Effect of vasoactive intestinal polypeptide and somatostatin on secretion of epidermal growth factor and bicarbonate from Brunner''s glands

The effect of VIP and somatostatin on secretion of epidermal growth factor and bicarbonate from Brunner's glands was investigated in the rat. Vasoactive intestinal polypeptide infused in doses of 10 and 100 ng/kg/h significantly increased epidermal growth factor and bicarbonate output, but the concentrations did not change. Somatostatin infused at doses of 1, 10, 100 and 1000 ng/kg/h against a background of VIP 100 ng/kg/h inhibited in dose-dependent fashion the stimulated epidermal growth factor and bicarbonate outputs from rat Brunner's gland pouches. Also basal secretion was inhibited by somatostatin. Infusion of antisomatostatin serum stimulated Brunner's gland secretion. By immunohistochemical studies of rat duodena, it was found that epidermal growth factor, is almost exclusively present in the secretory cells of Brunner's glands. It is concluded that VIP stimulates secretion of epidermal growth factor and bicarbonate from Brunner's glands, an effect which is inhibited by somatostatin. A possible role for somatostatin in the control of Brunner's gland secretion is suggested.     

Cysteamine-induced duodenal ulcer and the hepatoduodenal branch of the vagus nerve

We investigated the role of the autonomic nervous system in gastric acid secretion, somatostatin concentration and PAS-positive mucus production in Brunner's glands in cysteamine-induced duodenal ulcer. Vagotomized rats were used. No ulcers occurred in the groups with vagotomies of the hepatoduodenal, truncal or gastric branches after cysteamine administration. However, in the hepatoduodenal branch vagotomized group, there was an increase in gastric acid secretion after cysteamine administration. A similar increase was observed in the control group, but the decreases in somatostatin concentration and PAS-positive mucus seen in the control group were not found in the hepatoduodenal vagotomized group. These results suggest that the hepatoduodenal branch of the vagus nerve might play an important role in the ulcerogenic process of cysteamine-induced duodenal ulcer.     

Role of submandibular saliva and epidermal growth factor in gastric cytoprotection

The role of submandibular epidermal growth factor in protection of the gastric mucosa was investigated in rats. Removal of the submandibular glands and thereby submandibular epidermal growth factor (EGF) caused rats to develop gastric lesions (ulcerations and ulcers) after administration of the duodenal ulcerogen cysteamine. The median output of EGF in gastric juice was reduced from 45.6 pmol/12 h (total range 17.5-65.0) in unoperated controls to less than 0.06 pmol/12 h (total range less than 0.06-1.82) in rats given cysteamine after extirpation of the submandibular glands. The contents of EGF in the submandibular glands was unchanged during cysteamine treatment. Furthermore, the effects of intragastric instillation of exogenous EGF, infusion of saliva without EGF, and infusion of saliva with a high concentration of EGF on the development of cysteamine-induced gastric lesions were investigated in rats without submandibular glands. Exogenous EGF and saliva with a high but still physiological concentration of EGF significantly reduced the median area in the stomach displaying ulcers and ulcerations, whereas saliva without EGF had no effect. Although EGF is a known inhibitor of gastric acid secretion, the dose used in the present study had no effect on gastric acid secretion in chronic gastric fistula rats; removal of the submandibular glands also did not have any such effect. We conclude that exocrine secretion of submandibular EGF has a cytoprotective function in the stomach, an effect that may be physiological.     

Cysteamine-induced inhibition of mucosal and pancreatic alkaline secretion in rat duodenum

To determine the effect of cysteamine on the alkaline secretion by the duodenal epithelium, pancreas, and Brunner's glands in relation to the pathogenesis of duodenal ulceration, the alkaline secretion by various types of duodenal loops was comparatively studied. The results obtained were as follows: (1) Cysteamine significantly reduced both mucosal and pancreatobiliary alkaline secretion in the proximal duodenum of rats. (2) The ratio of contribution of pancreatobiliary alkaline secretion to total neutralization of acid in the proximal duodenum was 55.9% under continuous perfusion. (3) There was no significant difference between the amounts of alkali per unit volume of the proximal and distal duodenal loops. (4) The alkaline substance secreted by the proximal duodenal mucosa was confirmed to be the bicarbonate. From these findings, it has been concluded that the impairment of bicarbonate secretion by the mucosal epithelium of proximal duodenum, not by Brunner's glands, plays a causative role in cysteamine-induced duodenal ulceration.     

Effect of secretin and glucagon on Brunner''s gland secretion in the rat

Brunner's gland secretion in response to infusion of secretin and glucagon was studied in the rat. Secretin was infused in doses of 15, 150 and 1500 ng/kg/h. All dose significantly increased bicarbonate and protein output and depleted Brunner's glands of PAS-positive mucin. Bicarbonate secretion was related to plasma secretin concentration, and a marked stimulatory effect of secretin was found in very low, probably physiological, plasma concentrations. Maximal bicarbonate output was obtained at a plasma concentration of secretin about 20 pmol/l. Glucagon was infused at a rate of 1.0 micrograms/kg/h and did not influence secretion rate or cell morphology. Also large doses of 5.0 and 50.0 micrograms/kg/h had no effect on Brunner's gland secretion. It is concluded that secretin in very low plasma concentrations stimulates secretion of bicarbonate, protein and mucus from Brunner's glands in the rat, while glucagon has no effect, and it is suggested that secretin may be involved in the physiological regulation of Brunner's gland secretion.     

Functional and structural changes in the jejunum of the rat following cysteamine and stress-induced duodenal ulcer.

The effects of cysteamine and stress-induced duodenal ulcer on the functional and structural properties of the rat jejunum were investigated. The absorptive capacity of the jejunum was determined using alanine as the permeant solute and the single-pass perfusion technique. A statistically significant decrease (p < 0.01) in alanine absorption was observed after 8 h and 3 days of duodenal ulcer induction by stress and cysteamine respectively. However, alanine transport measured 7 days after cysteamine or stress ulcer induction showed no significant change from control values. Cysteamine and stress-induced duodenal ulcer did not show any significant change in water absorption across the jejunum when measured after 8 h, 3 and 7 days of ulcer induction. Microscopically, the jejunum of rats with 3-day cysteamine-induced ulcer exhibited diffuse type of apical derangements with excessive swelling of the villi and progressive degenerative changes. No such changes were noticed on the 7th day nor in the jejunum of the rats with stress-induced duodenal ulcer. The results suggest that cysteamine-induced duodenal ulcer produces an inhibition in the absorptive capacity of the jejunum which is time-dependent and reversible.     

An experimental study of adrenalin-stimulated gastric acid secretion and gastrin secretion in rats of cysteamine-induced duodenal ulcer]

It is known that cysteamine-induced duodenal ulcers in rats are similar to the human duodenal ulcers in some aspects. We investigated their similarities in view of adrenalin-stimulated gastric acid secretion and gastrin secretion in these rats. Acid outputs decreased in the control group by the administration of adrenaline, but in the cysteamine-administered group acid outputs increased dose dependently. Serum gastrin levels and plasma noradrenaline levels increased by cysteamine administration. The abnormal gastric acid secretion by the adrenalin infusion in the process of cysteamine-induced duodenal ulcers in rats, which was resembled to that of duodenal ulcer patients, was recognized.     

Cysteamine-induced duodenal ulcer and the hepatoduodenal branch of the vagus nerve

We investigated the role of the autonomic nervous system in gastric acid secretion, somatostatin concentration and PAS-positive mucus production in Brunner’s glands in cysteamine-induced duodenal ulcer. Vagotomized rats were used. No ulcers occurred in the groups with vagotomies of the hepatoduodenal, truncal or gastric branches after cysteamine administration. However, in the hepatoduodenal branch vagotomized group, there was an increases in gastric acid secretion after cysteamine administration. A similar increase was observed in the control group, but the decreases in somatostatin concentration and PAS-positive mucus seen in the control group were not found in the hepatoduodenal vagotomized group. These results suggest that the hepatoduodenal branch of the vagus nerve might play an important role in the ulcerogenic process of cysteamine-induced duodenal ulcer.     

Effect of secretin and somatostatin on secretion of epidermal growth factor from brunner's glands in the rat

The effect of secretin and somatostatin on secretion of epidermal growth factor (EGF) from Brunner's glands was investigated in rats. Secretin increased volume secretion and the median output of EGF rose from 720 fmol/5 hr (total range 460–1320) in controls to 2065 fmol/5 hr (total range 1560–2730) at a dose of 50 pmol/kg/hr of secretin. Somatostatin inhibited Brunner's gland secretion, but the total output of EGF remained unchanged. Secretin-stimulated volume secretion and secretion of EGF was significantly reduced by simultaneous infusion of somatostatin. This study has shown that secretin stimulates secretion of EGF as well as volume secretion from Brunner's glands. Somatostatin prevents the effect of secretin on Brunner's glands, which suggests a role for somatostatin in control of Brunner's gland secretion.     

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.     

Inhibition of cysteamine-induced duodenal ulcer in the rat by bile diversion. Enhancement of the ulcerogenic effect of cysteamine by taurocholic and glycocholic acids

Three groups of rats were twice given cysteamine subcutaneously in a dose of 20 mg/100 g body weight. Nine of 10 controls developed severe duodenal ulcers. In contrast, the ulcer formation was inhibited significantly in the rats submitted, before exposure to cysteamine, to a bile diversion operation consisting of jejunopylorostomy and Roux-en-Y anastomosis without gastric resection. However, rats submitted to the same operation but drinking a solution with 5 mmol/l sodium salts of taurocholic and glycocholic acid, 1:3, developed severe duodenal ulcers after cysteamine injections (8 of 10). The conclusion is that neither the chemical cysteamine nor hydrochloric acid alone can be made responsible for cysteamine-induced duodenal ulcer in the rat, but that bile salts clearly enhance the ulcerogenic property of cysteamine.     

Role of local motility changes in the pathogenesis of duodenal ulcers induced by cysteamine in rats

The possible role of local motility in the pathogenesis of duodenal ulcers was investigated in rats using cysteamine. Duodenal motor activity was measured as intraluminal pressure recordings by means of a balloon positioned in the proximal duodenum. Subcutaneous administration of cysteamine (100 mg/kg) produced two linear bandlike lesions in the proximal duodenum within 6 hr. This dose of cysteamine significantly increased gastric acid secretion in acute fistula rats, and decreased duodenal HCO₃ ^– secretion caused by acid. During this period, this agent inhibited gastric motility but did produce markedly enhanced contractions in the duodenum. The changes in duodenal motility appeared within 5–10 min and were dose-dependent for cysteamine (10–100 mg/kg). Pretreatment with subcutaneously administered atropine (10 mg/kg), 16,16-dmPGE₂ (30 g/kg) or dopamine (10 or 30 mg/kg) significantly reduced the development of duodenal lesions caused by cysteamine, the inhibition being 86.8%, 49.7%, 54.5% or 67.8%, respectively. In the presence of cysteamine, dopamine had minimal effect on both acid and HCO₃ ^– secretion, while atropine or 16,16-dmPGE₂ markedly inhibited acid secretion or increased HCO₃ ^– secretion, respectively. The enhanced duodenal motility induced by cysteamine was blocked partially by atropine and only slightly by 16,16-dmPGE₂. Dopamine showed a dose-dependent inhibition on the duodenal hypermotility following cysteamine, and at 30 mg/kg almost completely abolished the development of contractions. These results suggest that abnormal hypermotility in the duodenum may be partly involved in the pathogenesis of cysteamine-induced duodenal ulcers.     

Autoradiographic study on healing process of cysteamine-induced duodenal ulcer in rat

The healing process of cysteamine-induced duodenal ulcer was studied by [³H]thymidine autoradiography. After the development of ulcer in the duodenum, cell proliferation was markedly activated not only in the crypts but also in the Brunner's glands near the ulcer. In the initial stages of ulcer healing, they both contributed to form the surface covering regenerating epithelium. Granulation tissue also proliferated at the base of the ulcer. In later stages of ulcer healing, new crypts were formed in the floor of the ulcer. New villi regenerated from these crypts and Brunner's glands regenerated by proliferationin situ. The ulcer base then was completely covered with new villi and granulation tissue was replaced by dense fibrous connective tissue. The present study suggested that the Brunner's glands, together with the crypts of Lieberkühn, play an important role in the healing process of cysteamine-induced duodenal ulcer.     

Stimulation of duodenal mucosal bicarbonate secretion in the rat by brain peptides

Bicarbonate secretion by duodenal mucosa free of Brunner's glands was titrated in situ in anesthetized rats. Intracerebroventricular infusion of thyrotropin-releasing hormone (0.01-1 microgram/h), bombesin, gastrin-releasing peptide, or corticotropin-releasing factor increased the bicarbonate secretion and the transmucosal electrical potential difference. The increase in secretion in response to thyrotropin-releasing hormone and bombesin was prevented by cervical vagotomy. Intravenous administration of the alpha-adrenoceptor antagonist phentolamine increased the magnitude and duration of the response, suggesting that these two peptides in addition to eliciting vagal stimulation of the duodenal secretion, by sympathetic activation, inhibit the secretion. Intravenous thyrotropin-releasing hormone (3.6 mg/kg) did not affect the secretion, further indicating that effects were elicited within the central nervous system. Intracerebroventricular infusion of cholecystokinin-octapeptide or beta-endorphin had no effect on duodenal bicarbonate secretion or on the potential difference. The latter peptide was a potent stimulant of the secretion when injected intravenously and probably acts at a peripheral site. The central nervous control of duodenal mucosal bicarbonate secretion is thus influenced by some specific peptides that are known to occur in brain tissue, and duodenal protection against acid might be modulated by agents affecting this control.     

Relationship between tissue calcium content and duodenal ulcer in the rat

Since the effect of cellular calcium on cell injury has been in question, this study focused on the relationship between tissue calcium content and cysteamine-induced duodenal ulcer. Rats treated with cysteamine showed a high frequency and severity of duodenal ulcer, and the calcium content in the duodenal mucosa was elevated. Furthermore, the level of calcium content in duodenal mucosa was positively associated with the severity of the duodenal lesion. Whereas administration of calcium increased duodenal ulcerative response to cysteamine, verapamil afforded protection against ulceration. We conclude that calcium accumulation in duodenal mucosa is related to duodenal ulceration induced by cysteamine.     

Somatostatin in rat tissues is depleted by cysteamine administration

Administration of cysteamine (mercaptoethylamine) induces in rats severe perforating duodenal ulcers. Because the ulcerogenic properties of cysteamine are markedly reduced by treatment with somatostatin, we considered the possibility that cysteamine-induced duodenal ulcer might be mediated by depletion of tissue somatostatin, and thereby of its paracrine influences on gastrin and gastric acid secretion. To test this hypothesis, we measured the concentration of immunoreactive somatostatin (IR-somatostatin) in stomach and duodenal mucosa at intervals after administration of a single ulcerogenic dose (30 mg/kg by stomach tube). IR-somatostatin in these tissues fell rapidly to reach a minimum at 4 h (stomach 31%, duodenum 60% of control respectively). IR-somatostatin in hypothalamus and pancreas decreased gradually to a minimum at 7 h. Another duodenal ulcerogen, propionitrile (10 mg/100 g bw, s.c.) which is more toxic than cysteamine, and several stressful procedures including ether anesthesia, restraint and s.c. formalin did not lower stomach or duodenal IR-somatostatin. Gut, pancreas and hypothalamic VIP levels were not influenced by cysteamine. These findings suggest that cysteamine is a relatively specific depletor of tissue somatostatin. Because blood levels of somatostatin fell, and only trivial amounts of the peptide were found in the stomach lumen after cysteamine administration, it appears likely that this agent acts at the cellular level to cause breakdown of preformed somatostatin and/or to acutely reduce its synthesis.     

Effect of secretin on gastric function in normal subjects and in patients with duodenal ulcer.

The effect of constant intravenous infusion of secretin in doses of 0.25, 0.50, 1.50, and 3.0 mug per kg per hr on meal-stimulated acid secretion was measured in vitro titration to pH 5.0. The pattern and degree of secretin inhibition of food-stimulated acid secretion depended on when the secretin infusion was begun, the effect being more pronounced when the secretin was begun 1 hr before the test meal than when the meal and secretin infusions were begun simultaneously. Inhibition of acid secretion in normals was approximately the same as in 2 patients with pancreatic exocrine insufficiency who could secrete only small amounts of pancreatic bicarbonate in response to secretin. Secretin in dose of 0.25 and 0.5 mug per kg per hr inhibited acid secretion only slightly, whereas 3.0 mug per kg per hr completely stopped acid secretion. Inhibition of acid secretion by secretin was similar in controls and in patients with duodenal ulcer. Secretin also reduced the rise in serum gastrin concentration after the meal, and delayed gastric emptying; both responses were approximately the same in normals and in duodenal ulcer patients. Secretin inhibited basal gastric acid secretion but had no consistent effect on basal serum gastrin concentration.     

Effect of antisecretory agents and vagotomy on healing of “chronic” cysteamine-induced duodenal ulcers in rats

Penetrated cysteamine-induced duodenal ulcers in rats have a very prolonged course of healing. In this study, it was investigated how much the healing of these ulcers is accelerated by some treatments. The treatments included omeprazole, cimetidine, and truncal vagotomy. In addition, the effect of omeprazole and cimetidine on gastric acid secretion was investigated in chronic gastric fistula rats. After 25 days of treatment, significantly more rats in the treated groups had healed ulcers than in the control group. There was little further improvement up to 100 days of treatment, and the difference between treated and untreated groups decreased. The morphology of healing ulcers in treated and untreated rats was also compared. In controls, there was a simultaneous regeneration of mucosa and the submucosal Brunner's glands from the edges of the ulcer, the slow proliferation rate of the latter probably being decisive for the prolonged healing. In the treated rats, the mucosa first regenerated with formation of crypts and low villi and subsequently, the Brunner's glands were formed by proliferation from the bottom of the crypts.     

Bromophenacyl bromide, a phospholipase A2 inhibitor attenuates chemically induced gastroduodenal ulcers in rats

INTRODUCTION Phospholipids play an important role in the preservation of gastrointestinal homeostasis[1]. The gastric mucosa has a hydrophobic lining which is assumed to have protective functions against luminal acid as well as intrinsic and extrinsic cor…     

Immunohistochemical localisation of urogastrone to human duodenal and submandibular glands.

Urogastrone has been localised by immunostaining to granules of the cells of human duodenal (Brunner's) glands and their ducts and of acinar cells in the human submandibular gland. The immunoreactive peptide is present in large quantities in duodenal glands and their secretory ducts. Urogastrone or human epidermal growth factor promotes cellular proliferation in vivo as well as in vitro and inhibits gastric acid secretion and may, therefore, be one of the duodenal factors inhibiting gastric activity. Thus it may have an important regulatory and protective function for the intestinal mucosa and may possibly become a useful therapeutic agent.