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.

Abstract

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.

• Authors: Stefano Fiorucci, Elisabetta Antonelli, Vincenzo Brancaleone, Laura Sanpaolo, Stefano Orlandi, Eleonora Distrutti, Giancarlo Acuto, Carlo Clerici, Monia Baldoni, Piero Del Soldato, Antonio Morelli
• Journal: Journal of hepatology (J Hepatol) Vol. 39 Issue 6 Pg. 932-9 (Dec 2003) ISSN: 0168-8278 [Print] Netherlands
• PMID: 14642608 (Publication Type: Journal Article)

Chemical References

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

Topics

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