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.     

Candida albicans aggravates duodenal ulcer perforation induced by administration of cysteamine in rats

BACKGROUND: Candida sp are frequently isolated from the ascitic fluid of patients with perforated ulcers. The present study was performed to examine whether Candida infection may be involved in the process of ulcer perforation. METHODS: Male Wistar rats were divided into a saline group (n = 15) and a Candida group (n = 17). Cysteamine-HCl (Sigma; 31 mg/100 g) was administered thrice on day 1 to both groups of animals. Candida albicans at a density of 10(8) in 0.5 mL of saline was administered 1 h before, and 12 h and 24 h after the first administration of cysteamine in the Candida group. RESULTS: Perforated duodenal ulcers were observed in 94.1% of the rats in the Candida group, but only 26.7% of the rats in the saline group (P < 0.01). The area of the duodenal ulcers in the Candida group was 40.89 +/- 33.07 mm2, whereas that in the saline group was 16.53 +/- 20.4 mm2 (P < 0.05). The mortality rate was significantly higher in the Candida group than in the saline group. In the Candida group, colonization by C. albicans was recognized at the ulcer base, surrounded by marked granulocytic infiltration. The number of eosinophils infiltrating the ulcer base was also significantly greater in the Candida group than in the saline group. Immunohistochemical analysis revealed the expression of secretory aspartyl protease (SAP) in the region of the ulcer showing colonization by C. albicans in the Candida group. CONCLUSION: Candida albicans aggravates duodenal ulcer perforation in the experimental model of cysteamine-induced duodenal ulcer perforation. The present findings suggest that SAP and host-parasite relationships, including granulocyte-dependent mechanisms, may be involved in the aggravation of ulcer perforation by C. albicans.     

Duodenal ulcerogens cysteamine and propionitrile decrease duodenal neutralization of acid in the rat

Neutralization of acid was evaluated in rat proximal duodenal segments isolated from biliary and pancreatic secretions. Duodenal ulcerogenic doses of cysteamine produced a significant decrease in acid disposal 0.5–2 hr after treatment. Oral or subcutaneous administration of the duodenal ulcerogen was effective. The potent ulcerogen cysteamine produced a more pronounced decrease than propionitrile (a weak duodenal ulcerogen). The failure of ethanolamine, a nonulcerogenic structural analog of cysteamine to significantly alter acid disposal suggests that the effect is not due to the toxic properties of the duodenal ulcerogen. The results reinforce the concept that the duodenum is able to dispose of significant quantities of acid. The decrease in acid-handling may contribute to duodenal susceptibility to acid after treatment with ulcerogens and possibly reflects pathophysiologic changes early in duodenal ulceration.     

Functional and structural characteristics of the rat intestinal mucosa following ileo-jejunal transposition

The transformation of the rat ileal mucosa following interposition into the jejunum has been examined with respect to its functional and structural characteristics. Morphometric studies show that there is an increase in the size of the villi and crypts in the same proportions, such that the structures become longer than those of normal jejunal mucosa. There is no change in villus width or epithelial cell height and no evidence of mucosal damage. In agreement with these observations, there is an increase in the amount of DNA per unit weight mucosa in the transposed ileum. L-phenylalanine accumulation in vitro by transposed loops is reduced to the level of the control jejunum, whereas beta-methyl-D-glucose uptake is unchanged. Biochemical and histochemical determinations of various enzyme activities reveal that the levels in the transposed mucosa are much lower than in the controls. The results show that although certain features of the transposed ileum resemble those of the normal jejunum, this does not apply to all characteristics. It is argued that the ileal mucosa retains its normal functional properties, but undergoes hyperplastic changes, possibly as a result of contact with chyme that is richer in nutritive material, resulting in the establishment of a more immature cell population with a global reduction in enzyme levels and transport capacities.     

Plasma gastrin concentrations following sham feeding in duodenal ulcer patients.

Sham feeding experiments were performed in 20 duodenal ulcer (DU) patients by using adequate sham feeding and modified sham feeding (the 'chew-and-spit' technique). A 15-min sham feeding induced a marked secretion of gastric acid but only an insignificant increase in total gastrin or in gastrin17 concentrations in plasma. Nor did prolonged sham feeding (30 min) with intragastric neutralization significantly increase the gastrin concentrations. We conclude that sham feeding in DU patients induces a release of recognized gastrin components in amounts that are barely detectable radioimmunologically. Therefore, the acid secretory effects of vagally released gastrins in DU patients remains to be established.     

Influence of an acute hypercalcemia on the gastric secretion in duodenal ulcer, peptic ulcer of the jejunum and Zollinger-Ellison syndrome]

In 36 patients with ulcer without Zollinger-Ellison-syndrome (25 patients with recurrent duodenal ulcer, 11 with an ulcus pepticum jejuni after B II-resection of the stomach) and 2 patients suffering from ulcus pepticum jejuni with an ascertained gastrinoma the secretion of acid was compared after stimulation of pentagstrin (6 mug/kg) and calcium (4 mg Ca++/kg/h). The secretion of hydrochloric acid was statistically significantly stimulated in all patients suffering from ulcer by the hypercalcaemia (increase of the serum calcium concentration from 5.0 +/- 0.3 mval/1 to 6.2 +/- 0.8 mval/1). But in patients suffering from ulcer with gastrinoma the stimulatory effect was larger than in such patients without autonomous source of gastrin: the calcium-stimulated secretion of hydrochloric acid was on the average in cases of duodenal ulcer 40% (2 to 68%), in the ulcera peptica jejuni 47% (17 to 75%), in the 4 comparative examinations of the two patients with Zollinger-Ellison-syndrome, however, always more than 100% (106 to 177%) of the pentagastrin-stimulated peak secretion. The comparative test of the pentagastrin and calcium-stimulated secretion of hydrochloric acid could be a help for the proof of autonomous places of the formation of gastrin.     

HLA and duodenal ulcer.

One hundred and one white patients, consisting of 78 men and 23 women, with duodenal ulcer were HLA typed. An association was found between duodenal ulcer and HLA-B12.     

Role of prostanoids in experimental duodenal ulcer in rat

The purposes of this study were to determine whether inhibition of cyclooxygenase is a mechanism by which cysteamine and mepirizole produce duodenal ulcers, identify qualitative or quantitative differences in prostanoid production between gastric mucosa and duodenum, and determine whether differences in cyclooxygenase sensitivity to inhibition by aspirin exist between these two tissues. In fed female rats, gastric mucosal prostaglandin E₂ (PGE₂) and prostacyclin (PGI₂) generation was 235±25 and 832±40 ng/g/min, respectively, whereas full-thickness duodenal PGE₂ and PGI₂ generation was 665±46 and 662±49 ng/g/min, respectively. Over an intraperitoneal dose range of 0– 25 mg/kg, aspirin-induced cyclooxygenase inhibition was dose-dependent and similar for the two tissues. Duodenal ulceration (16.7 mm²) produced by cysteamine, 425 mg/kg, was associated with a 46% reduction in duodenal PGE₂ generation, while having no effect on PGI₂ generation; however, cysteamine, 213 mg/kg, produced no visible duodenal mucosa injury yet reduced duodenal PGE₂ generation 39% compared to control values. In fed male rats, gastric mucosal PGE₂ and PGI₂ generation was 179± 18 and 813± 61 ng/g/min, respectivley, whereas duodenal PGE₂ and PGI₂ generation was 321± 27 and 454± 38 ng/g/min, respectively. Duodenal ulceration (7.7 ± 2.3 mm²) produced by oral mepirizole was associated with a 63% reduction in duodenal PGE₂ generation compared to control values, while having no effect on PGI₂ generation. Subcutaneous aspirin, 100 mg/kg, which reduced duodenal PGE₂ generation to a greater degree than either ulcerogen, given in conjunction with pentagastrin, did not produce visible duodenal ulceration. It therefore seems unlikely that reduced PGE₂ generation within the duodenum is the primary mechanism of gross injury associated with these two ulcerogens.Supported by grant AM 17328 from NIADDK.     

Cholecystokinin-like activity in the duodenal mucosa of duodenal ulcer patients.

Cholecystokinin-like activity in the duodenal mucosa was measured by the bioassay method described by Ljungberg to elucidate its significance in 14 duodenal ulcer patients as well as in 13 normal subjects with no evidence of gastrointestinal diseases. The stage of duodenal ulceration was determined endoscopically according to the criterion of the Japanese Gastroenterological Endoscopic Society. The cholecystokinin-like activity in the duodenal mucosa of duodenal ulcer patients in active stage 1, which was considered as an early stage of active open duodenal ulceration, did not differ statistically from that of normal subjects, whereas that of duodenal ulcer patients in active stage 2 began to show a significant increase (p less than 0.05), and the cholecystokinin-like activity in the duodenal mucosa of duodenal ulcer patients in healing stage 1 or healing stage 2 was significantly higher than that in normal subjects (p less than 0.01). The cholecystokinin-like activity in the duodenal mucosa of duodenal ulcer patients in the scarring stage, however, returned to the normal range. It is concluded that cholecystokinin may act physiologically in the cure of duodenal ulcer.     

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.     

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.