CEREBRAL OXYGEN TRANSPORT WITH STABILIZED CELL FREE HEMOGLOBIN

稳定的无细胞血红蛋白的脑氧运输

• 批准号: 5213971
• 负责人: RAYMOND C KOEHLER
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5213971
• 关键词: albumins; amine oxidoreductase; anemia; arterioles; autoradiography; blood brain barrier; blood cell count; blood treatment; cats; cell free system; cerebral ischemia /hypoxia; electroencephalography; hemoglobin; high energy compound; infrared spectrometry; nitric oxide; nuclear magnetic resonance spectroscopy; oxygen transport; pia mater; respiratory oxygen; vasodilators

Oxygen transport to the brain is ordinarily well regulated in that decreases in arterial 02 content associated with anemic, hypoxic and CO hypoxia result in reciprocal increases in cerebral blood flow. In the case of anemia, it remains unclear if increased cerebral blood flow is a consequence of decreased viscosity or 02 availability. Differentiating these mechanisms is important because anemia is a common form of clinical hypoxia, hemodilution is routinely employed during cardiopulmonary bypass, and positive evidence of reduced infarction with hemodilution in experimental focal cerebral ischemia has prompted clinical trials in patients with stroke. Exchange transfusion with red cell free oxyhemoglobin provides a unique physiological tool for dissociating effects of 02 carrying capacity from viscosity when hematocrit is reduced. Chemical stabilization of hemoglobin preserves its tetrameric form and 02 binding cooperatively, and increases its circulating half- life compared to untreated hemoglobin. Our overall goal is to determine the mechanism of hematocrit-induced changes in the cerebral circulation under normal and ischemic conditions in anesthetized cats. First, we will determine the effect of reducing hematocrit with or without reductions in O2 carrying capacity on cerebral blood flow, cerebral 02 extraction and cerebral tissue oxyhemoglobin content, measured by near-infrared spectroscopy in vivo. After reducing hematocrit with free oxyhemoglobin or albumin, we will determine how well cerebral O2 transport is regulated when arterial PO2 is reduced. Second, we will show whether circulating free hemoglobin alters endothelial dependent and independent pial arteriolar dilation in vivo or alters blood-brain barrier permeability. Third, by using 31P magnetic resonance spectroscopy to measure brain high energy phosphates and intracellular pH, we will demonstrate if the threshold for producing cerebral ischemia is improved by reducing hematocrit and oxyhemoglobin affinity to augment O2 distribution and unloading. Fourth, we will determine whether free hemoglobin transfusion reduces the progression of cerebral infarction during middle cerebral artery occlusion by increasing tissue oxygenation as a consequence of increased perfusion of free hemoglobin in the ischemic territory. New insights derived from transfusions with oxyhemoglobin of different O2 affinities will distinguish viscosity, O2 carrying capacity, and O2 unloading mechanisms in the regulation of cerebral O2 transport during anemia and ischemia and will provide new strategies for increasing cerebral O2 availability.

氧气向大脑的运输通常在这方面得到很好的调节 动脉血中O2含量的降低与贫血、低氧和一氧化碳有关 低氧会导致脑血流量的相应增加。在 一例贫血，目前尚不清楚脑血流量增加是否 粘度降低或利用率降低的结果。差异化 这些机制很重要，因为贫血是一种常见的临床形式 低氧、血液稀释是心肺手术中的常规操作 旁路，以及血液稀释后梗塞减少的阳性证据 实验性局灶性脑缺血促使临床试验 中风患者。换血不含红细胞 氧合血红蛋白提供了一种独特的解离生理工具 红细胞压积降低时黏度对载脂能力的影响 减少了。化学稳定血红蛋白保持其四聚体 形成与02协同结合，增加其循环半衰期。 生命与未经治疗的血红蛋白相比。 我们的总体目标是确定红细胞压积诱导的机制 正常和缺血状态下脑循环的变化 在麻醉的猫身上。首先，我们将确定削减的效果。 脑组织载氧量降低或不降低时的红细胞压积 血流量、脑组织氧摄取和脑组织氧合血红蛋白 用近红外光谱分析方法测定其体内含量。减量后 红细胞压积与游离氧合血红蛋白或白蛋白，我们将确定有多好 当动脉血氧分压降低时，大脑的氧运输受到调节。第二, 我们将展示循环中的游离血红蛋白是否会改变内皮细胞 活体和非依赖性软膜小动脉扩张或改变 血脑屏障通透性。第三，通过使用31P磁共振 脑高能磷酸盐和细胞内高能磷酸盐的光谱测量 PH，我们将证明如果导致脑缺血的阈值 通过降低红细胞压积和氧合血红蛋白亲和力来提高 氧气的分配和卸载。第四，我们将确定是否免费 输注血红蛋白可降低脑梗塞的进展 增加组织氧合在大脑中动脉闭塞中的作用 由于心肌细胞内游离血红蛋白的灌流增加 缺血区。通过输血获得新的见解 氧合血红蛋白的不同O2亲和力会区分粘度、O2 携带能力和氧卸载机制在调节中的作用 在贫血和缺血期间脑氧转运，并将提供新的 提高大脑供氧能力的策略。