title: Endotoxin impairs biliary glutathione and HCO3- excretion and blocks the choleretic effect of nitric oxide in rat liver.
abstract: Cholestasis in patients with sepsis has been attributed to the effects of endotoxin (lipopolysaccharides, LPS) and LPS-induced cytokines, which are also potent stimulators of systemic and hepatic nitric oxide (NO) synthesis. NO donors stimulate bile acid-independent bile flow in normal rat liver, but the effects of LPS-induced NO on bile formation remain unclear. To address this question we examined the effects of NO and its mediator guanosine 3',5'-cyclic monophosphate (cGMP) on bile flow and biliary HCO3- and glutathione excretion in isolated perfused rat livers (IPRL) from LPS-treated rats. Portal and systemic NO2- + NO3- plasma levels were increased 47-fold in LPS-treated rats and were also elevated in perfusate (6-fold) and bile (9-fold) after isolating and perfusing livers from these animals. Bile flow, HCO3-, and glutathione output were decreased by 33%, 25%, and 81% in these IPRL, respectively. Stimulation of NO synthesis with L-arginine or inhibition of inducible NO synthesis with aminoguanidine did not change bile flow, although pretreatment with aminoguanidine inhibited NO production by 85%. Moreover, the choleretic effects of infusions of the NO donors sodium nitroprusside (SNP) and S-nitroso-acetyl-penicillamine were markedly reduced in endotoxemic IPRL compared with normal controls, and SNP-induced HCO3- and glutathione excretion were reduced by 61% and 86%, respectively. SNP-induced cyclic GMP production was 2.3-fold lower than in normals, but the choleretic effect of dibutyryl cGMP was only slightly reduced in endotoxemic livers. These findings indicate that LPS reduces bile acid-independent bile flow primarily by inhibiting biliary excretion of glutathione and to a lesser extent HCO3-, whereas LPS-induced NO does not modulate bile formation in endotoxemia. Thus, impairment of the major determinants of bile acid-independent bile flow by LPS may contribute significantly to the pathogenesis of the cholestasis of sepsis.
authors.affiliation: Department of Internal Medicine and Liver Center, Yale University School of Medicine, New Haven, CT 06520-8019, USA.
authors.forename: M
authors.initials: M
authors.lastname: Trauner
authors.forename: M H
authors.initials: MH
authors.lastname: Nathanson
authors.forename: S A
authors.initials: SA
authors.lastname: Rydberg
authors.forename: T A
authors.initials: TA
authors.lastname: Koeppel
authors.forename: C
authors.initials: C
authors.lastname: Gartung
authors.forename: W C
authors.initials: WC
authors.lastname: Sessa
authors.forename: J L
authors.initials: JL
authors.lastname: Boyer
mesh_terms: D000818:Animals; D001639:Bicarbonates / Q000378:metabolism*; D001646:Bile / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001639:Bicarbonates; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D005978:Glutathione