The vagus exerts trophic control of the stomach in the rat

Bilateral subdiaphragmatic truncal vagotomy results in great functional changes in the stomach although the changes in the gastric mucosal architecture are small. A trophic effect of the vagus on the stomach is revealed after unilateral vagal sectioning, taking advantage of the fact that, in the rat, each vagal trunk innervates only one side of the stomach, and that denervation of one side does not impair the functional capacity of the other. The denervated side of the stomach displayed atrophy that was reflected in reduced weight and height of the oxyntic mucosa and a reduced density of argyrophil cells. The lack of atrophy after bilateral vagotomy can be explained by counteracting forces, in that the subsequent rise in gastrin secretion (due to lack of acid feedback inhibition of gastrin release) probably masks antitrophic effects of the vagotomy per se. Interestingly, the number of somatostatin cells in the oxyntic mucosa was not reduced after unilateral vagotomy, nor was the weight of the antral mucosa or the density of enterochromaffin and gastrin cells in the antrum on the denervated side.     

Effects of Several Denervation Procedures on Distribution of Calcitonin Gene-Related Peptide and Substance P Immunoreactive in Rat Stomach

The effect of chemical deafferentation, vagotomy(VGX), and gangliosympathectomy (GSX) on the density offibers containing calcitonin gene-related peptide (CGRP)and substance P (Sub.P) in the rat gastric wall was studied. Chemical deafferentation bycapsaicin abolished the density of CGRP-immunoreactive(IR) fibers, not Sub.P-IR fibers. Ten days after VGX,the density of CGRP-IR or Sub.P-IR fibers in the mucosa was largely reduced, while no reductionof CGRP-IR and Sub.P-IR fibers was seen in submucosaland muscular layers. GSX significantly reduced thedensity of CGRP-IR fibers in the mucosa and caused a moderate decrease in the fibers in submucosaland muscular layers. Pretreatment with6-hydroxydopamine, a neurotoxin for noradrenergicnerves, did not affect the density of CGRP-IR fibers inthe gastric wall. The density of Sub.P-IR fibers in thegastric wall was not affected by GSX. These studiesindicate that the CGRP-IR and Sub.P-IR fibers in themucosa are susceptible to extrinsic nerve denervation compared with those in the submucosa and musclelayers, that a major portion of the CGRP-IR fibers inthe mucosa is of both vagal and spinal origin, and thata major portion of the Sub.P-IR fibers in the mucosa is of vagal origin. Furthermore, thepresent results support that CGRP-IR fibers, notSub.P-IR fibers, in the rat stomach arecapsaicin-sensitive.     

Effects of pyloroplasty, truncal vagotomy, and antrectomy on parietal cell regeneration in experimental gastric wounds in the rat. A light and electron microscopic study

Parietal cell regeneration in cauterized gastric wounds was studied in rats after antrectomy (Billroth I), pyloroplasty, and truncal vagotomy with pyloroplasty. Six to eight animals in each group were killed 90 or 130 days after operation, and in each rat stereological data were obtained from electron micrographs of 15 to 20 parietal cells from the wound area, from the normal mucosa beside the wounds, and from the mucosa in unoperated controls. Antrectomy reduced parietal cell size and mucosal thickness in normal mucosa and retarded parietal cell maturation and reduced mucosal thickness in the healing wounds. Pyloroplasty slightly reduced parietal cell size in normal mucosa and retarded maturation of the parietal cells in the wounds. If truncal vagotomy was added, the reduction in parietal cell size induced by the pyloroplasty was prevented in normal mucosa.     

The role of the antrum and the vagus nerve in the metabolism of histamine in the human gastric mucosa.

The effects of antrectomy and proximal gastric vagotomy on the metabolism of histamine in the human gastric mucosa were studied in the basal state and during pentagastrin stimulation in patients with duodenal or gastric ulcer disease. Mucosal biopsy specimens were taken from the antral and oxyntic gland areas, whereafter histamine content, histidine decarboxylase activity, and histamine methyltransferase activity were simultaneously assayed. Vagotomy was followed by a decrease in the acid secretory capacity and an increase in basal serum gastrin levels. Histamine content of the oxyntic mucosa increased after vagotomy, but the ability of pentagastrin to form new amounts of the amine was impaired. Antrectomy caused a decrease in acid secretion and a fall in gastrin concentrations. Basal histamine content and rate of amine formation in the remaining oxyntic mucosa were unaffected by antrectomy. Antrectomy impaired the ability of pentagastrin to release histamine. Histamine methyltransferase was not affected by pentagastrin, vagotomy, or antrectomy. In conclusion, both antral gastrin and the vagus nerve seem to exert a regulatory influence on the metabolism of histamine in the human oxyntic mucosa. The withdrawal of these factors either causes impaired ability of pentagastrin to release histamine from its storage site or counteracts the ability of pentagastrin to accelerate histamine synthesis.     

Peptide-containing nerve fibers in the stomach wall of rat and mouse

Peptide-containing nerve fibers were found to be numerous in the glandular stomach of the rat and mouse. The immunoreactive neuropeptides demonstrated included vasoactive intestinal polypeptide (VIP), peptide histidine isoleucine (PHI), gastrin-releasing peptide (GRP), substance P (SP), enkephalin, somatostatin, cholecystokinin, and neuropeptide Y (NPY). The density and distribution of the various peptide-containing fibers did not differ overtly between the pyloric and oxyntic gland areas except for the GRP fibers, which were fewer in the pyloric than in the oxyntic mucosa. The entire VIP nerve fiber population was found to also contain PHI. Immunoreactive NPY was found to occur in the VIP/PHI fibers (VIP/PHI/NPY fibers) in the smooth muscle and intramural ganglia of both rat and mouse and in the mucosa of the mouse. Mucosal VIP/PHI fibers in the rat did not contain any NPY-like material. Perivascular NPY fibers in both species and mucosal NPY fibers in the rat did not contain VIP or PHI. The mucosa harbored numerous GRP fibers and VIP/PHI (rat) or VIP/PHI/NPY (mouse) fibers, and a modest number of NPY (rat) and SP fibers. In the submucosa the peptide-containing nerve fibers were found mainly in the ganglia and around blood vessels. Blood vessels received a rich supply of NPY fibers; the number of perivascular VIP/PHI, GRP, and SP fibers was much lower by comparison. The smooth muscle and myenteric ganglia harbored not only VIP/PHI/NPY, GRP, and SP fibers but also enkephalin, somatostatin, and cholecystokinin fibers. Gastrin-releasing peptide, VIP/PHI/NPY, SP, and enkephalin nerve cell bodies occurred in the myenteric ganglia. As studied in the rat, vagal denervation did not affect the density and distribution of the various peptide-containing nerve fibers. After sympathectomy, mucosal and perivascular NPY fibers disappeared. The other types of peptide-containing nerve fibers were not affected.     

Lipopolysaccharide-induced gastroprotection is independent of the vagus nerve

This study was done to examine the role of the vagus nerve in a model of gastric injury during endotoxemia. In conscious rats, lipopolysaccharide (LPS; 20 mg/kg ip) treatment for 5 hr prevented macroscopic gastric injury caused by acidified ethanol (150 mM HCl/50% ethanol). In addition, LPS enhanced gastric luminal fluid accumulation, decreased gastric mucosal blood flow (laser Doppler), and increased plasma gastrin levels (radioimmunoassay). Subdiaphragmatic truncal vagotomy, performed 7 days prior to LPS inhibited LPS-induced fluid accumulation, further reduced gastric mucosal blood flow following LPS, and augmented LPS-induced gastrin release compared to those in pyloroplasty controls. Atropine (1 mg/kg ip) prevented LPS-induced fluid accumulation but did not influence the effects of LPS on blood flow or gastrin release. Neither vagotomy nor atropine negated LPS-induced gastroprotection. This is the first report to examine the role of cholinergic nerves in the stomach during endotoxemia. The data indicate that LPS causes accumulation of gastric luminal fluid in part through its effects on cholinergic nerves. In contrast, the effects of vagotomy on blood flow and gastrin release following LPS involve a noncholinergic pathway. However, LPS-induced gastroprotection is independent of the vagus nerve.     

Effect of cysteamine on gastric nerve fibers containing gastrin-releasing peptide in the rat

In rats, changes in gastric nerve fibers containing gastrin-releasing peptide (GRP) in cysteamine-induced duodenal ulcer were investigated in relation to the dynamics of gastrin-producing cells (G-cells). Marked increases in gastric acid secretion and serum gastrin level were observed from 2h after the administration of cysteamine. The number of G-cells was significantly decreased from 2h after the injection of cysteamine. Two and 4h after the administration of cysteamine, the G-cells showed ultrastructural changes characterized by a markedly decreased number of secretory granules. Circulating GRP levels were significantly elevated from 2h after the administration of cysteamine. In the control group given vehicle only, nerve fibers showing immunoreaction for GRP formed a fine network in the gastric wall and were densely distributed in the oxyntic mucosa, located close to capillaries and demonstrated varicosities that contained either small clear vesicles or GRP-immunopositive vesicles with large cores. Eight h after the administration of cysteamine, there was depleted GRP immunoreactivity, evidenced by a markedly decreased number of vesicles, with large electron-dense cores, in the oxyntic mucosa. These findings suggest that, in cysteamine-induced doudenal ulcer, alterations in gastric nerve fibers containing GRP may be related to hypergastrinemia.     

Effect of truncal vagotomy on neurotensin-like immunoreactivity release in dogs

To elucidate the relationship between the vagus nerve and circulating neurotensin release, mongrel dogs were given an intraduodenal infusion of a 50 ml water solution containing 10 g glucose (n = 4) or 5 g soybean oil (n = 7) over a period of 4 min before and after truncal vagotomy with pyloroplasty. In the prevagotomized animals only a slight increase of neurotensin-like immunoreactivity (NTLI) was observed following glucose infusion, while NTLI in response to fat infusion was significantly increased. After vagotomy, NTLI release following fat infusion was significantly decreased when compared to untreated control animals, suggesting that vagotomy causes a major alteration in circulating NTLI release and that the vagus nerve may play a definite role in fat-induced NTLI release.     

Effect of different denervation procedures on catecholamines in the gut

Sympathectomy has been used to study the role of the sympathetic nervous system in the control of gastric acid secretion. Conflicting results may reflect differences in the sympathectomy procedures used. In a previous study we showed a reduction of catecholamines by more than 90% in the gut wall of the rat after surgical upper abdominal sympathectomy. The aim of the present investigation was to ascertain whether chemical sympathectomy was equally effective and whether total denervation, including combined chemical and surgical sympathectomy together with bilateral truncal vagotomy, would lower the catecholamine levels further. The results showed that chemical sympathectomy reduced noradrenaline levels in fundus (oxyntic) and antrum mucosa to levels similar to those after surgical sympathectomy (less than 5%), but the reduction was less pronounced in the muscle layer of the fundus and antrum and in the pancreas and spleen. Combined surgical and chemical sympathectomy did not reduce noradrenaline more effectively than surgical sympathectomy alone. Vagotomy reduced catecholamines in the stomach by about 50%; in extragastric tissues vagotomy was without effect. Total denervation, including combined surgical and chemical sympathectomy plus vagotomy, did not reduce noradrenaline levels more than surgical sympathectomy alone, suggesting that the proportion of adrenergic fibers that derive from the vagus is quantitatively insignificant but that the vagus exerts a local control of the sympathetic stores of gastric catecholamines.(ABSTRACT TRUNCATED AT 250 WORDS)     

降钙素基因相关肽免疫反应纤维在大鼠心肌内的分布和密度

目的 观察降钙素基因相关肽免疫反应(CGRP-IR)纤维在大鼠心肌内的分布和密度，为心肌病的研究奠定形态学基础。方法 用免疫组织化学法显示大鼠心肌内的CGRP-IR纤维，计算其分布密度。结果在心房肌内和心室肌内均可见CGRP-IR纤维分布于心肌纤维之间，心房肌内CGRP-IR纤维的面积密度和数量密度均高于心室肌。结论 CGRP-IR纤维在大鼠心肌内分布广泛，其分布密度存在部位差异。     

Do Infiltrating Leukocytes Contribute to the Adaptation of Human Gastric Mucosa to Continued Aspirin Administration?

Stachura J, Konturek JW. Dembinski A, Domschke W. Do infiltrating leukocytes contribute to the adaptation of human gastric mucosa to continued aspirin administration? Scand J Gastroenterol 1994:29:966-972.

Background: Aspirin (ASA)-induced gastropathy decreases with continued ASA ingestion due to the development of gastric mucosal tolerance. However, the mechanism of the gastric mucosal adaptation to repeated ASA challenge is unknown.

Methods: The aim of the present study was to determine the density of leukocytes infiltrating the gastric mucosa in healthy subjects during prolonged treatment with ASA. In eight healthy volunteers ASA treatment (2 g/day) was continued for 14 days. Endoscopy was performed before medication, on the 3rd, 7th. and 14th day of ASA treatment, and on the 16th and 18th day (2 and 4 days after medication was stopped). Gastric damage was scored (Lanza score), and gastric biopsy specimens were taken from both the oxyntic and antral mucosa.

Results: ASA administration resulted in the development of hemorrhagic erosions, which were most severe on the 3rd day of the medication; later significant reduction of severity of the damage was observed. ASA administration caused an increased mucosal infiltration of leukocytes; leukocyte margination and adherence to endothelia were commonly observed in the gastric mucosa, particularly on the 3rd day of ASA treatment but not later on. Mast cell density increased significantly on the 3rd day of ASA treatment. Density of mast cells later decreased in the antral mucosa but continued to be significantly increased in the oxyntic mucosa up to the 14th day. There was a striking correspondence between mast cell density and endoscopic score of the mucosal damage. Eosinophil density increased significantly during ASA treatment and remained high even alter medication was withdrawn.

Conclusions: 1) Initial mucosal damage by ASA is followed by gastric adaptation on continuous exposure to this agent; 2) infiltrating leukocytes appear to contribute to the development of gastric mucosal adaptation to ASA; and 3) mast cell density reflects the endoscopic score of gastric damage by ASA.     

Trophic Effects in the Acid-Producing Part of the Rat Stomach after Pyloric Stenosis

Background: Pyloric stenosis produces gastric hypersecretion and is thought to stimulate the growth of the gastric mucosa in the rat, the dog, and man. However, the mechanisms behind the hypersecretion and the trophic effect of pyloric stenosis are little known. The purpose of the present study was to examine whether the postulated trophic effects described include growth of the histamine-producing enterochromaffin-like (ECL) cells and whether circulating gastrin can be held responsible.

Methods: Pyloric stenosis was produced in rats by tying a ligature around the pylorus, thereby narrowing the passage through the sphincter. The animals were left for 4 to 12 weeks.

Results: The operation dilated the stomach, increased the serum gastrin concentration approximately twofold, and increased the oxyntic mucosal weight, volume, and surface area but not the mucosal thickness and total DNA content. The interglandular space was increased, and the DNA concentration was reduced. The density of the ECL cells (that is, the number of ECL cells per visual field) was reduced at 4 weeks and back to control values at 8 and 12 weeks. The calculated total volume of the ECL cell population was unchanged at first but showed a less than twofold increase 12 weeks after the operation. The volume density of the ECL cells (that is, the proportion of the mucosa made up of ECL cells) was reduced at 4 and 8 weeks and was back to normal at 12 weeks. The ECL cells are rich in histidine decarboxylase (HDC); whenever the cells are stimulated, the enzyme activity increases. The HDC activity in the oxyntic mucosa was reduced at first and returned to control values 12 weeks later.

Conclusions: Pyloric stenosis per se does not affect the total number of oxyntic mucosal cells but causes the ECL cell population to grow somewhat, probably because of the moderate hypergastrinemia. Interestingly, however, there was no increase in the HDC activity, suggesting that the ECL cells are not much activated by the operation.     

Antral gastrin cell proliferation after vagotomy in rats.

The total number of antral gastrin cells, the antral surface area and the serum gastrin concentration were determined in two groups of rats. The animals had been submitted at random either to vagotomy and pyloroplasty or to pyloroplasty alone 3 weeks before. The indirect immunoperoxidase reaction and a direct quantitative histological method were used to count the gastrin cells. Radioimmunoassay was used to estimate the serum gastrin concentration. The total number of gastrin cells in the stomach was 52% (p less than 0.01) more elevated in the vagotomized animals. Both antral mucosal surface and calculated concentration of gastrin cells per square millimeter of mucosa were significantly higher (0.01 less than p less than 0.05) in this group of animals. The serum gastrin values were significantly (p less than 0.01) more elevated after vagotomy. These observations indicate that vagotomy may induce an antral gastrin cell hyperplasia which could explain in part the hypergastrinemia observed after this surgical procedure.     

Regional differences in concentrations of regulatory peptides in human colon mucosal biopsy

The study was undertaken to examine regional differences in the concentrations of five regulatory peptides in the human colonic mucosa. Biopsies were obtained during routine colonoscopy from 33 patients whose colonic mucosa was macroscopically and histologically normal. Regulatory peptides were extracted, and measured by specific radioimmunoassays. Concentrations of three peptides that are present predominantly in endocrine cells within colonic mucosa increased significantly towards the rectum: Mean concentrations of peptide YY, enteroglucagon, and somatostatin were about three times greater in the rectum than in the cecum. However, concentrations of two peptides that are present in mucosal nerve fibers diminished significantly towards the rectum: Mean rectal concentrations of vasoactive intestinal peptide and peptide histidine methionine were both about 0.6 of mean cecal concentrations. Concentrations of all five peptides were lower in biopsies taken from colonic polyps than in normal colonic mucosa. Regional differences in colonic mucosal concentrations of regulatory peptides probably reflect differences in the physiological functions of different parts of the colon.     

Reinnervation of villi of rat jejunum following severe mucosal damage

We studied the time course of the regeneration of the jejunal mucosa of the rat after it was damaged by exposure to the surfactant, benzalkonium chloride. We placed particular emphasis on assessing the morphology of the nerve fibers within the villi during and after regeneration. The application of benzalkonium chloride resulted in virtually complete loss of villi within the treated segment; however, the crypts were only partially damaged. The mucosa began to regenerate within 6 hr of the insult. The villus lengths and crypt depths returned to pretreatment values within two to four days. The mucosal innervation was assessed through immunohistochemistry for vasoactive intestinal peptide (VIP), neuropeptide Y (NPY), and neuron-specific enolase (NSE). At all stages of regeneration, VIP, NPY, and NSE immunopositive fibers within the lamina propria extended to the tips of the villi. The density of the immunopositive fibers in the lamina propria at four days after mucosal insult was similar to that in control tissues regardless of the neuronal marker visualized. We conclude that the nerve fibers innervating the small intestinal mucosa grow at a rate of approximately 100 m/day and that the entire length of each villus contains nerve fibers throughout the regeneration process. The innervation of the regenerated mucosa appears identical to that of control mucosa.Norman A. See is a Fellow of the American Foundation for Pharmaceutical Education.Supported by NIH grant AM32594 (P.B.) and NSF grant BNS-8820658 (M.E.).     

The Effects of Vagotomy on the Gastric Mucosa of the Rat

In order to determine the effects of vagotomy on the gastric mucosa, the operations of pyloroplasty and vagotomy, pyloroplasty alone, and a sham operation were carried out in rats, and the parietal and peptic cell populations of the stomach were estimated in each animal. From the differences detected between the three groups it was concluded that vagotomy significantly reduced the average number of peptic cells per unit area of the mucosa (33 %), the total peptic cell population (34 %), and the height of the mucosa (19 %). Pyloroplasty alone did not exert any significant effects although it tended to reduce the total parietal cell population.     

Evaluation of the trophic effect of longterm treatment with the histamine H2 receptor antagonist loxtidine on rat oxyntic mucosa by differential counting of dispersed cells.

To evaluate whether the general trophic effect of gastrin on the oxyntic mucosa is an indirect effect mediated by histamine H2 receptors, sustained 24 hour hypergastrinaemia was induced in Sprague-Dawley rats by treatment with the long acting and potent histamine H2 antagonist loxtidine for five months. The trophic effect was assessed by weight, enumeration of total mucosal cells, parietal cells, and enterochromaffin like cells in smears stained for the actual cells after enzymatic dispersion of the mucosa, and by biochemical analysis of oxyntic mucosal homogenates. The weight of the whole stomach and the oxyntic mucosa increased by 12.7% (p = 0.016) and 27.5% (p = 0.006), respectively. Total oxyntic mucosal protein content increased by 28.7% (p = 0.058). Total numbers of mucosal cells and parietal cells increased by 11.9% (NS) and 24.1% (NS), respectively. The amount of the parietal cell specific enzyme H+,K(+)-ATPase was unchanged. On the other hand, the number of enterochromaffin like cells and related parameters, histidine decarboxylase activity and histamine content of the oxyntic mucosa, showed a pronounced and significant increase. It is concluded that the general trophic effect of gastrin on the oxyntic mucosa is not mediated by the histamine H2 receptor. The tropic effect of gastrin on the parietal cell seems, in contrast with that on the enterochromaffin like cell, not to be specific but only reflecting the general trophic effect on the oxyntic mucosa.     

Effects of amino acids on pancreatic polypeptide before and after vagotomy in the dog

Summary We have previously indicated a marked influence of the vagus nerve on postprandial pancreatic polypeptide secretion. The present study was designed to determine whether the vagus nerve also plays a role in the regulation of pancreatic polypeptide secretion by absorbed nutrients. The pancreatic polypeptide responses to 17 intravenously administered amino acids, as well as arginine and glucose, were measured and compared with those 1 year after truncal vagotomy in conscious dogs. In response to the infusion of a mixture of amino acids (20 g during 60 min), plasma pancreatic polypeptide concentrations decreased in normal dogs. The effect was, however, completely reversed by vagotomy, with a significant pancreatic polypeptide release being observed (p < 0.05). Arginine (5 g during 60 min) also showed a similar, although not statistically significant, effect. After intravenous bolus-injection of glucose (0.5 g/kg body weight), a transient decrease of pancreatic polypeptide secretion was found; vagotomy abolished this response. These results suggest that the vagus nerve may have a suppressive role in the process of pancreatic polypeptide secretion induced by intravenous amino acid(s) and glucose.     

Effect of gastrin receptor blockade on endocrine cells in rats during achlorhydria.

Hyperplasia of the oxyntic enterochromaffinlike cells in response to long-lasting blockade of acid secretion is closely related to hypergastrinemia. In the present study, the effect of a specific gastrin receptor antagonist on proton pump inhibitor-induced changes on serum gastrin levels, mucosal height, as well as gastrin- and enterochromaffin-like cells was investigated in rats. The proton pump inhibitor BY 308 or the vehicle methylcellulose [Methocel (controls)] was administered for 2 weeks in the presence and absence of the gastrin receptor antagonist PD 136450 (CAM 1189). BY 308 significantly increased serum gastrin levels, gastrin cell density, and antral gastrin concentration. Concomitant application of PD 136450 did not alter this response. In the oxyntic stomach, mucosal height, enterochromaffinlike cell density, labeling index of enterochromaffinlike cells, and histamine concentration were elevated after treatment with BY 308. These increases were almost completely abolished by PD 136450. Even in normogastrinemic control rats, PD 136450 significantly decreased mucosal height of the oxyntic part of the stomach and the labeling index of enterochromaffinlike cells. The results show that (a) trophic effects of drug-induced achlorhydria are mediated by gastrin; (b) even in control rats (normogastrinemic), gastrin is a trophic factor for the oxyntic mucosa; and (c) antral gastrin cell hyperplasia in states of chronic achlorhydria is not mediated by gastrin itself.     

Sample taking problems in measuring actual histamine levels of human gastroduodenal mucosa: specific and general relevance in clinical trials on peptic ulcer pathogenesis and selective proximal vagotomy.

Changes in histamine storage in the oxyntic mucosa of duodenal ulcer patients and their reversal by vagotomy and the histamine H2-antagonist cimetidine supported the hypothesis that histamine could be a causal factor in peptic ulcer pathogenesis. The specificity of these findings was impaired by problems in biopsy taking, however, and in the preparative steps before measuring the actual histamine contents in all parts of the gastric mucosa and in the duodenum. A prospective trial was carried out in 190 patients to identify these sources of bias and to overcome them by appropriate study designs. Usually a direct correlation was found between weight of biopsy and mucosal histamine content. This problem was solved by selecting a biopsy forceps producing smaller variations in sample size, by limiting the time of cold ischaemia to four to five minutes only and by taking three biopsy specimens for each single histamine value. The actual histamine content of mucosal biopsies remained constant for about four to five minutes only. The 'disappearance' rate was faster in control subjects than in duodenal ulcer patients. Hence by variation of the cold ischaemia time any artefacts of differences between mucosal histamine levels in controls and duodenal ulcer patients could be produced. Using the optimised sample taking procedure mucosal histamine contents of several gastric regions and the duodenal bulb were measured in 24 patients with duodenal ulcer, after selective proximal vagotomy without drainage and in control subjects without any stomach disease (randomised controlled trial). The histamine content was lower in all parts of the upper gastrointestinal tract in duodenal ulcer patients than in controls and was raised again in all regions after selective proximal vagotomy. As the most likely hypothesis it is suggested that vagal reflexes with afferent fibres coming from the oxyntic mucosa stimulate histamine release in duodenal ulcer patients by efferent peptidergic neurones to all parts of the stomach and the duodenum where the ulcer lesion is situated.