Xenin-25 induces anion secretion by activating non-cholinergic secretomotor neurons in the rat ileum.

Xenin-25 is a neurotensin-like peptide that is secreted by enteroendocrine cells in the small intestine. Xenin-8 is reported to augment duodenal anion secretion by activating afferent neural pathways. The intrinsic neuronal circuits mediating the Xenin-25-induced anion secretion were characterized using Ussing chambered mucosa-submucosa preparation from the rat ileum. Serosal application of Xenin-25 increased the short-circuit current ( Isc) in a concentration-dependent manner. The responses were abolished by the combination of Cl- -free and HCO3 - -free solutions. The responses were almost completely blocked by TTX (10-6 M), but not by atropine (10-5 M) or hexamethonium (10-4 M). The selective antagonists for NTSR1, NK1, VPAC1, VPAC2 and capsaicin, but not 5-HT3 , 5-HT4 , NTSR2 and A803467, inhibited the responses to Xenin-25. The expression of VIP receptors in rat ileum was examined using RT-PCR. The Vipr1 PCR products were detected in the submucosal plexus and mucosa. Immunohistochemical staining showed the colocalization of NTSR1 and NK1 with SP- and calbindin-immunoreactive neurons in submucosal plexus, respectively. In addition, NK1 was also colocalized with non-cholinergic VIP secretomotor neurons. The present study indicates that Xenin-25-induced Cl- /HCO3 - secretion is involved in NTSR1 activation on intrinsic and extrinsic afferent neurons, followed by the release of SP and subsequent activation of NK1 expressed on non-cholinergic VIP secretomotor neurons. Finally, the secreted VIP may activate VPAC1 on epithelial cells to induce Cl- /HCO3 - secretion in the rat ileum. Activation of VIP-positive non-cholinergic secretomotor neurons by IPANs and extrinsic afferent neurons by postprandially released Xenin-25 may account for most of the neurogenic secretory response induced by Xenin-25.