Decreased substance P content in the rectal mucosa of diabetics with diarrhea and constipation.

Substance P (SP), vasoactive intestinal polypeptide (VIP), and somatostatin content in rectal mucosa were determined by radioimmunoassay (RIA) in 38 diabetic patients (12 with normal bowel function, 13 with diabetic diarrhea, and 13 with constipation) and in 10 nondiabetic controls with normal bowel function. SP content (picograms per milligram) in the rectal mucosa of diabetics with normal bowel function was significantly higher than that of nondiabetic controls (P < .05). SP content in the rectal mucosa of diabetics with diabetic diarrhea and constipation was significantly lower than in diabetics with normal bowel habits and nondiabetic controls (P < .05). No differences were found in the rectal mucosa content of VIP and somatostatin between the different groups of diabetics and controls. Diabetic diarrhea is a condition with an intermittent nature and frequently alternates with constipation. Our findings showing low levels of rectal mucosa SP in both conditions suggest a possible common role of SP in the pathogenesis of diabetic diarrhea and constipation.

Antioxidants inhibit ethanol-induced gastric injury in the rat. Role of manganese, glycine, and carotene.

BACKGROUND: Oxygen-derived radicals are implicated in the pathogenesis of tissue damage and ulcerogenesis. This study aimed to examine the effect of manganese, glycine, and carotene, oxygen radical scavengers, on ethanol-induced gastric lesions in the rat and on ethanol cytotoxicity in epithelial cell culture. METHODS: MnCl2 + glycine (12.5-50 mg/rat) were injected subcutaneously up to 6 h before oral administration of 1 ml of 96% ethanol, and 0.5 ml carrot juice or beta-carotene was given orally 30 min before the ethanol. Mucosal injury was evaluated 1 h later by gross and microscopic scoring. The effect of Mn2+ and carrot juice was also tested in monolayers of radiolabeled epithelial cells exposed to H2O2 + ethanol injury as expressed by the extent of the isotope leakage. RESULTS: Mn2+ and glycine pretreatment dose-dependently reduced ethanol-induced gastric lesion formation. Protection was maximal when treatment was applied 4 h before the insult. Gross damage was also markedly prevented by pretreatment with carotenes and dimethylthiourea (DMTU, 75 mg/kg intraperitoneally) but not by allopurinol. Mixtures of subtoxic concentrations of ethanol and H2O2 were highly lethal for epithelial cell monolayers. In this model, cell death was markedly attenuated by catalase, DMTU, Mn2+, and carrot juice. CONCLUSIONS: Ethanol-induced gastric mucosal damage may involve generation of oxygen-derived radicals, independent of the xanthine oxidase system. By acting as oxygen radical scavengers, Mn2+, glycine, and carotenes, like catalase and DMTU, provide significant gastroprotection.

The role of platelet activating factor [correction of actor] in acute gastric injury and its protection by sucralfate.

Platelet activating factor, a potent inflammatory mediator, has been reported to induce gastrointestinal damage, whereas its inhibition or antagonism is associated with mucosal protection. The aim of the present study was to elucidate the association between acute experimental gastric damage and mucosal platelet activating factor generation in the rat, and to evaluate the protective effect of sucralfate in relation to mucosal platelet activating factor formation. Gastric damage in the rat was induced by either subcutaneous injection of indomethacin 30 mg/kg or intragastric administration of aspirin 100 mg/kg, hydrochloric acid 0.6 N, taurocholate 30 mM, ethanol 96%, or sodium chloride 25%. All agents induced a significant increase in mucosal platelet activating factor levels concomitantly with induction of mucosal damage. Pretreatment with sucralfate 150 mg/rat provided a significant macroscopic and microscopic mucosal protection in all experimental models. This protection was associated with a significant decrease in mucosal platelet activating factor level in the hydrochloric acid, taurocholate, ethanol and hyperosmolar sodium chloride treated rats, whereas it remained unchanged in the aspirin and indomethacin treated rats. The data imply that platelet activating factor may have a limited role in the pathogenesis of indomethacin or aspirin induced damage, where other mechanisms such as cyclooxygenase inhibition dominate. In the damage induced by topical strong irritants, platelet activating factor may have a major pathogenetic role.

Rectal administration of nonsteroidal antiinflammatory drugs. Effect on rat gastric ulcerogenicity and prostaglandin E2 synthesis.

Oral administration of nonsteroidal antiinflammatory drugs induces gastroduodenal mucosal damage in experimental animals as well as in humans. The aim of the present study was to evaluate the effect of rectally administered nonsteroidal antiinflammatory drugs on gastric mucosal damage, as well as on mucosal prostaglandin E2 synthesis. Fasting male rats were treated intrarectally with 0.5 ml 1% NaHCO3 solution containing several concentrations of either indomethacin, aspirin, ibuprofen, diclofenac, ketoprofen, or sulindac and concomitantly received 1 ml of 150 mM HCL intragastrically. Control rats received intrarectally the vehicle only. After 4 h, lesions in the secretory part of the stomach were scored and mucosal prostaglandin E2 synthesis was determined by the ex vivo prostaglandin generation technique. Dose-dependent mucosal damage was observed in indomethacin- and diclofenac-treated rats. Ketoprofen damage did not show dose dependency. In sulindac- and aspirin-treated rats, as well as in controls, no damage was detected. All drugs induced a significant and comparable degree of inhibition of prostaglandin E2 synthesis. There was no correlation between the severity of the mucosal damage and the inhibition of prostaglandin E2 synthesis. The ulcerogenicity of rectally administered nonsteroidal antiinflammatory drugs is therefore not directly related to the degree of inhibition of prostaglandin E2 synthesis and is probably related to the specific chemical and pharmacokinetic properties of each individual drug.

Protection by mild irritants against indomethacin-induced gastric mucosal damage in the rat: role of prostaglandin synthesis.

"Mild irritants" have been shown to protect rat gastric mucosa from damage induced by noxious topical agents, supposedly by induction of mucosal prostaglandin (PG) biosynthesis. The protective effect of NaCl 5%, ethanol 20%, NaOH 0.075 N, HCl 0.35 N, salicylic acid 100 mg/kg and paracetamol 200 mg/kg was investigated in rats treated with an ulcerogenic dose (25 mg/kg) of indomethacin; mucosal PG synthesis was simultaneously determined. Significant protection was achieved only with NaCl 5%, salicylic acid and paracetamol. Salicylic acid and paracetamol significantly decreased acid secretion and enhanced PGE2 or 6-keto PGF1 alpha generation in control rats, while a small but significant change in the indomethacin-inhibited PG synthesis was observed after treatment with NaCl 5% or salicylic acid. We conclude that protection by "mild irritants" against indomethacin-induced mucosal damage may involve increased cytoprotective PG generation, as shown for paracetamol and salicylic acid, or partial blocking of indomethacin binding at the cyclooxygenase receptor site, as shown for NaCl 5% and salicylic acid.

Effect of misoprostol and cimetidine on gastric cell turnover.

The effects of misoprostol 200 micrograms q.i.d. and cimetidine 300 mg q.i.d. on gastric cell turnover were investigated in duodenal ulcer patients before and after four weeks of therapy. Endoscopic biopsies were incubated with 3H-thymidine. Glandular column length (number of cells per column) and the number of labelled cells per column were determined by autoradiography. There were no significant treatment effects on column length of the gastric pits of either the antrum or fundus. However, misoprostol and cimetidine had opposing effects on cell turnover. Misoprostol significantly decreased the number of labelled cells in antral (P less than 0.01) and fundic (P less than 0.001) gastric pits. However, cimetidine significantly increased (P less than 0.01) the number of labelled cells in antral and fundic columns. The increased gastric cell turnover caused by cimetidine may contribute to its activity in peptic ulcer disease. The decreased cell turnover induced by misoprostol does not appear to be a mechanism responsible for its well-established cytoprotective activity.

Effect of misoprostol and cimetidine on gastric cell labeling index.

The effect of misoprostol and cimetidine on gastric cell turnover was studied. Endoscopic biopsy specimens of fundic and antral mucosa were obtained from duodenal ulcer patients before and after 4 wk of therapy with cimetidine 1.2 g/day or misoprostol 800 micrograms/day. Biopsy specimens were incubated with [3H]thymidine. Glandular column length and number of labeled cells were determined after autoradiography. There was no significant difference in column length of antral or fundic glands before or after therapy with cimetidine and misoprostol. The number of antral and fundic labeled cells was significantly decreased after misoprostol treatment (3.6 +/- 0.3 and 4.6 +/- 0.4, mean +/- SE), as opposed to their respective number before therapy (6.9 +/- 0.5 and 8.3 +/- 0.8) (p less than 0.01). On the other hand, after treatment with cimetidine, the number of antral and fundic labeled cells was significantly higher (11.8 +/- 0.9 and 7.5 +/- 1.0, respectively) as compared with their number before therapy (5.7 +/- 0.5 and 5.6 +/- 0.6, respectively). The decreased gastric cell turnover induced by misoprostol indicates that the trophic effect of prostanoids on gastric mucosa is not due to an increase in cellular kinetics. The increased gastric cell turnover induced by cimetidine may contribute to its therapeutic effect in peptic ulcer disease.