Ethyl Nitrite and Subarachnoid Hemorrhage

亚硝酸乙酯与蛛网膜下腔出血

• 批准号: 7561636
• 负责人: HUAXIN SHENG
• 金额: $ 17.06万
• 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 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7561636
• 关键词: Acute; Address; Animals; Area; Autoradiography; Basic Science; Beds; Binding; Biochemical; Blood Vessels; Blood flow; Brain; Brain Edema; Brain Injuries; Breathing; Caliber; Cell Proliferation; Cerebrovascular Circulation; Cerebrovascular Spasm; Cerebrum; Cessation of life; Clinical; Clinical Trials; Clinical assessments; Cognitive; Cognitive deficits; Critiques; Cysteine; Data; Development; Dose; Edema; Ensure; Erythrocytes; Funding Mechanisms; Gases; Gelatin; Goals; Grant; Heme; Hemoglobin; Hemorrhage; Histologic; Histopathology; Human; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypotension; Hypoxia; Impaired cognition; Impairment; Injury; Ink; Investigation; Learning; Measurement; Mediating; Methods; Modeling; Molecular Weight; Motor; Mus; Nervous System Physiology; Neurologic; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitrites; Nutrient; Outcome; Oxygen; Patients; Performance; Perfusion; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Preparation; Production; Property; Public Health; Published Comment; Rattus; Reflex action; Reporting; Research; Research Personnel; Rodent; Role; Ruptured Aneurysm; Sensory; Simvastatin; Site; Subarachnoid Hemorrhage; Sum; Survivors; Syndrome; Testing; Theft; Therapeutic Agents; Time; Tissue Survival; Tissues; Transducers; Translating; Translational Research; Vasculitis; Vasodilation; Vasodilator Agents; Vasospasm; Weight; base; behavior test; brain tissue; clinical application; clinically relevant; cognitive function; density; design; ethyl nitrite; hemodynamics; human disease; improved; in vivo; morris water maze; mouse model; neuron loss; nitrosyl hemoglobin; nonhuman primate; novel; outcome forecast; pre-clinical; programs; 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）：

项目成果

Development of a simplified spinal cord ischemia model in mice.

• DOI: 10.1016/j.jneumeth.2010.04.003
• 发表时间: 2010-06-15
• 期刊: JOURNAL OF NEUROSCIENCE METHODS
• 影响因子: 3
• 作者: Wang, Zhengfeng;Yang, Wei;Britz, Gavin W.;Lombard, Frederick W.;Warner, David S.;Sheng, Huaxin
• 通讯作者: Sheng, Huaxin

Pharmacologically augmented S-nitrosylated hemoglobin improves recovery from murine subarachnoid hemorrhage.

• DOI: 10.1161/strokeaha.110.600569
• 发表时间: 2011-02
• 期刊: Stroke
• 影响因子: 8.3
• 作者: Sheng H;Reynolds JD;Auten RL;Demchenko IT;Piantadosi CA;Stamler JS;Warner DS
• 通讯作者: Warner DS