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

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 nitric oxide synthase (eNOS) and hepatic and plasma endothelin-1 (ET-1). Prehepatic portal hypertension induced by portal vein ligation (PVL) does not cause similar changes, suggesting that ET-1 in cirrhosis may modulate pulmonary eNOS and vascular tone. We assessed whether ET-1 altered eNOS expression and nitric oxide production in bovine pulmonary artery endothelial cells (BPAECs) and if a 2-wk low-level intravenous ET-1 infusion in PVL animals modulated pulmonary eNOS levels, microcirculatory tone, and 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 eNOS mRNA and nitrite production. ET-1 infusion in PVL animals caused increased 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 modulating eNOS and inducing pulmonary microcicrulatory vasodilatation.

Effects of nebulized N G-nitro-L-arginine methyl ester in patients with hepatopulmonary syndrome

“…2 Few experimental and clinical evidences in HPS suggest that enhanced pulmonary production of nitric oxide (NO) plays a key role in the development of intrapulmonary vascular dilatations. [3][4][5][6][7][8][9][10] Morphologically, the striking feature in HPS is widespread dilatation and increased number of pulmonary capillaries in alveolar regions 11 that suggest a vasculogenic rather than a vasoactive pathobiological process. 12 Studies with NO inhibitors in HPS, however, have highlighted that active NO-dependent pulmonary vasodilatation may contribute to the persistence of gas exchange abnormalities.…”

Nitric oxide in liver transplantation: Pathobiology and clinical implications

“…97 Excess N O production has been shown in experimental models of hepatic encephalopathy, a neuropsychiatric syndrome associated with cirrhosis and portosystemic shunting.98 In this case, the relevant isoform may be nNOS. Increases in nNOS mRNA, protein, and activity have been shown in experimental models of hepatic encepha10pathy.9~ Interestingly, the excess in N O production may contribute to encephalopathy through mechanisms of neurotransmission regulation or through alterations in cerebral perfusion.…”

Biliary cyst fluid from common bile duct–ligated rats stimulates endothelial nitric oxide synthase in pulmonary artery endothelial cells: A potential role in hepatopulmonary syndrome

“…Most recently, we have observed that delivery of a chronic low level ET-1 infusion to PVL animals triggers an increase in pulmonary eNOS levels, intrapulmonary vasodilatation, and gas exchange abnormalities indicative of HPS. 6 Together, these findings suggest that circulating ET-1 derived from the liver contributes to the development of experimental HPS.…”

“…Most recently, we have observed that delivery of a chronic low level ET-1 infusion to PVL animals triggers an increase in pulmonary eNOS levels, intrapulmonary vasodilatation, and gas exchange abnormalities indicative of HPS. 6 Together, these findings suggest that circulating ET-1 derived from the liver contributes to the development of experimental HPS.However, whether biliary production and release of ET-1 is involved in the unique susceptibility of CBDL animals to HPS remains undefined. We hypothesized that biliary obstruction may result in the release of mediators, including ET-1, from the obstructed biliary tree that reach the systemic circulation via disruption of the canalicular paracellular barrier and influence the pulmonary vasculature.…”

“…When cells reached 70% confluence, the media was changed and cells were stimulated with biliary cyst fluid at various dilution (1: 1,000, 1:100, or 1:10) for 24 hours for Western blotting, 12 hours for Northern blotting, or 1 hour for nitric oxide synthase (NOS) activity. The times for analysis were based on previously published work in BPAECs and other cultured vascular endothelial cells that demonstrate that maximal changes in eNOS messenger RNA (mRNA) and protein levels 6 or in NOS activity 9 after ET-1 stimulation occur near the chosen measurement time points. Prior to cell lysis, cell culture media was obtained from each well and stored at Ϫ80°C for NO measurement.…”