Endothelin-1 stimulation of endothelial nitric oxide synthase in the pathogenesis of hepatopulmonary syndrome

Biliary cirrhosis in the rat triggers intrapulmonary vasodilatation and gas exchange abnormalities that characterize the hepatopulmonary syndrome. Thi s vasodilatation correlates with increased levels of pulmonary microcircula tory endothelial nitric oxide synthase (eNOS) and hepatic and plasma endoth elin-1 (ET-1). Prehepatic portal hypertension induced by portal vein ligati on (PVL) does not cause similar changes, suggesting that ET-1 in cirrhosis may modulate pulmonary eNOS and vascular tone. We assessed whether ET-1 alt ered eNOS expression and nitric oxide production in bovine pulmonary artery endothelial cells (BPAECs) and if a 2-wk low-level intravenous ET-1 infusi on in PVL animals modulated pulmonary eNOS levels, microcirculatory tone, a nd gas exchange. ET-1 caused a 2.5-fold increase in eNOS protein in BPAECs, inhibitable with an endothelin B receptor antagonist, and an increase in e NOS mRNA and nitrite production. ET-1 infusion in PVL animals caused increa sed pulmonary eNOS levels, intrapulmonary vasodilatation, and gas exchange abnormalities without increasing pulmonary arterial pressure. ET-1 produced during hepatic injury may contribute to the hepatopulmonary syndrome by mo dulating eNOS and inducing pulmonary microcicrulatory vasodilatation.