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

M. Shiomi, Y. Wakabayashi, T. Sano, Y. Shinoda, Y. Nimura, Y. Ishimura, M. Suematsu

Research output: Contribution to journalArticle

68 Citations (Scopus)

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 amino-guanidine (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.

Original languageEnglish
Pages (from-to)108-115
Number of pages8
JournalHepatology
Volume27
Issue number1
DOIs
Publication statusPublished - 1998 Jan 29

ASJC Scopus subject areas

  • Hepatology

Fingerprint Dive into the research topics of 'Nitric oxide suppression reversibly attenuates mitochondrial dysfunction and cholestasis in endotoxemic rat liver'. Together they form a unique fingerprint.

  • Cite this