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.