16-16-dimethylprostaglandin-e2 and Intestinal-Diseases

We evaluated the effect of various PGE analogs specific to EP receptor subtypes on indomethacin-induced small intestinal lesions in rats and investigated the relationship of EP receptor subtype with the PGE action using EP receptor knockout mice. Animals were administered indomethacin subcutaneously, and they were killed 24 hr later. 16,16-dimethyl prostaglandin E2 (dmPGE2) or various EP agonists were administered intravenously 10 min before indomethacin. Indomethacin caused hemorrhagic lesions in the rat small intestine, accompanied with an increase in intestinal motility and the number of enteric bacteria as well as iNOS and MPO activities. Prior administration of dmPGE2 dose-dependently prevented intestinal lesions, together with inhibition of those functional changes. These effects of dmPGE2 were mimicked by prostanoids (ONO-NT-012 and ONO-AE1-329), only specific to EP3 or EP4 receptors, although the intestinal motility was inhibited only by ONO-AE1-329. Intestinal mucus secretion and fluid accumulation were decreased by indomethacin but enhanced by dmPGE2, ONO-NT-012, and ONO-AE1-329 at the doses that prevented intestinal lesions. Indomethacin also caused intestinal lesions in both wild-type and knockout mice lacking EP1 or EP3 receptors, yet the protective action of dmPGE2 was observed in wild-type and EP1 receptor knockout mice but not the mice lacking EP3 receptors. These results suggest that the intestinal cytoprotective action of PGE2 against indomethacin is mediated by EP3/EP4 receptors and that this effect is functionally associated with an increase of mucus secretion and enteropooling as well as inhibition of intestinal hypermotility, the former two processes mediated by both EP3 and EP4 receptors, and the latter by EP4 receptors.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Colony Count, Microbial; Cyclooxygenase Inhibitors; Gastrointestinal Motility; Indomethacin; Intestinal Diseases; Intestinal Mucosa; Intestine, Small; Male; Mice; Mice, Knockout; Mucus; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Peroxidase; Rats; Rats, Sprague-Dawley; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP3 Subtype; Receptors, Prostaglandin E, EP4 Subtype

Mefenamic acid, given orally to rats at a single dose of 1200 mg/kg, produced renal papillary necrosis (RPN) in 63% of animals. The incidence was reduced to 27% by 16,16-dimethyl PGE2 (dmPGE2), given at an oral dose of 0.75 mg/kg t.i.d. RPN is likely to be caused by the renal prostaglandin depletion elicited by mefenamic acid, an inhibitor of prostaglandin cyclooxygenase. Substitution with dmPGE2 reduces RPN presumably by preventing the prostaglandin depletion. We conclude that the prostaglandin used is cytoprotective for the kidney. Mefenamic acid, like most nonsteroidal anti-inflammatory compounds (NOSAC), produced ulcerations of the small intestine (jejunum and ileum). These were prevented by dmPGE2 (intestinal cytoprotection). Unlike most other NOSAC, however, mefenamic acid produced duodenal ulcers in nearly all animals (80%). Of these ulcers, 88% were perforated. Twenty-five of the twenty-six animals that died had a perforated ulcer. These duodenal ulcers were also prevented by dmPGE2. Mefenamic acid-induced ulcers could be used as an experimental model for testing agents with a potential for preventing or healing duodenal ulcers.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Duodenal Ulcer; Female; Intestinal Diseases; Kidney Papillary Necrosis; Mefenamic Acid; Prostaglandins E, Synthetic; Rats; Rats, Inbred Strains; Stomach Ulcer

The pathogenesis of aspirin- or indomethacin-induced gastric and/or intestinal lesions was studied in dogs. 16,16-Dimethyl PGE2 methyl ester (16-DMPGE2) at 2 or 10 microgram/kg in two divided doses given intramuscularly markedly inhibited gastric lesions produced by orally ingested aspirin at 200 mg/kg/day given twice daily for 1 or 5 days. While 16-DMPGE2 at the same dose also inhibited gastric lesions induced by a single oral administration of indomethacin at 20 mg/kg, gastric lesions including deep antral ulcers, produced by repeated administration of indomethacin, were not affected. Intestinal lesions produced by indomethacin given once, or for 5 or 10 days, were not affected. These results suggest that the lack of engoenous prostaglandins may be involved in the pathogenesis of gastric lesions produced by aspirin and indomethacin given once but may not be involved in the pathogenesis of indomethacin-induced deep lesions in the stomach and intestine.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Aspirin; Dogs; Gastric Mucosa; Indomethacin; Intestinal Diseases; Intestinal Mucosa; Male; Prostaglandins E, Synthetic; Stomach Diseases; Time Factors

Topics: 16,16-Dimethylprostaglandin E2; Animals; Cimetidine; Guanidines; Indomethacin; Intestinal Diseases; Intestine, Small; Male; Rats; Ulcer