Indomethacin influences regulatory peptides and increases DNA synthesis in the gastrointestinal tract of the rat.

Abstract

To examine the effect of long-term administration of indomethacin on regulatory peptides and DNA synthesis. Sprague-Dawley rats were treated with 1 mg/kg indomethacin subcutaneously or indomethacin and 500 micrograms/kg oral prostaglandin E2 or solvents for 2 months before labelling with methyl-3H-thymidine. The labelling index, growth fraction and the number of epithelial cells were determined on autoradiographs of the stomach small intestine and colon. Plasma and gastrointestinal tissue concentrations of regulatory peptides were analysed by radioimmunoassay. Indomethacin increased the concentration of somatostatin in the gastric fundus and ileum and reduced it in the colon. Prostaglandin E2 reduced the somatostatin concentration in the duodenum and colon. Indomethacin increased the concentration of neurotensin neurokinin A and glucagon in the distal small intestine and reduced the glucagon level in the colon. Prostaglandin E2 prevented such changes. Indomethacin increased DNA synthesis in the small intestine and produced hypoplasia of the villi. These changes were prevented by prostaglandin E2, except for the villous hypoplasia observed in the distal small intestine. Prostaglandin E2 reduced the labelling index in the antrum and colon. Endogenous prostaglandins selectively modulate the synthesis and/or release of regulatory peptides and regulate the outflow of cells from the epithelial surface. Indomethacin induces hypoplasia, which triggers a secondary trophic reaction in the epithelium that may, at least partially, be mediated by regulatory peptides.