Effect of exogenous melatonin on hepatic energetic status during ischemia/reperfusion: possible role of tumor necrosis factor-alpha and nitric oxide.
BACKGROUND
This study was designed to determine if the very potent antioxidant melatonin is able to reduce organ damage and improve energetic status in an in situ liver ischemia/reperfusion model.


METHODS
Total hepatic ischemia was induced in rats by occlusion of the hepatic artery, portal vein, and bile duct. A portojugular shunt was inserted. After 60 min of ischemia, reperfusion was established for a period of 120 min. Rats were assigned to one group receiving systemic melatonin administration or to another receiving only normal saline. Variables were observed at preischemia, after 60 min of ischemia, and at 30, 60, and 120 min of reperfusion.


RESULTS
Energy charge, measured as the arterial ketone body ratio, showed higher values in the melatonin group during the first 60 min of reperfusion. Rises in plasma nitrite, tumor necrosis factor (TNF)-alpha, aspartate aminotransferase, alanine aminotransferase, lipid peroxidation products, and inducible nitric oxide synthase (iNOS) expression were less severe with melatonin. Linear regression analysis demonstrated a significant correlation between nitrites and arterial ketone body ratio (R(2) = 0.2454). Bile production was higher with melatonin. Seven-day survival rates were 52% for control, 80% for melatonin, and 100% for sham groups.


CONCLUSIONS
Exogenous melatonin is capable of preserving the functional and energetic status during ischemia/reperfusion which is associated with reduced concentrations of TNF-alpha and inhibited expression of iNOS and NO production. This improvement may be due to an adequate preservation of the hepatic mitochondrial redox status.
Rodríguez-Reynoso
S
S
Surgical Research Division, Centro de Investigación Biomédica de Occidente, IMSS, Sierra Mojada 800, Guadalajara, Jal. CP 44340, México. galeno@mail.udg.mx
Leal
C
C
Portilla
E
E
Olivares
N
N
Muñiz
J
J
D020155:3-Hydroxybutyric Acid / Q000097:blood; D000090:Acetoacetates / Q000097:blood; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001219:Aspartate Aminotransferases / Q000097:blood; D019069:Cell Respiration / Q000187:drug effects / Q000502:physiology; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic; D007657:Ketone Bodies / Q000097:blood; D008099:Liver / Q000098:blood supply / Q000378:metabolism; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D008928:Mitochondria / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000097:blood; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000401:mortality; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D000090:Acetoacetates; D000975:Antioxidants; D007657:Ketone Bodies; D009573:Nitrites; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C016635:acetoacetic acid; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D008550:Melatonin; D020155:3-Hydroxybutyric Acid