Selective activation of melatonin receptors with ramelteon improves liver function and hepatic perfusion after hemorrhagic shock in rat

• Published in: Critical care medicine Vol. 36; no. 10; pp. 2863 - 2870
• Main Authors: Mathes, Alexander M, Kubulus, Darius, Waibel, Lina, Weiler, Julia, Heymann, Paul, Wolf, Beate, Rensing, Hauke
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD by the Society of Critical Care Medicine and Lippincott Williams & Wilkins 01-10-2008; Lippincott
• Subjects: Analysis of Variance; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Biological and medical sciences; Disease Models, Animal; Indenes - pharmacology; Infusions, Intravenous; Intensive care medicine; Liver Circulation - drug effects; Liver Circulation - physiology; Liver Diseases - etiology; Liver Diseases - prevention & control; Liver Function Tests; Liver, biliary tract, pancreas, portal circulation, spleen; Male; Medical sciences; Probability; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Melatonin - drug effects; Sensitivity and Specificity; Shock, Hemorrhagic - complications; Shock, Hemorrhagic - drug therapy; Shock, Hemorrhagic - physiopathology; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Surgery of the digestive system; Tryptamines - pharmacology; Shock; Agonist; Melatonin; Intensive care; Rat; Digestive system; Psychotropic; Liver; Rodentia; hemorrhagic shock; Hypnotic; Hemorrhage; luzindole; Liver function; Vertebrata; Mammalia; Ramelteon; Treatment; hepatic perfusion; ramelteon therapy; Animal; MT2 melatonin receptor; Resuscitation; Pineal hormone
• ISSN: 0090-3493; 1530-0293
• DOI: 10.1097/CCM.0b013e318187b863

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.
DESIGN:Prospective, randomized, controlled study.
SETTING:University research laboratory.
SUBJECTS:Male Sprague–Dawley rats (n = 10 per group).
INTERVENTIONS:Animals underwent hemorrhagic shock (mean arterial pressure 35 ± 5 mm Hg for 90 mins) and were resuscitated with shed blood and Ringerʼs 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.
MEASUREMENTS AND MAIN 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.