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.