Regulation Of Gastrin Research Articles

Research of influence and mechanism of combining exercise with diet control on a model of lipid metabolism rat induced by high fat diet

ObjectiveTo investigate the influence and mechanism of combining exercise with diet control on a model of lipid metabolism rat induced by high fat diet.MethodsTwenty-four male Wistar rats were randomly divided into 3 groups of 8: normal, model and intervention. The model group and intervention group were fed with high fat diet, while the normal group received basal feed. From day 1, the intervention group was randomly given interventions such as swimming exercise and dietary restriction. The interventions duration were 28 days. At the end of the experiment, the levels of rats’ body weight and liver weight were detected, the serum levels of total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) and hepatic triglyceride content (TG) were detected by using biochemical assay, serum level of gastrin (GAS), motilin (MTL) were assayed by the enzyme linked immunosorbent assay (ELISA).ResultsCompared with the level of body weight and liver weight in the normal rats, body weight and liver weight in the rat of the model group were significantly increase (P<0.05 or P<0.01). Plasma concentrations of TC, LDL-C and hepatic TG in the model group were significantly increased compared with those in the normal group (P<0.05 or P<0.01). The contents of GAS, MTL, HDL-C in the model rats’plasma were significantly reduced compared with those of the normal group (P<0.05 or P<0.01). Compared with those in the model group, rats’ body weight, liver weight, serum TC, LDL-C, and TG content of liver in the intervention group decreased significantly (P<0.05 or P<0.01). Meanwhile, serum content of GAS, MTL, HDL-C were significantly improved in the intervention rats compared to the model group.ConclusionThe action of combining exercise with diet control for lipid metabolism disorder might be related to regulation of GAS, MTL and other gastrointestinal hormones.

Gastrin regulation of parathyroid hormone like‐hormone (Pthlh) in gastric parietal cells

Gastrin regulation of parathyroid hormone like‐hormone (Pthlh) in gastric parietal cells

IL1B Induced Smad 7 Negatively Regulates Gastrin Expression

Background Helicobacter pylori elicited IL1B is one of the various modulators responsible for perturbation of acid secretion in gut. We have earlier reported that IL1B activated NFkB downregulates gastrin, a major modulator of acid secretion. However, we hypothesized that regulation of gastrin by IL1B would depend on the cell's ability to integrate inputs from multiple signaling pathways to generate appropriate biological response.Principal FindingIn this study, we report that IL1B induces Smad 7 expression by about 4.5 fold in gastric carcinoma cell line, AGS. Smad 7 resulted in transcriptional repression of gastrin promoter by about 6.5 fold when co -transfected with Smad 7 expression vector and gastrin-promoter luciferase in AGS cells. IL1B inhibited phosphorylation of Smad 3 and subsequently interfered with nuclear translocation of the positive Smad complex, thus occluding it off the gastrin promoter. IL1B promoter polymorphisms (-511T/-31C IL1B) are known to be associated with H. pylori associated gastro-duodenal ulcer. We observed that IL1B expressed from -31T promoter driven IL1B cDNA elicited 3.5 fold more Smad 7 than that expressed from the IL1B-31C variant in AGS cells. This differential activation of Smad 7 by IL1B promoter variants translated into differential downregulation of gastrin expression. We further analyzed Smad 7, NFkB, IL1B and gastrin expression in antral gut biopsy samples of patients with H. pylori associated duodenal ulcer and normal individuals. We observed that individuals with duodenal ulcer had significantly lower levels of IL1B, Smad 7, NFkB and corresponding higher level of gastrin expression.ConclusionPro-inflammatory cytokine IL1B repress gastrin expression by activating Smad 7 and subsequent inhibition of nuclear localization of Smad 3/4 complex. Polymorphic promoter variants of IL1B gene can modulate the IL1B expression which resulted in differential activation Smad 7 and consequent repression of gastrin expression, respectively. Analysis of H. pylori infected duodenal ulcer patient's gut biopsy samples also supported this observation.

In vivo analysis of mouse gastrin gene regulation in enhanced GFP-BAC transgenic mice.

Gastrin is secreted from a subset of neuroendocrine cells residing in the gastric antrum known as G cells, but low levels are also expressed in fetal pancreas and intestine and in many solid malignancies. Although past studies have suggested that antral gastrin is transcriptionally regulated by inflammation, gastric pH, somatostatin, and neoplastic transformation, the transcriptional regulation of gastrin has not previously been demonstrated in vivo. Here, we describe the creation of an enhanced green fluorescent protein reporter (mGAS-EGFP) mouse using a bacterial artificial chromosome that contains the entire mouse gastrin gene. Three founder lines expressed GFP signals in the gastric antrum and the transitional zone to the corpus. In addition, GFP(+) cells could be detected in the fetal pancreatic islets and small intestinal villi, but not in these organs of the adult mice. The administration of acid-suppressive reagents such as proton pump inhibitor omeprazole and gastrin/CCK-2 receptor antagonist YF476 significantly increased GFP signal intensity and GFP(+) cell numbers in the antrum, whereas these parameters were decreased by overnight fasting, octreotide (long-lasting somatostatin ortholog) infusion, and Helicobacter felis infection. GFP(+) cells were also detected in the anterior lobe of the pituitary gland and importantly in the colonic tumor cells induced by administration with azoxymethane and dextran sulfate sodium salt. This transgenic mouse provides a useful tool to study the regulation of mouse gastrin gene in vivo, thus contributing to our understanding of the mechanisms involved in transcriptional control of the gastrin gene.

Role of CCN2/CTGF in the proliferation of Mastomys enterochromaffin-like cells and gastric carcinoid development

Mastomys enterochromaffin-like (ECL) cell proliferation is initially gastrin driven, but once neoplasia develops, cells become gastrin autonomous. We hypothesized that CCN2 (CTGF), a mitogenic growth factor, may regulate ECL cell proliferation. A Mastomys GeneChip database was examined (dCHIP) to identify CCN2 expression levels. CCN2 in normal and tumor ECL cell preparations obtained using FACS (100 nM acridine orange) was examined by real-time PCR. CCN2 protein was identified in mucosal and ECL cell preparations by immunohistochemistry. Short-term cultured cells were stimulated with either CCN2 or CCN2 + EGF, and proliferation was measured (MTT assay). The ERK1/2 inhibitor PD-98059 (0.1-100 microM) was assessed in terms of CCN2 (1 ng/ml)-mediated proliferation and ERK1/2 phosphorylation. CCN2 transcript and protein was then examined in clinical gastric carcinoids. The ccn2 transcript was upregulated in tumor samples compared with the normal mucosa (+2.36-fold, P < 0.01). PCR demonstrated that ccn2 was not expressed in FACS-prepared (>98% pure) normal ECL cells but was elevated in tumor ECL cell fractions (41.3 +/- 10.7-fold). Immunostaining of the Mastomys gastric mucosa and FACS preparations confirmed that CCN2 protein was present in ECL tumors but not in normal ECL cells. Neither CCN2 nor CCN2 + EGF stimulated normal ECL cell proliferation. CCN2 stimulated tumor proliferation (EC50 approximately 0.01 ng/ml); EGF significantly augmented (P < 0.01) CCN2-induced tumor cell proliferation (EC50 = 20 pg/ml). PD-98059 inhibited CCN2-induced proliferation (-12 +/- 3%, P < 0.05) and ERK1/2 phosphorylation (-34 +/- 5%, P < 0.05) in tumor cells. In clinical samples, both CCN2 transcript and protein were elevated in gastrin-autonomous carcinoids (P < 0.02) compared with the normal mucosa. In conclusion, CCN2 may be a proliferative regulator of Mastomys ECL neoplastic proliferation once these cells become autonomous of gastrin regulation. Identification of CCN2 in gastric carcinoid tissue may be useful both as an indicator of ECL cell transformation and may define gastrin autonomy, a criteria of gastric carcinoid malignancy.

Mechanisms for regulation of gastrin and somatostatin release from isolated rat stomach during gastric distention.

To investigate the intragastric mechanisms for regulation of gastric neuroendocrine functions during gastric distention in isolated vascularly perfused rat stomach. Isolated vascularly perfused rat stomach was prepared, then the gastric lumen was distended with either 5,10 or 15 ml pH7 isotonic saline during a period of 20 min. During the distention, the axonal blocker tetrodotoxin (TTX), the cholinergic antagonist atropine, or the putative somatostatin-antagonist cyclo (7-aminoheptanoyl-Phe-D-Trp-Lys-Thr(Bzl)) were applied by vascular perfusion. The releases of gastrin and somatostatin were then examined by radioimmunoassay. The graded gastric distention caused a significant volume-dependent decrease in gastrin secretion (-183+/-75 (5 ml), -385+/-86 (10 ml) and -440+/-85 (15 ml) pg/20 min) and a significant increase of somatostatin secretion (260+/-102 (5 ml), 608+/-148 (10 ml) and 943+/-316 (15 ml) pg/20 min). In response to 10 ml distention, the infusion of either axonal blocker TTX (10(-6) M) or cholinergic blocker atropine (10(-7) M) had a similar affect. They both attenuated the decrease of gastrin release by approximately 50 %, and attenuated the increase of somatostatin release by approximately 40 %. The infusion of somatostatin-antagonist cyclo (7-aminoheptanoyl-Phe-D-Trp-Lys-Thr (Bzl)) (10(-6)M) attenuated the decrease of gastrin release by about 60 %. Furthermore, combined infusion of the somatostatin-antagonist and atropine completely abolished distention-induced inhibition of gastrin release. The present data suggest that distention of isolated rat stomach stimulates somatostatin release via cholinergic and non-cholinergic TTX-insensitive pathways. Both somatostatin and intrinsic cholinergic pathways are responsible for distention-induced inhibition of gastrin release.

Altered gastrin regulation in mice infected with Helicobacter felis.

Altered gastrin expression associated with Helicobacter pylori infection may contribute to the pathogenesis of peptic ulcer disease or gastric cancer in man, but gastrin has not been investigated in a murine model of Helicobacter infection. C57BL/6 mice were inoculated with Helicobacter felis and examined after 4-21 weeks for G and D cell numbers, antral gastrin and somatostatin mRNA, and luminal pH. In H. felis-infected mice, gastrin mRNA declined at four and six weeks after infection to 57% and 23%, respectively, of uninfected control values. Concurrently, somatostatin mRNA showed no change at four weeks and a modest 25% decrease at six weeks after infection. Similar reductions were noted in G and D cell numbers, resulting in a decrease in the G/D cell ratio after mice were infected with H. felis. Infected animals also showed a loss of parietal and chief cells, and an increased gastric pH. H. felis infection in C57BL/6 mice leads to an early suppression of G cell number and gastrin mRNA. These changes precede an alteration in somatostatin cell number and mRNA and, coupled with reductions in parietal and chief cells, may contribute both to severe impairment of gastric acid output and the potential for carcinogenic processes.

Active immunization against somatostatin alters regulation of gastrin in response to gastric acid secretagogues.

We have examined the coupling between somatostatin, gastrin, and gastric acidity, using sheep chronically immunized against somatostatin. All immunized sheep had high-titer (3.2 x 10(5) +/- 1.1 x 10(4) M), high-affinity (1.5 x 10(11) +/- 1.2 x 10(10) l/mol) antibodies. However, basal gastrin and gastric acidity were similar to those in control animals, indicating that an inhibitory somatostatin tone was not required for the maintenance of normal basal gastrin and gastric acidity. Omeprazole (a proton pump inhibitor) increased gastric pH to a similar extent in both the control and immunized groups but resulted in a smaller increase in plasma gastrin in the immunized sheep, thus calling into question the assumption that hypergastrinemia associated with hypochlorhydria is the result of somatostatin withdrawal. Pentagastrin- or histamine-stimulated somatostatin secretion reversed or attenuated the omeprazole-induced hypergastrinemia in control but not immunized sheep, demonstrating a functional role for somatostatin and the biological efficacy of the somatostatin immunization. In a separate series of omeprazole-treated sheep, restoration of an acidic gastric pH with intragastric HCl reversed the hypergastrinemia in both control and immunized animals. We conclude that somatostatin is not essential for the acid-mediated regulation of gastrin. The use of a chronically immunized model as opposed to the acute administration of somatostatin antibodies has important advantages in determining the steady-state regulatory role of somatostatin.

A functional in vitro model to examine signaling mechanisms in gastrin-mediated human cell growth.

Gastrin (G-17) is a trophic hormone with a high affinity for the cholecystokinin-B receptor (CCK-BR); the mechanisms linking receptor binding and activation of downstream events to cell growth are not known, and these studies have been hampered by the lack of a cell model. We have established a pancreatic carcinoid cell line, BON, which produces a number of gut hormones; however, these cells lack native CCK-BR. The purpose of our study was to develop a model cell line containing the CCK-BR and to characterize the cellular mechanisms involved in gastrin regulation of human cell growth. BON cells were transfected with an expression plasmid containing the human CCK-BR, and stable clones were selected using G418. Functional CCK-BR was confirmed by reverse transcriptase-polymerase chain reaction, 125I-gastrin binding, and mobilization of intracellular calcium ([Ca2+]i) in response to G-17. Stable transfectants were treated with G-17 (+/-) the CCK-BR antagonist, L365,260 (L-60); growth was assessed using a Coulter counter. G-17 stimulated the growth of the stable clones, whereas the selective CCK-BR antagonist, L-60, abolished this G-17-mediated trophic effect. We have shown that G-17, acting through the CCK-BR, mobilizes [Ca2+]i as a second messenger and stimulates cell growth. Our unique BON cell line, stably transfected with the human CCK-BR, provides a novel paradigm to further delineate signaling mechanisms in gastrin regulation of human cell growth.

A functional in vitro model to examine signaling mechanisms in gastrin-mediated human cell growth

Gastrin (G-17) is a trophic hormone with a high affinity for the cholecystokinin-B receptor (CCK-BR); the mechanisms linking receptor binding and activation of downstream events to cell growth are not known, and these studies have been hampered by the lack of a cell model. We have established a pancreatic carcinoid cell line, BON, which produces a number of gut hormones; however, these cells lack native CCK-BR. The purpose of our study was to develop a model cell line containing the CCK-BR and to characterize the cellular mechanisms involved in gastrin regulation of human cell growth. BON cells were transfected with an expression plasmid containing the human CCK-BR, and stable clones were selected using G418. Functional CCK-BR was confirmed by reverse transcriptase—polymerase chain reaction, 125I-gastrin binding, and mobilization of intracellular calcium ([Ca 2+] i) in response to G-17. Stable transfectants were treated with G-17 (±) the CCK-BR antagonist, L365,260 (L-60); growth was assessed using a Coulter counter. G-17 stimulated the growth of the stable clones, whereas the selective CCK-BR antagonist, L-60, abolished this G-17-mediated trophic effect. We have shown that G-17, acting through the CCK-BR, mobilizes [Ca 2+] i as a second messenger and stimulates cell growth. Our unique BON cell line, stably transfected with the human CCK-BR, provides a novel paradigm to further delineate signaling mechanisms in gastrin regulation of human cell growth.

Neural and paracrine regulation of gastrin and gastric acid secretion

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Effect of endogenous opioids on vagally induced release of gastrin, somatostatin and bombesin-like immunoreactivity from the perfused rat stomach

The aim of the present study was to evaluate the effect of the opiate receptor antagonist naloxone on vagally stimulated secretion of bombesin-like immunoreactivity (BLI), somatostatin and gastrin from the isolated rat stomach, which was perfused via the celiac artery with Krebs-Ringer buffer. Vagal stimulation was performed for 10 min with 1 ms, 10 V and 2, 5, 10 or 20 Hz, respectively. In control experiments BLI release increased significantly above basal secretion during a stimulation frequency of 10 Hz (1367 ± 357 pg/10 min; P < 0.001) and 20 Hz (996 ± 202 pg/10 min; P < 0.01), but not at 2 and 5 Hz. In comparison to the controls naloxone (10 −6 M) significantly increased BLI secretion at 5 Hz by 573 ± 150 pg/10 min ( P < 0.05), but attenuated the BLI response to higher stimulation frequencies of 10 and 20 Hz to 284 ± 143 pg/10 min ( P < 0.001) and 490 ± 114 pg/10 min ( P < 0.01), respectively. At 2 Hz naloxone had no effect on BLI release. As shown previously the cholinergic blocker atropine (10 −7 M) induced a significant BLI release during vagal stimulation at 2 Hz (680 ± 233 pg/10 min; P < 0.01) and 5 Hz (935 ± 324 pg/10 min; P < 0.05), but was without effect at 10 and 20 Hz compared to the controls. The effects of the combination of naloxone and atropine were similar to naloxone and atropine alone. Naloxone had no effect on vagal or GRP-induced regulation of gastrin and somatostatin release. In conclusion, the present data demonstrate that endogenous opioids contribute to vagal regulation of BLI secretion. Stimulatory or inhibitory actions of endogenous opioids depend on the stimulation frequency employed. Further studies in isolated nerve endings are required to discriminate direct from indirect actions of endogenous opioids on the BLI neurons.

Reciprocal changes in antral gastrin and somatostatin mRNA in pernicious anemia.

Somatostatin is involved in the regulation of gastrin by intragastric pH in animal models. To investigate whether this is so in man, we measured gastrin and somatostatin mRNA in endoscopic biopsies from six patients with hypergastrinemia and achlorhydria due to pernicious anemia and 12 age- and sex-matched controls. The pernicious anemia patients had significantly higher fasting plasma gastrin concentrations with a median (range) of 640 (420-3500) pmol/liter compared with 5 (2-58) pmol/liter, P < 0.001. The median gastrin mRNA/rRNA ratio was 10.4 (3.7-38.0) in the pernicious anemia patients compared with 1.7 (0.7-8.3) in the controls (P < 0.02), and it correlated strongly with the plasma gastrin concentration, r = 0.93, P < 0.0001. In contrast, the median somatostatin mRNA/rRNA ratio was lower in the pernicious anemia patients 0.84 (0.58-2.32) versus 2.04 (0.05-6.47) in the controls, P < 0.05. These findings suggest that in pernicious anemia gastric neutralization leads to hypergastrinemia through the modulation of antral gastrin synthesis by somatostatin.

Role of tyrosine kinases in gastrin induction of ornithine decarboxylase in colonic mucosa

An organ culture system was utilized to evaluate the role of tyrosine kinases (Tyr-k) and tyrosine-specific phosphorylation of proteins in gastrin regulation of ornithine decarboxylase (ODC) activity in colonic mucosa. Exposure of colonic mucosal explants to gastrin (50-100 ng G-17 I/ml) resulted in a profound stimulation of both Tyr-k and ODC activities compared with the corresponding basal levels. Whereas the maximal stimulation (ranging between 70 and 150%) of Tyr-k occurred within 10-15 min of exposure to gastrin, ODC activity was significantly stimulated (180%) 2 h after exposure to the hormone, and at 4 h it was found to be 750% above the corresponding basal level. Difluoromethylornithine (DFMO; 2 mM), an irreversible inhibitor of ODC, completely abolished the gastrin-mediated stimulation of ODC but not Tyr-k activity. On the other hand, genistein (100 micrograms/ml), a specific inhibitor of Tyr-k, caused a total suppression of the gastrin-induced stimulation of both Tyr-k and ODC. Gastrin also stimulated tyrosyl phosphorylation of a colonic mucosal membrane protein with molecular mass of 57 kDa, and genistein greatly attenuated this effect. We conclude that gastrin stimulates colonic mucosal ODC in vitro, and Tyr-k may be required for the regulation of this process.

Effect of vitamin D on gastrin and gastric somatostatin secretion from the isolated perfused rat stomach

We have studied the role of vitamin D in the regulation of gastrin and gastric somatostatin secretion from the isolated perfused rat stomach. In Ca-deficient vitamin D-deficient rats (Ca(−)D(−) group), the basal and bombesin-stimulated gastrin and gastric somatostatin release (basal IRGa, basal IRS, ΣΔ IRGa, and ΣΔ IRS) all were significantly lower than in Ca-replete vitamin D-replete rats (Ca(+)D(+) group), and also lower than in Ca-replete vitamin D-deficient rats (Ca(+)D(−) group) except for the basal IRGa. In the Ca(+)D(−) group, the basal IRGa and IRS, and ΣΔ IRS were not significantly lower than in the Ca(+)D(+) group. Although there was no significant impairment in basal IRGa, ΣΔ IRGa in the Ca(+)D(−) group was significantly lower than in the Ca(+)D(+) control group. Thus, the gastrin and gastric somatostatin secretion from the Ca-deficient vitamin D-deficient rats were impaired. In addition, the impaired gastrin and gastric somatostatin secretions seem to be caused not only by a decrease in serum Ca but also by the reduced effect of the vitamin D on the G and gastric D cells.

Neural regulation of gastrin and somatostatin secretion in rat gastric antral mucosa.

A muscle-stripped mucosal sheet obtained from rat antrum was mounted in an Ussing chamber and used to examine the regulation of gastrin and somatostatin secretion by antral neurons. The neurons were activated pharmacologically with 1,1-dimethyl-4-phenylpiperazinium (DMPP) or electrically by field stimulation using aluminum foil electrodes layered over the edge of the mucosal sheet. Field stimulation caused an increase in gastrin and somatostatin secretion that was dependent on the strength of the stimulus (10-30 V). Field stimulation at 30 V, 10 Hz, 4 ms caused a sixfold increase in gastrin and a twofold increase in somatostatin secretion that were nearly abolished by tetrodotoxin (85-89% inhibition). Atropine partially inhibited the gastrin response (34 +/- 6%) but had no effect on the somatostatin response. DMPP caused lesser, though significant, increases in gastrin (166%) and somatostatin (83%) secretion that were nearly abolished by hexamethonium (84-91%) but were not significantly affected by atropine. The increase in somatostatin secretion caused by DMPP and field stimulation, as well as the resistance of gastrin and somatostatin secretion to atropine, was consistent with preferential activation of noncholinergic neurons at the stimulatory modalities used. The pattern and magnitude of gastrin and somatostatin response to pharmacological and electrical stimulation of antral neurons were similar to those previously observed in the vascularly perfused whole rat stomach.

Regulation of gastrin and somatostatin secretion by gastric bombesin

Regulation of gastrin and somatostatin secretion by gastric bombesin

Role of the proximal duodenum in gastrin regulation following antrectomy.

Antrectomy is accepted as the most effective surgical treatment of recurrent duodenal ulcer after complete vagotomy. Although antrectomy is aimed at reducing serum gastrin levels, both human and experimental reports seem to indicate that gastrin concentrations may be unchanged following this operation. The probable source of gastrin has been considered to be the proximal third of the duodenum, since at this level increased tissue gastrin concentrations were found after antrectomy. The present study was carried out in order to gain insight into the mechanism by which the duodenum may compensate for the removal of the antrum. Forty white rats were randomly divided into two equal groups and underwent antrectomy with gastroduodenostomy or simple laparotomy. Three to four months after surgery, serum gastrin determinations were carried out by radioimmunoassay both in fasted and freely fed rats. The duodenum was then removed and its proximal third was used for G cell counts (immunoperoxidase method) and for assessment of G cell cytoplasmic granule distribution (electron-microscopic examination). Antrectomy significantly increased fasting serum gastrin levels (p less than 0.01), while it completely abolished the gastrin response to food ingestion (p less than 0.001). In antrectomized rats, the duodenal G cell number was significantly higher than in control rats (p less than 0.001), whilst the G cell cytoplasmic granule number remained unchanged. In conclusion, the present study indicates that in the rat the proximal duodenum increases its content of tissue gastrin following antrectomy mainly by enhancing the regional G cell density.

Vagal regulation of GRP, gastric somatostatin, and gastrin secretion in vitro.

The effect of electrical stimulation of the vagus nerves on the release of immunoreactive gastrin-releasing peptide (GRP), gastrin, and somatostatin was investigated using the isolated perfused rat stomach. Electrical stimulation (10 Hz, 1 ms duration, 10 V) of the peripheral end of the subdiaphragmatic vagal trunks produced a significant increase in both GRP and gastrin but a decrease in somatostatin. The infusion of atropine sulfate at a concentration of 10(-5) M augmented GRP release and reversed the decrease in somatostatin release in response to vagal stimulation to an increase above basal levels. However, the gastrin response to vagal stimulation was not affected by atropine. The infusion of hexamethonium bromide at a concentration of 10(-4) M significantly suppressed GRP release but did not affect gastrin secretion in response to vagal stimulation. On the other hand, the somatostatin response to vagal stimulation was completely abolished by hexamethonium. These findings lead us to conclude that the intramural GRP neurons might play an important role in the regulation of gastrin as well as somatostatin secretion and that somatostatin secretion may be controlled not only by a cholinergic inhibitory neuron but also by a noncholinergic, e.g., peptidergic stimulatory neuron, both of which may be regulated through preganglionic vagal fibers via nicotinic receptors. In addition, because the infusion of 10(-7) M GRP suppressed the somatostatin secretion, we suggest that either GRP should be excluded from the list of candidates for the noncholinergic stimulatory neurotransmitter for somatostatin secretion or that there are different mechanisms of action for endogenous and exogenous GRP.

Stimulation of gastrin secretion in vitro by intraluminal chemicals: Regulation by intramural cholinergic and noncholinergic neurons

The regulation of gastrin and somatostatin secretion by intraluminal chemicals was examined in an isolated vascularly perfused rat stomach, a preparation that maintains the integrity of intramural neural pathways and the polarity of stimulation. Intraluminal perfusion with alkaline solutions (0.1 M NaHCO3) increased gastrin secretion, whereas perfusion with acid solutions (pH 3.5-3.0) inhibited gastrin secretion. Perfusion with 0.5% or 5% peptone solutions stimulated gastrin secretion and inhibited somatostatin secretion. Both these responses were abolished by addition of the axonal blocker, tetrodotoxin (10−6 M), to the vascular perfusate, from which it was concluded that gastrin and somatostatin responses induced by peptone were mediated by intramural neurons. These neurons were both cholinergic and noncholinergic, because addition of an optimal dose of atropine (10−7 M) to the vascular perfusate inhibited only partially the gastrin response and converted the somatostatin response from decrease below basal levels—a typical cholinergic effect—to significant increase above basal levels. As shown previously, atropine had an identical effect on gastrin and somatostatin responses to transmural electrical stimulation of the antral region. The results are in accord with a model for the regulation of gastrin secretion by intramural cholinergic and noncholinergic neurons. A direct effect of intraluminal chemicals on gastrin and somatostatin cells was not detected in this study, but is not precluded.