title: Hypoxic pulmonary hypertension is prevented in rats with common bile duct ligation.
abstract: Biliary cirrhosis in the rat triggers intrapulmonary vasodilatation and gas-exchange abnormalities that characterize the hepatopulmonary syndrome. This vasodilatation correlates with increased levels of pulmonary microcirculatory endothelial NO synthase (eNOS) and hepatic and plasma endothelin-1 (ET-1). Importantly, during cirrhosis, the pulmonary vascular responses to acute hypoxia are blunted. The purpose of this work was to examine the pulmonary vascular responses and adaptations to the combination of liver cirrhosis and chronic hypoxia (CH). In addition to hemodynamic measurements, we investigated whether pulmonary expression changes of eNOS, ET-1 and its receptors (endothelin A and B), or heme oxygenase 1 in experimental cirrhosis affect the development of hypoxic pulmonary hypertension. We induced cirrhosis in male Sprague-Dawley rats using common bile duct ligation (CBDL) and exposed them to CH (inspired PO2 approximately 76 Torr) or maintained them in Denver (Den, inspired PO2 approximately 122 Torr) for 3 wk. Our data show 1) CBDL-CH rats had a persistent blunted hypoxic pulmonary vasoconstriction similar to CBDL-Den; 2) the development of hypoxic pulmonary hypertension was completely prevented in the CBDL-CH rats, as indicated by normal pulmonary arterial pressure and lack of right ventricular hypertrophy and pulmonary arteriole remodeling; and 3) selective increases in expression of ET-1, pulmonary endothelin B receptor, eNOS, and heme oxygenase 1 are potential mechanisms of protection against hypoxic pulmonary hypertension in the CBDL-CH rats. These data demonstrate that unique and undefined hepatic-pulmonary interactions occur during liver cirrhosis and chronic hypoxia. Understanding these interactions may provide important information for the prevention and treatment of pulmonary hypertension.
authors.affiliation: Cardiovascular-Pulmonary Research Laboratory, Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Imamura
authors.forename: Bao
authors.initials: B
authors.lastname: Luo
authors.forename: Jennifer
authors.initials: J
authors.lastname: Limbird
authors.forename: Andrea
authors.initials: A
authors.lastname: Vitello
authors.forename: Masahiko
authors.initials: M
authors.lastname: Oka
authors.forename: D Dunbar
authors.initials: DD
authors.lastname: Ivy
authors.forename: Ivan F
authors.initials: IF
authors.lastname: McMurtry
authors.forename: Chrystelle V
authors.initials: CV
authors.lastname: Garat
authors.forename: Michael B
authors.initials: MB
authors.lastname: Fallon
authors.forename: Ethan P
authors.initials: EP
authors.lastname: Carter
mesh_terms: D000818:Animals; D001783:Blood Flow Velocity; D001794:Blood Pressure; D003135:Common Bile Duct / Q000473:pathology / Q000503:physiopathology / Q000601:surgery; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control*; D000860:Hypoxia / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D008105:Liver Cirrhosis, Biliary / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D008168:Lung / Q000098:blood supply* / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D011652:Pulmonary Circulation; D051381:Rats; D017207:Rats, Sprague-Dawley