title: Adaptive cytoprotection mediated by prostaglandin I(2) is attributable to sensitization of CRGP-containing sensory nerves.
abstract: OBJECTIVE
  The phenomenon by which the gastric mucosa is protected in response to mild irritants has been called adaptive cytoprotection, a mechanism believed to be related to production of endogenous prostaglandins (PGs). We tested whether PGs generated by mild irritant prevent injury through the release of calcitonin gene-related peptide (CGRP) from the sensory nerves using prostanoid receptor-knockout mice.
  
  
  METHODS
  The stomach was doubly cannulated and perfused with 1 mol/L NaCl or 50% ethanol. CGRP levels in the perfusate were determined by enzyme immunoassay, and the injured area was estimated at the end of perfusion.
  
  
  RESULTS
  Preperfusion with mildly hypertonic saline (1 mol/L NaCl) increased generation of gastric PGE(2) and PGI(2) and reduced ethanol-induced mucosal damage. Exposure of ethanol after 1 mol/L NaCl increased intragastric CGRP levels from 166 +/- 27 to 713 +/- 55 pg/2 min (n = 4, P < 0.05), and the protective action of 1 mol/L NaCl was inhibited by indomethacin treatment. CGRP antagonist blocked 1 mol/L NaCl-induced protective effect. Intragastric perfusion of 50% ethanol after administration of PGI(2), but not of PGE(2), increased CGRP levels. Application of 1 mol/L NaCl to IP receptor-knockout mice (IP(-/-)) did not elicit the protective effects seen in the wild-type on ethanol-induced gastric mucosal lesions. Protective effect of 1 mol/L NaCl was observed in EP3 receptor-knockout mice (EP3(-/-)). CGRP level during ethanol perfusion was not increased in IP(-/-) but was increased in EP3(-/-) and wild-type counterparts after preperfusion of 1 mol/L NaCl.
  
  
  CONCLUSIONS
  These results indicate that the endogenous PGI(2) generated by 1 mol/L NaCl may have a protective role in gastric mucosal injury through enhancement of CGRP release from gastric mucosa. This mechanism may explain the adaptive cytoprotection observed after treatment with mild irritants.
authors.affiliation: Department of Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Boku
authors.forename: T
authors.initials: T
authors.lastname: Ohno
authors.forename: T
authors.initials: T
authors.lastname: Saeki
authors.forename: H
authors.initials: H
authors.lastname: Hayashi
authors.forename: I
authors.initials: I
authors.lastname: Hayashi
authors.forename: M
authors.initials: M
authors.lastname: Katori
authors.forename: T
authors.initials: T
authors.lastname: Murata
authors.forename: S
authors.initials: S
authors.lastname: Narumiya
authors.forename: K
authors.initials: K
authors.lastname: Saigenji
authors.forename: M
authors.initials: M
authors.lastname: Majima
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000222:Adaptation, Physiological / Q000187:drug effects; D000758:Anesthesia; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D002492:Central Nervous System Depressants / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism / Q000494:pharmacology; D011464:Epoprostenol / Q000378:metabolism*; D000431:Ethanol / Q000494:pharmacology; D005753:Gastric Mucosa / Q000187:drug effects / Q000294:innervation* / Q000378:metabolism*; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009475:Neurons, Afferent / Q000378:metabolism*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin / Q000235:genetics; D012965:Sodium Chloride / Q000494:pharmacology; D013276:Stomach Ulcer / Q000139:chemically induced / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002492:Central Nervous System Depressants; D010446:Peptide Fragments; C491910:Ptgir protein, mouse; C491909:Ptgir protein, rat; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin; C058636:calcitonin gene-related peptide (8-37); D000431:Ethanol; D012965:Sodium Chloride; D015121:6-Ketoprostaglandin F1 alpha; D011464:Epoprostenol; D015740:Calcitonin Gene-Related Peptide; D015232:Dinoprostone; D007213:Indomethacin