title: In vivo gene transfer of endothelial nitric oxide synthase decreases portal pressure in anaesthetised carbon tetrachloride cirrhotic rats.
abstract: 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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Laboratory of Hepatology, University Hospital Gasthuisberg, Leuven, B-3000 Leuven, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Van de Casteele
authors.forename: A
authors.initials: A
authors.lastname: Omasta
authors.forename: S
authors.initials: S
authors.lastname: Janssens
authors.forename: T
authors.initials: T
authors.lastname: Roskams
authors.forename: V
authors.initials: V
authors.lastname: Desmet
authors.forename: F
authors.initials: F
authors.lastname: Nevens
authors.forename: J
authors.initials: J
authors.lastname: Fevery
mesh_terms: D000818:Animals; D026481:Blotting, Far-Western; D002251:Carbon Tetrachloride; D004730:Endothelium, Vascular / Q000201:enzymology* / Q000503:physiopathology; D018014:Gene Transfer Techniques; D008099:Liver / Q000201:enzymology / Q000503:physiopathology; D008106:Liver Cirrhosis, Experimental / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D019001:Nitric Oxide Synthase / Q000235:genetics*; D017082:Portal Pressure / Q000235:genetics / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002251:Carbon Tetrachloride; D019001:Nitric Oxide Synthase