Luminal Nalpha-methyl histamine stimulates gastric acid secretion in duodenal ulcer patients via releasing gastrin.

Nalpha-methyl histamine is an unusual histamine metabolite which is produced in the stomach infected by Helicobacter pylori and which was shown in animals to stimulate gastric acid secretion and to release gastrin in vitro isolated G-cells, but no information is available regarding its influence on gastric secretion and gastrin release in duodenal ulcer patients before and after H. pylori eradication. In this study, we compared the effects of intragastric administration of single or graded doses of Nalpha-methyl histamine on gastric acid secretion and plasma gastrin levels in 16 male duodenal ulcer patients (aging from 35 to 48 years and weighing 65-82 kg) before and after the eradication of H. pylori. Furthermore, the gastric luminal histamine and gastrin contents were determined before and after H. pylori eradication. In H. pylori-infected duodenal ulcer patients, the intragastric application of Nalpha-methyl histamine failed to affect gastric acid secretion or plasma gastrin levels. Following eradication of H. pylori, gastric luminal histamine and gastrin, and both basal gastric acid secretion and plasma gastrin levels, were significantly reduced. Nalpha-methyl histamine given intragastrically in graded doses to such H. pylori-eradicated duodenal ulcer patients was found to increase dose-dependently gastric acid output reaching at a dose of 5 mg, about 80% of histamine maximum induced by i.v. infusion of 25 microg/kg h of histamine dihydrochloride. We conclude that Nalpha-methyl histamine is a potent luminally active stimulant of gastrin release and gastric acid secretion in H. pylori-eradicated patients when luminal histamine is low but is not effective in H. pylori infected patients when luminal histamine is enhanced, possibly due to desensitization of gastrin (G-cells) and acid-producing (parietal) cells by Nalpha-methyl histamine produced excessively in H. pylori-infected stomach.

Helicobacter pylori and impaired gastric secretory functions associated with duodenal ulcer and atrophic gastritis.

Previous study showed that duodenal ulcer (DU) patients infected with Helicobacter pylori (H. pylori) have increased basal and pentagastrin- or GRP-induced gastric acid secretion and that these disturbances reversed fully after eradication of H. pylori. This study was designed to compare the gastric acid secretory profile, plasma gastrin levels and growth factors (EGF and TGF alpha) expression in gastric mucosa in DU patients with those in atrophic gastritis patients before and six months after verified eradication of H. pylori. In DU patients, basal and stimulated (GRP and pentagastrin) gastric acid secretion was significantly higher than in healthy controls. Six months following the eradication of H. pylori with triple therapy (omeprazole+clarithromycin+amoxicillin), this secretion returned to normal value. In contrast, in patients with atrophic gastritis, such eradication of H. pylori resulted in a significant increase in basal and pentagastrin- and GRP-stimulated acid secretion. Mucosal expression of immunoreactive EGF and TGF alpha was significantly enhanced in H. pylori positive DU and atrophic gastritis patients but this elevation disappeared or was markedly decreased 6 months upon the eradication of H. pylori. We conclude that 1) H. pylori infection is accompanied both in DU and atrophic gastritis patients by an enhanced plasma gastrin and increased mucosal expression of EGF and TGF alpha, 2) basal and GRP-induced acid secretion is significantly elevated in DU, whereas that in atrophic gastritis patients is greatly reduced, and 3) the H. pylori eradication restores gastric acid and plasma gastrin release as well as the mucosal expression of growth factors in DU and atrophic gastritis.

Effects of ebrotidine on aspirin-induced gastric mucosal damage and blood flow in humans.

Nonsteroidal anti-inflammatory agents (NSAIDs) such as aspirin (ASA) damage the gastric mucosa both in normal subjects and in arthritic patients. The aim of this study was to investigate the protective action of a new H2-receptor antagonist, ebrotidine, in the prevention of ASA-induced acute mucosal injury in the stomach of healthy volunteers. In a double-blind randomized crossover study 10 male volunteers received treatment with either placebo plus ASA (500 mg) or ebrotidine (800 mg) plus ASA twice daily for 3 days with 10 days' washout period between treatments. The mean number of gastric erosions seen at endoscopy after treatment with ebrotidine plus ASA (2.0 +/- 0.3) was significantly lower than that after placebo plus ASA (3.7 +/- 0.2). This reduction in lesion core by ebrotidine was accompanied by a significant increase in gastric blood flow (by 15% in corpus and 26% in antrum), by a rise in transmucosal potential difference (by 12%), and by a decrease of mucosal microbleeding. Ebrotidine afforded substantial protection from ASA-induced injury to the gastric mucosa, and this was accompanied by increase of the mucosal blood flow. We conclude that ebrotidine provides mucosal protection for patients taking NSAIDs.

Gastric acid inhibitory profile of ebrotidine, a novel H2-receptor antagonist in humans.

This study was designed to assess the gastric secretory effects of ebrotidine, a novel H2 receptor antagonist, in humans. Three groups (A, B and C) of male subjects with normal gastric mucosa were used. Group A (6 subjects) was used to determine the dose-dependency of gastric inhibitory effect of ebrotidine on basal and pentagastrin-induced maximal acid output. Group B (8 subjects) was employed to examine the duration of the inhibitory effect of ebrotidine on basal and pentagastrin-induced acid secretion. In group C (6 subjects), the 24h pH-metry was assessed using intraluminal pH-electrode placed in the gastric corpus and connected to a portable recording unit. Single oral dose of ebrotidine (200, 400 or 800 mg) caused a dose-dependent reduction in basal and pentagastrin-induced acid secretion that at a dose of 800 mg amounted to about 89% and 93%, respectively. This inhibition was still observed after 6h and averaged 72% and 50%, respectively. After 12 and 24h upon the drug intake, both basal and pentagastrin-induced acid secretion returned to the control values. Single oral dose of ebrotidine (800 mg) caused a significant reduction in circadian acidity and resulted in a marked and significant reduction of intragastric acidity for about 6h upon the administration. This inhibition was accompanied by a transient increase in basal and postprandial gastrin levels. We conclude that ebrotidine is highly effective inhibitor of basal, pentagastrin-induced and circadian gastric acid secretion in humans.

Effects of nocloprost on gastric functions in man.

Previous studies in animals and humans demonstrated that nocloprost, a stable prostaglandin E2 analogue, shows very high gastroprotective potency, relatively weak gastric inhibitory activity, and low systemic bioavailability after oral administration. In this study the effects of nocloprost on gastric acid secretion and intraluminal pH and on gastric emptying and plasma gastrin levels were determined in humans. Nocloprost at doses of 50 and 100 micrograms was ineffective, but at a dose of 200 micrograms it reduced the response to pentagastrin significantly and that to a peptone meal by 30-50% and abolished plasma gastrin response without affecting the rate of gastric emptying. Nocloprost given at a dose of 100 micrograms three times daily 30 min before the major meals (breakfast, lunch, and dinner) did not affect intragastric pH significantly as monitored by continuous intraluminal pH-metry. We conclude that nocloprost does not affect gastric acid secretion or intraluminal pH when applied at a dose (50-100 micrograms) that is gastroprotective and that is proposed for peptic ulcer therapy. A higher dose (200 micrograms) of nocloprost causes moderate gastric acid inhibition and suppression of plasma gastrin release without affecting gastric emptying or causing any side effects.

Gastric protection by nocloprost against aspirin damage in humans. Possible role of epidermal growth factor.

Ten healthy young male subjects took part in a double-blind, placebo-controlled crossover study to assess the effects of nocloprost on gastric microbleeding and endoscopic mucosal injury induced by the administration of aspirin (2.5 g). In addition, basal and pentagastrin-induced gastric acid and pepsin secretion and salivary and plasma contents of epidermal growth factor (EGF) were measured after placebo plus aspirin or nocloprost plus aspirin treatment in these subjects. Nocloprost (100 micrograms/dose) significantly reduced spontaneous gastric microbleeding and almost completely prevented gastric mucosal injury induced by aspirin. Nocloprost failed to affect basal and pentagastrin-stimulated gastric acid and pepsin secretion but increased significantly the salivary outputs and plasma concentrations of EGF. In conclusion, nocloprost is effective in preventing gastric injury by aspirin even at a non-antisecretory dose, and this protection may involve an excessive release of EGF.

Cholecystokinin in the inhibition of gastric secretion and gastric emptying in humans.

Cholecystokinin (CCK) is known to inhibit gastric acid secretion and gastric emptying but its physiological role in the inhibition of gastric functions is not settled. In this study performed on 16 young male subjects, gastric acid secretion and emptying rate were determined after intragastric administration of 8% peptone meal alone or in combination with intravenous infusion of graded doses of CCK-8 (5-80 pmol/kg.h) or with addition of vegetable oil to meal without or with pretreatment with loxiglumide, a specific CCK antagonist. CCK-8 infusion at lower dose (5 pmol/kg.h) was ineffective but at higher doses (20-80 pmol/kg.h) it resulted in a significant reduction in acid output by 39 and 43% and a decrease in gastric emptying from 54% to 40 and 22%, respectively. Pretreatment with loxiglumide abolished almost completely the inhibition of both gastric acid and gastric emptying by CCK-8. Fat added to peptone meal reduced gastric acid secretion by 42-65% and decreased gastric emptying to 24-32%. The pretreatment with loxiglumide tended to reduce fat-induced inhibition of gastric acid secretion and gastric emptying but the difference in the inhibition of gastric functions between the tests without and with loxiglumide was not significant. This study provides evidence that exogenous CCK administered at pharmacological doses is a potent inhibitor of gastric acid secretion and gastric emptying and probably acts via specific CCK receptors. In contrast, fat induces inhibition of gastric acid secretion and gastric emptying that cannot be fully attributed to hormonally acting CCK.

Effects of colloidal bismuth subcitrate on aspirin-induced gastric microbleeding, DNA loss, and prostaglandin formation in humans.

Ten healthy young male subjects took part in a double-blind, placebo-controlled, crossover trial to assess the effect of colloidal bismuth subcitrate (De-No) on prostaglandin (PG) E2 generation and mucosal integrity in an aspirin (ASA)-treated stomach. After administration of ASA (2.5 g) plus placebo, a marked reduction in mucosal generation of PGE2 (by about 85%) was observed, and this was accompanied by a significant increase in gastric microbleeding and DNA loss and endoscopic and histologic damage of the mucosa. After the combination of De-Nol (300 mg four times daily) with ASA, mucosal generation of PGE2 showed a reduction similar to that in tests with ASA plus placebo, but gastric microbleeding and mucosal damage were significantly reduced. It is concluded that De-Nol has a protective action on ASA-induced gastric microbleeding and that this protection occurs despite a marked suppression of mucosal production of prostaglandins.

De-Nol stimulates gastric and duodenal alkaline secretion through prostaglandin dependent mechanism.

This study was designed to determine the effects of colloidal bismuth subcitrate De-Nol on gastric HCO3- secretion in 24 healthy subjects and on gastric and duodenal HCO3- secretion in dogs with gastric and duodenal fistulae. Alkaline secretion was measured after pretreatment with ranitidine to abolish the H+ secretion using a constant perfusion aspiration system and back titration of the perfusates to the original pH 6.0. Luminal release of PGE2 was also measured in the gastric and duodenal perfusates. Addition of De-Nol in gradually increasing concentrations resulted in step wise increments in gastric HCO3- secretion in man and in dogs reaching, respectively, about 80% and 55% of the maximal HCO3- response to 16, 16dimethyl-PGE2 (dmPGE2). The duodenal HCO3- response to De-Nol in dogs reached 72% of the dmPGE2 maximum. These effects were accompanied by a significant increase in luminal release of PGE2. Pretreatment with atropine reduced basal and in part De-Nol induced alkaline secretion, whereas pirenzepine did not affect this secretion in man and dogs. Aspirin (in man) and indomethacin (in dogs) reduced the release of PGE2 by about 80% and suppressed almost completely the gastric and duodenal HCO3- response to De-Nol in these species. This study provides evidence that De-Nol stimulates gastroduodenal alkaline secretion through a prostaglandin dependent mechanism.

Effects of protective drugs on gastric alkaline secretion in man.

This study was designed to determine the effects of sucralfate, De-Nol, and Maalox 70 on gastric HCO3 secretion in 34 healthy humans. Alkaline secretion was measured after pretreatment with ranitidine to abolish H+ secretion, using a constant perfusion-aspiration system and back-titration of the perfusates to the original pH 6.0. Luminal release of PGE2 was also measured in the gastric perfusates. Addition of sucralfate or De-Nol resulted in increments of gastric HCO3 secretion, reaching about 45% and 59%, respectively, of the maximal HCO3 response to 16,16-dimethyl PGE2 (dmPGE2). The highest response to Maalox 70 reached about 21% of dmPGE2 maximum. These effects of sucralfate, De-Nol, and Maalox 70 were accompanied by a significant increase in luminal release of PGE2. Pretreatment with atropine reduced basal and, in part, sucralfate-, De-Nol-, and Maalox 70-induced alkaline secretion, whereas pirenzepine did not affect this secretion. Aspirin reduced the release of PGE2 by about 80% and suppressed almost completely the gastric HCO3 response to sucralfate, De-Nol, and Maalox 70. This study provides evidence that sucralfate, De-Nol, and Maalox 70 stimulate gastric alkaline secretion via a prostaglandin-dependent mechanism.

Vagal cholinergic control of gastric alkaline secretion in normal subjects and duodenal ulcer patients.

Gastric alkaline secretion was determined in ranitidine treated healthy subjects and duodenal ulcer (DU) patients using gastric perfusion aspiration system and back titration of gastric perfusate to original pH 6.0. Basal alkaline secretion showed periodic fluctuations reaching peaks at phase III of the migrating motor complex (MMC) in the stomach. Mean basal alkaline secretion in healthy normals and DU patients averaged 1120 +/- 124 and 880 +/- 72 mumol/h, respectively and no correlation was found between basal and maximally stimulated gastric acid and alkaline secretion. Modified sham feeding in normal subjects and in DU patients increased this secretion to the peaks of about 28 and 36% of the maximal alkaline response to intragastric application of 16,16 dimethyl-PGE2 in these subjects. Vagotomy did not affect significantly basal alkaline secretion but prevented the rise in alkaline secretion induced by modified sham feeding. Atropine (5-20 micrograms/kg) decreased dose dependently basal, and prevented the modified sham feeding induced alkaline secretion, while pirenzepine (5-20 micrograms/kg) had little influence on basal, and did not affect the modified sham feeding induced, alkaline secretion. This study shows that basal gastric alkaline secretion fluctuates in phase with gastric motor activity, and is similar in normal and DU patients. Vagal stimulation strongly increases alkaline secretion, the effect being abolished by vagotomy and atropine, but not by pirenzepine, suggesting the involvement of M2 rather than M1 subtypes of muscarinic receptors in this stimulation.

Double blind controlled study on the effect of sucralfate on gastric prostaglandin formation and microbleeding in normal and aspirin treated man.

Two groups A and B each comprising 12 healthy young male subjects were used in a double blind, placebo controlled trial to assess the effects of 1.0 g sucralfate qid on prostaglandin (PG) generation and mucosal integrity in the intact and aspirin-treated stomach. Mucosal formation and luminal release of PGE2, 6-keto-PGE1 alpha and thromboxane B2, gastric microbleeding and DNA loss (integrity indicators) and basal and pentagastrin induced acid secretion were measured after placebo and sucralfate treatment in subjects without (group A) and with administration of 2.5 g aspirin (group B). Sucralfate significantly reduced spontaneous gastric microbleeding and DNA loss in group A and prevented blood loss but not DNA loss caused by aspirin in group B. The protective effects of sucralfate on spontaneous gastric microbleeding were accompanied by increased mucosal biosynthesis and luminal release of PGE2 and 6-keto-PGF1 alpha with a reduction in release of thromboxane B2. In aspirin treated subjects both mucosal generation and luminal release of prostaglandins and thromboxane B2 were greatly suppressed although sucralfate treatment did not influence these prostaglandins in spite of the reduction in mucosal damage. It is concluded that sucralfate has a potent protective action on spontaneous and aspirin treated gastric microbleeding in man and that this protection may be partly because of the increased mucosal biosynthesis of prostaglandins.

Effects of somatostatin-14 and somatostatin-28 on plasma hormonal and gastric secretory responses to cephalic and gastrointestinal stimulation in man.

This study was designed to determine the influence of cephalic and gastrointestinal meal stimulation on plasma levels of somatostatin-like immunoreactivity (SLI) and to compare plasma hormonal and gastric secretory effects of somatostatin-14 (SS-14) and its putative prohormone, somatostatin-28 (SS-28), in humans. Cephalic stimulation induced by modified sham feeding did not affect plasma SLI, whereas a gastric liver extract meal caused a significant increase in SLI. Infusion of SS-28 dose-dependently suppressed gastric acid, serum gastrin, and plasma pancreatic polypeptide (PP) responses to cephalic and gastrointestinal stimulation. SS-28 was equipotent with SS-14 as gastric inhibitor when compared on the basis of molar doses infused but was 4-10 times less potent on the basis of plasma SLI concentrations obtained. A lower and more physiological dose of SS-14 (75 pmol/kg-h) reduced gastric acid and PP responses but failed to affect the serum gastrin response to a meal; whereas a larger, pharmacological dose (500 pmol/kg-h) also suppressed serum gastrin responses. We conclude that meal releases SLI into the circulation and that SS-28 mimics the gastric secretory and plasma hormonal effects of SS-14 but is several times less potent than SS-14 in terms of circulating hormone levels.

Effect of meciadanol on gastric secretion and aspirin-induced gastric mucosal injury in humans.

The aim of this study was to assess the effects of a newly synthesized flavonoid, meciadanol, on gastric secretion and on aspirin-induced gastric mucosal injury in healthy humans. In vitro experiments have shown that meciadanol (INN proposed) inhibits histidine decarboxylase in gastric cells. In our study meciadanol did not affect either basal or pentagastrin-stimulated gastric acid secretion or pepsin secretion and did not produce any endoscopic or histological changes in the stomach or duodenum. Meciadanol prevented aspirin-induced microbleeding and aspirin-induced DNA loss, suggesting that gastric mucosal histamine is involved in the mucosal injury caused by aspirin.

Prostaglandins in peptic ulcer disease: effect of nonsteroidal anti-inflammatory compounds (NOSAC).

This study shows that human fundic mucosa generates various PGs, particularly PGE2, and thromboxanes and this generation appears to be significantly lower in gastric ulcer than in duodenal ulcer patients or normal subjects. Non-steroidal antiinflammatory compounds (NOSAC), such as aspirin and indomethacin, greatly reduce the PG biosynthesis and cause mucosal damage including mucosal erosions and haemorrhages observed at endoscopy, increased gastric microbleeding and DNA loss. In contrast, carprofen, a novel NOSAC with good antiinflammatory properties and gastric tolerance, failed to affect mucosal generation of PGs and did not influence gastric mucosal integrity. This study indicates that the deficiency of endogenous PGs may play a role in the pathogenesis ulcer and that the degree of gastric mucosal damage by NOSAC is closely related to the alteration in the capability of the mucosa to generate PGs.

Generation of prostaglandins in gastric mucosa of patients with peptic ulcer disease: effect of nonsteroidal antiinflammatory compounds.

Human fundic mucosa generates various prostaglandins (PGs), particularly PGE2, and tromboxanes. This generation appears to be significantly lower in gastric ulcer patients than in duodenal ulcer patients or normal subjects. Nonsteroidal antiinflammatory compounds (NOSAC), such as aspirin or indomethacin, greatly reduce the PG biosynthesis and cause mucosal damage, including mucosal erosions and hemorrhages observed at endoscopy, increased gastric microbleeding and DNA loss. In contrast, paracetamol or carprofen, a novel NOSAC, fails to affect mucosal generation of PGs and does not influence gastric mucosal integrity. This study indicates that endogenous PGs may be involved in the pathogenesis of gastric ulcer and that normal generation of mucosal PGs is essential for the mucosal integrity.

Action of omeprazole (a benzimidazole derivative) on secretory responses to sham feeding and pentagastrin and upon serum gastrin and pancreatic polypeptide in duodenal ulcer patients.

The effects of omeprazole, a benzimidazole derivative, have been determined on the secretory responses to modified sham feeding and pentagastrin, and upon serum gastrin and pancreatic polypeptide concentrations in duodenal ulcer patients. Intragastric administration of omeprazole in doses of 2 and 6 mumol/kg produced, respectively, about 50% and 90% reduction in acid outputs in responses to modified sham feeding and pentagastrin without affecting serum gastrin and pancreatic polypeptide response to modified sham feeding.

The use of carprofen, a non-steroidal antiinflammatory agent, in peptic ulcer diseases.

The effects of carprofen (Roche), a nonsteroid antiinflammatory agent, on gastric secretion, serum gastrin level, electropotential difference (PD), gastric microbleeding, DNA loss, and the generation of mucosal prostaglandins (PGs) were examined in 20 duodenal ulcer patients with active ulcer (15 patients) or in remission (5 patients). Carprofen administered for one-week period at a therapeutic dose (300 mg/day) was well tolerated by all ulcer patients and no adverse effects were observed during or after treatment. Endoscopy performed after carprofen treatment showed complete ulcer healing in 9 out of 15 patients and no exacerbations were observed in the rest of patients. No significant changes were observed in basal or pentagastrin-induced secretion, PD, gastric microbleeding and DNA loss. The generation of PGE2, 6-keto-PGF1 alpha and thromboxane B2 was not affected by the treatment with carprofen. This study indicates that carprofen shows excellent gastrointestinal tolerance in ulcer patients, and it might be useful in the treatment of arthritic patients with peptic ulcer disease.

Effect of enkephalin and naloxone on gastric acid and serum gastrin and pancreatic polypeptide concentrations in humans.

The effects of a synthetic enkephalin analogue with prolonged opioid activity, D-ala-2-enkephalin (ala-enk) and naloxone given alone or in combination, on vagally, pentagastrin- and histamine-induced gastric secretion and plasma hormonal responses to vagal stimulation have been studied in healthy subjects. D-ala-2-enkephalin reduced basal gastric acid and pepsin secretion, and caused a dose-dependent inhibition of gastric secretory responses to modified sham-feeding and pentagastrin but not to histamine. It increased serum gastrin concentration and suppressed plasma pancreatic polypeptide response to modified sham-feeding. Naloxone alone at lower dose levels did not affect gastric secretion and plasma hormonal concentrations but at higher doses it reduced both basal and modified sham-feeding-induced secretion. When combined with ala-enk it reversed in part gastric secretory and plasma hormonal changes induced by this peptide during modified sham-feeding and pentagastrin stimulation. These results indicate that (1) stable enkaphalin analogue inhibits basal and vagally or pentagastrin-induced gastric secretion, and affects plasma hormonal response to vagal stimulation, at least in part, via activation of opioid receptors and (2) endogenous opioid substances may be involved in the stimulation of gastric secretion in man.