the submucosa of the antrum of the rat stomach. Three days later, putative messenger compounds were administered via the probe. Their effects on basal (24 h fast) and omeprazole-stimulated (400 μmol/kg/day, 4 days peroral administration) gastrin release were monitored by continuous measurement (3 h) of gastrin in the perfusate (radioimmunoassay). Fasted rats (low microdialysate gastrin, 2.1 ± 0.1 pmol l − 1 ) were used to study stimulation of gastrin release. Omeprazole-treated rats (high microdialysate gastrin, 95.8 ± 6.7 pmol l − 1 ) were used to study suppression of gastrin release. The following agents raised the concentration of microdialysate gastrin (peak response): gastrin-releasing peptide (GRP) (11-fold increase at a near-maximal dose), carbachol (5-fold increase), serotonin (2-fold increase) and isoprenaline (20-fold increase). Adrenaline and noradrenaline induced transient but powerful elevation (40- and 20-fold increase). Somatostatin, galanin and bradykinin (at near-maximal doses) suppressed omeprazole-stimulated gastrin release (50% decrease). Calcitonin gene-related peptide, ghrelin, gastric inhibitory peptide, motilin, neurotensin, neuromedin U-25, peptide YY and vasoactive intestinal peptide were without effect on gastrin release, as were aspartate, γ-aminobutyric acid, glutamate, glycine, dopamine and histamine. The results support the view that G cells operate under neurocrine/paracrine control. They were stimulated by agents present in enteric neurons (GRP, galanin, choline ester and catechol amines) and in gastric endocrine cells (serotonin). They were inhibited by somatostatin (D cell peptide), galanin (neuropeptide) and by the inflammatory agent bradykinin.

Protective effect of (+)-catechin against gastric mucosal injury induced by ischaemia-reperfusion in rats

Ischaemia and reperfusion are known to induce gastric lesions, predominantly due to excessive formation of reactive oxygen metabolites, adhesion of neutrophils to endothelial cells, microvascular dysfunction, gastric acid secretion, endogenous histamine and gastrin release. We have studied the effect of (+)-catechin on a gastric ulcer model involving damage to gastric injury by ischaemia- reperfusion (I/R) in rats. (+)-Catechin 50 mg kg(-1)administered orally, once daily for three days after the initiation of I/R injury showed a significant (P<0.001) anti-ulcer activity against mucosal dam- age. However, (+)-catechin significantly decreased the lipid peroxidation and increased the level of catalase in the I/R condition. Elevated levels of alkaline phosphatase in the I/R group was significantly lowered (P<0.01) by (+)-catechin. The amount of H(+)K(+)ATPase was significantly decreased (P<0.001) in (+)-catechin-treated as compared with I/R rats. (+)-Catechin significantly decreased elevated plasma histamine (P<0.05) and corticosterone (P<0.05). The results suggested that (+)-catechin protected gastric mucosa against ischaemia-reperfusion-induced gastric ulcers by its antioxidant activity and mucus protection.

Gastrin release: Antrum microdialysis reveals a complex neural control

We used microdialysis to monitor local gastrin release in response to food, acid blockade and acute vagal excitation. For the first time, gastrin release has been monitored continuously in intact conscious rats in a physiologically relevant experimental setting in a fashion that minimizes confounding systemic effects. Microdialysis probes were placed in the submucosa on either side of the antrum, 3 days before the experiments. The concentration of gastrin in the antral submucosal compartment was about 20 times higher than in the microdialysate and estimated to be 5–10 times higher than in serum regardless of the prandial state. The rats were conscious during microdialysis except when subjected to electrical vagal stimulation. Acid blockade (omeprazole treatment of freely fed rats for 4 days), or bilateral sectioning of the abdominal vagal trunks (fasted, 3 days post-op.), raised the gastrin concentration in blood as well as microdialysate. The high gastrin concentration following omeprazole treatment was not affected by vagotomy. Vagal excitation stimulated the G cells: electrical vagal stimulation and pylorus ligation (fasted rats) raised the gastrin concentration transiently in both serum and microdialysate. Food intake induced a 2- to 3-fold increase in serum gastrin, while gastrin in antral microdialysate increased 10- to 15-fold. In unilaterally vagotomized rats (fasted, 3 days post-op.), food evoked a prompt peak gastrin release followed by a gradual decline on the intact side. On the vagotomized side of the antrum, the peak response seemed to be reduced while the microdialysate gastrin concentration remained elevated. Thus, unilateral vagotomy surprisingly raised the integrated gastrin response to food on the denervated side compared to the intact side, indicating that vagotomy suppresses an inhibitory as well as a stimulating effect on the G cells. While local infusion of atropine was without effect, infusion of the neuronal blocker tetrodotoxin (TTX) (which had no effect on basal gastrin) virtually abolished the food-evoked gastrin response and lowered the high microdialysate gastrin concentration in omeprazole-treated rats by 65%. We conclude that activated gastrin release, unlike basal gastrin release, is highly dependent on a neural input: 1) Vagal excitation has a transient stimulating effect on the G cells. The transient nature of the response suggests that the vagus has not only a prompt stimulatory but also a slow inhibitory effect on gastrin release. 2) Although vagal denervation did not affect the gastrin response to anacidity, the TTX experiments revealed that both food-evoked and anacidity-evoked gastrin release depends on neural input.

Gastrin: An Acid-Releasing, Proliferative and Immunomodulatory Peptide?

Gastrin release is affected by gastric inflammatory conditions. Antral G cells respond to inflammatory mediators by increasing gastrin secretion. Accumulating experimental evidence suggests that gastrin exerts immunomodulatory and proinflammatory effects. Gastrin could be a contributing factor to these pathologies, which may constitute a new justification for pharmacological blockade of gastrin action.