A growing literature has demonstrated that the renin-angiotensin system (RAS) involves in gut function. Angiotensin II (AnglI) stimulates Cl- secretion in intestine epithelial cells. However, the underlying signal pathway remains unexplored. Here, we explored that serosal application of Ang II (5 x 10(-8) M) significantly increased the baseline Isc compared to the control group in rat ileum. Tetrodotoxin (1TX) failed to suppress Isc evoked by Ang II. However, the Ang II-evoked Isc was significantly suppressed by the ATRi antagonist losartan instead of ATR2 antagonist PD123319. Of interest, both cyclooxygenase (COX)-1 inhibitor SC560 and COX-2 specific inhibitor ns398 blocked the Ang II-evoked Isc. Preincubation of submucosa/mucosa preparations with Ang II for 10 min significantly increased PGE2 production, which was abolished by either COX-1 or COX-2 inhibitor. In addition, the Ang II-induced PGE2 release was also attenuated by ATRi receptor antagonist rather than selective ATR2 receptor antagonist. Furthermore, preincubation of tissues for 15 min with forskolin, a cAMP activator, markedly blocked the Isc evoked by AnglI, while intracellular Ca2+ pump inhibitor thapsigargin, L-type Ca2+ channel blocker nicadipine or the epithelial Na+ channel blocker amiloride didn't show such function. These results suggest that Ang II evokes cAMP-activated intestinal anion secretion by stimulating PGE2 release through activation of ATR1. (C) 2017 Elsevier Inc. All rights reserved.