Mathes Alexander M, Kubulus Darius, Waibel Lina, Weiler Julia, Heymann Paul, Wolf Beate, Rensing Hauke
Department of Anesthesiology and Critical Care Medicine, Saarland University Hospital, Homburg, Germany.
Crit Care Med. 2008 Oct;36(10):2863-70. doi: 10.1097/CCM.0b013e318187b863.
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.
Prospective, randomized, controlled study.
University research laboratory.
Male Sprague-Dawley rats (n = 10 per group).
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.
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.
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.
褪黑素可能通过直接抗氧化特性减轻器官损伤，最近有研究表明其可通过受体依赖性效应减轻心脏和肝脏损伤。然而，褪黑素受体单独激活对器官保护的相关性（不包括直接抗氧化作用）尚未确定。本研究旨在探讨褪黑素受体激动剂及催眠物质雷美替胺治疗是否可改善大鼠失血性休克后的肝功能、肝脏灌注及肝脏完整性。
前瞻性、随机、对照研究。
大学研究实验室。
雄性Sprague-Dawley大鼠（每组10只）。
动物经历失血性休克（平均动脉压35±5mmHg，持续90分钟），然后用自体血和乳酸林格液复苏（2小时）。休克结束时，动物分别接受雷美替胺（1.0mg/kg静脉注射）、褪黑素受体拮抗剂鲁辛朵与雷美替胺联合用药（各1.0mg/kg静脉注射）或赋形剂治疗。
在体外，与褪黑素相比，雷美替胺在2,2'-联氮-双-(3-乙基苯并噻唑啉-6-磺酸)检测中无相关抗氧化能力。在体内，通过吲哚菁绿的血浆消失率评估肝功能，并进行活体显微镜检查以评估肝脏灌注指数、烟酰胺腺嘌呤二核苷酸磷酸自发荧光及肝脏完整性。与赋形剂对照组相比，雷美替胺治疗显著改善了吲哚菁绿的血浆消失率（7.89±2.12%对13.67±2.51%；p=0.006）、肝脏灌注指数（352.04±111.78pl/秒/毫米对848.81±181.38pl/秒/毫米；p=0.002）、烟酰胺腺嘌呤二核苷酸磷酸自发荧光及肝细胞损伤。鲁辛朵联合用药消除了雷美替胺对肝功能和烟酰胺腺嘌呤二核苷酸磷酸自发荧光的保护作用。
雷美替胺治疗可改善大鼠失血性休克后的肝功能、肝脏灌注及肝细胞完整性。这表明褪黑素受体单独激活可能足以实现器官保护，与直接抗氧化作用无关。因此，催眠药物雷美替胺可能在未来危重症患者的镇静方案中发挥有趣的作用。
