Indomethacin Fails to Induce Ulceration in the Gastrointestinal Tract of Newborn and Suckling Rats

Abstract

ABSTRACT. Little is known about the role of oral prostaglandins and maintenance of intestinal epithelial cell membrane integrity in suckling animals. The presence of prostaglandins in milk suggests that they may have potential cytoprotective effects. Thus, experiments were performed to determine whether indomethacin causes inflammation in the gastrointestinal tract of suckling animals. Rats were treated with daily intraperitoneal injections of indomethacin (10 mg/kg) starting on the 1st day of life. Unlike adult animals which develop intestinal lesions within 72 h, these rats did not develop intestinal ulcerations until weaning started on days 15 to 16. Indomethacintreated suckling animals prevented from weaning did not develop intestinal lesions until they had access to solid food on day 23. Indomethacin-treated rats had large reductions in jejunal prostaglandin E2 content. In addition, prostaglandin E2 was present in rat milk in relatively large concentration as determined by radioimmunoassay. These studies suggest that exogenous prostaglandins present in milk may protect the intestine of suckling rats from indomethacin-induced inflammation; however, once weaning commences, prostaglandin insufficiency may develop lea& ing to intestinal lesions. We s~eculate that suckling rats treated with indomethacin did-not develop ulcerat6e lesions, despite a marked reduction in intestinal prostaglandin content, possibly due to prostaglandins present in milk. (Pediatr Res 20: 598-601,1986) glandin F,, have also been found in significant amounts, suggesting that milk contains the parent compounds thromboxane A2 and prostacyclin (4-6). They are also found in commercially obtained whole milk and low-fat milk (7), but not in infant formulas (6). Prostaglandin in milk has been demonstrated to be effective in promoting healing of peptic ulcers and in protecting the gastroduodenal mucosa against experimentally induced ulcers (7). In addition, administration of oral prostaglandin E2 to humans has been demonstrated to protect the gastrointestinal mucosa from blood loss induced by indomethacin (8). Thus, considerable information exists about the importance of oral prostaglandins in maintaining integrity of the gastrointestinal epithelial cell membrane in adults. However, very little is known about similar functions of prostaglandins in suckling animals. The presence of prostaglandins in milk suggest that they may play an important role in the function and adaptation of the gastrointestinal tract to extrauterine life. The significance of prostaglandin cytoprotection in the gastrointestinal tract of stressed newborns has not been determined. Exogenous prostaglandin in breast milk could have cytoprotective effects on the gastrointestinal tract. Thus, to evaluate the role of oral prostaglandins in maintenance of gastrointestinal mucosal integrity in suckling animals, experiments were performed in suckling rats to explore whether indomethacin causes inflammation in the immature gastrointestinal tract. A preliminary report has been publish...

Indomethacin, Dexamethasone, and Intestinal Damage in Infant Rats

“…The lack of intestinal damage in infant rats with indomethacin treatment was previously described by Bedrick et al (10), who speculated that prostaglandins in mother's milk protect the infant small intestine from the effects of indomethacin. If this was the case, artificially fed infant rats should exhibit intestinal damage in response to indomethacin, whereas rats suckled by their mothers would not.…”

“…2). Bedrick and Holtzapple (10) confirmed the well‐known fact that Prostaglandin E 2 (PGE 2 ) synthesis is significantly inhibited by indomethacin (39–43), but the intestinal PGE 2 production in their experiments was not inhibited differently at infancy compared to adulthood. Their results indicate that the difference in intestinal damage to indomethacin between infancy and adulthood cannot be attributed to different degrees of inhibition in PGE 2 synthesis.…”

“…pothesized by Bedrick et al (10). Although indomethacin treatment resulted in significant but relatively small decreases in villous lengths in the ileum when compared to dexamethasone, this effect occurred to the same degree for artificially fed and mother-reared infant rats.…”

“…The infant rats given indomethacin appeared to grow better than the saline administered control rats. In a review of the literature, Bedrick and Holtzapple (10) also found a failure to induce intestinal ulceration by indomethacin when given to preweaned rats. Their indomethacin‐treated suckling rats did not develop intestinal ulcerations until weaning started at approximately 20 days of age.…”

Prostaglandin Stability in Human Milk and Infant Gastric Fluid

“…Prostaglandins are present in fresh human [6][7][8] and bovine milk [9], but not in pro prietary infant formulas [7], Milk macro phages are active in producing and secreting prostaglandins and are probably the source of prostaglandins in milk [10,11]. It has been suggested that the cytoprotective effect of milk prostaglandins may be exerted by direct topical action on the gastrointestinal mucosa [12,13]. In view of their very rapid degradation in human tissues [14], studies were performed to evaluate the stability of prostaglandins in fresh human milk and neo natal gastric secretions.…”