title: The eNOS cofactor tetrahydrobiopterin improves endothelial dysfunction in livers of rats with CCl4 cirrhosis.
abstract: In cirrhosis, intrahepatic endothelial dysfunction is one of the mechanisms involved in the increased resistance to portal blood flow and therefore in the development of portal hypertension. Endothelial nitric oxide synthase (eNOS) uncoupling due to deficiency of tetrahydrobiopterin (BH4) results in decreased production of NO and plays a major role in endothelial dysfunction in other conditions. We examined whether eNOS uncoupling is involved in the pathogenesis of endothelial dysfunction of livers with cirrhosis. Basal levels of tetrahydrobiopterin and guanosine triphosphate (GTP)-cyclohydrolase (BH4 rate-limiting enzyme) expression and activity were determined in liver homogenates of control and rats with CCl4 cirrhosis. Thereafter, rats were treated with tetrahydrobiopterin, and eNOS activity, NO bioavailability, assessed with a functional assay, and the vasodilator response to acetylcholine (endothelial function) were evaluated. Livers with cirrhosis showed reduced BH4 levels and decreased GTP-cyclohydrolase activity and expression, which were associated with impaired vasorelaxation to acetylcholine. Tetrahydrobiopterin supplementation increased BH4 hepatic levels and eNOS activity and significantly improved the vasodilator response to acetylcholine in rats with cirrhosis. In conclusion, the impaired response to acetylcholine of livers with cirrhosis is modulated by a reduced availability of the eNOS cofactor, tetrahydrobiopterin. Tetrahydrobiopterin supplementation improved the endothelial dysfunction of cirrhotic livers.
authors.affiliation: Hepatic Hemodynamic Laboratory, Liver Unit, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
authors.forename: Vasilica
authors.initials: V
authors.lastname: Matei
authors.forename: Aina
authors.initials: A
authors.lastname: Rodríguez-Vilarrupla
authors.forename: Ramon
authors.initials: R
authors.lastname: Deulofeu
authors.forename: Dolors
authors.initials: D
authors.lastname: Colomer
authors.forename: Mercedes
authors.initials: M
authors.lastname: Fernández
authors.forename: Jaime
authors.initials: J
authors.lastname: Bosch
authors.forename: Juan-Carlos
authors.initials: JC
authors.lastname: Garcia-Pagán
mesh_terms: D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002251:Carbon Tetrachloride / Q000633:toxicity; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology*; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D011169:Portal Vein / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D016896:Treatment Outcome; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D001708:Biopterins; D002251:Carbon Tetrachloride; D019001:Nitric Oxide Synthase; C003402:sapropterin