NCX-1000, a NO-releasing derivative of ursodeoxycholic acid, selectively delivers NO to the liver and protects against development of portal hypertension.
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.
Fiorucci
S
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
E
Morelli
O
O
Mencarelli
A
A
Casini
A
A
Mello
T
T
Palazzetti
B
B
Tallet
D
D
del Soldato
P
P
Morelli
A
A
D000818:Animals; D002251:Carbon Tetrachloride / Q000494:pharmacology; D003094:Collagen / Q000378:metabolism; D006975:Hypertension, Portal / Q000378:metabolism / Q000517:prevention & control*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000503:physiopathology; D008297:Male; D009566:Nitrates; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012459:Salicylates / Q000378:metabolism* / Q000494:pharmacology; D014580:Ursodeoxycholic Acid / Q000378:metabolism* / Q000494:pharmacology / Q000031:analogs & derivatives
C433771:2-methyl-3-(2-((4-nitrooxybutyloxy)carbonyl)vinyl)phenyl ursodeoxycholic acid ester; D009566:Nitrates; D020030:Nitric Oxide Donors; D012459:Salicylates; D009569:Nitric Oxide; D014580:Ursodeoxycholic Acid; D003094:Collagen; D002251:Carbon Tetrachloride