A. Robert

Several prostaglandins (PG) were found earlier to be cytoprotective for the stomach and the intestine. We now report that mild irritants, given intragastrically, are also cytoprotective by stimulating the release of PG by the stomach. Several "mild irritants," 10-20% ethanol, 0.2-0.35 M HCl, 0.05-0.075 M NaOH, 2-4% NaCl, and water at 70 degrees C, were given orally to fasted rats. Fifteen minutes later, one of the following necrotizing agents was administered orally: 100% ethanol, 0.6 M HCl, 0.2 M NaOH, 25% NaCl solution, and boiling water. One hour later, the stomachs were removed and necrotic lesions graded. The mild irritants inhibited the necrotic lesions dose dependently. After a single treatment, protection lasted 1 h; repeated administrations maintained cytoprotection for as long as the mild irritants were being given. Indomethacin, an inhibitor of PG synthesis, abolished cytoprotection by mild irritants. After oral administration of NaOH at cytoprotective concentrations (0.01-0.1 M), the amounts of PGE2, PGF2 alpha, and thromboxane B2 formed by the gastric mucosa increased steadily up to threefold. The protection elicited by mild irritants is called "adaptive cytoprotection." The increased synthesis of PG may represent a physiological, natural defense mechanism that may be necessary to maintain cellular integrity of the gastrointestinal mucosa, in spite of the hostile environment caused by luminal contents.

15-Methyl PGE2 and 16,16-dimethyl PGE2 were found (1) to be 40 and 100 times, respectively, more potent than PGE2 after intravenous administration in inhibiting histamine-stimulated gastric secretion in dogs with a denervated (Heidenhain) gastric pouch, (2) to be active orally and intrajejunally, whereas PGE2 was inactive, and (3) to exert antisecretory activity for longer duration than PGE2. 16,16-Dimethyl PGE2 was about 2.5 times more potent than 15-methyl PGE2. Volume, acid concentration, and output, and pepsin output (but not concentration) were reduced in a dose-dependent manner. In the rat, 16,16-dimethyl PGE2 also inhibited gastric secretion and prevented the formation of ulcers produced by various methods: gastric ulcers (Shay, and steroid induced) and duodenal ulcers (secretogogue induced). In this species, 1l816-dimethyl PGE2 was 2 to 50 times more potent than PGE2, depending on the endpoint, and was active orally. These prostaglandins appear to inhibit gastric acid secretion by acting directly on the parietal cells, and making these unresponsive to most stimulants. Vomiting was a side effect of the prostaglandin analogues in the dog, but almost exclusively when these were given orally. After intravenous or intrajejunal administration at doses inhibiting gastric secretion by 80%, vomiting was seen only once. These results suggest that 15-methyl PGE2 and 16,16-dimethyl PGE2 may be of value in the treatment of peptic ulcer.