CELL-FREE 02 CARRIERS: CEREBROVASCULAR CONTROL & STROKE

无细胞 02 载体：脑血管控制

• 批准号: 6490949
• 负责人: RAYMOND Charles KOEHLER
• 金额: $ 49.14万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-01-01 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6490949
• 关键词: anemia; bilirubin; blood /plasma substitute; blood cell count; blood viscosity; brain circulation; cats; cerebral ischemia /hypoxia; cytochrome P450; endothelin; genetically modified animals; heme oxygenase; hemoglobin; laboratory mouse; oxygen tension; potassium channel; stroke; vasomotion

Anemia results in increased cerebral blood flow attributable to decreased blood viscosity and O2 carrying capacity. Attenuating the decrease in O2 carrying capacity by exchange transfusion with cell-free tetrameric crosslinked hemoglobin attenuates the increase in blood flow at reduced hematocrit independent of potential nitric oxide scavenging. During focal cerebral ischemia, in contrast, blood flow is promoted in the ischemic regions. In the present proposal, cell-free polymeric hemoglobin, which has a higher O2 carrying capacity than tetrameric hemoglobin, will be used as a physiologic tool to dissociate effects of viscosity from O2 carrying capacity on cerebrovascular regulation. Further, experimental studies of anemia are largely based on acute reductions in hematocrit, yet clinical anemia is usually a chronic condition. The overall goals of the proposal are to determine a) the mechanisms of changes in cerebral blood flow, baseline arteriolar diameter and vascular reactivity during acute and chronic reductions in hematocrit with and without reductions in O2 carrying capacity, and b) the role of heme oxygenase in ameliorating focal ischemic injury when plasma-based hemoglobin is exchanged for red cell- based hemoglobin. Specifically, the role of cytochrome p450 omega-hydroxylase activity, ATP-sensitive potassium channels and endothelin in the differential pial arteriolar diameter responses to albumin versus hemoglobin exchange transfusions will be determined pharmacologically. P450 omega-hydroxylase activity is O2 dependent in the physiological range and produces 20-HETE, a potent constrictor, whereas K-ATP channels are involved in hypoxic vasodilation. Endothelin has been reported to increase after tetrameric hemoglobin transfusion and may contribue to cerebral vasoconstriction. The role of P450 metabolites and endothelin in depressed vascular CO2 reactivity two days after hemoglobin transfusion will be studied. The contribution of heme oxygenase to endothelial dependent dilation and potential upregulation of this contribution during chronic anemia will be investigated both pharmacologically and in transgenic animals deficient in heme oxygenase -2. Reduction of infarct volume by hemoglobin transfusion at reduced hematocrit during focal cerebral ischemia may depend on adequate amounts of heme oxygenase to metabolize extravasated hemoglobin into antioxidant bilirubin. This mechanism will be investigated by using transgenic animlas deficient constitutive heme oxygenase -2 and inducible heme oxygenase -1, by infusion or bilirubin, and by prior hemoglobin transfusion as a preconditioning stimulus to upregulate heme oxygenase -1 before ischemia. These studies will render new insights into cerebrovascular regulation during anemia and into novel methodologies for hemodynamically ameliorating injury from stroke.

贫血导致大脑血流增加，这是由于血液粘度降低和O2承载能力的增加。 通过与无细胞四聚体交联血红蛋白交换输血来减少O2承载能力的降低可减少血细胞比容下血流量的增加，而与潜在的一氧化氮清除无关。 相反，在局灶性脑缺血期间，缺血区域促进了血流。 在本建议中，与四聚体血红蛋白具有更高的O2承载能力的无细胞聚合物血红蛋白将被用作一种生理工具，以使粘度从O2携带能力对脑血管调节的持续能力解散。 此外，贫血的实验研究主要基于血细胞比容的急性减少，但临床贫血通常是一种慢性病。 The overall goals of the proposal are to determine a) the mechanisms of changes in cerebral blood flow, baseline arteriolar diameter and vascular reactivity during acute and chronic reductions in hematocrit with and without reductions in O2 carrying capacity, and b) the role of heme oxygenase in ameliorating focal ischemic injury when plasma-based hemoglobin is exchanged for red cell- based hemoglobin. 具体而言，将在药理学上确定细胞色素P450欧米茄羟化酶活性，ATP敏感的钾通道和内皮素对白蛋白与血红蛋白交换的反应的反应。 P450欧米茄 - 羟化酶活性取决于生理范围的O2，并产生20-HETE，这是一种有效的收缩器，而K-ATP通道则参与低氧血管舒张。 据报道，内皮素在四聚体血红蛋白输血后增加，并可能有助于脑血管收缩。 血红蛋白输血两天后，P450代谢产物和内皮素在抑郁的血管二氧化碳反应性中的作用将被研究。 血红素加氧酶对慢性贫血期间这种贡献的内皮依赖性扩张和潜在上调的贡献将在药理学和转基因动物中均缺乏血红素氧酶-2。 局灶性脑缺血期间血红蛋白输血减少的梗塞体积减少可能取决于血红素加氧酶的足够量以将外闭血红蛋白代谢为抗氧化剂胆红素。 将通过输注或胆红素使用转基因动画症和可诱导的血红素氧酶-1以及通过输注或胆红素的诱导型血红素氧酶-1以及通过先前的血红蛋白输血作为预处理刺激以上调血红素加氧酶-1之前的先进刺激。 这些研究将使人们对贫血期间的脑血管调节以及中风的血液动力学改善损伤的新方法进行新的见解。