title: Nitric oxide suppression reversibly attenuates mitochondrial dysfunction and cholestasis in endotoxemic rat liver.
abstract: This study aimed to examine whether nitric oxide (NO) plays a causal role in endotoxin-induced dysfunction of biliary transport. Rats were treated with intraperitoneal injection of endotoxin (O111B4, 4 mg/kg). At 2 hours, the liver was excised and perfused ex vivo with taurocholate (TC)-containing Krebs-Ringer solution under monitoring bile output and NO2 in the perfusate and tissue cyclic guanosine monophosphate (cGMP) levels as indices of NO production. The endotoxin treatment evoked a marked decrease in the bile acid-dependent bile formation concurrent with the increasing NO2 output, cGMP elevation, and a reduction of hepatic adenosine triphosphate (ATP) contents and oxygen consumption. Perfusion with 1 mmol/L aminoguanidine (AG), an inhibitor of inducible NO synthase, but not with L-nitroarginine methyl ester, an inhibitor of the constitutive form of the enzyme, significantly reversed the endotoxin-induced increment of the bile formation in concert with the recovery of oxygen consumption and ATP levels. Laser confocal microfluorography of the liver lobules using rhodamine 123 (Rh), a fluoroprobe sensitive to mitochondrial membrane potential, revealed that endotoxin elicited a significant mitochondrial dysfunction panlobularly. The AG administration reversed the endotoxin-induced decrease in mitochondrial membrane potential. Collectively, up-regulation of NO by inducible NO synthase accounts for a mechanism through which endotoxin impairs the bile formation, and its suppression serves as a therapeutic strategy for improvement of hepatobiliary function.
authors.affiliation: First Department of Surgery, Nagoya University School of Medicine, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Shiomi
authors.forename: Y
authors.initials: Y
authors.lastname: Wakabayashi
authors.forename: T
authors.initials: T
authors.lastname: Sano
authors.forename: Y
authors.initials: Y
authors.lastname: Shinoda
authors.forename: Y
authors.initials: Y
authors.lastname: Nimura
authors.forename: Y
authors.initials: Y
authors.lastname: Ishimura
authors.forename: M
authors.initials: M
authors.lastname: Suematsu
mesh_terms: D000818:Animals; D001646:Bile / Q000187:drug effects / Q000502:physiology; D002779:Cholestasis / Q000503:physiopathology*; D017259:Dimaprit / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism; D019446:Endotoxemia / Q000503:physiopathology*; D004731:Endotoxins / Q000494:pharmacology; D005456:Fluorescent Dyes; D005470:Fluorometry; D006146:Guanidines / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D008930:Mitochondria, Liver / Q000502:physiology*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020112:Rhodamine 123; D012235:Rhodamines
chemical_list: D004731:Endotoxins; D005456:Fluorescent Dyes; D006146:Guanidines; D008070:Lipopolysaccharides; D012235:Rhodamines; D020112:Rhodamine 123; D009569:Nitric Oxide; C071989:APT; C004479:pimagedine; D017259:Dimaprit