Adenosine deaminase activity in the human duodenal mucosa in relation to gastric acid secretion.

Adenosine deaminase (ADA) activity was estimated in mucosal specimens obtained endoscopically from the duodenal bulb. Three groups of subjects were studied: 1. 9 patients with achlorhydria, 2. 12 subjects with normal gastric acid secretion, 3. 5 patients with hypersecretion. Enzyme activity was measured by determination of ammonia liberated from the substrate according to the Chaney and Marbach method. In patients with hypersecretion the ADA activity was lower than in those with achlorhydria (p less than 0.001) and normal acid secretion (p less than 0.02). A significant negative correlation between ADA activity in the duodenal bulb mucosa and basal and maximal gastric acid outputs was found. The present study seems to indicate a possible relationship between gastric acid secretion and duodenal ADA activity.     

The role of gastric and duodenal pH in the cysteamine-induced duodenal ulcer in the rat

Many secretory studies reported an increase in gastric acid secretion by the duodenal ulcerogen cysteamine. A detailed analysis of these experiments, especially the results from rats with chronic gastric fistula suggest that direct stimulation of gastric acid secretion may not be the primary mechanism of the duodenal ulcerogenic action of cysteamine. We used a different approach and measured the pH at the site of ulceration in the proximal duodenum. A duodenal ulcerogenic dose of cysteamine did not change the pH at the anterior or posterior wall of the duodenum during 4 hr. In the same dose and by the same route of administration, cysteamine nevertheless induced duodenal ulcers in 24 hr. These experiments demonstrate that in addition to the effect on gastric acid secretion, other factors are needed to the effect on gastric acid secretion, other factors are needed to explain the early duodenal ulcerogenic action of cysteamine.     

Physiological Activity of Peptides Isolated from Human Gastric and Duodenal Ulcerous Tissues

Some drug formulations containing digestive enzymes were shown to stimulate gastric and duodenal secretion owing to low-molecular-weight peptides (LMWPs) generated during isolation of the enzymes from raw biological materials. Similar LMWPs were found in gastric and duodenal ulcerous tissues. It was concluded that, transferred with the blood and the lymph, the LMWPs produced in such tissues continuously stimulate the exocrine function of the pancreas (probably, through a system of immunoreceptors). Persistent pancreatic hypersecretion results in functional failure of the gland and in chronic pancreatitis.     

Free amino acids in basal and vagally stimulated gastric secretion

The concentrations of the individual free amino acids were determined in one hour fraction of basal secretion and peak hydrogen ion secretion following stimulation with 2-deoxy-D-glucose (2-DG) (group I) or insulin (group II). Group I consisted of 9 patients with duodenal ulcer having hypersecretion of gastric acid as determined by histamine test; 7 patients with duodenal ulcer who underwent truncal vagotomy and had insulin test performed two weeks after the operation formed group II. The total concentration of free amino acids was similar in basal and in stimulated gastric juice in both groups. Also the concentrations of the individual amino acids did not change significantly after stimulation. There was, however, a significant increase following stimulation in the output of amino acids both in group I and in group II. This increase was parallel to that in the volume of gastric juice, which suggests that a definite amount of free amino acids is always present in the gastric juice, and that the secretion of these acids is not under vagal control.     

Helicobacter pylori and hormones.

Helicobacter pylori affects gastric acid secretion via several mechanisms. One of these is by changing gastric regulatory physiology. The infection elevates plasma gastrin levels and decreases gastric mucosal expression of the inhibitory peptide somatostatin. These changes may be due to products of H. pylori itself or inflammatory cytokines released in H. pylori infection: acid secretion is inhibited less by a low intra-gastric pH, infusions of cholecystokinin and gastric distention in infected persons. Eradication of H. pylori rapidly decreases basal acid secretion and gastrin-releasing, peptide-stimulated acid secretion. There are now reports that maximally-stimulated acid secretion, a measure of the parietal cell mass, falls significantly six and 12 months after eradication of H. pylori from duodenal ulcer patients. This might be due to withdrawal of the trophic effect of gastrin. However H. pylori can also decrease gastric acid secretion, both through the mechanisms described in Dr. Cave''s paper and by causing gastric mucosal atrophy with loss of parietal cells. The net effect on acid presumably depends on which mechanism predominates. The processes involved may be crucial determinants of clinical outcome. For example, infection with little atrophy and high acid secretion is associated with duodenal ulcers, while infection with atrophy and low acid secretion increases the risk of gastric cancer of the intestinal-type.     

Effects of the synthetic PGE1 derivative misoprostol on basal, stimulated and nocturnal acid secretion in duodenal ulcer cases. Mechanism of action

We studied the antisecretory effect of the synthetic PGE1 derivative misoprostol. Basal, histamine-stimulated and nocturnal acid secretion were determined on separate days in 3 groups of endoscopically confirmed duodenal ulcer patients. Misoprostol or placebo were given in random order in doses of 200, 400 and 800 mcg. H+ concentration, acid output and pH of gastric content were determined. Additionally, the effect of misoprostol on purified and gastric mucosa carbonic anhydrase was determined according to Maren's micromethod. Misoprostol reduced dose-dependently basal acid secretion (by 54% after 200 mcg, by 82% after 400 mcg and, respectively, by 94% after 800 mcg) as well as stimulated secretion which was reduced after the same doses by 22% (p less than 0.05), 48% and 64% (p less than 0.001), respectively. Nocturnal secretion was significantly reduced for a period of 4 h, with a consecutive rise of gastric pH. In vitro, misoprostol inhibited dose-dependently purified and gastric mucosa carbonic anhydrase basal activity. In conclusion, misoprostol inhibits basal, nocturnal and histamine-stimulated secretion in duodenal ulcer patients, an effect which could be mediated by inhibition of carbonic anhydrase.     

Peptic ulceration,gastric secretion,and renal transplantation.

Fifty-four patients on haemodialysis for chronic renal failure underwent renal transplantation. Basal and maximum acid output and the incidence of peptic ulcer before transplantation were not significantly different from those of controls. But after renal transplantation the incidence of symptoms of peptic ulcer was high (22%) and four out of six patients who developed gastrointestinal bleeding died from this complication. In men peak acid output was significantly increased after renal transplantation and was associated with a 30% incidence of symptoms of peptic ulcer compared with 10% in women, who showed no significant change in mean basal or peak acid output. Peptic ulceration after transplantation was not associated with steroid dosage, hyperparathyroidism, or the height of blood urea concentrations. Given criteria of a history of dyspepsia, abnormal barium meal findings, or gastric hypersecretion, it was not possible to identify patients at risk from peptic ulceration or life-threatening complications after renal transplantation. Thus the routine screening of these patients for peptic ulcer has no practical value, and the incidence of fatal complications is not high enough to justify routine prophylactic anti-ulcer surgery aimed at reducing acid secretion before renal transplantation.     

Somatostatin release from perifused rat and human gastric mucosa

In the present study the release of somatostatin-like immunoreactivity (SLI) was evaluated in vitro from isolated rat antral and fundic mucosa and from biopsy specimens of human antral mucosa. Perifusion of antral mucosa with Earle's balanced salt solution showed a pH-dependent release of SLI. SLI release did not change in response to a reduction from pH 7 during the baseline period to pH 3, whereas a significant increase occurred when the pH was changed to 2.5 or 2, respectively. Fundic SLI release remained at baseline levels during the decrease of the pH value of the buffer solutions. Atropine at doses of 10(-6) to 10(-4) M did not alter acid-induced SLI release from the isolated antral mucosa, suggesting different mechanisms in vitro compared to the acid-induced SLI release in vivo. SLI release from human mucosa was 450 +/- 217 pg/min X mg wet weight in response to perifusion with the buffer pH 2 in 7 control subjects. No significant difference was observed in patients with duodenal ulcer or acute gastritis, whereas gastric ulcer patients had significantly lower values (66 +/- 44) compared to controls and duodenal ulcer patients. These data do not support the hypothesis that impaired somatostatin production and release might be a pathogenetic factor for gastric acid hypersecretion and development of duodenal ulcer.     

Cimetidine for duodenal ulceration in patients undergoing haemodialysis.

Peptic ulcer is a common problem in advanced renal failure, but most drugs for ulcers are hazardous in this condition. In a small open study cimetidine was given to nine patients with acid hypersecretion and endoscopically diagnosed duodenal ulceration who were undergoing haemodialysis. The patients obtained good pain relief and suffered no serious side effects. Both basal and stimulated acid output fell considerably and the plasma gastrin response to food increased during treatment. Two patients with recurrent vomiting during haemodialysis had a striking response to cimetidine, which suggested that such vomiting may be acid-mediated in some patients. These preliminary results suggest that cimetidine may prove to be an advance in the management of peptic ulcer in uraemic patients.     

An explanation of gastric hypersecretion in the pylorus-ligated rat

The hypersecretion of gastric acid in the pylorus-ligated rat has been shown to be of vagal origin. The present series of experiments were performed to identify the stimulus. The pyloric sphincter was ligated in a series of Sprague Dawley rats. Along with pylorus ligation, various other surgical manipulations were performed. Intestinal obstruction by ligation approximately 20 cm aboral to the cecum reduced unstimulated gastric secretion in the pylorus-ligated rat. However, perfusion of the lower small intestine with bicarbonate (143 mEq/L) stimulated secretion. Perfusion with either saline or deoxycholic acid (20 mEq/L) did not alter secretion. This supports a role for bicarbonate in the hypersecretion of gastric acid in the pylorus-ligated rat. The reflex appears to involve the myenteric plexus, since section of the pylorus seemed to attenuate gastric secretion. Plasma from animals with pylorus ligation, either alone or with intestinal ligation, equally inhibited gastric secretion. This suggests that while some factor inhibiting gastric secretion may be present, it appears to be unrelated to pylorus ligation.     

Role of cholecystokinin in the intestinal fat- and acid-induced inhibition of gastric secretion.

This study was designed to determine the role of cholecystokinin (CCK) in the inhibition of gastric HCl secretion by duodenal peptone, fat and acid in dogs with chronic gastric and pancreatic fistulas. Intraduodenal instillation of 5% peptone stimulated both gastric HCl secretion and pancreatic protein secretion and caused significant increments in plasma gastrin and CCK levels. L-364,718, a selective antagonist of CCK-A receptors, caused further increase in gastric HCl and plasma gastrin responses to duodenal peptone but reduced the pancreatic protein outputs in these tests by about 75%. L-365,260, an antagonist of type B receptors, reduced gastric acid by about 25% but failed to influence pancreatic response to duodenal peptone. Addition of 10% oleate or acidification of peptone to pH 3.0 profoundly inhibited acid secretion while significantly increasing the pancreatic protein secretion and plasma CCK levels. Administration of L-364,718 reversed the fall in gastric HCl secretion and significantly attenuated pancreatic protein secretion in tests with both peptone plus oleate and peptone plus acid. Exogenous CCK infused i.v. in a dose (25 pmol/kg per h) that raised plasma CCK to the level similar to that achieved by peptone meal plus fat resulted in similar inhibition of gastric acid response to that attained with fat and this effect was completely abolished by the pretreatment with L-364,718. We conclude that CCK released by intestinal peptone meal, containing fat or acid, exerts a tonic inhibitory influence on gastric acid secretion and gastrin release through the CCK-A receptors.     

Helicobacter pylori modulation of gastric acid

Helicobacter pylori plays major causative roles in peptic ulcer disease and gastric cancer. Elevated acid secretion in patients with duodenal ulcers (DUs) contributes to duodenal injury, and diminished acid secretion in patients with gastric cancer allows carcinogen-producing bacteria to colonize the stomach. Eradication of H. pylori normalizes acid secretion both in hyper-secreting DU patients and hypo-secreting relatives of gastric cancer patients. Therefore, we and others have asked how H. pylori causes these disparate changes in acid secretion. H. pylori gastritis more or less restricted to the gastric antrum in DU patients is associated with increased acid secretion. This is probably because gastritis increases release of the antral acid-stimulating hormone gastrin and diminished mucosal expression of the inhibitory peptide somatostatin. Bacterial products and inflammatory cytokines including TNFalpha may cause these changes in endocrine function. Gastritis involving the gastric corpus tends to diminish acid secretion, probably because bacterial products and cytokines including IL-1 inhibit parietal cells. Pharmacological inhibition of acid secretion increases corpus gastritis in H. pylori-infected subjects, so it is envisaged that gastric hypo-secretion of any cause might become self-perpetuating. H. pylori-associated mucosal atrophy will also contribute to acid hypo-secretion and is more likely in when the diet is high in salt or lacking in antioxidant vitamins. Data on gastric acid secretion in patients with esophagitis are limited but suggest that acid secretion is normal or slightly diminished. Nevertheless, H. pylori infection may be relevant to the management of esophagitis because: (i) H. pylori infection increases the pH-elevating effect of acid inhibiting drugs; (ii) proton pump inhibitors may increase the tendency of H. pylori to cause atrophic gastritis; and (iii) successful eradication of H. pylori is reported to increase the likelihood of esophagitis developing in patients who had DU disease. Points (ii) and (iii) remain controversial and more work is clearly required to elucidate the relationship between H. pylori, acid secretion, gastric mucosa atrophy and esophagitis.     

Day-Night and Individual Differences in Response to Constant-Rate Ranitidine Infusion

Twelve ulcer patients with inactive disease received constant-rate infusions of ranitidine, in doses of 6.25 and 10.0 mg/hr, during separate 24-h spans. Gastric pH and serum ranitidine concentrations were monitored. Serum ranitidine concentrations did not vary significantly after attainment of steady-state. For the group, gastric acidity was controlled above pH 4 during the day; however, at night, when gastric acid secretion was greatest under placebo conditions, ranitidine less effectively controlled gastric pH. There was individual variation in response to ranitidine. Patients (8/12) evidencing control of gastric acidity (pH ± 4) for at least 16 h when infused with ranitidine (6.25 mg/h) were considered re-sponders. Those (4/12) not so well controlled were designated poor responders. With parenteral infusion of 6.25, as well as 10.0 mg/h ranitidine, responders evidenced a relatively high 24-h mean pH and only minor day-night variation in gastric acidity. In contrast, poor responders were characterized by a low 24-h mean pH and high-amplitude circadian variation in gastric acidity. Poor responders evidenced statistically significant (p < 0.05) lower gastric pH responses to parenteral infusions than did responders. A similar, significant difference between the two groups was observed when the percentage of time that gastric pH was maintained below 4 was considered. Differences between responders and poor responders to ranitidine infusion are unknown. Since Zollinger-Ellison syndrome patients were not included in the study, observed differences in drug response cannot be ascribed to hypersecretion of gastric acid.     

The role of secretin in the control of gastric secretion and emptying in the dog

It is well established that duodenal acidification strongly inhibits gastric acid secretion, gastric emptying rate and gastrin release. These effects are at least partly mediated via hormonal pathways, but it is not known whether they are mediated by the release of one peptide named in the past enterogastrone, or by several peptides acting together. The effects of duodenal acidification on gastric acid secretion and gastrin release can be reproduced by infusion of small doses of secretin and plasma secretin levels increase during duodenal acidification or after a meal. This peptide is thus the most probable candidate as an enterogastrone. It has however never been clearly shown that administration of low doses of secretin do decrease gastric emptying rate as well as acid secretion. Experiments were performed on four dogs with gastric fistulas. A peptone solution was infused into the stomach. The experiments were repeated during infusion of synthetic secretin. Our results indicate that infusion of low doses of secretin reproduce all the effects of duodenal acidification: a significant inhibition of gastric acid secretion, gastrin release and gastric emptying rate.     

Effects of endothelin-1 on duodenal bicarbonate secretion and mucosal integrity in rats

Effects of endothelin-1 on gastric acid secretion, duodenal HCO3- secretion, and duodenal mucosal integrity were investigated in anesthetized rats, in comparison with those of TY-10957, a stable analogue of prostacyclin. A rat stomach mounted on an ex-vivo chamber or a proximal duodenal loop was perfused with saline, and gastric acid or duodenal HCO3- secretion was measured using a pH-stat method and by adding 100 mM NaOH or 10 mM HCl, respectively. Duodenal lesions were induced by mepirizole (200 mg/kg) given subcutaneously. Intravenous administration of endothelin-1 (0.6 and 1 nmol/kg) caused an increase of duodenal HCO3- secretion with concomitant elevation of blood pressure; this effect was antagonized by co-administrahon of BQ-123 (ET(A) antagonist; 3 mg/kg, i.v.) and significantly mitigated by vagotomy. Likewise, endothelin-1 caused a significant decrease in histamine-stimulated acid secretion, and this effect was also significantly antagonized by BQ-123. Although TY-10957 (10 and 30 mg/kg, i.v.) produced a temporal decrease of blood pressure, this agent caused not only an increase of duodenal HCO3- secretion, independent of vagal nerves, but also a decrease of acid secretion as well. In addition, both endothelin-1 and TY-10957 significantly prevented mepirizole-induced duodenal lesions at the doses that caused an increase of duodenal HCO3- secretion and a decrease of gastric acid secretion. These results suggest that endothelin-1 affects the duodenal mucosal integrity by modifying both gastric acid and duodenal HCO3- secretions, the effects being mediated by ET(A) receptors.     

Solanum paniculatum L. (Jurubeba): potent inhibitor of gastric acid secretion in mice.

Solanum paniculatum L. is used commonly in Brazilian folk medicine for the treatment of liver and gastrointestinal disorders. The freeze-dried aqueous extracts (WEs) obtained from distinct parts of the plant (flowers, fruits, leaves, stems and roots) were tested to determine their antiulcer and antisecretory gastric acid activities using mice. The aqueous extracts of roots, stems and flowers inhibited gastric acid secretion in pylorus-ligated mice with ED50 values of 418, 777 and 820 mg/kg body wt. (i.d.), respectively. Extracts of leaves (0.5-2 g/kg body wt., i.d.) did not affect gastric secretion, whereas fruit extracts (0.5-2 g/kg body wt., i.d.) stimulated gastric acid secretion. The stimulatory effect of the fruit extract was inhibited by pretreatment with atropine (5 mg/kg body wt., i.m.) but not with ranitidine (80 mg/kg body wt., i.p.) suggesting that the fruit extract activates the muscarinic pathway of gastric acid secretion. In contrast, administration of the root extract into the duodenal lumen inhibited histamine- and bethanechol-induced gastric secretion in pylorus-ligated mice. In addition, the aqueous extract of roots (ED50 value, 1.2 g/kg body wt., p.o.) protected the animals against production of gastric lesions subsequent to the hypersecretion induced in mice by stress following cold restraint. This effect was not reproduced when the lesions were induced by blockade of prostaglandins synthesis via subcutaneous injection of indomethacin. Thus, antiulcer activity of the plant extracts appears to be related directly to a potent anti-secretory activity. No toxic signs were observed following administration of different extracts up to 2 g/kg body wt., p.o. Collectively, the results validate folk use of Solanum paniculatum L. plant to treat gastric disorders.     

Role of gastrin in duodenal mechanisms of inhibition of gastric secretion in the dog and man

Gastrin serum levels after acidification of the second portion of the duodenum were studied, in dogs and humans, while simultaneously measuring secretin levels and gastric acid secretion. After duodenal acidification in dogs, a 50% inhibition of gastric acid secretion with parallel 100% increases in the serum secretin levels was noted whereas gastrin serum levels did not change (after duodenal acidification). In humans, a 25% inhibition of gastric acid secretion with parallel 50% (not significative) increases in the secretin serum levels was noted. In the entire group gastrin levels did not change, but in 35.2% of the subjects a little increment without statistical significance was noted. It is concluded that the inhibition mechanism of gastric acid secretion after duodenal acidification is more important in dog than in man, and that, probably, gastrin does not play an important role in this mechanism.     

Prostaglandin E in peptic ulcer disease

Prostaglandin E₁ and E₂ inhibit gastric secretion in vivo and in vitro under a variety of conditions. It is not known whether these compounds may play a role in normal gastric secretory physiology or in the pathophysiology of peptic ulcer disease. Six normal adults and six patients with documented duodenal ulcer disease were studied under basal conditions and during gastric secretory stimulation with betazole. Prostaglandin E in plasma and gastric juice was measured by radioimmunoassay. Prostaglandin E was significantly higher in the plasma of normal volunteers both in the basal state and during stimulation. Gastric juice prostaglandin E was also significantly higher in normal volunteers during the basal state but the difference disappeared during stimulation. The relative deficiency of prostaglandin E in the ulcer group may indicate a role for prostaglandins in the pathophysiology of gastric hypersecretion.     

Effect of vagotomy on the duodenal mechanisms regulating gastric secretion

Gastric acid secretion, gastrin and secretin serum levels after duodenal acidification were studied in 6 dogs, before and after a troncular vagotomy was performed in each one. After duodenal acidification in normal dogs, a 45.2% inhibition of gastric acid secretion with parallel 55-84% increases in the serum secretin levels, without changes in the serum gastrin levels, was noted. When a troncular vagotomy was performed in the same dogs, duodenal acidification produced a 20% (non significant) inhibition of gastric acid secretion with parallel 34-72% increases in the serum secretin levels and without changes in the serum gastrin levels. It is concluded that vagus nerve is necessary to assess a physiological inhibition of gastric secretion after duodenal acidification and it is suggested that humoral and nervous factors are implicated and coexist in these mechanisms.     

Inhibition of gastric secretion in treatment of pancreatic insufficiency.

The content of pancreatic enzymes in the duodenum was studied in two patients with pancreatic achylia after a standard meal supplemented with commercial pancreatic extract. Gastric transit of the enzymes, with appearance of near-normal amounts in the duodenal contents, occurred only after inhibition of gastric secretion and buffering of residual gastric acid with antacids. Gastric inhibition and neutralisation of acid are therefore necessary for the satisfactory treatment of patients with pancreatic exocrine insufficiency but normal gastric function.