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.     

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.     

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 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.     

Epidermal growth factor inhibits cysteamine-induced duodenal ulcers

The effect of the duodenal ulcerogen cysteamine on secretion of epidermal growth factor from Brunner's gland pouches was studied in the rat. Total output of immunoreactive epidermal growth factor was reduced to approximately 55%, compared with controls, 5 h after administration of cysteamine (300 mg/kg, s.c.). Furthermore, measurements on tissue extracts of the pouches revealed that 5 h after cysteamine treatment, Brunner's glands were depleted of epidermal growth factor. The effect on ulcer development of intraduodenally applied exogenous epidermal growth factor (1 micrograms/kg . h) also was studied. Luminal epidermal growth factor significantly inhibited the formation of cysteamine-induced duodenal ulcer, compared with controls receiving saline. The effect was not due to inhibition of gastric acid secretion or stimulation of duodenal bicarbonate secretion since the dose of epidermal growth factor used, when tested on chronic fistula rats, had no effect on acid secretion and did not influence bicarbonate secretion from Brunner's gland pouches. These results demonstrate that epidermal growth factor has a cytoprotective effect on the duodenal mucosa, and it is suggested that inhibition of synthesis and secretion of endogenous epidermal growth factor may be a pathogenetic factor in cysteamine-induced duodenal ulcer.     

Cysteamine induces duodenal ulcer in the mouse

A new model of duodenal ulcer disease has been developed in the mouse. The ulcers were produced after either oral or subcutaneous administration of cysteamine which has been shown to cause duodenal ulcer in the rat. Cysteamine induced duodenal ulcers in a time- and dose-dependent manner after oral administration. The new mouse model shares many similarities with both the rat model and human ulcer disease. Cysteamine caused a significant increase in gastric acidity and pepsin activity. The mouse can be protected against the cysteamine-induced duodenal ulcer by either the dopamine agonist lergotrile or histamine H2 receptor antagonist cimetidine. This new model of duodenal ulcer disease in the mouse may represent a simple and inexpensive way to screen for new antiulcerogenic drugs.     

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.     

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…     

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.     

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.     

Somatostatin and gastrin content of gastric antral mucosa in ulcer disease

Gastrin and somatostatin containing cells are abundant in the gastric antral mucosa suggesting a role for these peptides in gastric physiology, presumably acid secretion. The concentration of these peptides in antral mucosa in ulcer disease is controversial, some finding normal levels, others decreased somatostatin levels. Biopsies of antral mucosa from patients with ulcer disease and non-ulcer dyspepsia were obtained at endoscopy, and somatostatin and gastrin concentration were measured by specific radioimmunoassay. Levels were similar in non-ulcer, duodenal and gastric ulcer patients but prior treatment with H₂-receptor antagonists in duodenal ulcer patients led to a fall in somatostatin and a rise in gastrin mucosal levels. It is thus unlikely that a lack of somatostatin or an increase in gastrin are factors in the pathogenesis of duodenal ulcer, but the cells may behave abnormally in ulcer disease.     

Effect of pirenzepine and atropine on peptone meal-stimulated gastric secretion and plasma gastrin in healthy volunteers, patients with duodenal ulcer and vagotomized patients

The aim of this study was to compare the effects of atropine with those of placebo and pirenzepine on food-induced gastrin release, and gastric and acid secretion. Three groups of subjects were studied: 8 healthy volunteers; 8 duodenal ulcer patients, and 6 vagotomized patients. Gastric acid secretion and serum gastrin were studied in each subject on 3 different days, after placebo, atropine or pirenzepine, given in random order. In each group, acid secretion was significantly depressed by atropine and pirenzepine. Unlike pirenzepine, atropine induced a significantly increase in serum gastrin in both healthy volunteers and duodenal ulcer patients. None of the treatments caused differences in gastrin response in vagotomized patients.     

Effect of systemic gastric acid stimulation and intragastric pH changes on synchronous antral gastrin and somatostatin release in anesthetized,nonatropinized duodenal ulcer patients and controls

The synchronous changes in antral gastrin and somatostatin release in anesthetized, nonatropinized duodenal ulcer patients and control subjects were investigated by serial intraoperative blood sampling from the right gastroepiploic vein. The mean basal antral plasma gastrin and somatostatin concentrations of the two groups did not differ significantly. The significantly greater gastric acid secretory response to systemic gastric acid stimulation (pentagastrin stimulation) in duodenal ulcer patients compared with that of control subjects was not linked to any difference in antral somatostatin release pattern. The decrease in antral plasma gastrin release was significantly lower after acid instillation and the increase was significantly higher after alkali instillation in duodenal ulcer patients compared with those of controls, indicating an abnormal gastrin response to intragastric pH changes in duodenal ulcer patients, which was again not found to be coupled to any significant difference in antral somatostatin release. The results suggest that an abnormal somatostatin-mediated inhibition of gastrin release and/or gastric acid secretion does not exist in duodenal ulcer patients.     

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.     

Effects of somatostatin deficiency on cell distribution within the Langerhans islets

Insulin, glucagon and somatostatin (SLI) in the pancreas and the gastrointestinal tissue of rats were measured following a high (300 mg/kg) or low (150 mg/kg) dose of cysteamine, given intermittently for 14 days. In addition, the effect of prolonged cysteamine-induced depletion of pancreatic SLI upon the cell distribution within the Langerhans islets was compared with that of chronic insulin-deficient rats produced by streptozotocin. The high or low dose of cysteamine reduced pancreatic SLI to 8.3% and gastrointestinal SLI to 5.6% of control levels without duodenal ulcer. The high dose of cysteamine also reduced pancreatic insulin to 37% of controls without hyperglycemia. No change in the glucagon concentration was observed. In SLI-deficient rats, distribution of A and B cells was similar to that of controls, even though D cells were rarely seen. In insulin-deficient rats, however, the number of A and D cells per islet area increased with a concomitant decrease in B cells. Intermittent administration of a low dose of cysteamine, thus, appears to be useful to produce a chronic SLI-deficient rat. However, a high dose of cysteamine is not a specific depletor of pancreatic SLI. Although insulin may be important to maintain normal cell distribution within the islets, pancreatic SLI may not have such a role.     

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.     

Basic fibroblast growth factor and PDGF in GI diseases

This chapter is focused on the relatively recent investigations demonstrating a pharmacological and pathophysiological role for bFGF and PDGF in ulcerative and inflammatory lesions in the upper and lower GI tract. Our initial animal model experiment revealed a potent healing of chronic cysteamine-induced duodenal ulcer in rats treated by intragastric administration of bFGF-w, the acid-resistant bFGF-CS23 or PDGF-BB without decreasing gastric acid secretion or concentration. Subsequently we and others have demonstrated that these peptides accelerate the healing of chronic gastric ulcers, chronic erosive gastritis and ulcerative colitis. Contrary to the potent ulcer healing properties of bFGF and PDGF, these growth factors exert no or modest acute gastroprotection. Nevertheless, new biochemical, molecular biological and immunohistochemical studies indicate that both bFGF and PDGF play a pathophysiological role in the natural history of ulcer healing.     

Effects of cysteamine on canine splanchnic D-cells

It has recently been reported that the oral administration of cysteamine causes a depletion of somatostatin content in various tissues of the rat concomitant with duodenal ulcer. Producing somatostatin deficient animals is important for understanding the role of somatostatin in the homeostasis of ingested nutrients. The present experiment was designed to investigate the acute and chronic effects of cysteamine on canine splanchnic D-cells. When 2 g of cysteamine was administered to normal mongrel dogs, it caused a bloody stool. However, somatostatin-like immunoreactivity (SLI) levels in the peripheral vein did not change although the insulin, glucagon and glucose levels increased. In isolated perfused canine pancreases, cysteamine (10 microM-10 mM) showed no specific effect on the somatostatin secretion. The chronic effect of systeamine on the canine D-cells was studied by using dogs to which cysteamine was administered 3 times (2 g, P.O., every 10 days) at least 4 weeks before the experiment (cysteamine dogs). Hormone secretions from the perfused pancreases isolated from the cysteamine dogs were normal. The increases in somatostatin-14 levels in the pancreaticoduodenal vein, short gastric vein and gastroepiploic vein in response to the intragastric administration of 1N HCl were also normal. The SLI contents and the characteristics in molecular size of tissue extracts from the cysteamine dogs were similar to those of normal dogs. Thus, it is concluded that cysteamine has no specific effect on canine splanchnic D-cells.     

Acid, pepsin, and mucus secretion in patients with gastric and duodenal ulcer before and after colloidal bismuth subcitrate (De-Nol).

Basal and pentagastrin stimulated gastric secretion was measured in seven patients with duodenal, and six with gastric ulcers before and after four weeks' treatment with colloidal bismuth subcitrate (as De-Nol), one tablet four times a day. Each duodenal and all but one of the gastric ulcers healed. After De-Nol there were no significant changes in basal, or pentagastrin stimulated volume, acid output, or primary parietal component. There were marked decreases in basal (duodenal ulcer -25%; gastric ulcer -16%) and pentagastrin stimulated total pepsin outputs, (duodenal ulcer -42%, gastric ulcer -36%). There were insignificant decreases in basal output of mucus, but postpentagastrin stimulated mucus output was significantly inhibited (p less than 0.05) in patients with duodenal (-16%) and with gastric ulcer (-27%). The drop in gastric proteolysis after De-Nol is unlikely to be because of the healing of the ulcers and is more likely to be because of the drug. The ulcer healing efficacy of De-Nol may be related to this decline in the proteolytic action of gastric juice, but is unlikely to be because of a quantitative change in mucus, or in acid secretion.     

Role of mucosal blood flow in duodenal ulcer formation induced by dulcerozine

To clarify the role of mucosal blood flow in the pathogenesis of ulcer formation, the authors investigated dulcerozine-induced duodenal ulcers in rats. Administration of dulcerozine, 500 mg/kg by intragastric route or 250 mg/kg given intraperitoneally, induced acute ulcers in the duodenum, but not the stomach, in all rats. Using the pyloric ligation method, it was determined that although dulcerozine significantly increased gastric acid secretion, no duodenal ulcers were observed in these animals. The administration of 1 ml of 0.1 N HC1 every hour for 6 hours did not induce duodenal ulceration. The mucus glycoprotein content of the corpus, antrum and proximal duodenum did not differ following dulcerozine administration. Duodenal mucosal blood flow, which was measured by an electrolytically generated hydrogen gas clearance technique, decreased significantly following dulcerozine administration even in pylorus-ligated rats. In contrast, there was an increase in the gastric mucosal blood flow following administration of the drug. Therefore, not only an increase in gastric acid secretion but also a decrease in duodenal mucosal blood flow are suggested to be responsible for dulcerozine-induced duodenal ulceration.