Melatonin abates liver ischemia/reperfusion injury by improving the balance between nitric oxide and endothelin.
BACKGROUND
Melatonin exerts complex physiological and pharmacological effects on multiple systems and organs. We hypothesized that melatonin might abate ischemia/reperfusion (I/R) injury in the liver by inhibiting excessive oxidative stress and keeping nitric oxide (NO) from being scavenged by free radicals. The aim of the present study was to investigate whether melatonin protects the liver from I/R injury and, if so, by what underlying mechanism.


METHODS
Under anesthesia, Wistar rats were intraperitoneally injected with 20 mg/kg melatonin (dissolved in physiological saline containing 4% ethanol, Mel group), 4% alcohol (Alc group), or physiological saline (NS group). The artery, portal vein and bile duct of the left lobe of the liver were clamped for 60 minutes and then released. At different time points after I/R, the rats were sacrificed and blood samples were collected to measure the levels of serum alanine aminotransferase (ALT), lactic dehydrogenase (LDH), and NO. Hepatic tissue samples were collected for measuring endothelin expression by immunohistochemical staining and for routine morphological and histological examination.


RESULTS
The levels of both ALT and LDH in the Mel group were significantly reduced for up to 24 hours after I/R compared with the Alc and NS groups (P<0.05). The levels of NO in the Mel group were significantly elevated for up to 12 hours after I/R relative to the NS group (P<0.05). The NO levels were also elevated at 0.5 and 6 hours after I/R in the Alc group (P<0.05). The immunohistochemical staining of hepatic tissue showed that endothelin-positive cells were significantly fewer in the Mel group than in the Alc and NS groups at 6 hours after I/R (P<0.01). The necrosis of hepatocytes and the destruction of hepatic cords in the Alc and NS groups were greatly improved in Mel-treated rats, which is in concert with our functional data.


CONCLUSIONS
Pretreatment with melatonin increased NO bioavailability and decreased endothelin expression, and consequently played a protective role in preserving both liver function and structure during ischemia and reperfusion injury.
Zhang
Wen-Hai
WH
Department of 5th General Surgery, Second Affiliated Hospital (Shengjing Hospital), China Medical University, Shenyang 110004, China. surgeonzwh@126.com
Li
Jian-Yi
JY
Zhou
Yong
Y
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D016232:Endothelins / Q000378:metabolism*; D004801:Eosine Yellowish-(YS); D006416:Hematoxylin; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008550:Melatonin / Q000627:therapeutic use*; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*
D016232:Endothelins; D009569:Nitric Oxide; D007770:L-Lactate Dehydrogenase; D000410:Alanine Transaminase; D008550:Melatonin; D004801:Eosine Yellowish-(YS); D006416:Hematoxylin