title: Overexpression of endothelin-1 mRNA and protein in portal hypertensive gastric mucosa of rats: a key to increased susceptibility to damage?
abstract: BACKGROUND
  Portal hypertension predisposes gastric mucosa to increased injury by various noxious factors. Because endothelin-1 (ET-1) is a potent vasoconstrictor that enhances gastric mucosal injury, we examined ET-1 expression in the portal hypertensive (PHT) gastric mucosa and its possible role in increased mucosal susceptibility to damage.
  
  
  METHODS
  In gastric specimens of PHT or sham-operated rats, ET-1 mRNA expression was studied by S1-nuclease protection assay and ET-1 protein by enzyme immunoassay and immunostaining. We also determined the extent of ethanol-induced gastric mucosal necrosis in PHT and sham-operated rats after administering either a placebo or FR 139317, a selective ETA receptor antagonist.
  
  
  RESULTS
  In PHT stomachs ET-1 mRNA expression and protein concentration were significantly increased compared with sham-operated controls: mRNA expression (ET-1/glyceraldehyde-3-phosphate-dehydrogenase ratio), 0.54 +/- 0.18 versus 0.30 +/- 0.08; protein concentration, 7.36 +/- 2.21 pg/mg versus 3.93 +/- 0.40 pg/mg, respectively; both p < 0.01. Immunofluorescence signal of ET-1 protein was predominantly localized to endothelia of gastric mucosal and submucosal vessels. In PHT stomachs FR 139317 significantly reduced mucosal necrosis (percentage of necrotic area, from 24.9 +/- 5.9% to 10.8 +/- 4.0%; p < 0.01), although it had no effect on sham-operated controls.
  
  
  CONCLUSIONS
  Portal hypertension activates the ET-1 gene with overexpression of ET-1 protein in the gastric mucosa. Protection of PHT gastric mucosa by ETA receptor antagonist against damage indicates that overexpression of ET-1 plays an important role in increased susceptibility of PHT gastric mucosa to injury.
authors.affiliation: Department of Surgery and Medicine, DVA Medical Center, Long Beach, Calif. 90822, USA.
authors.forename: M
authors.initials: M
authors.lastname: Ohta
authors.forename: T H
authors.initials: TH
authors.lastname: Nguyen
authors.forename: A S
authors.initials: AS
authors.lastname: Tarnawski
authors.forename: R
authors.initials: R
authors.lastname: Pai
authors.forename: Y P
authors.initials: YP
authors.lastname: Kratzberg
authors.forename: K
authors.initials: K
authors.lastname: Sugimachi
authors.forename: I J
authors.initials: IJ
authors.lastname: Sarfeh
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000096:biosynthesis*; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D000431:Ethanol / Q000633:toxicity; D005753:Gastric Mucosa / Q000098:blood supply* / Q000187:drug effects / Q000473:pathology; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000096:biosynthesis; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D006975:Hypertension, Portal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D007211:Indoles / Q000494:pharmacology; D009336:Necrosis; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D014158:Transcription, Genetic; D014680:Veins; D014699:Venules
chemical_list: D001381:Azepines; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D007211:Indoles; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; C079574:FR 139317; D000431:Ethanol; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases