NCX-1000, a nitric oxide-releasing derivative of ursodeoxycholic acid, ameliorates portal hypertension and lowers norepinephrine-induced intrahepatic resistance in the isolated and perfused rat liver

J Hepatol. 2003 Dec;39(6):932-9. doi: 10.1016/s0168-8278(03)00393-3.


Background/aims: We studied whether acute administration of NCX-1000, a nitric oxide (NO)-releasing derivative of ursodeoxycholic acid (UDCA), to animals with established liver cirrhosis decreases intrahepatic resistance and modulates hepatic vascular hypereactivity to norepinephrine (NE).

Methods: Four-week bile duct ligated (BDL) cirrhotic and control, sham-operated, rats were treated orally with 28 mg/kg per day NCX-1000 or 15 mg/kg per day UDCA for 5 days. Isolated normal and cirrhotic livers were perfused with NE, from 10 nM to 30 microM, in a recirculating system.

Results: NCX-1000 administration to BDL cirrhotic rats decreased portal pressure (P<0.01) without affecting mean arterial pressure and heart rate. In the isolated perfused liver system, administration of NE resulted in a dose-dependent increase of intrahepatic resistance. Vasoconstriction caused by 30 microM NE was reduced by 60% in animals treated with NCX-1000 (P<0.001), while UDCA was uneffective. The same portal pressure lowering effect was documented in cirrhotic and sham operated rats. Administration of NCX-1000 to BDL and sham operated rats resulted in a similar increase of nitrite/nitrate and cGMP concentrations in the liver.

Conclusions: By selectively delivering NO to the liver, NCX-1000 increases cGMP concentrations and effectively counteracts the effect of endogenous vasoconstrictors on the hepatic vascular tone.

MeSH terms

  • Animals
  • Bile / metabolism
  • Blood Pressure / drug effects
  • Drug Interactions
  • Hypertension, Portal / drug therapy*
  • Hypertension, Portal / physiopathology
  • In Vitro Techniques
  • Liver Circulation / drug effects*
  • Liver Cirrhosis / drug therapy
  • Liver Cirrhosis / physiopathology
  • Male
  • Nitrates / pharmacokinetics
  • Nitrates / pharmacology*
  • Nitric Oxide Donors / pharmacology*
  • Norepinephrine / pharmacology*
  • Perfusion
  • Rats
  • Rats, Wistar
  • Ursodeoxycholic Acid / analogs & derivatives
  • Ursodeoxycholic Acid / pharmacokinetics
  • Ursodeoxycholic Acid / pharmacology*
  • Vascular Resistance / drug effects
  • Vasoconstriction / drug effects
  • Vasoconstrictor Agents / pharmacology*


  • 2-methyl-3-(2-((4-nitrooxybutyloxy)carbonyl)vinyl)phenyl ursodeoxycholic acid ester
  • Nitrates
  • Nitric Oxide Donors
  • Vasoconstrictor Agents
  • Ursodeoxycholic Acid
  • Norepinephrine