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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.JH

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+Show Affiliations

Fiorucci S
Clinica di Gastroenterologia ed Epatologia, Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Perugia, Perugia, Italy. fiorucci@unipg.it
Antonelli E
No affiliation info available
Brancaleone V
No affiliation info available
Sanpaolo L
No affiliation info available
Orlandi S
No affiliation info available
Distrutti E
No affiliation info available
Acuto G
No affiliation info available
Clerici C
No affiliation info available
Baldoni M
No affiliation info available
Del Soldato P
No affiliation info available
Morelli A
No affiliation info available

MeSH

AnimalsBileBlood PressureDrug InteractionsHypertension, PortalIn Vitro TechniquesLiver CirculationLiver CirrhosisMaleNitratesNitric Oxide DonorsNorepinephrinePerfusionRatsRats, WistarUrsodeoxycholic AcidVascular ResistanceVasoconstrictionVasoconstrictor Agents

Pub Type(s)

Journal Article

Language

eng

PubMed ID

14642608

Citation

Fiorucci, Stefano, et al. "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." Journal of Hepatology, vol. 39, no. 6, 2003, pp. 932-9.
Fiorucci S, Antonelli E, Brancaleone V, et al. 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;39(6):932-9.
Fiorucci, S., Antonelli, E., Brancaleone, V., Sanpaolo, L., Orlandi, S., Distrutti, E., Acuto, G., Clerici, C., Baldoni, M., Del Soldato, P., & Morelli, A. (2003). 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. Journal of Hepatology, 39(6), 932-9.
Fiorucci S, et al. 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;39(6):932-9. PubMed PMID: 14642608.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Fiorucci,Stefano, AU - Antonelli,Elisabetta, AU - Brancaleone,Vincenzo, AU - Sanpaolo,Laura, AU - Orlandi,Stefano, AU - Distrutti,Eleonora, AU - Acuto,Giancarlo, AU - Clerici,Carlo, AU - Baldoni,Monia, AU - Del Soldato,Piero, AU - Morelli,Antonio, PY - 2003/12/4/pubmed PY - 2004/8/4/medline PY - 2003/12/4/entrez SP - 932 EP - 9 JF - Journal of hepatology JO - J Hepatol VL - 39 IS - 6 N2 - 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. SN - 0168-8278 UR - https://www.unboundmedicine.com/medline/citation/14642608/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_ DB - PRIME DP - Unbound Medicine ER -