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.
OBJECTIVE
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.
Fiorucci
Stefano
S
Clinica di Gastroenterologia ed Epatologia, Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Perugia, Perugia, Italy. fiorucci@unipg.it
Antonelli
Elisabetta
E
Brancaleone
Vincenzo
V
Sanpaolo
Laura
L
Orlandi
Stefano
S
Distrutti
Eleonora
E
Acuto
Giancarlo
G
Clerici
Carlo
C
Baldoni
Monia
M
Del Soldato
Piero
P
Morelli
Antonio
A
D000818:Animals; D001646:Bile / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D004347:Drug Interactions; D006975:Hypertension, Portal / Q000188:drug therapy* / Q000503:physiopathology; D066298:In Vitro Techniques; D008102:Liver Circulation / Q000187:drug effects*; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D009566:Nitrates / Q000493:pharmacokinetics / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009638:Norepinephrine / Q000494:pharmacology*; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
C433771:2-methyl-3-(2-((4-nitrooxybutyloxy)carbonyl)vinyl)phenyl ursodeoxycholic acid ester; D009566:Nitrates; D020030:Nitric Oxide Donors; D014662:Vasoconstrictor Agents; D014580:Ursodeoxycholic Acid; D009638:Norepinephrine