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In vivo gene transfer of endothelial nitric oxide synthase decreases portal pressure in anaesthetised carbon tetrachloride cirrhotic rats
  1. M Van de Casteele1,,
  2. A Omasta1,,
  3. S Janssens2,
  4. T Roskams3,
  5. V Desmet3,
  6. F Nevens1,
  7. J Fevery1
  1. 1Laboratory of Hepatology, University Hospital Gasthuisberg, Leuven, B-3000 Leuven, Belgium
  2. 2Laboratory of Experimental Cardiology, University Hospital Gasthuisberg, Leuven, B-3000 Leuven, Belgium
  3. 3Laboratory of Histochemistry, University Hospital Gasthuisberg, Leuven, B-3000 Leuven, Belgium
  1. Correspondence to:
    Dr J Fevery, Division of Liver and Pancreatic Diseases, University Hospital Gasthuisberg, B-3000 Leuven, Belgium;


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 (CCl4) cirrhotic rat liver.

Aims: To study whether an increase in hepatic NOS 3 could be obtained in the CCl4 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 CCl4 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 CCl4 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 CCl4 cirrhosis.

  • nitric oxide
  • nitric oxide synthase
  • cirrhotic rats
  • gene transfer
  • portal hypertension
  • Ad5, recombinant adenovirus serotype 5
  • β-Gal, β-galactosidase
  • CCl4, carbon tetrachloride
  • NO, nitric oxide
  • NOS 3, constitutive endothelial nitric oxide synthase (NOS isoform 3)

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  • Both M Van de Casteele and A Omasta contributed equally to this work.