Luminal adenosine signaling regulates duodenal bicarbonate secretion via A2B receptor and CFTR in rats

Abstract

Duodenal bicarbonate secretion (DBS) is increased by luminal ATP, via activation of enterocyte brush border P2Y1 receptors. Increased DBS augments the activity of intestinal alkaline phosphatase (IAP) activity, which degrades luminal ATP, acting as a negative feedback loop. Since IAP dephosphorylates ATP to ADP, AMP, and adenosine (ADO), and since adenosine deaminase (ADA) is highly expressed in duodenal brush border, we hypothesized that luminal ADO signaling is also involved in DBS regulation.We measured DBS with flow‐through pH and CO2 electrodes, testing the effect of perfusion of ATP, ADP, AMP or ADO with or without adenosine receptor (A1‐3R) agonists or antagonists, or CFTR inhibitor CFTRinh‐172 on DBS. We also examined the effect of inhibitors of ADA or concentrative nucleoside transporter (CNT) on DBS.Perfusion of ATP, ADP, AMP or ADO uniformly increased DBS. A2BR agonist NECA increased DBS, whereas ADO‐augmented DBS was inhibited by A2BR antagonist MRS1754 and abolished by CFTRinh‐172. Other AR agonists or antagonists had no effect. A2BR was immunolocalized to the brush border of duodenal villi whereas A2AR to the endothelium. ADA inhibitor EHNA and CNT inhibitor formycin B enhanced ADO‐induced DBS.Luminal ADO stimulates DBS via A2BR and CFTR. IAP, ADA and CNT may coordinately regulate luminal ADO concentration to modulate ADO‐P1R signaling in rat duodenum.VA Merit Review, NIH‐NIDDK R01 DK54221