S-Nitrosylated Hemoglobin and Ischemic Brain Injury

S-亚硝基化血红蛋白与缺血性脑损伤

• 批准号: 7828174
• 负责人: DAVID WARNER
• 金额: $ 19.5万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7828174
• 关键词: Acute; Adult; Adverse effects; Alteplase; Animals; Blood; Blood Platelets; Blood Pressure; Blood flow; Body part; Brain; Brain Part; Breathing; Cerebral Infarction; Cerebral Ischemia; Cerebral perfusion pressure; Cerebrovascular Circulation; Cerebrovascular Spasm; Cerebrum; Data; Diagnosis; Disease; Dose; Effectiveness; Endothelium; Erythrocytes; Filament; Gases; Goals; Hemoglobin; Human; Hypertension; Hypotension; Hypoxia; Impairment; Infant; Infarction; Investigation; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Laboratories; Lasers; Measures; Middle Cerebral Artery Occlusion; Modeling; Muscle; Neurologic; Nitric Oxide; Organ; Outcome; Oxygen; Oxyhemoglobin; Pneumoperitoneum; Pulmonary artery structure; Rattus; Risk; Severities; Simvastatin; Specificity; Stroke; Subarachnoid Hemorrhage; Surgical Flaps; System; Therapeutic; Tissue Survival; Tissues; Vasodilation; Vasodilator Agents; Work; brain tissue; deoxyhemoglobin; ethyl nitrite; experience; hemodynamics; improved; inhaled nitric oxide; meetings; novel; public health relevance; relating to nervous system; restoration; therapeutic target

DESCRIPTION (provided by applicant): Ischemic stroke is caused by cerebral blood flow (CBF) inadequate to allow brain tissue survival. It is known from humans treated with tissue plasminogen activator that ischemic tissue can be salvaged from infarction by thrombolytic CBF restoration. This improves outcome. Thus, improved CBF is a therapeutic target. Various compounds, known to either donate nitric oxide (NO) or upregulate eNOS expression (e.g., simvastatin), increase CBF in ischemic tissue and improve experimental stroke outcome. While the common mechanism appears to be increased NO bioactivity and vasodilation, most such compounds are impractical as stroke therapeutics because of either delayed onset of action, or lack of specificity for ischemic tissue causing the dose to be limited by systemic hypotension. A novel mechanism for selective vasodilation is allosterically- modulated delivery of hemoglobin borne nitric oxide bioactivity. S-nitrosylated hemoglobin (SNO-Hb) is stable in the oxygenated form but unstable when O2 is offloaded. This offers opportunity to selectively increase NO bioactivity along PO2 gradients between blood and ischemic tissue while maintaining hemodynamic stability. Ethyl nitrite is an inhaled gas that markedly increases SNO-Hb. Ethyl nitrite decreases severity of pulmonary artery hypertension in adult and infant humans, and selectively decreases end-organ ischemia in models of pneumoperitoneum, cerebral vasospasm and free muscle flaps and has no effect on blood pressure. We propose projects to investigate effects of modulating SNO-Hb on cerebral ischemic outcome. Using an established, physiologically-controlled rat middle cerebral artery occlusion (MCAO) model, we will 1) Define acute effects of 20 ppm ethyl nitrite inhalation on absolute CBF during and after filament MCAO and measure amount of tissue at risk for cerebral infarction as a function of the fraction of inspired oxygen (Fi02), 2) Define ethyl nitrite efficacy in a long-term outcome rat model of permanent focal ischemic stroke as a function of Fi02, and 3) Define ethyl nitrite efficacy in a long-term outcome rat model of temporary focal ischemic stroke as a function of Fi02. Preliminary studies in this model have shown that treatment with ethyl nitrite either during or after transient focal ischemia causes rapid and reversible increases in laser Doppler CBF. Preliminary data indicates lack of an adverse effect on platelet function. We, therefore, predict improved outcome in both temporary and permanent MCAO. PUBLIC HEALTH RELEVANCE: The goal of this project is to determine the effectiveness of an inhaled gas, ethyl nitrite, in improving blood flow during an experimental stroke in rats. We have evidence that indicates that ethyl nitrite will selectively improve blood flow to the part of the brain that is experiencing a stroke, but that will do so with little or no effect on blood flow to other parts of the body. We will then examine whether this effect is important in reducing the amount of tissue damage and neurologic impairment caused by the stroke.

描述（由申请人提供）：缺血性中风是由脑血流（CBF）不足引起的，以允许脑组织存活。从用组织纤溶酶原激活剂治疗的人类中知道，可以通过溶栓CBF恢复从梗塞中挽救缺血组织。这改善了结果。因此，改善的CBF是一个治疗靶标。各种化合物，已知可以捐赠一氧化氮（NO）或上调eNOS表达（例如辛伐他汀），增加缺血组织中的CBF并改善实验性中风结果。尽管共同的机制似乎没有增加生物活性和血管舒张性，但由于作用延迟，或缺乏缺血性组织的特异性，因此大多数此类化合物作为中风治疗不切实际，导致剂量受到全身性高血压的限制。选择性血管舒张的新型机制是血红蛋白传播一氧化氮生物活性的变构调节递送。 S-亚硝基化血红蛋白（SNO-HB）以氧化形式稳定，但在O2被卸载时不稳定。这提供了机会，可以选择性地提高血液和缺血组织之间PO2梯度的生物活性，同时保持血液动力学稳定性。亚硝酸盐是一种吸入的气体，可显着增加SNO-HB。亚硝酸盐可降低成人和婴儿人类肺动脉高血压的严重程度，并有选择地降低肺炎，脑血管痉挛和自由肌肉瓣的模型中的末端器官缺血，并且对血压没有影响。我们建议的项目旨在调查调节SNO-HB对脑缺血结果的影响。 Using an established, physiologically-controlled rat middle cerebral artery occlusion (MCAO) model, we will 1) Define acute effects of 20 ppm ethyl nitrite inhalation on absolute CBF during and after filament MCAO and measure amount of tissue at risk for cerebral infarction as a function of the fraction of inspired oxygen (Fi02), 2) Define ethyl nitrite永久性局灶性缺血性中风的长期结局大鼠模型的功效与FI02的函数，3）在临时局灶性缺血性中风的长期结局大鼠模型中定义了亚硝酸盐疗效作为FI02的函数。该模型中的初步研究表明，在短暂性局灶性缺血期间或之后用亚硝酸盐治疗会导致激光多普勒CBF的快速和可逆增加。初步数据表明缺乏对血小板功能的不利影响。因此，我们预测临时和永久性MCAO的结果都改善了。公共卫生相关性：该项目的目的是确定吸入气体（乙基亚硝酸盐）在大鼠实验中风期间改善血液流动的有效性。我们有证据表明，乙基亚硝酸盐会有选择地改善流向中风的大脑部分的血液流动，但这将对流向人体其他部位的血液流动几乎没有影响。然后，我们将检查这种影响对于减少由中风引起的组织损伤和神经系统损害的量是否重要。