Ethyl Nitrite and Subarachnoid Hemorrhage

亚硝酸乙酯与蛛网膜下腔出血

• 批准号: 7470927
• 负责人: HUAXIN SHENG
• 金额: $ 20.48万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7470927
• 关键词: Acute; Area; Autoradiography; Basic Science; Beds; Binding; Biochemical; Blood Vessels; Blood flow; Brain; Brain Edema; Brain Injuries; Breathing; Caliber; Cerebral hemisphere hemorrhage; Cerebrovascular Circulation; Cerebrovascular Spasm; Cerebrum; Cessation of life; Clinical; Clinical Trials; Cognitive; Cognitive deficits; Condition; Cysteine; Development; Disruption; Dose; Edema; Ensure; Erythrocytes; Exposure to; Gases; Gelatin; Goals; Grant; Heme; Hemoglobin; Hemorrhage; Histologic; Histopathology; Human; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypotension; Hypoxia; Impaired cognition; Impairment; Injury; Ink; Intervention; Investigation; Learning; Modeling; Molecular Weight; Motor; Mus; Nervous System Physiology; Neurologic; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitrites; Numbers; Nutrient; Outcome; Oxygen; Patients; Performance; Perfusion; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Production; Property; Public Health; Reflex action; Research; Role; Ruptured Aneurysm; Sensory; Simvastatin; Site; Subarachnoid Hemorrhage; Survivors; Syndrome; Testing; Theft; Tissue Survival; Tissues; Transducers; Translating; Translational Research; Vasodilation; Vasodilator Agents; Vasospasm; Week; Weight; brain tissue; clinical application; clinically relevant; cognitive function; concept; density; design; ethyl nitrite; hemodynamics; improved; morris water maze; nerve injury; neuron loss; nitrosyl hemoglobin; novel; outcome forecast; research study; response; sensor

DESCRIPTION (provided by applicant): Cerebral vasospasm develops following subarachnoid hemorrhage (SAH), especially in patients with aneurysm rupture and causes major neurological and cognitive deficits and death. Current therapy has had limited impact on vasospasm-induced injury and outcome. Nitric oxide (NO) is decreased after SAH, which is believed to be a major factor contributing to vasospasm. Increasing NO by treatment with NO donors or precursors has been tried for almost two decades. These agents do increase vessel diameter supporting a role of NO in the pathomechanism. However, nonselective vasodilation also results in complications (e.g., systemic hypotension and steal syndrome) that have limited clinical application. S-nitrosyl-hemoglobin (SNO-Hb) carries both O2 and NO and has the capacity of selectively releasing NO in tissue beds with low O2 tension. This may serve to provide sufficient flow to allow tissue survival and improved long-term function. This proposal is designed to translate biochemical properties of SNO-Hb into new therapy and determine if increased SNO-Hb, caused by the novel s-nitrosylating agent, ethyl nitrite, improves tissue perfusion and outcome. The specific aims include acute (72 hrs post-SAH) examination of the effect of ethyl nitrite on regional cerebral blood flow (rCBF), tissue edema, neurological function, and cerebral arterial narrowing in an established mouse SAH model which has previously led to positive clinical trials of HMG-CoA reductase inhibitors. In addition, effects of ethyl nitrite on long-term (4 weeks post-SAH) cognitive function and selective neuronal cell death will be examined. The study will use rCBF autoradiography, tissue edema wet-dry weight analysis, validated neurological function tests (e.g. motor, sensory, and reflexes), rotarod performance, learning set Morris water maze testing, ink-gelatin vascular casting and brain histopathology. To test for a dose-dependent effect, the results will be compared amongst sham mice and SAH mice treated with 0, 1, 10 or 20 ppm ethyl nitrite. We also will explore potential beneficial interactions between ethyl nitrite and simvastatin. In pilot experiments 20 ppm ethyl nitrite significantly increased SNO-Hb and reduced neurological deficit and improved SAH-induced arterial narrowing at 72 h following injury without adverse hemodynamic effects. The significance of the proposed studies is to prove that selective local arterial dilation can be achieved by increasing SNO-Hb through inhalation of ethyl nitrite and that NO can modulate development of SAH induced cerebral vasospasm. This translational research will significantly contribute to improved public health. This proposal is designed to examine if administration of ethyl nitrite, an s-nitrosylating agent selectively releasing nitric oxide in hypoxic area, can ameliorate subarachnoid hemorrhage induced cerebral vasospasm, subsequent cerebral blood flow reduction and tissue edema, as well as neurological and cognitive functional deficits.

描述(由申请人提供)： 脑血管痉挛发生在蛛网膜下腔出血(SAH)后，尤其是在动脉瘤破裂的患者中，并导致严重的神经和认知功能障碍和死亡。目前的治疗方法对血管痉挛引起的损伤和预后的影响有限。一氧化氮(NO)在SAH后降低，这被认为是导致血管痉挛的一个主要因素。近二十年来，人们一直在尝试通过不使用捐赠者或前体的治疗来增加NO。这些药物确实增加了血管直径，支持了NO在发病机制中的作用。然而，非选择性血管扩张也会导致并发症(如全身性低血压和盗血综合征)，限制了临床应用。S亚硝酰血红蛋白(SNO-Hb)同时携带O2和NO，具有在低氧压条件下选择性释放NO的能力。这可能有助于提供足够的血流，以允许组织存活和改善长期功能。这项建议旨在将SNO-Hb的生化特性转化为新的治疗方法，并确定由新型亚硝酸乙酯-S引起的SNO-Hb增加是否可以改善组织灌注量和预后。具体目标包括急性(SAH后72小时)检测亚硝酸乙酯对小鼠SAH模型中局部脑血流量(RCBF)、组织水肿、神经功能和脑动脉狭窄的影响，该模型此前已导致HMG-CoA还原酶抑制剂的阳性临床试验。此外，还将研究亚硝酸乙酯对长期(SAH后4周)认知功能和选择性神经细胞死亡的影响。这项研究将使用rCBF放射自显影、组织水肿湿/干重分析、经过验证的神经功能测试(例如运动、感觉和反射)、旋转臂性能、学习设置Morris水迷宫测试、墨水-明胶血管铸型和脑组织病理学。为了测试剂量依赖效应，将在假小鼠和注射了0、1、10或20ppm乙基亚硝酸乙酯的SAH小鼠之间进行比较。我们还将探索亚硝酸乙酯和辛伐他汀之间潜在的有益相互作用。在先导性实验中，20ppm亚硝酸乙酯在伤后72小时显着升高SNO-Hb，减少神经功能缺失，改善SAH诱导的动脉狭窄，而没有不良的血流动力学影响。本研究的意义在于证明吸入亚硝酸乙酯增加SNO-Hb可实现选择性局部动脉扩张，并证实NO对SAH所致脑血管痉挛的发生有调节作用。这项转化研究将对改善公共卫生做出重大贡献。本研究旨在研究在缺氧区选择性释放一氧化氮的S亚硝酸乙酯能否改善蛛网膜下腔出血所致的脑血管痉挛、随后的脑血流量减少和组织水肿，以及神经和认知功能障碍。