title: Xenin Augments Duodenal Anion Secretion via Activation of Afferent Neural Pathways.
abstract: Xenin-25, a neurotensin (NT)-related anorexigenic gut hormone generated mostly in the duodenal mucosa, is believed to increase the rate of duodenal ion secretion, because xenin-induced diarrhea is not present after Roux-en-Y gastric bypass surgery. Because the local effects of xenin on duodenal ion secretion have remained uninvestigated, we thus examined the neural pathways underlying xenin-induced duodenal anion secretion. Intravenous infusion of xenin-8, a bioactive C-terminal fragment of xenin-25, dose dependently increased the rate of duodenal HCO3-secretion in perfused duodenal loops of anesthetized rats. Xenin was immunolocalized to a subset of enteroendocrine cells in the rat duodenum. The mRNA of the xenin/NT receptor 1 (NTS1) was predominantly expressed in the enteric plexus, nodose and dorsal root ganglia, and in the lamina propria rather than in the epithelium. The serosal application of xenin-8 or xenin-25 rapidly and transiently increased short-circuit current in Ussing-chambered mucosa-submucosa preparations in a concentration-dependent manner in the duodenum and jejunum, but less so in the ileum and colon. The selective antagonist for NTS1, substance P (SP) receptor (NK1), or 5-hydroxytryptamine (5-HT)3, but not NTS2, inhibited the responses to xenin. Xenin-evoked Cl-secretion was reduced by tetrodotoxin (TTX) or capsaicin-pretreatment, and abolished by the inhibitor of TTX-resistant sodium channel Nav1.8 in combination with TTX, suggesting that peripheral xenin augments duodenal HCO3-and Cl-secretion through NTS1 activation on intrinsic and extrinsic afferent nerves, followed by release of SP and 5-HT. Afferent nerve activation by postprandial, peripherally released xenin may account for its secretory effects in the duodenum.
authors.affiliation: Greater Los Angeles Veterans Affairs Healthcare System Los Angeles, California (I.K., Y.A., J.D.K.); Departments of Medicine (I.K., Y.A., K.M., J.D.K.) and Surgery (J.D.K.), David Geffen School of Medicine at UCLA, Los Angeles, California; Department of Medical Biochemistry, Kobe Pharmaceutical University, Kobe, Kobe, Japan (I.K.); and Graduate School of Integrated Pharmaceutical and Nutritional Sciences, University of Shizuoka, Japan (A.K.).
authors.forename: Izumi
authors.initials: I
authors.lastname: Kaji
authors.affiliation: Greater Los Angeles Veterans Affairs Healthcare System Los Angeles, California (I.K., Y.A., J.D.K.); Departments of Medicine (I.K., Y.A., K.M., J.D.K.) and Surgery (J.D.K.), David Geffen School of Medicine at UCLA, Los Angeles, California; Department of Medical Biochemistry, Kobe Pharmaceutical University, Kobe, Kobe, Japan (I.K.); and Graduate School of Integrated Pharmaceutical and Nutritional Sciences, University of Shizuoka, Japan (A.K.).
authors.forename: Yasutada
authors.initials: Y
authors.lastname: Akiba
authors.affiliation: Greater Los Angeles Veterans Affairs Healthcare System Los Angeles, California (I.K., Y.A., J.D.K.); Departments of Medicine (I.K., Y.A., K.M., J.D.K.) and Surgery (J.D.K.), David Geffen School of Medicine at UCLA, Los Angeles, California; Department of Medical Biochemistry, Kobe Pharmaceutical University, Kobe, Kobe, Japan (I.K.); and Graduate School of Integrated Pharmaceutical and Nutritional Sciences, University of Shizuoka, Japan (A.K.).
authors.forename: Ikuo
authors.initials: I
authors.lastname: Kato
authors.affiliation: Greater Los Angeles Veterans Affairs Healthcare System Los Angeles, California (I.K., Y.A., J.D.K.); Departments of Medicine (I.K., Y.A., K.M., J.D.K.) and Surgery (J.D.K.), David Geffen School of Medicine at UCLA, Los Angeles, California; Department of Medical Biochemistry, Kobe Pharmaceutical University, Kobe, Kobe, Japan (I.K.); and Graduate School of Integrated Pharmaceutical and Nutritional Sciences, University of Shizuoka, Japan (A.K.).
authors.forename: Koji
authors.initials: K
authors.lastname: Maruta
authors.affiliation: Greater Los Angeles Veterans Affairs Healthcare System Los Angeles, California (I.K., Y.A., J.D.K.); Departments of Medicine (I.K., Y.A., K.M., J.D.K.) and Surgery (J.D.K.), David Geffen School of Medicine at UCLA, Los Angeles, California; Department of Medical Biochemistry, Kobe Pharmaceutical University, Kobe, Kobe, Japan (I.K.); and Graduate School of Integrated Pharmaceutical and Nutritional Sciences, University of Shizuoka, Japan (A.K.).
authors.forename: Atsukazu
authors.initials: A
authors.lastname: Kuwahara
authors.affiliation: Greater Los Angeles Veterans Affairs Healthcare System Los Angeles, California (I.K., Y.A., J.D.K.); Departments of Medicine (I.K., Y.A., K.M., J.D.K.) and Surgery (J.D.K.), David Geffen School of Medicine at UCLA, Los Angeles, California; Department of Medical Biochemistry, Kobe Pharmaceutical University, Kobe, Kobe, Japan (I.K.); and Graduate School of Integrated Pharmaceutical and Nutritional Sciences, University of Shizuoka, Japan (A.K.) jake@ucla.edu.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Kaunitz
mesh_terms: D000344:Afferent Pathways / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004386:Duodenum / Q000187:drug effects* / Q000378:metabolism*; D005768:Gastrointestinal Hormones / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism; D009475:Neurons, Afferent / Q000187:drug effects* / Q000378:metabolism*; D009496:Neurotensin / Q000494:pharmacology*; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D005768:Gastrointestinal Hormones; C077659:xenin 25; D009496:Neurotensin