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）：缺血性卒中是由脑血流量（CBF）不足以使脑组织存活引起的。从用组织纤溶酶原激活剂治疗的人类中已知，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是治疗目标。已知提供一氧化氮（NO）或上调eNOS表达的各种化合物（例如，辛伐他汀），增加缺血组织中CBF并改善实验性中风结果。虽然常见的机制似乎是增加NO生物活性和血管舒张，但大多数此类化合物作为中风治疗剂是不切实际的，因为延迟起效或缺乏对缺血组织的特异性，导致剂量受到全身性低血压的限制。选择性血管舒张的一种新机制是变构调节血红蛋白携带的一氧化氮生物活性的递送。S-亚硝基化血红蛋白（SNO-Hb）在氧合形式下是稳定的，但在O2卸载时不稳定。这提供了选择性地增加NO生物活性的机会，沿着血液和缺血组织之间的PO 2梯度，同时保持血液动力学稳定性。亚硝酸乙酯是一种吸入性气体，可显著增加SNO-Hb。亚硝酸乙酯降低成人和婴儿肺动脉高压的严重程度，并选择性地减少终末器官缺血模型的气腹，脑血管痉挛和游离肌瓣，对血压没有影响。我们提出的项目，以调查的影响，调节SNO-Hb对脑缺血的结果。使用建立的生理学控制的大鼠大脑中动脉闭塞（MCAO）模型，我们将1）确定在细丝MCAO期间和之后吸入20 ppm亚硝酸乙酯对绝对CBF的急性作用，并测量作为吸入氧分数（FiO 2）的函数的处于脑梗塞风险的组织的量，2）将亚硝酸乙酯在永久性局灶性缺血性中风的长期结果大鼠模型中的功效定义为FiO 2的函数，和3）确定亚硝酸乙酯在暂时性局灶性缺血性中风的长期结果大鼠模型中作为FiO 2的函数的功效。该模型的初步研究表明，在短暂性局灶性缺血期间或之后用亚硝酸乙酯治疗可导致激光多普勒CBF快速且可逆的增加。初步数据表明对血小板功能无不良影响。因此，我们预测临时和永久性MCAO的结局均会改善。公共卫生关系：该项目的目标是确定吸入气体亚硝酸乙酯在大鼠实验性中风期间改善血流的有效性。我们有证据表明，亚硝酸乙酯将选择性地改善血液流向正在经历中风的大脑部分，但这样做对血液流向身体其他部位的影响很小或没有影响。然后，我们将研究这种作用是否在减少中风引起的组织损伤和神经功能障碍方面很重要。