Assessing the impact of cerebral injury after cardiac surgery: Will determining the mechanism reduce this injury?
Assessing the impact of cerebral injury after cardiac surgery: Will determining the mechanism reduce this injury?
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DOI：
10.1016/s0003-4975(99)00445-2
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发表时间：
1999-06-01
影响因子：
4.6
通讯作者：
Johnston, MV
中科院分区：
文献类型：
--
作者：
Baumgartner, WA;Walinsky, PL;Johnston, MV
背景在接受心脏手术的患者中，中枢神经系统功能障碍继续产生显著的发病率和相关的死亡率。使用闭胸犬心肺转流模型，犬在18 ℃下经历2小时的低温停循环（HCA），随后复苏和恢复3天。通过种属特异性行为量表、选择性神经元坏死的组织学模式、微透析流出物的生化分析和N-甲基-D-天冬氨酸（NMDA）谷氨酸受体亚型表达的受体放射自显影对动物进行功能评估。使用选择性NMDA（谷氨酸）受体拮抗剂（MK 801）和AMPA拮抗剂（NBQX），谷氨酸兴奋性毒性的发展中的HCA诱导的脑损伤的记录和验证。采用微透析技术研究了一氧化氮（NO）在神经细胞死亡中的作用。精氨酸加氧通过NO合酶（nNOS）的作用转化为NO加瓜氨酸（CIT）。在HCA和再灌注期间，脑脊液和犬皮质匀浆中的CIT恢复增加。这些研究表明，HCA后的神经毒性涉及到nNOS表达的显著和早期诱导，以及导致脑中NO产生广泛增加的神经元过程。为了进一步研究脑中兴奋性氨基酸的产生，我们假设以下情况：HCA-->上箭头谷氨酸盐，上箭头天冬氨酸盐，上箭头甘氨酸-->上箭头囊内Ca（2+）-->上箭头NO + CIT。使用相同的动物制备，我们证明，HCA引起增加脑内谷氨酸和天冬氨酸，持续到20小时后HCA。HCA还导致CIT（NO）的产生，导致持续和延迟的神经损伤。NO的作用的确证性证据通过使用特异性nNOS抑制剂7-硝基吲唑的进一步实验来证明。动物进行2小时的HCA，然后进行生理和NO生产的评价。7-硝基吲唑使CIT（NO）产生减少58.4 +/-28.3%。此外，与未治疗的HCA对照组相比，用这种药物治疗的狗具有上级神经功能。这些实验已经证明了谷氨酸兴奋性毒性在神经损伤中的作用，并暗示NO是引起坏死和凋亡的重要神经毒素。对脑损伤的病理生理机制的持续研究将最终产生一种安全可靠的神经保护剂策略。具体的干预剂将包括谷氨酸受体拮抗剂和具体的神经元NO合酶抑制剂。(C)1999年，美国胸外科医师协会（Society of Thoracic Surgeons）
Background. Central nervous system dysfunction continues to produce significant morbidity and associated mortality in patients undergoing cardiac surgery. Using a closed-chest canine cardiopulmonary bypass model, dogs underwent 2 h of hypothermic circulatory arrest (HCA) at 18 degrees C, followed by resuscitation and recovery for 3 days. Animals were assessed functionally by a species-specific behavioral scale, histologically for patterns of selective neuronal necrosis, biochemically by analysis of microdialysis effluent, and by receptor autoradiography for N-methyl-D-aspartate (NMDA) glutamate receptor subtype expression.Results. Using a selective NMDA (glutamate) receptor antagonist (MK801) and an AMPA antagonist (NBQX), glutamate excitotoxicity in the development of HCA-induced brain injury was documented and validated. A microdialysis technique was employed to evaluate the role of nitric oxide (NO) in neuronal cell death. Arginine plus oxygen is converted to NO plus citrulline (CIT) by the action of NO synthase (nNOS). CIT recovery in the cerebrospinal fluid and from canine cortical homogenates increased during HCA and reperfusion. These studies demonstrated that neurotoxicity after HCA involves a significant and early induction of nNOS expression, and neuronal processes leading to widespread augmentation of NO production in the brain.To further investigate the production of excitatory amino acids in the brain, we hypothesized the following scenario: HCA--> up arrow glutamate, up arrow aspartate, up arrow glycine--> up arrow intracenular ca(2+)--> up arrow NO + CIT. Using the same animal preparation, we demonstrated that HCA caused increased intracerebral glutamate and aspartate that persists up to 20 h post-HCA. HCA also resulted in CIT (NO) production, causing a continued and delayed neurologic injury. Confirmatory evidence of the role of NO was demonstrated by a further experiment using a specific nNOS inhibitor, 7-nitroindazole. Animals underwent 2 h of HCA, and then were evaluated both physiologically and for NO production. 7-Nitroindazole reduced CIT (NO) production by 58.4 +/- 28.3%. In addition, dogs treated with this drug had superior neurologic function compared with untreated HCA controls.Conclusions. These experiments have documented the role of glutamate excitotoxicity in neurologic injury and have implicated NO as a significant neurotoxin causing necrosis and apoptosis. Continued research into the pathophysiologic mechanisms involved in cerebral injury will eventually yield a safe and reliable neuroprotectant strategy. Specific interventional agents will include glutamate receptor antagonists and specific neuronal NO synthase inhibitors. (C) 1999 by The Society of Thoracic Surgeons.