Role of nitrite and hemoglobin in vascular NO homeostasis in the fetus and adult

亚硝酸盐和血红蛋白在胎儿和成人血管 NO 稳态中的作用

• 批准号: 7907552
• 负责人: Arlin B Blood
• 金额: $ 37.22万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7907552
• 关键词: Address; Adult; Affect; Affinity; Animal Model; Anions; Arteries; Basic Science; Binding; Biochemical; Biochemical Pathway; Blood; Blood Vessels; Brain Hypoxia-Ischemia; Contracts; Data; Diffusion; Disease; Dissociation; Erythrocytes; Fetal Hemoglobin; Fetus; Foundations; Heme; Hemoglobin; Hemoglobin H; Homeostasis; Hypoxia; In Vitro; Injury; Intracranial Hemorrhages; Ischemia; Knowledge; Life; Mammals; Measures; Mediating; Mediator of activation protein; Metabolism; Methemoglobin; Mitochondria; Molecular Conformation; Necrotizing Enterocolitis; Newborn Infant; Nitric Oxide; Nitrites; Oxygen; Oxygen Consumption; Oxyhemoglobin; Pathway interactions; Perinatal; Persistent Fetal Circulation Syndrome; Physiological; Plasma; Play; Production; Ptosis; Reaction; Regulation; Research; Role; Route; Sheep; Source; Stress; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Vasodilation; Work; base; deoxyhemoglobin; design; fetal; fetal blood; glycosylated-nitric oxide complex hemoglobin A; in vivo; innovation; insight; instrument; iron nitrosyl; neonatal hypoxic-ischemic brain injury; nitrogen trioxide; nitrosyl hemoglobin; novel; public health relevance; research study; response; therapeutic evaluation; tool

DESCRIPTION (provided by applicant): Matching oxygen delivery with need is of fundamental physiological importance, especially during the perinatal period when oxygen supply to the fetus is often compromised. Nitric oxide (NO) is a key endogenous defense against hypoxia/ischemia by 1) vasodilating arteries to increase oxygen delivery and 2) decreasing oxygen consumption at the level of the mitochondria and hence temporarily reducing oxygen need. Compelling recent evidence indicates that nitrite, NO2-, a ubiquitous anion in the blood of mammals, can be converted to NO by reaction with deoxyhemoglobin. Many experiments suggest that this reaction constitutes a significant source of NO during hypoxia/ischemia. Because the fetus has lower oxygen reserves and is more subject to interrupted oxygen supply than the adult, it would seem logical for protective mechanisms against hypoxia/ischemia to be more pronounced during perinatal life. The production of NO from the reaction between nitrite and deoxyhemoglobin is favored by increased concentrations of nitrite, hemoglobin and H+, all of which are elevated in the blood of hypoxic fetuses more than the adult. The rate of nitrite reduction to NO is also affected by hemoglobin conformation, being maximal when hemoglobin is 40 to 60% oxygen saturated, a range that occurs normally in the fetus but only during hypoxia in the adult. This also suggests the rate of NO production from nitrite and deoxyhemoglobin may be elevated in the fetus compared to the adult. This project will address the general hypothesis that the nitrite/deoxyhemoglobin pathway is a more prevalent source of NO in the fetus than in the adult. Four aspects of the hypothesis will be tested by four specific aims. The first will use chronically instrumented near-term fetal sheep to determine the effects of circulating nitrite on the fetal cardiovasculature and oxygen consumption, and whether these effects are potentiated by hypoxia. The second will examine whether fetal iron-nitrosyl hemoglobin, a byproduct of nitrite metabolism in deoxygenated blood, releases NO more rapidly in vivo than that of adult blood, and hence is a more ready source of NO. In the third aim, in vitro studies are proposed which will determine whether fetal blood is more effective than adult blood at producing vasoactive quantities of NO from nitrite. Finally, we will investigate the physiological importance of a recently discovered reaction between nitrite, NO, and methemoglobin, which may explain how the erythrocyte is capable of releasing vasoactive amounts of NO. The results of these studies will provide a novel and thorough assessment of the reaction of nitrite with deoxyhemoglobin as a source of NO during fetal responses to hypoxia/ischemia. Furthermore, they will provide insight into the therapeutic potential of nitrite as a tool in the treatment of hypoxic/ischemic stress. PUBLIC HEALTH RELEVANCE: Project Narrative Nitrite, upon conversion to nitric oxide (NO) by reaction with deoxyhemoglobin, has been proposed as a key mediator of protective responses to hypoxia/ischemia. If so, nitrite holds wide- ranging potential as a therapeutic agent for the treatment of diseases and injury involving hypoxic/ischemic stress.

描述（由申请人提供）：将氧气输送与需求相匹配具有基本的生理重要性，特别是在胎儿的氧气供应经常受到损害的围产期。一氧化氮 (NO) 是抵抗缺氧/缺血的关键内源性防御手段，其作用是：1）舒张血管以增加氧气输送；2）减少线粒体水平的耗氧量，从而暂时减少需氧量。最近令人信服的证据表明，亚硝酸盐（NO2-）是哺乳动物血液中普遍存在的阴离子，可以通过与脱氧血红蛋白反应转化为一氧化氮（NO）。许多实验表明，该反应构成缺氧/缺血期间NO的重要来源。由于胎儿的氧气储备较低，并且比成人更容易受到氧气供应中断的影响，因此在围产期，针对缺氧/缺血的保护机制更加明显，这似乎是合乎逻辑的。亚硝酸盐、血红蛋白和 H+ 浓度的增加有利于亚硝酸盐和脱氧血红蛋白之间反应产生一氧化氮，所有这些物质在缺氧胎儿的血液中的升高程度都高于成人。亚硝酸盐还原成 NO 的速率也受血红蛋白构象的影响，当血红蛋白氧饱和度为 40% 至 60% 时达到最大，该范围在胎儿中正常发生，但仅在成人缺氧时发生。这也表明，与成人相比，胎儿中亚硝酸盐和脱氧血红蛋白产生一氧化氮的速率可能更高。该项目将解决以下一般假设：亚硝酸盐/脱氧血红蛋白途径是胎儿中比成人中更普遍的一氧化氮来源。该假设的四个方面将通过四个具体目标进行检验。第一个将使用长期仪器检测的近足胎羊来确定循环亚硝酸盐对胎儿心血管和耗氧量的影响，以及这些影响是否因缺氧而增强。第二个项目将检查胎儿亚硝酰铁血红蛋白（脱氧血液中亚硝酸盐代谢的副产物）在体内释放一氧化氮的速度是否比成人血液更快，因此是更容易获得的一氧化氮来源。第三个目标是进行体外研究，以确定胎儿血液是否比成人血液更有效地从亚硝酸盐产生血管活性量的一氧化氮。最后，我们将研究最近发现的亚硝酸盐、NO 和高铁血红蛋白之间的反应的生理重要性，这可能解释红细胞如何能够释放血管活性量的 NO。这些研究的结果将为胎儿缺氧/缺血反应期间亚硝酸盐与脱氧血红蛋白作为一氧化氮来源的反应提供新颖而全面的评估。此外，他们还将深入了解亚硝酸盐作为治疗缺氧/缺血应激工具的治疗潜力。公共健康相关性：项目叙述 亚硝酸盐通过与脱氧血红蛋白反应转化为一氧化氮 (NO)，已被提议作为缺氧/缺血保护性反应的关键介质。如果是这样，亚硝酸盐作为治疗缺氧/缺血应激相关疾病和损伤的治疗剂具有广泛的潜力。