Inhibition Of Gastrin Secretion Research Articles

The effect of porcine hydrolysed collagen on gastric ulcer scores, gastric juice pH, gastrin and amino acid concentrations in horses

SummaryGastric ulcers are common in horses. The purpose of this study was to test the effect of porcine hydrolysed collagen (PHC) on gastric ulcer scores and gastric juice pH in horses. We hypothesise that PHC‐administration will result in improved gastric lesion scores and act synergistically with omeprazole to improve treatment efficacy. Thoroughbred horses (n = 10) were studied in a 2‐period, 2‐treatment crossover design, where the PHC (45 g) was administered twice daily. Horses were treated for 56 days. Gastroscopy was performed and gastric juice pH measured on Days 0, 14, 28, 42, 49 and 56. Nonglandular gastric ulcer number (NGN) and severity (NGS) and glandular ulcer number (GN) and glandular severity (GS) scores were assigned by an investigator masked to treatment and serum gastrin and amino acid concentrations. By Day 42, 2 weeks after discontinuing omeprazole treatment, NGN and NGS scores returned to pretreatment values and serum gastrin was higher when compared to values measured on Day 28. By Day 49, after the feed‐deprivation period, NGN and NGS were similar to pretreatment values. By Day 56, mean NGN score was significantly lower in PHC‐treated horses, compared to controls. Mean gastric juice pH significantly increased in both groups on Day 28 and the pH was significantly (P = 0.0127) higher in the PHC‐treated horses. Serum amino acid concentrations were not significantly different 2 h after feeding PHC and hydroxyproline was not detected. Serum gastrin concentration did not increase 2 h after feeding in the PHC‐fed horses. The PHC fed to horses enhanced the effects of omeprazole on increased gastric juice pH, inhibited gastrin secretion after feeding and resulted in fewer nonglandular ulcers after long‐term feeding (56 days) in stall‐confined horses undergoing intermittent feeding.

The Effect of Proton Pump Inhibitors on Glycemic Control in Patients with Type 2 Diabetes.

Background: Type 2 diabetes patients have decreased pancreatic beta cell mass with a decline in beta cell function. Gastrin has increased beta cell proliferation in vitro and in animal studies. High gastric acid levels inhibit gastrin secretion. Proton pump inhibitors (PPIs) lower gastric acid, subsequently increasing gastrin levels. This may stimulate beta cell proliferation and function, and improve glycemic control. Studies with small numbers of type 2 diabetes patients have shown a slightly lower A1C in those taking PPI versus non-PPI users. Methods: This study was a retrospective multicenter electronic data analysis using data obtained from health care facilities within Veterans Integrated Service Network (VISN) 21. Patients were included if they had established care within VISN 21 and had type 2 diabetes with an A1C > 6.5%, were started on a PPI concurrently with stable doses of metformin or sulfonylurea (SFU) monotherapy, had at least two documented A1C values, and had a medication possession ratio >80% for metformin, SFU, or a PPI. Veterans were excluded if they were using insulin, combination antihyperglycemic therapy, or oral corticosteroids. A control group not using PPI was also identified. Results: There was a statistically significant decrease in A1C within each group. However, there was no statistically significant difference between the PPI and control group in the post-A1C. Conclusion: In patients with type 2 diabetes, A1C improved in both groups, but PPI addition did not affect glycemic control. Future randomized controlled trials are needed to determine the value of PPIs as a treatment option for patients with type 2 diabetes.

PACAP 1–38 as neurotransmitter in the porcine antrum

The concentration of PACAP 1–38 in porcine antrum amounted to 15.4±7.9 and 20.3±8 pmol/g tissue in the mucosal and muscular layers. PACAP immunoreactive (IR) fibres innervated the muscular (co-localised with VIP) and submucosal/mucosal layers (some co-storing VIP and CGRP) including myenteric and submucosal plexus and blood vessels. Only myenteric nerve cell bodies contained PACAP-IR (co-storing VIP). In isolated perfused antrum, vagus nerve stimulation (8 Hz) and capsaicin (10 −5 M) increased PACAP 1–38 release. PACAP 1–38 (10 −9 M) increased substance P (SP), gastrin releasing peptide (GRP) and VIP release. PACAP 1–38 (10 −8 M) inhibited gastrin secretion and stimulated somatostatin secretion and motility dose-dependently. PACAP-induced motility was strongly inhibited by the antagonist PACAP 6–38 but also by atropine and substance P-antagonists (CP99994/SR48968) but PACAP 6–38 had no effect on vagus-induced secretion or motility. Conclusion: PACAP 1–38 may be involved in antral motility and secretion by interacting with cholinergic, SP-ergic, GRP-ergic and/or VIP-ergic neurones, and may also be involved in afferent reflex pathways.

Effects of prostaglandins on gastrin release from canine antral mucosal cells in primary culture

Evidence in vivo indicates that endogenous and exogenous prostaglandins can alter gastrin secretion. We have used primary cultures containing canine antral G-cells to study the cellular actions of prostaglandins on gastrin secretion, comparing the effects of prostaglandin E2 (PGE2) and its synthetic analogue enprostil. Enprostil (10(-10)-10(-6) M) inhibited gastrin secretion in response to bombesin, carbachol, and forskolin, the latter a receptor-independent activator of adenylate cyclase. This inhibition by enprostil was reversed by treatment with pertussis toxin (200 ng/ml, 8 h). However, enprostil did not inhibit the postreceptor stimuli 8-bromoadenosine 3',5'-cyclic monophosphate (10(-3) M), calcium ionophore A-23187 (10(-7) M), or 4 beta-phorbol 12-myristate 13-acetate (10(-8) M). In contrast, whereas PGE2 inhibited forskolin-stimulated gastrin release, PGE2 did not inhibit the response to carbachol or bombesin in control cultures. However, in pertussis toxin-treated cultures, PGE2 inhibition was reversed and, in contrast, the responses to bombesin, carbachol, and possibly forskolin were augmented. Indomethacin at a dose of 10(-5) M did not alter basal or bombesin-stimulated gastrin secretion. However, the somatostatin antibody CURE-S6 enhanced the response to forskolin and enhanced inhibition by PGE2, suggesting that endogenous somatostatin produced an inhibitory tone in these cultures and excluding the possibility that PGE2 acted via release of endogenous somatostatin. Our data suggest that in cultured antral cells gastrin release is regulated by inhibitory and stimulatory prostaglandin mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)

Gastrin secretion induced by distention is mediated by gastric cholinergic and vasoactive intestinal peptide neurons in rats

Background: The present study was designed to identify the mechanism by which distention regulates gastrin secretion. Methods: The distal stomach of the isolated vascularly perfused rat was distended to varying degrees for 10-minute periods with an air-filled balloon. Results: Low distention caused a decrease in gastrin (39% ± 5%; P < 0.001) and an increase in somatostatin (58% ± 4%; P < 0.001) secretion. High distention caused an opposite effect, i.e., an increase in gastrin (49% ± 11%; P < 0.01) and a decrease in somatostatin (44% ± 11%; P < 0.01) secretion. All responses were abolished by the axonal blocker, tetrodotoxin. Atropine had no effect on the responses to low distention, but converted the pattern of response with high distention to that observed with low distention. Both high and low distention were accompanied by a sustained increase in vasoactive intestinal peptide (VIP) secretion. The selective VIP antagonist, VIP[10–28], abolished both the gastrin and somatostatin responses to low distention. Conclusions: Low gastric distention activates preferentially VIP neurons that stimulate somatostatin and thus inhibit gastrin secretion. Increasing distention leads to progressive recruitment of cholinergic neurons that cause a reversal in the pattern to one of increase in gastrin and decrease in somatostatin secretion.

Somatostatin restraint of gastrin secretion in pigs revealed by monoclonal antibody immunoneutralization.

We studied the functional coupling between antral somatostatin and gastrin cells in isolated perfused porcine antrum using immunoneutralization with monoclonal antibodies against somatostatin. Their binding affinity was 10(11) l/mol, and the final binding capacity was 11.7 nmol/ml. Antibody infusion within 1 min increased gastrin secretion, reaching a rate of 349 +/- 64% (means +/- SE, n = 7) of basal secretion (59 +/- 5 pmol/l) after 5 min. The effect of somatostatin at 10(-9) mol/l, which inhibited gastrin secretion from 58 +/- 11 to 14 +/- 3 pmol/min (n = 4), was abolished by antibody infusion. Electrical stimulation of the vagus nerves (n = 7) performed during antibody infusion increased gastrin secretion from 224 +/- 61 to 328 +/- 55 pmol/min, not significantly different from the increase in control experiments from 43 +/- 9 to 118 +/- 20 pmol/min, indicating that the vagal stimulation of gastrin secretion does not depend on mechanisms involving somatostatin. We conclude that paracrine antral somatostatin secretion is one of the most important factors regulating basal gastrin secretion in pigs.

Somatostatin is an essential paracrine link in acid inhibition of gastrin secretion.

We studied the functional coupling between antral somatostatin and gastrin cells in pigs using isolated perfused preparations of the antrum with intact supply of the vagus nerves. Luminal acidification significantly inhibited gastrin secretion to 61 +/- 3% of basal secretion and increased somatostatin output 9-fold. Intra-arterial infusion of somatostatin to concentrations of 10(-10) and 10(-9) mol/l inhibited gastrin secretion to 18 +/- 9 and 33 +/- 11% of basal secretion. Electrical stimulation of the vagus nerves and intra-arterial infusion of gastrin-releasing polypeptide (GRP; 10(-9) mol/l) significantly increased both gastrin and somatostatin secretion. Addition to the perfusate of Fab fragments of somatostatin antibodies abolished the effect of somatostatin at 10(-10) mol/l and the acid inhibition of gastrin secretion, but had no effect on the response to vagus stimulation of GRP infusion. We conclude that a local release of somatostatin is essential for the acid-induced inhibition of gastrin secretion, whereas changes in the local somatostatin concentration are unlikely to play a major role in vagally or GRP-induced gastrin secretion.

Mechanism for increase of gastrin release by secretin in Zollinger-Ellison syndrome

In patients with Zollinger-Ellison syndrome, serum gastrin level is increased by secretin and is decreased by somatostatin. To elucidate the cellular mechanism for these actions, we investigated the direct effects of secretin and somatostatin on dispersed gastrinoma cells from a patient with Zollinger-Ellison syndrome. In the presence of 3-isobutyl-1-methylxanthine, secretin significantly stimulated gastrin release from dispersed gastrinoma cells, which was inhibited by somatostatin. In the presence of guanosine 5′-triphosphate, furthermore, secretin enhanced adenylate cyclase activation in the membranes from these cells, and this activation was reduced by somatostatin, whereas neither secretin nor somatostatin affected inositol phospholipid turnover. On the other hand, removal of guanosine 5′-triphosphate from incubation medium abolished both the stimulatory effect of secretin and the inhibitory effect of somatostatin on adenylate cyclase activation. Furthermore, pertussis toxin pretreatment reversed the ability of somatostatin to inhibit secretin-induced increase in gastrin release and activation of adenylate cyclase. Thus, in this gastrinoma patient, secretin and somatostatin appeared to act directly on gastrinoma cells to stimulate and inhibit gastrin secretion, respectively, by modulating adenylate cyclase activation, probably via guanine nucleotide-binding proteins.

The significance of gastrin in the pathogenesis and therapy of peptic ulcer disease.

Gastrin, a polypeptide hormone secreted by G (gastrin)-cells in the antroduodenal mucosa, is not only a potent stimulant of gastric acid secretion but also exerts trophic actions on the parietal, chief and enterochromaffin-like cells in the oxyntic mucosa. Gastrin plays a crucial role in the pathogenesis of hypergastrinaemic peptic ulcer disease, i.e. in the Zollinger-Ellison syndrome, antral G-cell hyperfunction and retained excluded antrum after subtotal gastrectomy. In patients with normogastrinaemic duodenal ulcer disease the feedback mechanism between gastric acid and gastrin secretion is impaired, while in gastric ulcer patients gastrin secretion is appropriately regulated by gastric acid. Antisecretory drugs may exert varying effects on gastrin secretion. Potent antisecretory drugs, such as omeprazole, increase serum and antral gastrin concentrations, whereas histamine H2-receptor antagonists, such as cimetidine, ranitidine, famotidine and roxatidine, have little influence on gastrin. Interestingly, antisecretory doses of prostaglandin E2-analogues, such as enprostil and arbaprostil [15(R)-15-methylprostaglandin E2], inhibit gastrin secretion, while gastrin is not influenced by prostaglandin E1-analogues, e.g. misoprostol. Somatostatin and the somatostatin-analogue SMS 201-995 reduce serum gastrin levels and gastric acid secretion.

Characterization of the in vivo and in vitro inhibition of gastrin secretion from gastrinoma by a somatostatin analogue (SMS 201-995)

Earlier experiments characterized the effect of SMS 201-995 on gastrin secretion from gastrinoma in vivo. The results showed that the somatostatin analogue inhibits basal as well as secretin- and calcium-stimulated gastrin secretion. The current study examined the effect of SMS 201-995 on gastrin secretion from gastrinoma in vitro. Gastrinoma cells were prepared in cell culture or acute cell dispersion to study basal gastrin release. In cell culture, SMS 201-995 at 10 −9M, 10 −8M, and 10 −7 M significantly stimulated gastrin secretion (basal medium gastrin, 157 ± 7.9 pg/ml; with SMS 201-995 10 −9 M, 786 ± 62 pg/ml; with SMS 201-995 10 −8 M, 569 ± 72 pg/ml; and with SMS 201-995 10 −7 M, 258 ± 26 pg/ml). In contrast, in acute cell dispersion, the somatostatin analogue inhibited gastrin secretion (basal medium gastrin, 12.8 ± 1.3 ng/ml; with SMS 201-995 10 −9M, 9.0 ± 0.1 ng/ml; with SMS 201-995 10 −8 M, 8.4 ± 1.5 ng/ml; and with SMS 201-995 10 −7 M, 7.9 ± 0.2 ng/ml). Gastrinoma cells were prepared in cell culture to study the effect of SMS 201-995 on gastrin secretion stimulated by secretin and by post-receptor increases in adenosine cyclic nucleotide. The somatostatin analogue inhibited gastrin secretion stimulated by secretin (10 −6 M) (797 ± 48 pg/ml for secretin alone, compared with 396 ± 9.4 pg/ml for secretin plus SMS 201-995). SMS 201-995 did not inhibit gastrin secretion stimulated by dibutryl cyclic AMP (10 −7 M) (617 ± 62 pg/ml for dibutryl cyclic AMP alone, compared with 778 ± 55 pg/ml for the two together). In vitro, SMS 201-995 inhibits basal gastrin secretion from gastrinoma prepared in acute cell dispersion, but not gastrinoma in cell culture, probably due to differences in basal secretory rates. The effect in vitro is less than that in vivo. SMS 201-995 does not inhibit postreceptor increases in adenosine nucleotide. This indirectly supports the hypothesis that SMS 201-995 acts in gastrinoma cells to inhibit gastrin secretion by inhibition of adenylate cyclase activity.

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.

Inhibition of gastrin secretion by pirenzepine (LS 519) in treatment of gastric ulcer.

The effects of pirenzepine on the serum gastrin levels in the basal state and in response to a liquid test meal were investigated in nine patients with gastric ulcer. Single-dose administration of the drug caused a significant decrease in the basal gastrin level and significant inhibition of the serum gastrin response. When measured 12 h after the end of drug treatment for 7 days, the serum gastrin levels in the basal state and in response to a test meal tended to be high, but the differences were not statistically significant.

Inhibition of gastrin secretion by sulpiride treatment in duodenal ulcer patients

The serum gastrin response to whole beef extract was measured in 14 duodenal ulcer patients before and after sulpiride administration. A significant inhibition of response was found both after acute intramuscular injection of the drug and after oral administration for 1 week. Fasting serum gastrin was also significantly reduced after chronic treatment; gastric acid secretion did not change. Although the mechanism of the gastrin-lowering action of sulpiride is unknown, it could be mediated by some known effect(s) of the drug, such as modifications in brain monoamine metabolism or perhaps reduced growth hormone secretion.

Immunohistochemical localization of somatostatin in endocrine cells of the rat stomach

Using an immunohistochemical technique involving unlabeled antibody and the peroxidaseanti-peroxidase complex, we have localized somatostatin (or growth hormone-release inhibiting hormone), a hypothalamic hormone which can also inhibit gastrin secretion, in the rat stomach. Somatostatin was found to be present in a few cells in the mucosa of the pyloric antrum. These cells are characterized by the presence of secretory granules of about 150–250 nm in diameter and are probably endocrine cells.

Direct inhibitions of basal and arginine-induced plasma gastrin secretion by somatostatin in anesthetized dogs.

Effect of somatostatin on plasma gastrin levels was investigated in anesthetized dogs. Somatostatin was infused into the right gastroepiploic artery and plasma gastrin levels in the right gastroepiploic, superior pancreaticoduodenal and peripheral veins were measured by radioimmnuoassay. Somatostatin suppressed basal gastrin level promptly in the right gastroepiploic vein and impaired the normal gastrin secretion in response to intravenous infusion of arginine. The inhibitory effect of somatostatin on the plasma gastrin secretion was quite clearly demonstrated in the right gastroepiploic vein. It appears likely that the inhibition of gastrin secretion by somatostatin resulted in direct action on the gastrin secretory cell.

Effects of somatostatin on gastric secretion and gastrin release in man.

Somatostatin, a recently synthesized hypothalamic growth hormone release-inhibiting factor (GIF), was used in the cyclic and linear form. In all subjects studied, the cyclic GIF inhibited gastrin secretion during basal conditions as well as during a standard food stimulus, with immediate rebound after the infusion was stopped. Similar responses were observed in a hypophysectomized patient, indicating that this effect of GIF was independent of suppression of growth hormone secretion. Cyclic and linear GIF, when administered in normal subjects during an infusion of synthetic human gastrin I, almost totally suppressed gastric secretion. The results indicate that GIF is a potent inhibitor of gastric secretion and gastrin release.