Effects of N-acetylcysteine administration in hepatic microcirculation of rats with biliary cirrhosis.
OBJECTIVE
Increased intrahepatic resistance (IHR) in cirrhosis is due to fibrosis and hepatic endothelial dysfunction (HED). Besides producing fibrosis, increased reactive oxygen species (ROS) promotes ROS-related nitration of anti-oxidative enzymes in cirrhotic livers. Tyrosine nitration (nitrotyrosilation)-related inactivation of anti-oxidative enzymes is increased in cirrhotic livers. This study investigates effects of N-acetylcysteine (NAC) administrations in bile-duct-ligation (BDL) rats.


METHODS
This study measured portal venous pressure (PVP), IHR, hepatic endothelial function, hepatic levels of anti-oxidants and oxidants, type III procollagen (PIIIP), proteins expression of thromboxane synthase (TXS), nitrotyrosine, manganese superoxide dismutase (MnSOD), and hepatic NOx and thromboxane A(2) (TXA(2)) production in perfusates.


RESULTS
The improvement of HED was associated with decreased PVP and IHR, hepatic protein and mRNA levels of PIIIP, protein expression of TXS and nitrotyrosine, oxidants and production of TXA(2) in NAC-treated BDL rat livers. Conversely, hepatic NOx production, anti-oxidants, and protein expression of MnSOD were increased in NAC-treated BDL rat livers.


CONCLUSIONS
In NAC-treated cirrhotic rats, the decrease in IHR was mainly caused by its anti-oxidative effect-related prevention of hepatic fibrogenesis associated with the decrease of oxidants-related nitrotyrosilation and improvement of HED.
Yang
Ying-Ying
YY
Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital Taipei, Taiwan.
Lee
Kuei-Chuan
KC
Huang
Yi-Tsau
YT
Wang
Ying-Wen
YW
Hou
Ming-Chih
MC
Lee
Fa-Yauh
FY
Lin
Han-Chieh
HC
Lee
Shou-Dong
SD
D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001652:Bile Ducts; D004195:Disease Models, Animal; D016166:Free Radical Scavengers / Q000494:pharmacology*; D008026:Ligation; D008102:Liver Circulation / Q000187:drug effects*; D008105:Liver Cirrhosis, Biliary / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D008111:Liver Function Tests; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D016877:Oxidants / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D011347:Procollagen / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014655:Vascular Resistance / Q000187:drug effects
D000975:Antioxidants; D016166:Free Radical Scavengers; D016877:Oxidants; D010446:Peptide Fragments; D011347:Procollagen; D012333:RNA, Messenger; C041876:procollagen Type III-N-terminal peptide; C002744:3-nitrotyrosine; D014443:Tyrosine; D013482:Superoxide Dismutase; D013930:Thromboxane-A Synthase; D000111:Acetylcysteine