Platelet-derived growth factor BB mediated regulation of 12-lipoxygenase in porcine aortic smooth muscle cells

BACKGROUND & AIMS: Recently, we postulated a new concept of duodenal ulcer pathogenesis suggesting that antral Helicobacter pylori infection blocks inhibitory pathways to the gastrin and parietal cells, resulting in an increased and prolonged postprandial acid secretion. the aim of this study was to examine duodenal acid load and duodenal bulb pH after a meal before and after eradication of H. pylori. METHODS: Using a marker-dilution method and a pH electrode in the duodenal bulb, gastric emptying, acid secretion, gastrin release, duodenal acid load, and duodenal bulb pH were studied during 2 hours after peptone meals of pH 7.0 and 2.0 in 8 H. pylori-negative controls and 8 H. pylori-infected subjects before and 6 months after eradication. RESULTS: The H. pylori-infected subjects had an increased gastric emptying, gastrin release, and acid secretion, higher duodenal acid load, and lower duodenal bulb pH after the meals. These responses were normalized after eradication. CONCLUSIONS: H. pylori-infected subjects have an increased and prolonged postprandial acid secretion, partly caused by an impaired low pH inhibition of acid secretion, gastrin release, and gastric emptying, resulting in an increased duodenal acid load and a prolongation of low pH in the duodenal bulb, as a general prerequisite for the development of duodenal ulcer disease.     

The vagus

The surgical physiology of the vagus is reviewed with respect to vagotomy in the treatment of duodenal ulcer. All types of vagotomy (truncal, selective gastric, or proximal gastric) produce similar reduction in acid secretion and comparable elevation in serum gastrin. The evidence is mounting that the vagus may have opposing influences on gastrin release: stimulation and inhibition. Division of only the extragastric vagal branches leads to withdrawal of an inhibitory mechanism rendering the denervated stomach more sensitive to the action of gastrin. The loss of this vagally controlled inhibitory mechanism, rather than more meticulous dissection, may explain the higher incidence of more complete vagotomies in selective than in truncal vagotomy. Proximal gastric vagotomy may be the ideal elective operation yet devised for duodenal ulcer. It does, however, cause elevation in serum gastrin and more than 90 per cent of patients after this operation will have positive insulin test in two to four years. This is higher than the positivity seen with truncal vagotomy. Results of controlled trials are needed before this operation becomes fully established.     

The effect of antral distension on acid secretion and plasma gastrin in duodenal ulcer patients

The effect of antral balloon distension on acid secretion and the plasma gastrin concentration was studied in 8 duodenal ulcer patients. Antral distension significantly increased the acid secretion to about 30% of the peak acid response to pentagastrin without any change in the plasma gastrin concentration. Antral distension and concomitant intragastric neutralization, with the intention of facilitating release of antral gastrin, produced about the same acid response and did not evoke any plasma gastrin increment. The results suggest that the acid response to antral distension in duodenal ulcer patients is evoked without contribution of the gastrin mechanism, and that the acid response is probably mediated via a pyloro-oxyntic reflex. In this respect the duodenal ulcer patient seems to differ from the healthy subject, in whom antral distension produces no acid response, and from the dog, in which release of gastrin as well as pyloro-oxyntic reflex participate in the acid response to antral distension.     

Gastrin and its role in the development of ulcer disease

Helicobacter pylori infected patients have increased gastrin release which shows a marked fall after cure of the infection. Recent studies indicate that inflammatory cells and cytokines play an important role in the pathogenesis of Helicobacter-associated hypergastrinemia. Views differ regarding the impact of gastrin on acid secretion. Current evidence suggests that gastrin is responsible for at least some of the increased acid secretion seen in duodenal ulcer patients.     

Zollinger-Ellison syndrome and antral G-cell hyperfunction in patients with resistant duodenal ulcer disease

We measured basal and pentagastrin-stimulated acid secretion, as well as basal and meal-stimulated plasma gastrin concentration to determine, in 67 patients affected by resistant duodenal ulcer, whether their condition could be related to gastric acid secretion and/or gastrin-related syndromes. We then compared them to 46 duodenal ulcer control patients. The outpatients were investigated consecutively. The resistant duodenal ulcer patients differed from the controls only in their higher complication rates (bleeding or perforation, P < 0.05). We identified five patients in the resistant duodenal ulcer group with Zollinger-Ellison syndrome and 12 with antral G cell hyperfunction, whereas in the control group only one patient was affected by antral G cell hyperfunction. IgG anti-Helicobacter pylori antibodies were positive for the presence of infection in 7 of the hypergastrinaemic patients. When Zollinger-Ellison syndrome or antral G cell hyperfunction were excluded, no differences could be found in gastric acid secretion, or basal and meal-stimulated plasma gastrin levels, between the resistant and control duodenal ulcer patients, except for basal acid hypersecretion (resistant duodenal ulcer 16% vs duodenal ulcer 2% P = 0.0144). In the presence of duodenal ulcer disease resistant to H2-blockers, it is mandatory to measure basal plasma gastrin concentration since it was possible to diagnose the gastrin-related syndromes, Zollinger-Ellison syndrome and antral G cell hyperfunction, in 26% of this group of patients.     

Differences in antral response to meat extract in duodenal ulcer patients

Although acid secretion is important in the pathogenesis of duodenal ulcer formation, the antral phase of gastric secretion has not been adequately studied. In 60 duodenal ulcer and 12 normal patients, basal, antral and peak acid secretion was investigated. Antral function was assessed by instilling meat extract sodium and measuring acid and serum gastrin output. Two groups of patients were thus identified: 1. Antral responders in whom meat extract caused a significant increase in serum gastrin and acid output. 2. Antral nonresponders in whom meat extract did not significantly lead to an elevation in gastrin and acid output.     

Target for anti-ulcer agents--pH, H. pylori or NO?

Although until recently the reduction of gastric acid secretion was the primary aim in the treatment of peptic ulcer disease, it is now recognised that the presence of Helicobacter pylori and not only acid is required to produce duodenal ulcer. Accordingly, the part played by gastric acid has been relegated to the contributor to the effects of H pylori infection. Recent research into the pathogenesis and treatment of peptic ulcer disease suggests the locus of receptors for acid stimulants, such as acetylcholine, histamine and gastrin, to be the immune cell in the lamina propria of gastric mucosa, and not the parietal cell. Thus the effects of acid stimulants, as well as those of mediators of other gastro-intestinal functions, such as oesophageal and gastroduodenal bicarbonate secretion, may be directly transmitted to the effector cells via macrophages and plasma cells. Nitric oxide (NO) may be the agent mediating the interaction between immune and epithelial cells. If these findings are validated and confirmed in man, they may pave the way for new approaches to the treatment of acid-related disorders, resulting in therapeutic strategies that do not necessitate the eradication of H pylori.     

Some thoughts on tolerance

In 4 duodenal ulcer patients the morphology of parietal cells has been studied before and one year after proximal gastric vagotomy (PGV). The average basal gastric acid secretion of the 4 patients was reduced from 9.2 m.mol/h before to 0.9 m.mol/h one year after PGV (90% reduction). The reduction in acid secretion was not accompanied by changes in the morphology of the parietal cells. Light microscopical studies indicated that the average cell size was about the same before and one year after PGV. Electron micro scopical studies showed only negligible changes in the parietal cell ultrastructure.     

Association between serum gastrin levels, gastric acid secretion and age in early gastric cancer

This study evaluated the effect of gastric acid secretion and serum gastrin response on tumor differentiation for early gastric cancer according to patients' age. We investigated the association between serum gastrin levels, gastric acid secretion and the histologic types of 335 early gastric carcinomas limited to the mucosal and submucosal layers in comparison with 450 gastric and 197 duodenal ulcers. The preoperatively examined basal acid output, maximal acid output and peak acid output after administration of tetragastrin and serum gastrin levels before and after ingestion of a test meal were determined. Patients with differentiated cancer and duodenal ulcer showed a significant negative correlation between gastric acid secretion and age, while the former group also had a significant positive correlation between serum gastrin levels and age. On the other hand, patients with undifferentiated cancer did not show any such correlation between gastric acid and age, but showed a significant positive correlation between serum gastrin, integrated gastrin response and age. Patients with gastric ulcer did not show any such correlations. These data suggest that both low acid secretion and endogenous hypergastrinemia, especially in the elderly, may play an important role in differentiated and undifferentiated gastric carcinomas.     

Parietal cells in the duodenal bulb and their relation to Helicobacter pylori infection

AIM: To investigate the prevalence, and relation to Helicobacter pylori, of parietal cells in the duodenal bulb using a monoclonal antibody directed against H+,K(+)-ATPase (HK12.18). METHODS: Twenty six patients with duodenal ulcer disease and 16 healthy controls were studied. H pylori status was determined by gastric histology and culture and by the 13C-urea breath test. Four biopsy specimens were taken from the duodenal bulb and stained with HK12.18. The presence/absence and number of parietal cells in the duodenal bulb were assessed blindly by a histopathologist. RESULTS: The overall prevalence of parietal cells in the duodenal bulb was 31% (13/42) and was similar in patients with duodenal ulcer and in controls, and in H pylori positive and negative subjects. The median (range) number of parietal cells in the duodenal bulb was 7.5 (4-20) parietal cells/subject, and was similar in all four groups. CONCLUSIONS: The prevalence of parietal cells in the duodenal bulb (31%) is notably higher than previously reported in endoscopic studies, and is in keeping with reports from studies on necropsy/operative specimens. There was no difference in the prevalence or number of parietal cells in the duodenal bulb between patients with duodenal ulcer and controls, regardless of H pylori status. These findings suggest that parietal cells in the duodenal bulb do not contribute to the pathogenesis of duodenal ulcer.     

Theoretical and practical implications of calcitonin therapy in gastroduodenal ulcer

Calcitonin (CT) inhibits basal and pentagastrin stimulated gastric acid and pepsin secretion by 60 to 70% when CT is infused over a short period of time. Vagal and histamine-mediated stimulations are less diminished. A long-term infusion of CT inhibits persitently basal and pentagastrin-stimulated acid and pepsin secretion over more than 24 hours in patients with duodenal ulcer, stress bleeding and Zollinger-Ellison-Syndrome. To date, the therapeutic efficiency of CT in gastroduodenal bleeding has not been evaluated in a controlled trial. CT inhibits gastric secretion also after oral application. In an endoscopically controlled double blind trial we were not able to demonstrate a significant benefit of oral CT in patients with gastric ulcer. In ulcer bleeding CT does not apear reasonable in comparison with histamine-H2-receptor antagonists which apparently is more efficient and less costly.     

Lansoprazol ++ : a new proton pump inhibitor

Lansoprazole is the new proton pump inhibitor, decreasing the volume of gastric acid secretions and inhibiting secretion of gastric acid and pepsin. Lansoprazole appears to be more effective in therapy of gastric ulcer and duodenal ulcer in comparison with H2-receptor antagonists and omeprasole. Reflux oesophagitis and Zollinger-Ellison syndrome are also healed by Lansoprazole. The best results in the treatment of patients with peptic ulcer, reflux oesophagitis and Zollinger-Ellison syndrome were occurred after a daily 30 mg dose of Lansoprazole. Treatment of patients with duodenal ulcer should be continued for 2 to 4 week and the case of gastric ulcer a well as reflux oesophagitis should be prolonged till 4 to 8 week. Lansoprazole is well tolerated, reported adverse effects are similar to the incidence observed in patients treated with other proton pump inhibitors.     

Effect of Tityus serrulatus scorpion toxin on serum gastrin levels in anaesthetized rat

Scorpion toxin induces gastric secretion of acid and pepsin in rats. These effects seem to be mediated by the release of acetylcholine and histamine. However, the role of gastrin in the scorpion-toxin-induced gastric secretion is unknown. We describe the effects of the T1 fraction purified from Tityus serrulatus scorpion venom on serum and on antral tissue gastrin levels in anaesthetized rats. Gastrin levels in serum and in the antral mucosa were measured before and at intervals 5, 15, 30, 60, 90 up to 120 min after the intravenous injection of saline or the T1 fraction of scorpion venom (0.25 mg/kg) into anaesthetized rats. Antral G-cells were submitted to immunocytochemistry and electron microscopy. The data on gastrin were correlated with the gastric juice volume, and the acid and pepsin output increases induced by toxin. Scorpion toxin induced a significant increase in volume, acid output and pepsin output of gastric juice and gastrin serum levels 15-60 min after injection. Simultaneous measurements of antral gastrin levels did not show significant effects. The number of dense, intermediate and empty granules per microm(2) in the cytoplasm of antral G-cells was not significantly changed 60 min after saline or toxin injection. Scorpion toxin significantly increased serum gastrin; levels in rats.     

NCI? What is it? What do they do?

BACKGROUND: Omeprazole, a H+/K+ ATPase inhibitor, has been shown to reduce gastric bicarbonate secretion in cats. However, there has been no study on the effect of omeprazole on bicarbonate secretion in patients with duodenal ulcer (DU). METHODS: Fifteen men with duodenal ulcer (mean age 38 years, range 22-57) were included. Baseline gastric acid output, bicarbonate secretion, and parietal and nonparietal secretions were estimated before and after omeprazole therapy (20 mg/day) for four weeks. RESULTS: Omeprazole administration did not significantly alter bicarbonate secretion (3.3 [1.2] vs 2.4 [0.4] mmol/h), though there was significant reduction in gastric acidity (44.2 [6.6] vs 20.7 [4.6] mmol/L, p < 0.01). CONCLUSION: Omeprazole reduces acid secretion but does not affect gastric bicarbonate secretion in patients with DU.     

Transplantation of hepatocytes for prevention of intracranial hypertension in pigs with ischemic liver failure

BACKGROUND: How Helicobacter pylori infection affects gastric acid secretion is still unclear. METHODS: Gastric juice pH, ammonia concentration in gastric juice, serum gastrin level, and grade of gastritis in accordance with the Sydney System were determined for patients with gastric ulcer (GU) and duodenal ulcer (DU) before and after treatment with lansoprazole and amoxicillin, and results were compared with those of H. pylori-negative controls. RESULTS: Scores for H. pylori density, atrophy, metaplasia, and activity of gastritis in the corpus were higher in patients with GU, especially those with proximally located GU, than in those with DU. Gastric juice pH was significantly higher in GU patients than in DU patients and controls. After H. pylori eradication, gastric juice pH and serum gastrin levels in both GU and DU patients were significantly decreased to control levels. In patients without eradication, no significant changes in these factors were observed. CONCLUSIONS: These findings suggest that H. pylori infection and gastritis in the corpus suppress acid secretion and increase gastric juice pH, resulting in hypergastrinemia, and that eradication of H. pylori normalizes acid secretion and serum gastrin levels.     

Gastritis duodenitis, and circulating levels of gastrin in duodenal ulcer before and after vagotomy

Biopsy specimens have been taken from five standard sites in the stomach and from the duodenal bulb in order to investigate the association of gastritis and duodenitis with duodenal ulcer. Twenty patients with chronic duodenal ulcer were investigated in this manner and in addition had gastric secretion tests and a radio-immune assay of serum gastrin under differing conditions. The patients were then treated either by a truncal vagotomy and pyloroplasty (TVP) or by a highly selective vagotomy without a drainage procedure (HSV). All the investigations were repeated three months postoperatively. Duodenal ulcer was usually associated with gastriitis, although this varied in extent and severity from patient to patient. In nearly all the patients, gastritis was present at the pyloric end of the stomach and along the lesser curve. In more than half of the patients, gastritis was also present in the body of the stomach but the fundus was usually spared. Chronic duodenitis was found in the duodenal bulb in all these patients. After vagotomy there was a marked increase in both the extent and severity of the proximal gastritis in both treatment groups but the distal gastritis remain almost unchanged. There was little change in the incidence of duodenitis after vagotomy but its severity was lessened. No correlation was found between the peak acid output (PAO) in response to Histalog and the severity of the gastritis or the duodenitis either before or after operation, with one exception. The postoperative PAO was significantly less in those patients who developed a severe proximal gastritis after vagotomy. No relationship was found between the severity of the distal gastritis and the levels of serum gastrin. No correlation was found between either the basal or peak acid output and the corresponding serum gastrin levels before or after vagotomy.     

Circadian gastric acidity in Helicobacter pylori positive ulcer patients with and without gastric metaplasia in the duodenum

BACKGROUND: The presence of gastric metaplasia allows helicobacter pylori to colonise the duodenum and this condition is thought to be acquired as a response to acid hypersecretion. This functional disorder, however, is present only in a subgroup of duodenal ulcer patients and, in addition, surface gastric metaplasia has been frequently found in the proximal duodenum of normal subjects and patients with non-ulcer dyspepsia, who cannot be certainly considered as acid hypersecretors. AIMS: To clarify the role of acid in inducing gastric type epithelium in the duodenum. This study aimed at assessing whether the pattern of circadian gastric acidity differs between H pylori positive duodenal ulcer patients with and without duodenal gastric metaplasia. PATIENTS: Seventy one patients with duodenal ulcer confirmed by endoscopy and who were found to be positive for H pylori infection by histology on antrum biopsy specimens were enrolled into this study. METHODS: Gastric type epithelium in the duodenum was found in 49 of 71 ulcer patients (69%). Continuous 24 hour gastric pH metry was performed in 50 healthy subjects and in the two subgroups of duodenal ulcer patients with and without gastric metaplasia in the duodenum. Gastric acidity was calculated for 24 hours (1700-1659), night (2000-0759) and day-time (0800-1959). RESULTS: Ulcer patients without gastric metaplasia showed a significantly higher gastric acidity (p < 0.001) than controls for every time interval considered, while the ulcer subgroup with gastric metaplasia was more acid than healthy subjects (p < 0.001) during the whole 24 hour period and the daytime. There was no difference between the two subgroups of duodenal ulcer patients with and without gastric metaplasia during the various time segments analysed. CONCLUSION: The findings confirm that the circadian gastric acidity of duodenal ulcer patients is higher than that of controls. As there is no difference in gastric pH between duodenal ulcer patients with and without gastric metaplasia, gastric hyperacidity is not specific to patients with duodenal gastric metaplasia. It is probable that this histological change is a non-specific response to mucosal injury resulting from various factors and not exclusively to acid.     

Helicobacter pylori infection after gastrectomy and vagotomy in duodenal ulcer patients

The eradication of Helicobacter pylori (Hp) is known to reduce the recurrence rate of duodenal ulcer (DU) to similar extent as gastrectomy but it is not clear what is the prevalence of Hp in DU patients after surgical interventions such as gastrectomy or vagotomy. The purpose of this study was to evaluate the influence of gastrectomy or truncal vagotomy with pyloroplasty on the prevalence of Hp in 51 DU patients just before and 6-8 months after these procedures. Using C14-urea breath test (UTB), rapid CLO-test and histology of the biopsy samples of gastric mucosa obtained during gastroscopy, the Hp was detected in all DU subjects submitted to operation. Following distal gastric resection (antrectomy) with Billroth II anastomosis (N = 32) due to an ulcer resistance to conservative therapy, peptic ulceration was not observed during 6-8 months in any of the examined subjects and the Hp was only rarely observed (only in 3 out of 32 operated patients). Histologically, in antral biopsies taken prior to surgery, all DU patients presented chronic active gastritis. After the surgery, the absence of Hp was confirmed also by histology. Histological evaluation of gastrectomy stump biopsies revealed typical chronic gastritis with concomitant foveolar hyperplasia and focal gland dilation. Following selective vagotomy and pyloroplasty (N = 19), the scarring of duodenal bulb (without active ulcer) was seen in 4 out of 19 operated patients but the Hp was detected in all (100%) cases. Gastric biopsies prior and after vagotomy revealed chronic active gastritis associated with Hp infection. Basal plasma gastrin was reduced after gastrectomy by about 30% and basal and maximal pentagastrin-induced acid secretion was decreased by about 60% and 70%, respectively. Vagotomy did not reduce activity of the mucosal inflammation and the incidence of Hp. Basal plasma gastrin level was increased by about 60%, while basal and pentagastrin induced acid secretion was decreased by 25% and 40%, respectively. Because of the high ulcer recurrence rate after vagotomy as opposed to low recurrence after gastrectomy, it is reasonable to conclude that (1) the disappearance of Hp and reduction in plasma gastrin and gastric acid secretion were probably the major factors responsible for the high efficacy of gastrectomy in prevention of ulcer recurrence, (2) in non-complicated DU, gastric surgery should be avoided and replaced by conservative anti-Hp therapy involving both antisecretory or bismuth agents and antimicrobial drugs which should provide similar therapeutic effects as surgery and (3) vagotomy should be eliminated as the method of treatment of DU because of the high recurrence of peptic ulceration and the failure of this procedure to affect the Hp status.     

Electroconvulsive shock and norepinephrine uptake kinetics in the rat brain

1 The effect of isoprenaline on gastric secretion evoked by various means has been studied in conscious rats provided with Pavlov and Heidenhain pouches. 2 Interdigestive acid secretion in the Pavlov pouch was reduced by isoprenaline, whereas pepsin secretion was unaltered. 3 Central vagal stimulation effected by 2-deoxy-D-glucose injection evoked a gastric secretory response that was substantially reduced by isoprenaline. 4 2-Deoxy-D-glucose increased the mobilization of gastric mucosal histamine, an effect that was prevented by isoprenaline. 5 Isoprenaline infusion alone induced a slight increase in histamine mobilization and also a considerable elevation of immunoreactive serum gastrin concentration. 6 The secretory response to food in the Pavlov pouch was almost abolished by isoprenaline. 7 Although the acid response to histamine in the Heidenhain pouch was susceptible to isoprenaline inhibition, that to methacholine was not. 8 Pepsin secretion in the Heidenhain pouch preparation stimulated by histamine or methacholine seemed to be enhanced by isoprenaline.     

Histamine and peptic ulcer: a prospective study of mucosal histamine concentration in duodenal ulcer patients and in control subjects suffering from various gastrointestinal diseases

In a prospective study the histamine content of the mucosa of the body of the stomach was measured in 100 patients consisting of control subjects, patients with duodenal ulcer and patients suffering from various gastrointestinal diseases. The histamine content was found to be 43 mug/g in male control subjects (median) while in duodenal ulcer patients levels attained were significantly lower by about 30 per cent. In all the other groups of patients histamine concentrations in gastric mucosa were found to be "normal". Since in most species it is extremely diffcult to alter the mucosal histamine concentration by any form of treatment, the diminished histamine content of the gastric mucosa in patients with duodenal ulcer seems remarkable. Among several possible explanations offered for this finding we think the most likely is that histamine release is increased in duodenal ulcer disease.