title: Luminal 5-HT stimulates colonic bicarbonate secretion in rats.
abstract: OBJECTIVE
  The bioactive monoamine 5-HT, implicated in the pathogenesis of functional gastrointestinal disorders, is abundantly synthesized and stored in rat proximal colonic mucosa and released to the gut lumen and subepithelial space. Despite much data regarding its expression and function, the effects of luminal 5-HT on colonic anion secretion have not been fully investigated.
  
  
  METHODS
  We measured short-circuit current (Isc ) as an indicator of ion transport in mucosa-submucosa or mucosa-only preparations of rat proximal colon. Total CO2 output was measured in vitro and in vivo. Immunohistochemistry was performed to investigate the localization of 5-HT4 , NOS1 and NOS2.
  
  
  RESULTS
  Luminal 5-HT gradually increased the amplitude and sustained the elevation of Isc . Luminal 5-HT-evoked ΔIsc was acetazolamide sensitive and HCO3 (-) dependent, consistent with cytosolic carbonic anhydrase-dependent electrogenic HCO3 (-) secretion, while not affected by tetrodotoxin (TTX), atropine or indomethacin. Pretreatment with the selective 5-HT4 antagonist GR113808, but not antagonists for 5-HT3 , 5-HT6 or 5-HT7 , inhibited luminal 5-HT-evoked ΔIsc . Furthermore, luminal cisapride and tegaserod increased Isc to the same extent as did 5-HT in the presence of indomethacin and TTX. Removal of the submucosa or pretreatment with NOS inhibitors enhanced luminal 5-HT-evoked ΔIsc , suggesting that NO synthesized in the submucosa suppresses mucosal anion secretion. NOS1 and NOS2 were immunostained in the submucosal neurons and glial cells respectively. Luminal 5-HT-evoked HCO3 (-) secretion was confirmed in vivo, inhibited by co-perfusion of GR113808, but not by ondansetron.
  
  
  CONCLUSIONS
  A novel apical 5-HT4 -mediated HCO3 (-) secretory pathway and an NO-dependent inhibitory mechanism are present in the proximal colon. Luminal 5-HT-evoked HCO3 (-) secretion may be important for the maintenance of mucosal integrity by regulating luminal pH.
authors.affiliation: Department of Medicine, University of California, Los Angeles, CA, USA.|Brentwood Biomedical Research Institute, Los Angeles, CA, USA.
authors.forename: I
authors.initials: I
authors.lastname: Kaji
authors.affiliation: Department of Medicine, University of California, Los Angeles, CA, USA.|Brentwood Biomedical Research Institute, Los Angeles, CA, USA.|Greater Los Angeles Veterans Affairs Healthcare System, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Akiba
authors.affiliation: College of Letters and Sciences, University of California, Los Angeles, CA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Said
authors.affiliation: Department of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Narimatsu
authors.affiliation: Department of Medicine, University of California, Los Angeles, CA, USA.|Department of Surgery, School of Medicine, University of California, Los Angeles, CA, USA.|Brentwood Biomedical Research Institute, Los Angeles, CA, USA.|Greater Los Angeles Veterans Affairs Healthcare System, CA, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Kaunitz
mesh_terms: D000818:Animals; D001639:Bicarbonates / Q000378:metabolism*; D003106:Colon / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology
chemical_list: D001639:Bicarbonates; D012702:Serotonin Antagonists; D044422:Receptors, Serotonin, 5-HT4; D009569:Nitric Oxide; D012701:Serotonin