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NCX-1000, a NO-releasing derivative of ursodeoxycholic acid, selectively delivers NO to the liver and protects against development of portal hypertension.
Proc Natl Acad Sci U S A. 2001 Jul 17; 98(15):8897-902.PN

Abstract

Portal hypertension resulting from increased intrahepatic resistance is a common complication of chronic liver diseases and a leading cause of death in patients with liver cirrhosis, a scarring process of the liver that includes components of both increased fibrogenesis and wound contraction. A reduced production of nitric oxide (NO) resulting from an impaired enzymatic function of endothelial NO synthase and an increased contraction of hepatic stellate cells (HSCs) have been demonstrated to contribute to high intrahepatic resistance in the cirrhotic liver. 2-(Acetyloxy) benzoic acid 3-(nitrooxymethyl) phenyl ester (NCX-1000) is a chemical entity obtained by adding an NO-releasing moiety to ursodeoxycholic acid (UDCA), a compound that is selectively metabolized by hepatocytes. In this study we have examined the effect of NCX-1000 and UDCA on liver fibrosis and portal hypertension induced by i.p. injection of carbon tetrachloride in rats. Our results demonstrated that although both treatments reduced liver collagen deposition, NCX-1000, but not UDCA, prevented ascite formation and reduced intrahepatic resistance in carbon tetrachloride-treated rats as measured by assessing portal perfusion pressure. In contrast to UDCA, NCX-1000 inhibited HSC contraction and exerted a relaxing effect similar to the NO donor S-nitroso-N-acetylpenicillamine. HSCs were able to metabolize NCX-1000 and release nitrite/nitrate in cell supernatants. In aggregate these data indicate that NCX-1000, releasing NO into the liver microcirculation, may provide a novel therapy for the treatment of patients with portal hypertension.

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Authors+Show Affiliations

Fiorucci S
Clinica di Gastroenterologia ed Epatologia, Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Perugia, 06122 Perugia, Italy. fiorucci@unipg.it
Antonelli E
No affiliation info available
Morelli O
No affiliation info available
Mencarelli A
No affiliation info available
Casini A
No affiliation info available
Mello T
No affiliation info available
Palazzetti B
No affiliation info available
Tallet D
No affiliation info available
del Soldato P
No affiliation info available
Morelli A
No affiliation info available

MeSH

AnimalsCarbon TetrachlorideCollagenHypertension, PortalLiverLiver CirrhosisMaleNitratesNitric OxideNitric Oxide DonorsRatsRats, WistarSalicylatesUrsodeoxycholic Acid

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11447266

Citation

Fiorucci, S, et al. "NCX-1000, a NO-releasing Derivative of Ursodeoxycholic Acid, Selectively Delivers NO to the Liver and Protects Against Development of Portal Hypertension." Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 15, 2001, pp. 8897-902.
Fiorucci S, Antonelli E, Morelli O, et al. NCX-1000, a NO-releasing derivative of ursodeoxycholic acid, selectively delivers NO to the liver and protects against development of portal hypertension. Proc Natl Acad Sci U S A. 2001;98(15):8897-902.
Fiorucci, S., Antonelli, E., Morelli, O., Mencarelli, A., Casini, A., Mello, T., Palazzetti, B., Tallet, D., del Soldato, P., & Morelli, A. (2001). NCX-1000, a NO-releasing derivative of ursodeoxycholic acid, selectively delivers NO to the liver and protects against development of portal hypertension. Proceedings of the National Academy of Sciences of the United States of America, 98(15), 8897-902.
Fiorucci S, et al. NCX-1000, a NO-releasing Derivative of Ursodeoxycholic Acid, Selectively Delivers NO to the Liver and Protects Against Development of Portal Hypertension. Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8897-902. PubMed PMID: 11447266.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - NCX-1000, a NO-releasing derivative of ursodeoxycholic acid, selectively delivers NO to the liver and protects against development of portal hypertension. AU - Fiorucci,S, AU - Antonelli,E, AU - Morelli,O, AU - Mencarelli,A, AU - Casini,A, AU - Mello,T, AU - Palazzetti,B, AU - Tallet,D, AU - del Soldato,P, AU - Morelli,A, Y1 - 2001/07/10/ PY - 2001/7/12/pubmed PY - 2001/8/31/medline PY - 2001/7/12/entrez SP - 8897 EP - 902 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc Natl Acad Sci U S A VL - 98 IS - 15 N2 - Portal hypertension resulting from increased intrahepatic resistance is a common complication of chronic liver diseases and a leading cause of death in patients with liver cirrhosis, a scarring process of the liver that includes components of both increased fibrogenesis and wound contraction. A reduced production of nitric oxide (NO) resulting from an impaired enzymatic function of endothelial NO synthase and an increased contraction of hepatic stellate cells (HSCs) have been demonstrated to contribute to high intrahepatic resistance in the cirrhotic liver. 2-(Acetyloxy) benzoic acid 3-(nitrooxymethyl) phenyl ester (NCX-1000) is a chemical entity obtained by adding an NO-releasing moiety to ursodeoxycholic acid (UDCA), a compound that is selectively metabolized by hepatocytes. In this study we have examined the effect of NCX-1000 and UDCA on liver fibrosis and portal hypertension induced by i.p. injection of carbon tetrachloride in rats. Our results demonstrated that although both treatments reduced liver collagen deposition, NCX-1000, but not UDCA, prevented ascite formation and reduced intrahepatic resistance in carbon tetrachloride-treated rats as measured by assessing portal perfusion pressure. In contrast to UDCA, NCX-1000 inhibited HSC contraction and exerted a relaxing effect similar to the NO donor S-nitroso-N-acetylpenicillamine. HSCs were able to metabolize NCX-1000 and release nitrite/nitrate in cell supernatants. In aggregate these data indicate that NCX-1000, releasing NO into the liver microcirculation, may provide a novel therapy for the treatment of patients with portal hypertension. SN - 0027-8424 UR - https://www.unboundmedicine.com/medline/citation/11447266/NCX_1000_a_NO_releasing_derivative_of_ursodeoxycholic_acid_selectively_delivers_NO_to_the_liver_and_protects_against_development_of_portal_hypertension_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=11447266 DB - PRIME DP - Unbound Medicine ER -