OVEREXPRESSION OF ENDOTHELIN-1 MESSENGER-RNA AND PROTEIN IN PORTAL HYPERTENSIVE GASTRIC-MUCOSA OF RATS - A KEY TO INCREASED SUSCEPTIBILITY TO DAMAGE

Background. Portal hypertension predisposes gastric mucosa to increase d injury by various noxious factors. Because endothelin-1 (ET-1) is a potent vasoconstrictor that enhances gastric mucosal injury, we examin ed ET-1 expression in the portal hypertensive (PHT) gastric mucosa and its possible role in increased mucosal susceptibility to damage. Meth ods. In gastric specimens of PHT or sham-operated rats, ET-1 mRNA expr ession 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 r ats after administering either a placebo or FR 139317, a selective ETA receptor antagonist. Results. In PHT stomachs ET-1 mRNA expression an d protein concentration were significantly increased compared with sha m-operated controls: mRNA expression (ET-1/glyceraldehyde-3-phosphate- dehydrogenase ratio), 0.54 +/- 0.18 versus 0.30 +/- 0.08; protein conc entration 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 predomin antly localized to endothelia of gastric mucosal and submucosal vessel s. In PHT stomachs FR 139317 significantly reduced mucosal necrosis (p ercentage of necrotic area, from 24.9 +/- 5.9% to 10.8 +/- 4.0 %; p < 0.01), although if had no effect on sham-operated controls. Conclusion s. Portal hypertension activates the ET-1 gene with overexpression of ET-1 protein in the gastric mucosa. Protection of PHT gastric mucosa b y ETA receptor antagonist against damage indicates that overexpression of ET-1 plays an important role in increased susceptibility of PHT ga stric mucosa to injury.