Background & aims: Portal hypertension predisposes gastric mucosa to increased injury. The aim of this study was to determine whether overexpression of constitutive nitric oxide synthase (cNOS) is responsible for increased susceptibility of portal-hypertensive (PHT) gastric mucosa to damage.
Methods: In gastric specimens from PHT and sham-operated rats, cNOS messenger RNA expression was determined by Northern blotting and cNOS protein expression by Western blotting, immunohistochemistry, and enzyme activity assay. Extent of ethanol-induced gastric mucosal necrosis, mucosal blood flow, and gastric NOS activity in PHT and sham-operated rats was determined after administration of N(omega)-nitro-L-arginine methyl ester (L-NAME) or saline.
Results: cNOS messenger RNA level, cNOS enzyme activity, and fluorescence signals for cNOS were increased significantly in PHT rats compared with controls. Inhibition of overexpressed cNOS by L-NAME (5 mg/kg) significantly reduced ethanol-induced mucosal necrosis and normalized blood flow in PHT gastric mucosa, whereas this dose of L-NAME significantly increased mucosal necrosis in sham-operated rats.
Conclusions: Portal hypertension activates the cNOS gene with overexpression of cNOS protein in endothelia of gastric mucosal vessels. Excessive NO production by overexpressed cNOS may play an important role in the increased susceptibility of PHT gastric mucosa to damage.