Melatonin pretreatment improves liver function and hepatic perfusion after hemorrhagic shock.
Exogenous administration of pineal hormone melatonin (MEL) has been demonstrated to attenuate organ damage in models of I/R and inflammation by antioxidative effects. However, specific organ-protective effects of MEL with respect to hemorrhagic shock have not been investigated yet. In the present study, we evaluated the role of MEL pretreatment for hepatic perfusion, redox state, and function after hemorrhage and resuscitation, with emphasis on MEL receptor activation. In a model of hemorrhagic shock (MAP 35 +/- 5 mmHg for 90 min) and reperfusion (2 h), we measured nicotinamide adenine dinucleotide phosphate (reduced form; NADPH) autofluorescence, hepatic microcirculation, and hepatocellular injury by intravital microscopy, as well as plasma disappearance rate of indocyanine green (PDRICG) as a sensitive maker of liver function in rat. Pretreatment with 10 mg kg(-1) MEL (i.v.) 15 min before induction of hemorrhage resulted in a significantly improved PDR(ICG) compared with controls (MEL/shock, 15.02% min(-1) +/- 2.9 SD vs. vehicle/shock, 6.18 +/- 4.6 SD; P = 0.001). Intravital microscopy after reperfusion revealed an improved hepatic perfusion index, redox state, and reduced hepatocellular injury in pretreated animals compared with the vehicle group. Melatonin receptor antagonist luzindole (LZN; 2.5 mg kg(-1)) almost completely abolished the protective effects of MEL pretreatment with respect to liver function (MEL + LZN/shock PDR(ICG), 7.31% min(-1) +/- 3.4 SD). Beneficial effects regarding hepatic perfusion, redox state, and cellular injury were not influenced by LZN, indicating that they may depend on antioxidative effects of MEL. However, liver function after hemorrhage is effectively maintained by MEL pretreatment via receptor-dependent pathways.
Department of Anesthesiology, Critical Care Medicine and Pain Management, Saarland University Hospital; Kirrberger Strasse; D-66421 Homburg (Saar), Germany.
Alexander M
AM
Mathes
Darius
D
Kubulus
Sascha
S
Pradarutti
Alexander
A
Bentley
Julia
J
Weiler
Beate
B
Wolf
Stephan
S
Ziegeler
Inge
I
Bauer
Hauke
H
Rensing
D000818:Animals; D004195:Disease Models, Animal; D007208:Indocyanine Green / Q000493:pharmacokinetics; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D008102:Liver Circulation / Q000187:drug effects*; D008297:Male; D008550:Melatonin / Q000008:administration & dosage / Q000494:pharmacology*; D009249:NADP / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control / Q000628:therapy
D009249:NADP; D007208:Indocyanine Green; D008550:Melatonin