Melatonin receptors mediate improvements of liver function but not of hepatic perfusion and integrity after hemorrhagic shock in rats.
OBJECTIVE
Melatonin has been demonstrated to attenuate organ damage in models of ischemia and reperfusion. Melatonin treatment before hemorrhagic shock has been shown to improve liver function and hepatic perfusion. Proposed mechanisms of the pineal hormone involve direct inactivation of reactive oxygen species and induction of antioxidative enzymes. However, recent evidence suggests a strong influence of melatonin receptor activation for these effects. Specific protection of organ function by melatonin after hemorrhage has not been investigated yet. In this study, we evaluated whether melatonin therapy after hemorrhagic shock improves liver function and hepatic perfusion, with emphasis on melatonin receptor activation.


METHODS
Prospective, randomized, controlled study.


METHODS
University research laboratory.


METHODS
Male Sprague-Dawley rats, 200-300 g (n = 10 per group).


METHODS
Animals underwent hemorrhagic shock (mean arterial pressure, 35 +/- 5 mm Hg for 90 mins) and were resuscitated with shed blood and Ringer's solution. At the end of shock, animals were treated with either melatonin (10 mg/kg, intravenously), melatonin receptor antagonist luzindole (2.5 mg/kg, intravenously) plus melatonin (10 mg/kg, intravenously), luzindole alone (2.5 mg/kg, intravenously), or vehicle.


RESULTS
After 2 hrs of reperfusion, either liver function was assessed by plasma disappearance rate of indocyanine green or intravital microscopy of the liver was performed for evaluation of hepatic perfusion, hepatocellular redox state, and hepatic integrity. Compared with vehicle controls, melatonin therapy after hemorrhagic shock significantly improved plasma disappearance rate of indocyanine green, hepatic redox state, hepatocellular injury, and hepatic perfusion index. Coadministration of luzindole completely abolished the protective effect with respect to liver function only, and improvements regarding hepatic redox state, perfusion, and integrity were comparable with melatonin treatment alone.


CONCLUSIONS
Melatonin therapy after hemorrhagic shock improves liver function, hepatic perfusion, redox state, and hepatic integrity. With respect to liver function, beneficial effects of the pineal hormone seem to be dependent on melatonin receptor activation.
Mathes
Alexander M
AM
Department of Anesthesiology and Critical Care Medicine, Saarland University Hospital, Homburg (Saar), Germany.
Kubulus
Darius
D
Weiler
Julia
J
Bentley
Alexander
A
Waibel
Lina
L
Wolf
Beate
B
Bauer
Inge
I
Rensing
Hauke
H
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D004396:Coloring Agents / Q000378:metabolism; D004195:Disease Models, Animal; D007208:Indocyanine Green / Q000378:metabolism; D008099:Liver / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008111:Liver Function Tests; D008297:Male; D008550:Melatonin / Q000627:therapeutic use*; D008833:Microcirculation / Q000187:drug effects / Q000503:physiopathology; D009249:NADP / Q000378:metabolism; D011446:Prospective Studies; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D044094:Receptors, Melatonin / Q000187:drug effects* / Q000378:metabolism; D012016:Reference Values; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D016896:Treatment Outcome
D000975:Antioxidants; D004396:Coloring Agents; D044094:Receptors, Melatonin; D009249:NADP; D007208:Indocyanine Green; D008550:Melatonin