左西孟旦对全脑短暂性缺血/缺氧后初始复苏期脑代谢的影响。
The effects of levosimendan on brain metabolism during initial recovery from global transient ischaemia/hypoxia.
机构信息
Department of Anaesthesiology, RWTH Aachen University Hospital, Pauwelstrasse 30, Aachen, D-52074, Germany.
出版信息
BMC Neurol. 2012 Aug 24;12:81. doi: 10.1186/1471-2377-12-81.
BACKGROUND
Neuroprotective strategies after cardiopulmonary resuscitation are currently the focus of experimental and clinical research. Levosimendan has been proposed as a promising drug candidate because of its cardioprotective properties, improved haemodynamic effects in vivo and reduced traumatic brain injury in vitro. The effects of levosimendan on brain metabolism during and after ischaemia/hypoxia are unknown.
METHODS
Transient cerebral ischaemia/hypoxia was induced in 30 male Wistar rats by bilateral common carotid artery clamping for 15 min and concomitant ventilation with 6% O2 during general anaesthesia with urethane. After 10 min of global ischaemia/hypoxia, the rats were treated with an i.v. bolus of 24 μg kg-1 levosimendan followed by a continuous infusion of 0.2 μg kg-1 min-1. The changes in the energy-related metabolites lactate, the lactate/pyruvate ratio, glucose and glutamate were monitored by microdialysis. In addition, the effects on global haemodynamics, cerebral perfusion and autoregulation, oedema and expression of proinflammatory genes in the neocortex were assessed.
RESULTS
Levosimendan reduced blood pressure during initial reperfusion (72 ± 14 vs. 109 ± 2 mmHg, p = 0.03) and delayed flow maximum by 5 minutes (p = 0.002). Whereas no effects on time course of lactate, glucose, pyruvate and glutamate concentrations in the dialysate could be observed, the lactate/pyruvate ratio during initial reperfusion (144 ± 31 vs. 77 ± 8, p = 0.017) and the glutamate release during 90 minutes of reperfusion (75 ± 19 vs. 24 ± 28 μmol·L-1) were higher in the levosimendan group. The increased expression of IL-6, IL-1ß TNFα and ICAM-1, extend of cerebral edema and cerebral autoregulation was not influenced by levosimendan.
CONCLUSION
Although levosimendan has neuroprotective actions in vitro and on the spinal cord in vivo and has been shown to cross the blood-brain barrier, the present results showed that levosimendan did not reduce the initial neuronal injury after transient ischaemia/hypoxia.
背景
心肺复苏后神经保护策略是目前实验和临床研究的重点。左西孟旦因其具有心脏保护特性、改善体内血液动力学效应和减少体外创伤性脑损伤而被提出作为一种有前途的药物候选物。左西孟旦对缺血/缺氧期间和之后脑代谢的影响尚不清楚。
方法
在全身麻醉下用 6%氧气通过双侧颈总动脉夹闭 15 分钟诱导 30 只雄性 Wistar 大鼠短暂性脑缺血/缺氧。在 10 分钟的全脑缺血/缺氧后，大鼠接受静脉注射 24μgkg-1左西孟旦负荷量，然后连续输注 0.2μgkg-1min-1。通过微透析监测能量相关代谢物乳酸、乳酸/丙酮酸比值、葡萄糖和谷氨酸的变化。此外，还评估了其对整体血液动力学、脑灌注和自动调节、脑水肿和新皮层中促炎基因表达的影响。
结果
左西孟旦降低了再灌注初期的血压（72±14 与 109±2mmHg，p=0.03）并延迟了 5 分钟的血流峰值（p=0.002）。虽然在透析液中未观察到乳酸、葡萄糖、丙酮酸和谷氨酸浓度的时间过程有任何影响，但在再灌注初期的乳酸/丙酮酸比值（144±31 与 77±8，p=0.017）和再灌注 90 分钟时的谷氨酸释放（75±19 与 24±28μmol·L-1）较高在左西孟旦组中。白细胞介素 6、白细胞介素 1β、肿瘤坏死因子α 和细胞间黏附分子 1 的表达增加、脑水肿程度和脑自动调节不受左西孟旦影响。
结论
尽管左西孟旦在体外具有神经保护作用，在体内对脊髓具有神经保护作用，并已被证明可以穿过血脑屏障，但本研究结果表明，左西孟旦并不能减轻短暂性缺血/缺氧后神经元的初始损伤。
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