Sodium Caprate Increases Electrogenic Anion Secretion via TRPV4, ATP‐P2Y and VIP‐VPAC1 Pathways in Rat Duodenum

Abstract

Although luminal short‐chain (SCFA) and long‐chain fatty acids (LCFA) stimulate mucosal protective duodenal bicarbonate secretion (DBS), the role of medium‐chain fatty acids (MCFA) in DBS has not been studied. Thus, we examined the effects of MCFA on DBS in vivo and short‐circuit current (Isc) in the Ussing chamber.MCFA (C6‐C12, 0.1 – 30 mM) were applied to the mucosal or serosal bath of the Ussing chamber mounted with the muscle‐stripped mucosa‐submucosa preparations of rat proximal duodenum. A duodenal loop was perfused with sodium caprate (C10, 1 mM) in anesthetized rats with total CO2 output measured.Among MCFA, sodium caprate (C10) dose‐dependently (1 – 30 mM luminally and 0.1 – 3 mM serosally) increased Isc, which was sustained > 10 min after reaching a plateau, whereas other MCFA (C6, C8, and C12) had little effect. The luminal caprate (10 mM)‐induced Isc increase was delayed by luminal addition of ibuprofen (1 mM), a sodium‐dependent monocarboxylate transporter‐1 (SMCT‐1) inhibitor. In contrast, serosal caprate (1 mM)‐induced Isc increase was partially inhibited by serosally applied ruthenium red (0.1 mM), the selective TRPV4 antagonist HC067047 (0.1 mM), suramin (0.5 mM) and abolished by the VPAC1 antagonist PG97‐269 (1 μM), whereas capsaicin pretreatment (10 μM), the selective TRPA1 antagonist HC030031 (0.1 mM), atropine (10 μM), or selective 5‐HT3 or 5‐HT4 receptor antagonists had no effect. The selective TRPV4 agonist GSK1016790 (10 μM) increased Isc, whereas the selective MCFA receptor GPR84 agonist ZQ16 had little effect on Isc. Luminal perfusion of caprate increased the rate of DBS in vivo.These results suggest that luminal caprate is absorbed via SMCT1, followed by stimulation of DBS via the TRPV4‐ATP/P2Y‐VIP/VPAC1 pathways in rat duodenum. This provides a new therapeutic pathway to enhance duodenal mucosal defenses.Support or Funding InformationVA Merit Review and Shire Pharmaceuticals