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 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