Selective activation of melatonin receptors with ramelteon improves liver function and hepatic perfusion after hemorrhagic shock in rat.
OBJECTIVE
Melatonin may attenuate organ damage via direct antioxidative properties, and was recently demonstrated to reduce cardiac and hepatic injury through receptor-dependent effects. However, the relevance of an isolated activation of melatonin receptors for organ protection, excluding direct antioxidant effects, has not been established yet. This study was designed to investigate whether therapy with melatonin receptor agonist and hypnotic substance ramelteon may improve liver function, hepatic perfusion, and hepatic integrity after hemorrhagic shock in rat.


METHODS
Prospective, randomized, controlled study.


METHODS
University research laboratory.


METHODS
Male Sprague-Dawley rats (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 lactate (2 hrs). At the end of shock, animals were treated with ramelteon (1.0 mg/kg intravenously), melatonin receptor antagonist luzindole plus ramelteon (each 1.0 mg/kg intravenously), or vehicle.


RESULTS
In vitro, ramelteon displayed no relevant antioxidant capacity in an 2,2'-Azino-bis-(3-ethylbenzthiazoline-6-sulfonic acid) assay, compared with melatonin. In vivo, liver function was assessed by plasma disappearance rate of indocyanine green, and intravital microscopy was performed for evaluation of hepatic perfusion index, nicotinamide adenine dinucleotide phosphate autofluorescence, and hepatic integrity. Compared with vehicle controls, ramelteon therapy significantly improved plasma disappearance rate of indocyanine green (7.89 +/- 2.12% vs. 13.67 +/- 2.51%; p = 0.006), hepatic perfusion index (352.04 +/- 111.78 pl/sec/mm vs. 848.81 +/- 181.38 pl/sec/mm; p = 0.002), nicotinamide adenine dinucleotide phosphate autofluorescence and hepatocellular injury. Coadministration of luzindole abolished the protective effect of ramelteon with respect to liver function and nicotinamide adenine dinucleotide phosphate autofluorescence.


CONCLUSIONS
Ramelteon therapy improves liver function, hepatic perfusion, and hepatocellular integrity after hemorrhagic shock in rat. This demonstrates that an isolated activation of melatonin receptors may be sufficient for organ protection, independent from direct antioxidant effects. The hypnotic ramelteon could thus play an interesting role in future sedation concepts for critical care patients.
Mathes
Alexander M
AM
Department of Anesthesiology and Critical Care Medicine, Saarland University Hospital, Homburg, Germany.
Kubulus
Darius
D
Waibel
Lina
L
Weiler
Julia
J
Heymann
Paul
P
Wolf
Beate
B
Rensing
Hauke
H