Nitrite-derived nitric oxide by xanthine oxidoreductase protects the liver against ischemia-reperfusion injury.
BACKGROUND
It was demonstrated that xanthine oxidoreductase (XOR), during ischemia, catalyzes the formation of nitric oxide (NO) from nitrite (NO2-) and this NO2- -derived NO protects the isolated perfused rat heart against the damaging effects of ischemia-reperfusion (I/R) when conventional nitric oxide synthase (NOS)-dependent NO production is impaired. Liver is one of the organs with the highest XOR concentration. This study was designed to determine whether NO2- -derived NO by XOR protects liver against I/R injury in vivo. For its minute amounts and active reactivity, NO can not be detected directly in real time in vivo by this time. We have to prove the above hypothesis indirectly.


METHODS
Wistar rats were pretreated with saline, NOS inhibitor L-NAME (10 mg/kg intravenously), XOR inhibitor allopurinol (1.5 mg/kg orally), L-NAME +allopurinol and NO scavenger carboxy-PTIO (0.6 mg/kg intravenously) respectively (12 animals per group). And then, they were subjected to total liver ischemia for 40 minutes followed by reperfusion. Blood samples and liver tissues were obtained for analysis after 3 hours of reperfusion. Survival was also investigated.


RESULTS
Allopurinol-treated animals exhibited further increased serum alanine aminotransferase(ALT) levels and liver myeloperoxidase(MPO) activities, but further decreased liver adenosine triphosphate(ATP) stores after I/R compared to saline-treated counterparts (830.5+/-108.3 U/L, 56.5+/-11.0 U/mg protein and 1.93+/-0.47 mumol/g vs. 505.8+/-184.2 U/L, 41.5+/-10.2 U/mg protein and 3.05+/-0.55 micromol/g respectively, P < 0.01, P < 0.05 and P < 0.01 respectively). The hepatocyte injury was further exacerbated and the overall survival rate was significantly decreased after I/R in animals given by allopurinol compared to those pretreated by saline (P < 0.05). L-NAME and allopurinol co-treated animals exhibited more severe liver injury (P < 0.05 and P<0.01)and a further decreased overall survival rate (P < 0.05)compared to L-NAME or allopurinol alone-treated counterparts, but they were not different from carboxy-PTIO treated animals (P > 0.05).


CONCLUSIONS
NO2- -derived NO by XOR in the hypoxic and acidic environment induced by hepatic I/R protects the liver against I/R injury in vivo.
Lu
Ping
P
Department of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. luliu@public.wh.hb.cn
Liu
Fang
F
Yao
Zhong
Z
Wang
Chun-You
CY
Chen
Dao-Da
DD
Tian
Yuan
Y
Zhang
Jing-Hui
JH
Wu
Yi-Hua
YH
D000255:Adenosine Triphosphate / Q000378:metabolism; D000410:Alanine Transaminase / Q000097:blood; D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D008099:Liver / Q000098:blood supply* / Q000378:metabolism*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009573:Nitrites / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology*; D016019:Survival Analysis; D014968:Xanthine Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism*
D004791:Enzyme Inhibitors; D009573:Nitrites; D009569:Nitric Oxide; D000493:Allopurinol; D000255:Adenosine Triphosphate; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D014968:Xanthine Dehydrogenase; D000410:Alanine Transaminase; D019331:NG-Nitroarginine Methyl Ester