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: 8280213
• 负责人: Arlin B Blood
• 金额: $ 36.01万
• 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/8280213
• 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; Health; Heme; Hemoglobin; Hemoglobin H; Homeostasis; Hypoxia; In Vitro; Injury; Intracranial Hemorrhages; Ischemia; 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; 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）：与需要相匹配的供氧具有基本的生理重要性，特别是在围产期，胎儿的供氧经常受到损害。一氧化氮（NO）是一种关键的内源性防御缺氧/缺血：1)血管舒张动脉增加氧气输送，2)减少线粒体水平的氧气消耗，从而暂时减少氧气需求。最近令人信服的证据表明，亚硝酸盐，NO2-，一种在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的反应转化为NO。许多实验表明，这种反应是缺氧/缺血时一氧化氮的重要来源。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，防止缺氧/缺血的保护机制似乎更为明显。缺氧胎儿血液中亚硝酸盐、血红蛋白和H+浓度的升高有利于亚硝酸盐和脱氧血红蛋白之间的反应产生NO，这些浓度在缺氧胎儿血液中均高于成人。亚硝酸盐还原为一氧化氮的速率也受血红蛋白构象的影响，当血红蛋白达到40 - 60%的氧饱和时达到最大值，这个范围通常发生在胎儿身上，但只有在成人缺氧时才会发生。这也表明，与成人相比，胎儿体内亚硝酸盐和脱氧血红蛋白产生一氧化氮的速率可能会升高。该项目将解决一般假设，即亚硝酸盐/脱氧血红蛋白途径是胎儿比成人更普遍的NO来源。假设的四个方面将通过四个具体目标进行检验。第一项研究将使用长期仪器的近期胎羊来确定循环亚硝酸盐对胎儿心血管系统和氧气消耗的影响，以及这些影响是否因缺氧而增强。第二项研究将检验胎儿铁亚硝基血红蛋白（缺氧血液中亚硝酸盐代谢的副产物）在体内是否比成人血液更快地释放NO，因此是否更容易成为NO的来源。在第三个目标中，提出了体外研究，以确定胎儿血液是否比成人血液更有效地从亚硝酸盐中产生血管活性量的NO。最后，我们将研究最近发现的亚硝酸盐、一氧化氮和高铁血红蛋白之间反应的生理重要性，这可能解释红细胞如何能够释放血管活性的一氧化氮。这些研究的结果将为胎儿缺氧/缺血反应中亚硝酸盐与脱氧血红蛋白作为NO来源的反应提供一个新的和全面的评估。此外，他们将深入了解亚硝酸盐作为治疗缺氧/缺血性应激的工具的治疗潜力。亚硝酸盐与脱氧血红蛋白反应转化为一氧化氮（NO）后，已被认为是缺氧/缺血保护反应的关键介质。如果是这样，亚硝酸盐作为治疗包括缺氧/缺血性应激的疾病和损伤的药物具有广泛的潜力。