RESUMO
BACKGROUND: Portal hypertension in cirrhosis results from enhanced intrahepatic resistance to an augmented inflow. The former is partly due to an imbalance between intrahepatic vasoconstriction and vasodilatation. Enhanced endothelin-1 and decreased activity of hepatic constitutive endothelial nitric oxide synthase (NOS 3) was reported in carbon tetrachloride (CCl(4)) cirrhotic rat liver. AIMS: To study whether an increase in hepatic NOS 3 could be obtained in the CCl(4) cirrhotic rat liver by in vivo cDNA transfer and to investigate a possible effect on portal pressure. METHODS: Hepatic NOS 3 immunohistochemistry and western blotting were used to measure the amount of NOS 3 protein. Recombinant adenovirus, carrying cDNA encoding human NOS 3, was injected into the portal vein of CCl(4) cirrhotic rats. Cirrhotic controls received carrier buffer, naked adenovirus, or adenovirus carrying the lac Z gene. RESULTS: NOS 3 immunoreactivity and amount of protein (western blotting) were significantly decreased in CCl(4) cirrhotic livers. Following cDNA transfer, NOS 3 expression and the amount of protein were partially restored. Portal pressure was 11.4 (1.6) mm Hg in untreated cirrhotic (n=9) and 11.8 (0.6) in lac Z transfected (n=4) cirrhotic rats but was reduced to 7.8 (1.0) mm Hg (n=9) five days after NOS 3 cDNA transfer. No changes were observed in systemic haemodynamics, in liver tests or urinary nitrates, or in NOS 3 expression in lung or kidney, indicating a highly selective transfer. CONCLUSIONS: NOS 3 cDNA transfer to cirrhotic rat liver is feasible and the increase in hepatic NOS 3 leads to a marked decrease in portal hypertension without systemic effects. These data indicate a major haemodynamic role of intrahepatic NOS 3 in the pathogenesis of portal hypertension in CCl(4) cirrhosis.
Assuntos
Endotélio Vascular/enzimologia , Cirrose Hepática Experimental/fisiopatologia , Óxido Nítrico Sintase/genética , Pressão na Veia Porta/fisiologia , Animais , Far-Western Blotting , Tetracloreto de Carbono , Endotélio Vascular/fisiopatologia , Técnicas de Transferência de Genes , Fígado/enzimologia , Fígado/fisiopatologia , Cirrose Hepática Experimental/enzimologia , Cirrose Hepática Experimental/genética , Masculino , Pressão na Veia Porta/genética , Ratos , Ratos WistarRESUMO
Inhibition by ethanol of the activities of lysosomal exoglycosidases in stomach, small intestine, liver and brain of rats exposed to cadmium (Cd2+) was determined. Out of the glycosidases tested the most distinct effect of Cd2+ and ethanol administered to the rats in vivo was observed in the small intestinal mucosa in a decreasing order: N-acetyl-beta-hexosaminidase, beta-galactosidase and alpha-fucosidase.
