Stimulation of gastroduodenal HCO3- secretion by lubiprostone mediated by different prostaglandin EP receptor subtypes

Abstract

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 ex-vivo 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 CFTRinh-172 (a cystic fibrosis transmembrane conductance regulator (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 and duodenum in a manner that was mediated by different EP receptor subtypes; the former was mediated by EP1 receptors, while the latter was mediated by both EP3 and EP4 receptors. CFTR/ClC-2 may be involved in the response observed in the duodenum, but not in the stomach.

Keywords

• lubiprostone
• HCO3- secretion
• prostaglandin EP receptor subtypes
• stomach
• duodenum
• rat