Nitric oxide suppression reversibly attenuates mitochondrial dysfunction and cholestasis in endotoxemic rat liver


  • A preliminary account pertinent to a portion of this work was presented at the Annual Meeting of the American Society for the Study of the Liver Diseases, November 1996, Chicago, IL


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 vivowith taurocholate (TC)-containing Krebs-Ringer solution under monitoring bile output and NO2in 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 NO2output, 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.