title: Leptin receptor blockade reduces intrahepatic vascular resistance and portal pressure in an experimental model of rat liver cirrhosis.
abstract: Increased hepatic vascular resistance mainly due to elevated vascular tone and to fibrosis is the primary factor in the development of portal hypertension in cirrhosis. Leptin, a hormone associated with reduction in nitric oxide bioavailability, vascular dysfunction, and liver fibrosis, is increased in patients with cirrhosis. We aimed at evaluating whether leptin influences the increased hepatic resistance in portal hypertension. CCl4-cirrhotic rats received the leptin receptor-blocker ObR antibody, or its vehicle, every other day for 1 wk. Hepatic and systemic hemodynamics were measured in both groups. Hepatic nitric oxide production and bioavailability, together with oxidative stress, nitrotyrosinated proteins, and liver fibrosis, were evaluated. In cirrhotic rats, leptin-receptor blockade significantly reduced portal pressure without modifying portal blood flow, suggesting a reduction in the intrahepatic resistance. Portal pressure reduction was associated with increased nitric oxide bioavailability and with decreased O2(-) levels and nitrotyrosinated proteins. No changes in systemic hemodynamics and liver fibrosis were observed. In conclusion, the present study shows that blockade of the leptin signaling pathway in cirrhosis significantly reduces portal pressure. This effect is probably due to a nitric oxide-mediated reduction in the hepatic vascular tone.
authors.affiliation: Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Villarroel 170, 08036 Barcelona, Spain. jcgarcia@clinic.ub.es.
authors.forename: María Gabriela
authors.initials: MG
authors.lastname: Delgado
authors.forename: Jordi
authors.initials: J
authors.lastname: Gracia-Sancho
authors.forename: Giusi
authors.initials: G
authors.lastname: Marrone
authors.forename: Aina
authors.initials: A
authors.lastname: Rodríguez-Vilarrupla
authors.forename: Ramon
authors.initials: R
authors.lastname: Deulofeu
authors.forename: Juan G
authors.initials: JG
authors.lastname: Abraldes
authors.forename: Jaume
authors.initials: J
authors.lastname: Bosch
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: García-Pagán
mesh_terms: D000818:Animals; D000906:Antibodies; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000473:pathology*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D017082:Portal Pressure / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D054411:Receptors, Leptin / Q000037:antagonists & inhibitors*; D014655:Vascular Resistance / Q000187:drug effects*
chemical_list: D000906:Antibodies; D054411:Receptors, Leptin; D009569:Nitric Oxide
keywords: ObR; endothelium; fibrosis; nitric oxide; portal hypertension