Gastrin Inhibition Research Articles

Role of an anti-gastrin vaccine (PAS) alone and in combination with a PD-1 antibody on growth and metastases of gastric cancer.

334 Background: Gastric cancer is a leading cause of cancer-related deaths worldwide. Many of those with advanced gastric cancer are responsive to immune checkpoint antibody therapy, although the median survival even with these new agents is less than 12 months. The gastrointestinal peptide, gastrin, has been shown to stimulate growth of gastric cancer through the cholecystokinin-B receptor (CCK-BR) and the inhibition of gastrin’s action results in decreased growth. In the current investigation we studied the effects of a cancer vaccine, Polyclonal Antibody Stimulator (PAS) that targets the gastrin peptide on growth of gastric cancer in mice. Methods: RNA was extracted from NCC-S1 and YTN-16 murine gastric cancers and analyzed by qRT-PCR for gastrin, CCK-BR, and PD-L1 expression. YTN-16 (5x106) cells were injected subcutaneously in (N = 40) syngeneic female C57BL/6 mice. Mice were divided into 4 groups of equal tumor size and treated with PBS (control), PD-1 antibody (PD-1 Ab) 50 μg, PAS 250μg, or the combination of the PD-1 Ab and PAS given at one week after tumor inoculation (week 0) and at weeks 1, 3, and 6. A PAS booster was also given at week 9.Tumor growth rate was monitored weekly with calipers. At the end of treatment, tumors were excised, weighed and analyzed with Masson’s trichrome stain for fibrosis, and for Ki67, CD8 T-cells, and M2-polarized macrophages by immunohistochemistry. Metastases were counted and confirmed by histology. Results: Gastrin, CCK-BR, and PD-L1 expression were confirmed by qRT-PCR in the gastric cancer cells. PAS monotherapy (P = 0.023) or PAS in combination with PD-1 Ab (P = 0.0003) resulted in significantly slowed tumor growth and with no metastases observed. Tumor weights were 40-52% smaller in mice treated with PAS or the combination therapy compared to PBS or PD-1 Ab, respectively, but this difference did not reach significance (P = 0.09). PD-1 Ab monotherapy did not change tumor size compared to PBS-treated control mouse tumors. Ki67 staining was decreased by 62-67% and fibrosis staining was decreased by 51-61% in tumors of mice treated with PAS monotherapy or in combination with PD-1 Ab, respectively (P < 0.0001). PAS monotherapy resulted in a 4-fold increase of CD8+ T-cells and a 56% decrease in M2-polarized macrophages (P = 0.0001) compared to control tumors. PAS and PD-1 Ab combination therapy resulted in an additive effect with 29% more CD8+ T-cells (P < 0.05) and 54% fewer M2-polarized macrophages (P < 0.0001) compared to tumors of PAS monotherapy-treated mice. Conclusions: Treatment of mice with an anti-gastrin vaccine, PAS, slows growth of gastric cancer and prevents metastases. PAS vaccination improves the effectiveness of PD-1 Ab therapy in part by decreasing tumor fibrosis and altering the tumor immune cell signature. This study suggests that addition of PAS to immune checkpoint antibody therapy in gastric cancer may be beneficial.

Immunohistochemical localizations of secretin, cholecystokinin, and somatostatin in the rat small intestine after acute cisplatin treatment

Cisplatin (CDDP) is an antitumor platinum complex that causes the well-studied side effect of renal tubular failure. In the present study, the acute effects of CDDP treatment on the localization of gut hormones in the rat small intestine were examined by immunohistochemistry. Male Sprague–Dawley rats were used for these experiments. Rats were injected intravenously with CDDP (3 mg/kg) in saline or were left untreated (control). After the rats were euthanized at 1, 3, 5, or 10 days after CDDP treatment, the small intestines (duodenum, jejunum, and ileum) were quickly removed, fixed, embedded in paraffin, and cut. No mucosal toxicity was detected by histopathological observation in any of the intestines of CDDP-treated rats. The immunohistochemical detection was performed using anti-secretin, anti-cholecystokinin (CCK), and anti-somatostatin with the avidin–biotin-immuno-peroxidase procedure. The total number of immunoreactive cells per complete cross-section was counted. In the duodenum, the numbers of secretin-immunoreactive cells and somatostatin-immunoreactive cells were dramatically increased 5 days after CDDP treatment. In the jejunum, the number of CCK-immunoreactive cells was increased 1 day after CDDP treatment and those of secretin-immunoreactive cells and CCK-immunoreactive cells were increased 5 days after CDDP treatment. In the ileum, the number of CCK-immunoreactive cells was increased 1 day after CDDP treatment. The change in the secretin-immunoreactive cell count may be caused by metabolic inhibition of gastrin following CDDP-induced nephrotoxicity. The change in the CCK-immunoreactive cell count may promote the excretion of bile. Therefore, somatostatin may regulate secretin and CCK secretion. We conclude that the distribution of these hormone-immunoreactive cells in the rat small intestine might be controlled by CDDP-induced nephrotoxicity without gut mucosal toxicity.

Demonstration of Acid Secretion in the Gastric Pouch through the Pentagastrin Stimulation Test

Introduction: The aim of this study is to determine the relationship of hydrochloric acid secretion in gastric pouch (GP), an orthotopic neobladder using a stomach segment, to gastrin. Material and Method: Pentagastrin (PG) stimulation test (PGST) was applied in 10 patients who had had GP surgery 5–70 months ago, and their urinary pH changes in the next 2 h were observed. Results: Significant pH decreases (from 6.6 ± 0.6 to 2.9 ± 1.0 in the mean) 30–75 min after injection of PG, demonstrating gastrin-triggered acid secretion in GP were observed in all patients. The pH values were normalized in 2 h (6.6 ± 1.0 in the mean). Conclusion: In PGST, urinary pH decreases, demonstrating the close relationship between gastrin release and acid secretion in the GP. Inhibition of gastrin by any means may be useful in keeping the urinary pH on physiological levels.

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.

Neurohormonal regulation of secretion from isolated rat stomach ECL cells: a critical reappraisal

ECL cells are endocrine/paracrine cells in the oxyntic mucosa. They produce, store and secrete histamine and chromogranin A-derived peptides such as pancreastatin. The regulation of ECL-cell secretion has been studied by several groups using purified ECL cells, isolated from rat stomachs. Reports from different laboratories often disagree. The purpose of the present study was to re-evaluate the discrepancies by studying histamine (or pancreastatin) secretion from standardized preparations of pure, well-functioning ECL cells. Cells from rat oxyntic mucosa were dispersed by pronase digestion, purified by repeated counter-flow elutriation and subjected to density gradient centrifugation. The final preparation consisted of more than 90% ECL cells (verified by histamine and/or histidine decarboxylase immunocytochemistry). They were maintained in primary culture for 48 h before they were exposed to candidate stimulants and inhibitors for 30 min after which the medium was collected for determination of mobilized histamine (or pancreastatin). Gastrin-17 and sulphated cholecystokinin octapeptide (CCK-8s) raised histamine secretion 4-fold, the EC 50 for both peptides being around 100 pM. The neuropeptide pituitary adenylate cyclase activating peptide (PACAP-27) (5-fold increase) and the related neuropeptides vasoactive intestinal peptide (VIP) and peptide histidine isoleucine (PHI) (3-fold increase) mobilized histamine with similar potency (EC 50 ranging from 80 to 140 pM). Adrenaline, isoprenaline and terbutaline stimulated secretion by activating a β 2 receptor subtype, while acetylcholine and carbachol were without effect. Secretion experiments were invariably run in parallel with a gastrin standard curve. Somatostatin, prostaglandin E 2 (PGE 2) and the PGE 1 congener misoprostol inhibited PACAP- and gastrin-stimulated secretion by more than 90%, with IC 50 values ranging from 90–720 (somatostatin) to 40–200 (misoprostol) pM. The neuropeptide galanin inhibited secretion by 60–70% with a potency similar to that of somatostatin. Proposed inhibitors such as peptide YY, neuropeptide Y and the cytokines interleukin 1-β and tumor necrosis factor α induced at best a moderate inhibition of gastrin- or PACAP-stimulated secretion at high concentrations, while calcitonin gene-related peptide, pancreatic polypeptide and histamine itself were without effect. Inhibition of gastrin- or PACAP-stimulated secretion was routinely compared to a somatostatin standard curve. In conclusion, gastrin, PACAP, VIP/PHI and adrenaline stimulated secretion. Somatostatin and PGE 2 were powerful inhibitors of both gastrin- and PACAP-stimulated secretion; although equally potent, galanin was less effective than somatostatin and PGE 2.

Acid-sensitive and alkaline-sensitive sensory neurons regulate pH dependent gastrin secretion in rat.

We examined the role of capsaicin-sensitive afferent neurons in pH-dependent gastrin secretion in the rat stomach. The change in serum gastrin levels relative to changes in luminal pH (using omeprazole for luminal alkalization or 0.1 N HCl for luminal acidification) was studied after oral administration of 4% lidocaine or capsaicin-induced ablation of afferent neurons. The increase of serum gastrin levels by luminal alkalization was significantly inhibited (50%) after administration of 4% lidocaine. Capsaicin pretreatment (125 mg/kg subcutaneously over two days) inhibited the change in serum gastrin levels both the luminal alkalization (38%) and acidification (66%). Antral gastrin contents, somatostatin contents, gastrin mRNA expression, and somatostatin mRNA expression were not significantly affected by capsaicin pretreatment. Our results indicate that capsaicin-sensitive afferent neurons participate in the secretion of gastrin by luminal alkalization and inhibition of gastrin by luminal acidification.

Somatostatin-14 modulates acid-dependent inhibition of meal-stimulated gastrin via muscarinic pathways in dogs

Intraluminal antral acidification inhibits gastrin and stimulates somatostatin-14 (S-14) release, but a functional relationship in the postprandial state has not been established. To examine whether meal-stimulated S-14 mediates inhibition of gastrin release by gastric acid, the effects of omeprazole on circulating levels of S-14 separated from S-28 by gel permeation chromatography, and gastrin were measured without and with atropine in dogs. Compared to controls, pretreatment with omeprazole decreased postprandial plasma levels of S-14 and S-28 (both P<0.01) and increased gastrin ( P<0.001). Atropine selectively converted the S-14 response after omeprazole to a peak sixfold increase 40 min after meal ingestion ( P<0.001), which was also significantly above S-14 values after atropine alone and controls, but reduced plasma levels of S-28 and gastrin to baseline. Infusions of the somatostatin analogue, cyclo-[7-aminoheptanoyl-Phe- d-Trp-Lys-Thr(BZL)] increased postprandial gastrin twofold above controls ( P<0.05), and when administered after omeprazole reversed the inhibition of gastrin by atropine, without altering S-14 levels. In contrast, infusions of S-14, which simulated S-14 levels after omeprazole-atropine, and of [ d-Trp 8]-S-14, which abolished meal-stimulated S-14 responses, did not alter postprandial elevations of plasma gastrin. This study suggests that in conscious dogs muscarinic inhibitory pathways selectively regulate S-14 secretion, are amplified at neutral gastric pH and reciprocally link S-14 to gastrin secretion in the gastric phase of meal ingestion. Postprandial regulation of gastrin release by S-14 includes neurocrine interactions with muscarinic receptor activation; endocrine or paracrine regulation seem less likely.

Gastric effects of the CCK-B/gastrin receptor ligand CI-988 in cynomolgus monkeys

We have previously demonstrated that the CCK-B/gastrin receptor ligand CI-988 induces gastric gland degeneration and atrophy in cynomolgus monkeys, an effect consistent with gastrin receptor antagonism and inhibition of gastrin's trophic effects on oxyntic mucosa. However, gastrin receptor ligands of the dipeptoid chemical series to which CI-988 belongs have been reported to act as agonists or antagonists towards gastrin-related events, depending on the animal model and the functional endpoint examined. To investigate further these apparently conflicting data, basal gastric acid secretion was monitored acutely in conscious monkeys given CI-988 orally at 10 mg/kg or intravenously at 0.01 μmol/kg/hr and histological changes in gastric mucosa were evaluated in monkeys given CI-988 orally at 5, 25 or 75 mg/kg/day for 4 weeks. Degeneration and atrophy of gastric glands occurred at 25 and 75 mg/kg with statistically significant decrements in gastric mucosal height at 75 mg/kg. In addition, CI-988 stimulated gastric acid secretion when given either orally or intravenously. Co-administration of the structurally unrelated CCK-B/gastrin antagonist L-365 260 completely blocked CI-988-stimulated acid secretion, confirming that CI-988's agonist effect on acid secretion is mediated by the gastrin receptor. Assuming that gastric mucosal degeneration is the result of inhibition of gastrin's trophic activity, CI-988 appears to induce paradoxical agonist and antagonist gastrin-receptor mediated effects.

Somatostatin receptor subtype 2 mediates inhibition of gastrin and histamine secretion from human, dog, and rat antrum

BACKGROUND & AIMS: In gastric antrum, somatostatin exerts a tonic inhibitory influence on gastrin and histamine secretion. Five different subtypes of somatostatin receptors, designated sst1-5, have been identified. sst2, sst3, and sst5 subtypes have been localized to the stomach by molecular biological techniques. The aim of this study was to identify the sst subtype regulating gastrin and histamine secretion in human, dog, and rat stomach. METHODS: Mucosal segments from human, dog, and rat antrum were superfused with various concentrations of somatostatin 14 and somatostatin analogues selective for sst2, sst3, and sst5. Gastrin and histamine were measured by radioimmunoassay. RESULTS: Somatostatin 14 and the sst2 agonist EC 5-20 inhibited gastrin and histamine secretion from all three species in a concentration- dependent manner, whereas the sst3 and sst5 agonists had no significant effect. Neutralization of endogenous somatostatin with the somatostatin antibody increased gastrin and histamine secretion. The increases were not affected by the gastrin antagonist but were abolished by the sst2 agonist, implying that the inhibitory influence of ambient somatostatin is exerted directly on the histamine cell rather than indirectly via changes in gastrin secretion. CONCLUSIONS: Somatostatin inhibits gastrin and histamine secretion in human, dog, and rat antrum by activating sst2 receptors on gastrin and histamine cells. (Gastroenterology 1996 Oct;111(4):919-24)

Fundic somatostatin-mediated inhibition of gastrin- stimulated acid secretion is defective in H. pylori gastritis

Fundic somatostatin-mediated inhibition of gastrin- stimulated acid secretion is defective in H. pylori gastritis

Characterization of the somatostatin receptor subtype mediating inhibition of gastrin and histamine secretion from the antrum of human, dog, and rat stomach: [formula omitted], L. Harrington, R. McCuen, D.H. Coy, G.M. Makhlouf, and M.L. Schubert. Medical College of Virginia and McGuire Veterans Affairs Medical Center, Richmond, VA

Characterization of the somatostatin receptor subtype mediating inhibition of gastrin and histamine secretion from the antrum of human, dog, and rat stomach: [formula omitted], L. Harrington, R. McCuen, D.H. Coy, G.M. Makhlouf, and M.L. Schubert. Medical College of Virginia and McGuire Veterans Affairs Medical Center, Richmond, VA

Differential kinetics for immunoneutralization of circulating gastrin by gastrin monoclonal antibody and its Fab 1 fragment in rats

The kinetics of gastrin immunoneutralization were studied in rats treated with a mouse monoclonal IgG antibody to gastrin (CURE GAS 93) and with the Fab 1 prepared from this antibody. Clearance studies using specific ELISA measurements of serum IgG of Fab determined the T 1 2 for IgG as 59.3 ± 3.5 h and for Fab 1 as 7.3 ± 0.7 h. Gastrin was immunoneutralized in rats for up to 16 days using alternate day IP injections of anti-gastrin immunoglobulin. Gastric acid secretion stimulated by gastrin-17, but not histamine, was inhibited 48 h after the last dose of antibody, indicating specific inhibition of gastrin. Peak serum levels of antibody were observed 8 h after IP administration and indicated an estimated 70% absorption of the administered dose. Fab 1 fragments completely blocked gastric acid secretion stimulated by gastrin-17, but not histamine, 4 h after IV administration; however, this effect was not observed 24 h after administration. This study demonstrates the effectiveness of chronic immunoneutralization of gastrin and defines the effective period of immunoneutralization for intact IgG and for the Fab 1 fragment.

Asymptomatic H. pylori infection impairs pH inhibition of gastrin and acid secretion during second hour of peptone meal stimulation.

H. pylori infection is associated with acid-peptic disease, although its role in the pathogenesis is unclear. The purpose of this study was to determine if chronic infection in asymptomatic subjects impairs the inhibition of meal-stimulated gastrin and acid secretion that is observed normally at low intragastric pH. Presence of infection was determined by both C-14 urea breath test and serology. Acid secretion was measured under basal conditions and in response to peptone meal stimulation and pentagastrin. Plasma gastrin concentrations were determined by radioimmunoassay under basal conditions and during peptone meal stimulation. Intragastric titration with 1% peptone during the first hour, and 8% peptone during the second hour, was performed at both pH 7.0 and 2.5 on different days to compare the inhibition of gastrin and acid secretion. Compared to noninfected subjects, asymptomatic individuals infected with H. pylori had significantly increased: (1) basal gastrin values (P < 0.005); (2) 8% peptone-stimulated gastrin responses at both pH 7.0 and 2.5 (P < 0.05); and (3) 8% peptone-stimulated acid output at pH 2.5 (P = 0.01). During the second hour of peptone-stimulation, subjects infected with H. pylori had significantly decreased inhibition of gastrin (52% vs 95%) (P = 0.002) and acid (30% vs 81%) (P = 0.01) secretion from pH 7.0 to 2.5. Thus, chronic infection with H. pylori results in impaired inhibition of gastrin and acid secretion at low intragastric pH during the second hour of peptone meal stimulation. These defects may be unrelated to the pathogenesis of acid-peptic disease, since they occur in asymptomatic subjects infected with H. pylori.

Octreotide long term treatment of acromegaly: effect of drug withdrawal on serum growth hormone/insulin-like growth factor-I concentrations and on serum gastrin/24-hour intragastric pH values.

We studied a possible persistence of low GH concentrations after drug withdrawal in eight acromegalic patients who had been receiving octreotide treatment continuously for 42 months. Since octreotide induces chronic active gastritis, intragastric pH and serum gastrin were also determined before and during drug withdrawal. Results were compared to the respective pretreatment (pre-Tx) values. GH and insulin-like growth factor-I (IGF-I) increased after 4 weeks of octreotide withdrawal to pre-Tx values (GH, 12-h profile, 4.5 +/- 0.6, 2.6 +/- 0.7, and 5.6 +/- 1.1 micrograms/L; IGF-I, three samples, 3.4 +/- 0.4, 0.8 +/- 0.1, and 2.5 +/- 1.0 IU x 10(3)/L; means +/- SE, pre-Tx, on and off octreotide). A reduced insulin and augmented glucose response to oral glucose during therapy normalized after octreotide withdrawal (insulin, 527 +/- 84, 289 +/- 62, and 733 +/- 110 pmol/L; glucose, 6.2 +/- 0.3, 8.5 +/- 0.4, and 6.8 +/- 0.2 mmol/L; pre-Tx, on and off octreotide, means +/- SE). During octreotide treatment, the median 24-h intragastric pH value was 2.8 (pre-Tx pH not determined), and the median serum gastrin concentration (areas under the curve of 12-h profiles) was 1275 +/- 153 ng/L.12 h (n = 7). During octreotide withdrawal, pH decreased to 1.4, while serum gastrin increased to a median of 2937 +/- 472 ng/L.12 h. We conclude that GH and IGF-I suppression by long term octreotide therapy does not persist after drug withdrawal, indicating a need for life-long treatment. Octreotide-induced insulin suppression and glucose elevation are reversible. A high gastric pH during treatment may facilitate the development of octreotide-related gastritis. The gastrin increase during octreotide withdrawal probably reflects a response to chronic active gastritis after release from octreotide-induced gastrin inhibition.

Role of serum fasting gastrin in screening for hypergastrinemic syndromes in duodenal ulcer disease

Basal serum gastrin levels were measured in 237 patients with endoscopically confirmed duodenal ulcer and were higher than normal in 16 cases. Protein meal gastrin stimulation was performed on this group of 16 patients and on a control group of 48 patients with normal basal gastrin concentrations but high rates of either ulcer recurrence or of complications (e.g., bleeding or perforation); 21 patients from the two groups were also tested for serum gastrin inhibition with secretin. Four cases (25%) of antral G-cell hyperfunction were found in the first group, plus 1 case compatible with Zollinger-Ellison syndrome (6.2%). Only 1 case (2%) of antral G-cell hyperfunction was found among the 48 controls. These results suggest the clinical utility of routine basal gastrin measurement in screening for hypergastrinemic patients with duodenal ulcer disease.

Inhibition of gastrin‐ and histamine‐stimulated gastric acid secretion by gastrin and cholecystokinin antagonists in the rat

The gastric acid inhibitory activities of a peptide-like gastrin receptor antagonist, Boc-beta Ala-Trp-Leu-Asp-O(CH2)2-Ph-4-F (CH-486), a nonpeptide gastrin/CCK-B antagonist (L-365,260), and a CCK-A antagonist (L-364,718), were investigated in the gastric lumen-perfused anaesthetized rat. A single i.v. injection of CH-486, 100 mumol/kg, reduced acid secretion stimulated by pentagastrin, 15 micrograms kg/h, to unstimulated levels, with no recovery within 50 min. Histamine-, 0.1 mumol kg/min, and carbamylcholine-, 0.1 mg kg/h, stimulated acid secretion were also reduced to unstimulated levels by CH-486, 100 mumol/kg, although with these latter two stimulants the inhibition was transient. L-365,260 and L-364,718, 10 mumol/kg, significantly inhibited both pentagastrin- and histamine-stimulated acid secretion, the latter again transiently. We conclude that the non-selective nature of the gastric acid inhibitory activity of gastrin antagonists might allow novel approaches to control gastric acid secretion in peptic ulcer disease.

Protective action of panthetin on the denervated stomach

Bilateral subdiaphragmal vagotomy was performed in sexually-mature Wistar male rats. To prevent neurodystrophic processes in the stomach mucous membrane some animals were injected pantetine subcutaneously at a dose of 30 mg/kg 5 times daily for 10 days. Pantetine injected to vagotomized animals decreased destructive lesions in the stomach mucous membrane. Enhanced biosynthesis and the inhibition of gastrin and serotonin release from G and Ec cells respectively have been observed. The results obtained substantiate the use of pantetine for the pharmacological correction of postoperative complications in patients after vagotomy.

The effect of secretin on acid and pepsin secretion and gastrin release in the totally isolated vascularly perfused rat stomach

The effect of secretin on acid and pepsin secretion and gastrin release in the totally isolated vascularly perfused rat stomach was studied. With the phosphodiesterase inhibitor isobutyl methylxanthine (IMX) added to the vascular perfusate, baseline acid secretion was 4.7 +/- 1.1 (mean +/- S.E.M.) mumol/h and baseline pepsin output 1147 +/- 223 micrograms/h. Secretin significantly inhibited acid output to a minimum of 1.4 +/- 0.2 mumol/h at a concentration of 25 pM in the vascular perfusate (P less than 0.01). Pepsin output was not significantly different from baseline at any of the secretin doses tested. Threshold secretin concentration for acid inhibition was 5 pM. IMX stimulated gastrin output from 48 +/- 9 pM in the basal state to 95 +/- 13 pM after IMX (P less than 0.01). Secretin inhibited gastrin release only at the maximal dose of 625 pM, when gastrin concentration in the venous effluent decreased from 93 +/- 19 to 68 +/- 19 pM after secretin. Thus, in the totally isolated vascularly perfused rat stomach secretin in physiological concentrations inhibits acid secretion by a direct action on the acid secretory process and not via gastrin inhibition. The study also suggests that gastrin release at least in part is mediated via increased intracellular cAMP.

Hypergastrinemia Develops Within 24 Hours of Truncal Vagotomy in Dogs

Postvagotomy hypergastrinemia may result from withdrawal of tonic vagal inhibitory mechanism(s) or from G-cell hyperplasia secondary to diminished acid secretion. Early development of hypergastrinemia, after vagotomy, would favor the first mechanism, whereas delayed development would favor the second. We sought to distinguish between these two mechanisms and to determine whether alterations in somatostatin release might mediate postvagotomy hypergastrinemia. We measured plasma concentrations of gastrin and somatostatinlike immunoreactivity basally and in response to meal (pH controlled at 5.5) and to insulin hypoglycemia before and after truncal vagotomy in 11 dogs. Basal and postprandial hypergastrinemia were established within 24 and 48 h after vagotomy, respectively. Basal and meal-stimulated plasma somatostatinlike immunoreactivity concentrations were unaltered by vagotomy, although insulin hypoglycemia-induced rises in plasma somatostatinlike immunoreactivity were abolished by vagotomy. Our data suggest that neither G-cell hyperplasia nor alterations in somatostatin release explain postvagotomy hypergastrinemia in the dog. The observations support the hypothesis that postvagotomy hypergastrinemia results from the withdrawal of a tonic vagal inhibitory mechanism of gastrin release that is independent of somatostatin. Whether the tonic vagal inhibition of gastrin is direct or indirect is unknown.

Somatostatin-14 and -28: clearance and potency on gastric function in dogs.

To examine the significance of somatostatin-14 (S-14) and somatostatin-28 (S-28) in gastric physiology, we compared their relative potencies on acid secretion in the dog. On a molar infusion basis, S-14 and S-28 appeared to be equipotent, causing 50% inhibition of peptone meal-stimulated acid secretion at a dose of 400 pmol . kg-1 . h-1. However, comparison of the plasma half lives (t 1/2) of the two peptides revealed that S-28 disappeared at a much slower rate (t 1/2 = 2.84 +/- 0.15 min, mean +/- SE, n = 7) than S-14 (t 1/2 = 0.57 +/- 0.06 min). When acid-inhibitory effect was compared against increment in plasma concentrations produced by peptide infusion, S-14 was roughly 10-fold more potent than S-28. No alteration of gastrin response to peptone was observed at a dose of S-14 or S-28 that completely abolished acid secretion, suggesting that regulation of acid secretion is not mediated by gastrin inhibition. Thus, S-14 is a potent and possibly important physiological inhibitor of gastric acid secretion. Although circulating S-28 may have importance in regulation of some biological functions, it appears to play a less prominent role in regulation of gastric secretion.