Calcitonin and secretin inhibit bombesin-stimulated serum gastrin and gastric acid secretion in man

The effect of intravenously administered calcitonin and secretin on bombesin-stimulated serum gastrin and gastric acid secretion was studied in 7 volunteers. Secretin G.I.H. (1 C.U./kg per h) and calcitonin (0.5 I.U./kg per h) significantly ($\text{P < 0.05}$) inhibited the serum gastrin and gastric acid responses to bombesin-14 (90 pmol/kg per h). Inhibition of gastrin release could not fully account for the inhibition of gastric acid secretion.     

辣椒素敏感传入神经和NO中介大鼠胃扩张引起的胃酸分泌和胃粘膜血流量变化

目的和方法：本文采用氢气清除法测定胃粘膜血流量以及大剂量辣椒素使传入神经失去功能的技术,观察大鼠胃扩张过程中引起胃酸分泌和胃粘膜血流量(gastric mucosal blood flow,GMBF)的变化以及传入神经和内源性NO在这一效应中的作用。结果：①大鼠胃扩张引起胃酸分泌时GMBF增加。②预先用大剂量辣椒素消除传入神经作用可阻断胃扩张引起的GMBF脚增加效应,并部分阻断胃酸分泌。③预先静脉注射一氧化氮(nitric oxide,NO)生物合成阻断剂L-nitro-L-arginine methyl ester(L-NAME)胃扩张引起的GMBF增多效应消失,同时胃酸分泌减弱。结论：辣椒素敏感传入神经和内源性NO参与胃扩张引起的胃酸分泌及胃粘膜血流增多效应。     

Gastric mucosal integrity: gastric mucosal blood flow and microcirculation. An overview

The stomach is in a state of continuous exposure to potentially hazardous agents. Hydrochloric acid together with pepsin constitutes a major and serious threat to the gastric mucosa. Reflux of alkaline duodenal contents containing bile and pancreatic enzymes are additional important injurious factors of endogenous origin. Alcohol, cigarette smoking, drugs and particularly aspirin and aspirin-like drugs, and steroids are among exogenous mucosal irritants that can inflict mucosal injury. The ability of the stomach to defend itself against these noxious agents has been ascribed to a number of factors constituting the gastric mucosal defense. These include mucus and bicarbonate secreted by surface epithelial cells, prostaglandins, sulfhydryl compounds and gastric mucosal blood flow. The latter is considered by several researchers to be of paramount importance in maintaining gastric mucosal integrity. The aim of this paper is to review the experimental and clinical data dealing with the role of mucosal blood flow and in particular the microcirculation in both damage and protection of the gastric mucosa.     

Neurotensin interacts with carbachol, secretin, and caerulein in the stimulation of the exocrine pancreas of the rat in vitro

In the present investigation the effect of neurotensin on pancreatic secretion of isolated pancreatic lobules from the rat was examined. We found a dose- and time-dependent stimulation of amylase release beginning with a concentration of 10(-9) M neurotensin. This response was potentiated by the cholinergic agonist carbachol, the gastrointestinal peptide secretin, and the CCK analogue caerulein. As we found neurotensin-immunoreactive nerves within the pancreas and as neurotensin-like immunoreactivity is present in the circulation (found previously), neurotensin may well be a further peptide taking part in the regulation of exocrine pancreatic secretion either as a hormone or a neurotransmitter. Neurotensin would then cooperate with cholinergic mechanisms, secretin, and CCK.     

The effect of atropine on bombesin and gastrin releasing peptide stimulated gastrin, pancreatic polypeptide and neurotensin release in man

The effects of 1-h infusions of bombesin and gastrin releasing peptide (GRP) at 50 pmol/kg per h and neurotensin at 100 pmol/kg per h on gastrin, pancreatic polypeptide (PP) and neurotensin release in man were determined following either saline or atropine infusion (20 micrograms/kg). Bombesin produced a rise in plasma neurotensin from 32 +/- 6 to 61 +/- 19 pmol/l and of PP from 26 +/- 8 to 36 +/- 7 pmol/l. There was a further rise of plasma PP to 50 +/- 13 pmol/l after cessation of the infusion. GRP had no significant effect on plasma neurotensin, but compared to bombesin, produced a significantly greater rise in plasma PP from 34 +/- 6 to 66 +/- 19 pmol/l during infusion. There was no post-infusional increase. At this dose, GRP was as effective as bombesin in releasing gastrin, although unlike bombesin its effect was enhanced by atropine. Neurotensin produced a rise in plasma PP from 17 +/- 4 to 38 +/- 8 pmol/l. Atropine blocked the release of PP during GRP and neurotensin infusion. Atropine had no effect on neurotensin or PP release during bombesin infusion, but did block the rise in plasma PP following bombesin infusion. We conclude that, in contrast to meal-stimulated neurotensin release, bombesin-stimulated neurotensin release is cholinergic independent. Despite structural homology, bombesin and GRP at the dose used are dissimilar in man in their actions and sensitivity to cholinergic blockade.     

A microsphere study on the effects of somatostatin and secretin on regional blood flow in anesthetized dogs

The endogenous peptides somatostatin and secretin are effective in the therapy of upper gastrointestinal tract bleeding and acute pancreatitis. The clinical effects may be partly brought about by changes in the regional blood flow. To evaluate the effects of somatostatin (50 and 100 μg/min over 6–8 min) and secretin (0.1 and 0.5 U · kg^?1 · min^?1 over 3–5 min) on tissue blood flow, particularly of the gastrointestinal tract, the tracer microsphere reference sample method was used in anesthetized dogs.Infusion of somatostatin significantly diminished gastric and pancreatic blood flow whereas no changes of duodenal and ileal blood flow could be obtained. Blood flow through spleen, kidneys and adrenal glands was increased but no changes were observed in the blood flow of other tissues. Cardiac hemodynamics remained unchanged.Secretin increased the blood flow of the duodenum, the kidneys and the adrenal glands and diminished gastric blood flow without changing pancreatic, ileal, hepatic, pulmonary and muscle blood flow. Cerebral, pituitary and myocardial blood flow was increased by a higher dose of secretin. It also evoked a slight but significant positive ino- and chronotropic effect. Since secretin and somatostatin differ in their respective effects on gastrointestinal blood flow it is suggested that the previously reported beneficial effects of both peptides on upper gastrointestinal bleeding cannot solely be attributed to changes in regional blood flow.     

Gastric mucosal blood flow changes in Helicobacter pylori infection and NSAID-induced gastric injury

Background. The impact of H. pylori infection on gastric mucosal blood flow and NSAID‐induced gastric damage is unclear. Aim. To study the effects of H. pylori infection on gastric mucosal blood flow, both at basal conditions and after NSAID exposure, and its relation with mucosal damage and nitric oxide production. Methods. Gastric mucosal blood flow, nitric oxide production and gastric damage were assessed in time after H. pylori SS1 or E. coli inoculation in mice. Experiments were conducted in basal conditions or after oral exposure to indomethacin (20 mg/kg). Results. H. pylori infected mice exhibited a significant increase in gastric blood flow and gastric nitric oxide production 1 week after infection, but those parameters returned to basal levels by 4 weeks. NSAID challenge elicited a similar reduction in gastric blood flow [25–35%] in H. pylori‐infected and control animals. However, only 1 week H. pylori‐infected mice, which exhibited a significant baseline hyperemia, were able to maintain gastric blood flow values within the normal range after NSAID exposure. NSAID‐induced gastric damage was increased in H. pylori‐infected mice by 4 weeks, but not 1 week after infection. Conclusions. Underlying H. pylori infection aggravates acute NSAID‐induced gastric damage. However, at early phases, gastric hyperemia associated with increased nitric oxide production may exert some protective role.     

The effect of somatostatin and 16,16-dimethyl-prostaglandin E2 on bombesin-stimulated canine gastric acid, plasma gastrin and pancreatic polypeptide secretion

We studied the effect of the intravenous infusion of 16,16-dimethylprostaglandin E2 methyl ester (di-M-PGE2) and somatostatin on bombesin-stimulated gastric acid secretion, plasma gastrin and plasma pancreatic polypeptide in four chronic gastric fistula dogs. Bombesin-stimulated gastric acid secretion was significantly inhibited by somatostatin and virtually abolished by di-M-PGE2. Both agents caused significant, but indistinguishable inhibition of gastrin release (P less than 0.05). Bombesin-stimulated pancreatic polypeptide release was also significantly inhibited by both somatostatin and di-M-PGE2; the inhibitory effect of somatostatin was significantly greater than that of di-M-PGE2 (P less than 0.05). This study provides further evidence in support of the complex interrelationships between agents responsible for the modulation of gastrointestinal physiology.     

Inhibition of gastric acid secretion and mucosal blood flow induced by intraventricularly applied neurotensin in rats

To investigate the central effect of neurotensin in gastric functions, changes in gastric acid secretion and mucosal blood flow (MBF) following administration were examined in rats anesthetized with urethane. Neurotensin in doses 1–10 μg/animal injected into the lateral ventricle decreased the basal value of both gastric acid output and MBF. This effect of neurotensin on these gastric parameters was completely blocked by pretreatment of animals with reserpine (2 mg/kg, i.p., 24 hr) or 6-OH-dopamine (250 μg/animal, intraventricularly, 10–14 days). These results indicate that exogenously applied neurotensin induces an inhibition of gastric functions by a central mechanism and suggest that an interaction exists between central catecholamines and the effect of neurotensin on gastric functions.     

Effect of neurotensin and neurotensin fragments on gastric acid secretion in man

The effect of intravenous infusion of neurotensin (NT) and NT-fragments on pentagastrin stimulated gastric acid secretion was investigated in healthy subjects. Neurotensin was infused in three doses (72, 144 and 288 pmol/kg per h). An N-terminal fragment (NT 1-8), a C-terminal fragment (NT 8-13) and an NT-analogue, substituted at the C-terminal tyrosine residue (Phe11-NT) were infused in two doses (72 and 144 pmol/kg per h). Concentrations of the infused peptides were measured in peripheral venous blood by radioimmunoassay. Plasma levels of NT 1-13, NT 1-8 and Phe11-NT increased in a dose-dependent manner; NT 1-13 to 50 (34-69), 78 (54-113) and 143 (112-242) pmol/l (medians and range) at 72, 144 and 288 pmol/kg per h, NT 1-8 to 405 (340-465) and 1215 (915-1300) pmol/l, and Phe11-NT to 200 (110-245) and 390 (250-410) pmol/l at 72 and 144 pmol/kg per h, respectively. Increases in plasma levels of NT 8-13 could not be detected during the infusion, suggesting that the fragment is rapidly metabolized in man. Neurotensin 1-13 inhibited gastric acid secretion in a dose-dependent manner and the decrease in gastric acid secretion was linearly related to plasma levels of NT 1-13. Neurotensin 1-8 and NT 8-13 inhibited gastric acid secretion only at 144 pmol/kg per h, while the analogue Phe11-NT had no effect. The results showed that the inhibition of gastric acid secretion produced by NT was dose-dependent and linearly related to circulating levels of NT, and that under physiological conditions this effect presumably is elicited by the C-terminal part of the peptide.     

Gastric effects and side effects of synthetic secretin in man

The gastric effects of synthetic secretin given in a depot reparation as subcutaneous injection or in different doses as intravenous infusion were studied in 10 healthy volunteers. Peptone-stimulated gastric acid secretion and serum gastrin were significantly suppressed with a clear dose-response inhibition of acid output. There was a significant correlation between percentage inhibition of acid secretion and plasma secretin concentrations which were greatly above those seen physiologically. Serum lipase and trypsin increased significantly. Most subjects lost fluid from diuresis and diarrhoea, so that serum sodium and total protein concentrations also increased significantly. These side effects cast doubt on the clinical value of prolonged infusions of pharmacological doses of synthetic secretion in critically ill patients.     

Effect of peripherally-injected glucagon-like peptide-1 on gastric mucosal blood flow

The aim of this study was to investigate the mechanisms involved in the effect of glucagon-like peptide-1 (GLP-1) on the decrease in gastric mucosal blood flow (GMBF) induced by intragastric ethanol.After preparation of the stomach for GMBF recording, a probe was placed to the gastric mucosa and basal GMBF recordings were obtained by a laser Doppler flowmeter after a 30-minute stabilization period. Following GLP-1 (1000 ng/kg; i.p.) injection, 1 ml of absolute ethanol was applied to the gastric chamber and GMBF was recorded continuously during a 30-minute period. GLP-1 (1000 ng/kg; i.p.) prevented the decrease in GMBF induced by ethanol. Nitric oxide (NO) synthase inhibitor L-NAME, (30 mg/kg; s.c.), calcitonine gene-related peptide (CGRP) receptor antagonist CGRP-(8–37) (10μg/kg; i.p.), and cyclooxygenase inhibitor indomethacin (5 mg/kg; i.p.) all inhibited the GMBF-improving effect of GLP-1.We concluded that, NO, CGRP and prostaglandins may be involved in the effect of peripherally-injected GLP-1 on GMBF reduction induced by intraluminal ethanol.     

Peptide histidine valine-42 stimulates gastric acid secretion in man

The effect of peptide histidine valine-42 (PHV-42) on gastric acid secretion was studied in man. PHV-42 was infused into 5 healthy volunteers at a dose of 10 pmol/kg/min. This dose caused a significant stimulation of basal gastric acid and potassium output. there were no significant changes in circulating gastrin throughout the infusion. In 2 subjects with a background of submaximal pentagastrin stimulation, PHV-42 infusion at the same dose did not alter acid secretion in either subject. The previous observation that PHV-42 is found particularly in the stomach and the new finding that it stimulates basal gastric secretion suggest the possibility that PHV-42 could have a role in local control of acid secretion.     

The role of the Asp-32 residue of cholecystokinin in gastric acid secretion and gastrin receptor recognition

The aspartic acid residue at the penultimate position is known to be essential for the hormonal activity of CCK and gastrin on gastric acid secretion. This residue was successively replaced by beta-aspartic acid, beta-alanine, and glutamic acid in the C-terminal heptapeptide of CCK 27-33. The analogues obtained were tested on rat gastric acid secretion and for recognition by gastrin receptors. The replacement by beta-aspartic or beta-alanine decreased gastric secretion and gastrin receptor recognition. In contrast, replacement by glutamic acid affected these two parameters less. The nature of the N-blocking group (Boc or Z) also influenced these activities, Boc derivatives being more potent than Z derivatives. The results were compared to those previously obtained on pancreatic secretion and on stimulation of gall bladder contraction where the modifications were found capable of differentiating between cholecystokinin, pancreozymin and gastrin activities.     

L-lactic acid secreted from gastric mucosal cells enhances growth of Helicobacter pylori

BACKGROUND: Helicobacter pylori mainly inhabit the mucus layer in the gastric mucosa. However, mechanisms involving H. pylori colonization and proliferation in gastric mucosa are not well established. This study focuses on elucidating the role of gastric mucosal cells on growth of H. pylori. MATERIALS AND METHODS: H. pylori was co-cultured with the murine gastric surface mucosal cells (GSM06), and the growth of H. pylori on the cells was assessed by enumerating the colony-forming units (CFU). The H. pylori growth factor in the culture media conditioned by GSM06 cell was purified by HPLC, and the chemical structure of the growth factor was identified by analyses of (1)H- and (13)C-NMR spectra. RESULTS: A marked increase in the number of CFU of H. pylori was observed in the GSM06 cells. The enhanced H. pylori growth was also observed when indirectly incubated with GSM06 cells through semi-permeable membrane. In addition, culture media conditioned by GSM06 cell stimulated H. pylori growth approximately one thousand-fold. By bioassay-guided purification, the H. pylori growth factor was isolated from the conditioned medium of GSM06 cells and identified as L-lactic acid. The H. pylori growth-enhancing activity under microaerobic condition was well correlated with L-lactic acid concentrations in the conditioned media. CONCLUSIONS: This study demonstrates that L-lactic acid secreted by gastric mucosal cells enhances the growth of H. pylori, and this L-lactic acid-dependent growth of H. pylori may be important to the long-term colonization of H. pylori in the stomach.     

Effects of pectin-induced passive linkage of gastric H on the gastric acid secretion and on the development of ethanol- and salicylate-induced gastric mucosal lesions in rats

The aim of this study was to evaluate the effects of intragastrically given pectin-induced physicochemical properties and actions on active gastric acid secretion and on the development of ethanol- and aspirin-induced gastric mucosal lesions. The observations were carried out on CFY-strain rats, fasted for 24 h before the experiments with water ad libitum. The observations were carried out in two experimental series. A) The gastric mucosal lesions were produced by intragastrically given 96% ethanol or aspirin prepared with 0.2 M HCl. Different doses of pectin (100, 50 and 25 mg.kg^–1, respectively) were administered intragastrically 30 min before giving necrotizing agents. The number of gastric lesions was noted 1 h after the administration, while the severity of gastric mucosal lesions was scored by semi-quantitative scale. B) The effects of pectin were studied on the volume and H⁺ secretion of the stomach in 4-h pylorus-ligated rats. It has been found that: 1) the gastric mucosal lesions could be produced in 100% of rats by the application of both necrotizing agents. 2) Pectin in doses of 50–100 mg.kg^–1 increased the number of gastric mucosal lesions in both models, while no increase was produced by the application of 25-mg.kg^–1 dose. 3) The severity of mucosal lesions increased significantly after the administration of all doses of pectin. 4) The pectin-induced increase of gastric lesions (number) showed a dose-response effect. 5) The pectin produced a significant increase in the volume of gastric secretion and gastric H⁺ secretion. It has been concluded that: a) pectin-induced physicochemical changes are able to enhance the aggression to gastric mucosa produced by ethanol and aspirin; b) a positive correlation exists between the linkage of H⁺ to pectin and significant active metabolic response in the rat stomach; c) pectin alone stimulates the active metabolic process of the gastric H⁺ secretion.     

Central noradrenergic inhibition of gastric mucosal blood flow and acid secretion in rats

To investigate the role of central noradrenaline (NA) in gastric functions, changes in mucosal blood flow (MBF) and acid secretion following electrical stimulation of the lateral hypothalamic area (LHA) and the effects of NA on these parameters were examined in rats anesthetized with urethane. NA 10 μg/animal injected into the lateral ventricle decreased the basal value of both the gastric MBF and acid output, while the same dose of acetycholine or dopamine was without effect. Repetitive electrical stimulation of LHA at 10 cycles/sec, 0.5 mA, 2 msec for 10 min elicited a significant, reproducible increase in both gastric MBF and acid output. NA 10 μg/animal injected into the lateral ventricle completely blocked these increases induced by the electrical stimulation. These data suggest that a central noradrenergic inhibitory mechanism is involved in regulation of the gastric MBF and acid secretion.     

Inhibition of gastric and pancreatic secretions by cerebroventricular injections of gastrin-releasing peptide and bombesin in rats

It has been suggested that mammalian gastrin-releasing peptide (GRP) and bombesin (BBS) might inhibit gastric secretion by a central nervous system action. The present investigations were intended to define the gastric effect and to look for an effect on the exocrine pancreas. Wistar male rats were provided with a chronic cannula allowing cerebroventricular injections in the 3rd ventricle, and with chronic gastric and/or pancreatic fistulas allowing the collection of gastric and/or pancreatic secretions in conscious animals. Both basal secretions were studied. Gastric secretion was stimulated with a 75 mg/kg s.c. injection of 2-deoxyglucose (2-dGlc). The dose range of bombesin was 0.01–1 μg (6–600 pmol) and GRP was 0.01–10 μg/rat (3.5 pmol to 3.5 nmol). A significant dose related decrease of basal gastric secretion was observed with the two peptides. The gastric acid response to 2-dGlc was inhibited by both peptides in a dose-related fashion and the reduction of gastric acid output mainly resulted from a decrease in the volume of gastric juice. The exocrine pancreatic secretion was also decreased by 30–55% after GRP but the BBS inhibitory effect was poorly dose-related. No significant difference was found after removal of gastric secretion, indicating that most of the pancreatic inhibition was independent of gastric secretion.