Stimulation of Gastroduodenal HCO3- Secretion by Lubiprostone in Rats Mediated by Different EP Receptor Subtypes

We examined the stimulatory effects of lubiprostone, a bicyclic fatty acid derived from prostaglandin E1 and a Chloride Channel type-2 opener (ClC-2), on HCO3 - secretion in the rat stomach and duodenum, with a focus on the EP receptor subtypes involved in this action. Under urethane anesthesia, an exvivo chambered stomach or a duodenal loop was perfused with saline, and HCO3 - secretion was measured at pH 7.0 using a pH stat-method. Lubiprostone (0.1-30 µM) was perfused in the chamber or loop for 10 min. Indomethacin, ONO-8711 (an EP1 antagonist), or AE5-599 (an EP3 antagonist) was given s.c. 1 h before the lubiprostone treatment, while AE3-208 (an EP4 antagonist) or CFTRinh172 (a CFTR inhibitor) was given i.p. 30 min before. Lubiprostone dose-dependently and significantly increased HCO3 - secretion in both the stomach (≥10 µM) and duodenum (≥1 µM). The stimulatory effect in the stomach was significantly abrogated by a pretreatment with the EP1 antagonist, but not the EP3/EP4 antagonists or CFTR inhibitor, while that in the duodenum was significantly attenuated by the EP3/EP4 antagonists as well as the CFTR inhibitor. Indomethacin had no effect on the response of either tissue to lubiprostone. These results suggest that lubiprostone stimulated HCO3 - secretion in the stomach