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 ET A 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 ER 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 ET A receptor antagonist against damage indicates that overexpression of ET-1 plays an important role in increased susceptibility of PHT gastric mucosa to injury.