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Luminal 5‐ HT stimulates colonic bicarbonate secretion in rats
Author(s) -
Kaji I,
Akiba Y,
Said H,
Narimatsu K,
Kaunitz J D
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13216
Subject(s) - medicine , endocrinology , chemistry , tegaserod , tetrodotoxin , submucosa , secretion , in vivo , carbenoxolone , biology , biochemistry , microbiology and biotechnology , irritable bowel syndrome , intracellular , gap junction
Background and Purpose 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. Experimental Approach We measured short‐circuit current ( I sc ) as an indicator of ion transport in mucosa‐submucosa or mucosa‐only preparations of rat proximal colon. Total CO 2 output was measured in vitro and in vivo. Immunohistochemistry was performed to investigate the localization of 5‐HT 4 , NOS1 and NOS2. Key Results Luminal 5‐ HT gradually increased the amplitude and sustained the elevation of I sc . Luminal 5‐ HT ‐evoked Δ I sc was acetazolamide sensitive and HCO 3 − dependent, consistent with cytosolic carbonic anhydrase‐dependent electrogenic HCO 3 − secretion, while not affected by tetrodotoxin ( TTX ), atropine or indomethacin. Pretreatment with the selective 5‐ HT 4 antagonist GR 113808, but not antagonists for 5‐ HT 3 , 5‐ HT 6 or 5‐ HT 7 , inhibited luminal 5‐ HT ‐evoked Δ I sc . Furthermore, luminal cisapride and tegaserod increased I sc 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 Δ I sc , suggesting that NO synthesized in the submucosa suppresses mucosal anion secretion. NOS 1 and NOS 2 were immunostained in the submucosal neurons and glial cells respectively. Luminal 5‐ HT ‐evoked HCO 3 − secretion was confirmed in vivo , inhibited by co‐perfusion of GR 113808, but not by ondansetron. Conclusions and Implications A novel apical 5‐ HT 4 ‐mediated HCO 3 − secretory pathway and an NO ‐dependent inhibitory mechanism are present in the proximal colon. Luminal 5‐ HT ‐evoked HCO 3 − secretion may be important for the maintenance of mucosal integrity by regulating luminal pH .