In humans, prostaglandins of the E1 class stimulate duodenal mucosal bicarbonate secretion, whereas the cyclooxygenase inhibitor, indomethacin, decreases both mucosal PGE2 and bicarbonate production. The purpose of this study was to determine whether a synthetic prostaglandin E1, enisoprost, diminished the inhibitory effects of indomethacin on mucosal bicarbonate secretion. In seven healthy subjects the proximal 4 cm of duodenum was isolated by occluding balloons. The isolated test segment was perfused with 154 mM NaCl (2 ml/min, 37 degrees C). Each subject participated in four separate tests in random order. Indomethacin, 50 mg, or placebo was given 13 and 1 hr before testing. After measuring basal bicarbonate secretion, either 100 micrograms of prostaglandin E1 or placebo (in 154 mM NaCl) was perfused into the test segment over 30 min. As anticipated, PGE1 significantly increased duodenal mucosal bicarbonate secretion, and indomethacin decreased resting bicarbonate secretion. Indomethacin pretreatment significantly enhanced (P less than 0.03) the mucosa's response to PGE1 compared to PGE1 alone. These results further support the observations that endogenous prostaglandins, in part, regulate human proximal duodenal bicarbonate secretion. Furthermore, suppression of endogenous prostaglandin generation results in an increased sensitivity of the duodenal mucosa to PGE1.