Nitric Oxide Metabolism and Transport

一氧化氮代谢和运输

• 批准号: 9356063
• 负责人: Alan Schechter
• 金额: $ 43.79万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9356063
• 关键词: Active Biological Transport; Acute; Ammonia; Animals; Area; Ascorbic Acid; Binding; Biological; Blood; Blood Circulation; Blood Platelets; Blood Pressure; Blood Vessels; Blood coagulation; Blood flow; Brain; Breathing; Canis familiaris; Cardiovascular Diseases; Cardiovascular system; Cells; Cerebrovascular Circulation; Cerebrum; Chronic; Diet; Disease; Endocrine; Erythrocytes; Exercise; Frequencies; Functional disorder; Gases; Haptoglobins; Hemoglobin; Hemolytic Anemia; Hormones; Human; In Vitro; Infusion procedures; Ions; Laboratories; Lactobacillus; Lead; Left; Legal patent; Licensing; Liver Failure; Measures; Metabolic; Metabolism; Methemoglobin; Methodology; Microbe; Muscle; NOS1 gene; Nitrates; Nitric Oxide; Nitrites; Oral cavity; Organ; Organism; Oxygen; Pathway interactions; Patients; Pharmaceutical Preparations; Plasma; Process; Production; Property; Pulmonary Hypertension; Reaction; Reporting; Research; Rodent; Rodent Model; Role; Sickle Cell; Sickle Cell Anemia; Signal Transduction; Syndrome; Systemic blood pressure; Tissues; United States National Institutes of Health; Venous; Work; XDH gene; animal imaging; ascorbate; base; brain tissue; chemical reduction; commensal microbes; falls; human subject; in vivo; interest; microbiome; microorganism; nitrogen metabolism; older patient; oxidation; oxymyoglobin; programs; vascular bed; volunteer

The results of nitric oxide (NO) infusions in normal volunteers and NO infusions and inhalation in experimental animals confirms that NO can be transported as a hormone and thus has the potential to be a pharmacological agent (i.e., a drug). We believe that the lack of vascular effects in our sickle cell patients is due to the presence of circulating hemoglobin and that this contributes to the pathophysiology of this and other chronic and acute hemolytic syndromes, especially the pulmonary hypertension complications which we have found to be severe and of high frequency in older patients. We have analyzed the effects of methemoglobin formation on blood pressure and other cardiovascular parameters in dogs to see if the ferric species of hemoglobin-which could be pharmacologically effected- is safe as has been assumed. To our suprise we find that infusions of methemoglobin lead to prolonged increases in blood pressure and systemic resitance and believe that the mechanisms relates to reduction of methemoglobin to ferrous hemoglobin by plasma ascorbate and the destruction of plasma or cellular NO and nitrite by this species. We also find that NO-bioactivity destruction appears to occur in tissues to a much greater extent than in the vascular bed. An alternative approach to mitigate the effects of cell-free hemoglobin is the infusion of haptoglobin or other agents which may bind hemoglobin or some of its degradation products. Studies of these pathways, in animals and possibly patients, are now being planned. We have recently resumed our work on platelet and blood clotting inhibition by nitrite and are studying the effects of changes in ambient oxygen levels on the processes in rodent models using the TEG methodologies. In recent work we have demonstrated that nitrate ions can be converted to nitrite (and then NO) or to ammonia by various commensal bacteria, depending on oxygen concentration and pH. The half dozen species of microorganisms that we have been studying, especially related to the Lactobacilli, are prevalent in the human oral cavity and gut. We believe that these reactions are important in determining overall nitrogen metabolism in humans and especially the roles of nitrite, NO, and perhaps even nitrate ions in regualting the cardiovascular system. They may also be relevant for the production of ammonia in humans normally and in disease, such as with liver failure. Our second major new project has been to measure nitrate and nitrite levels in various rodent organs. The most surprising result was our finding of very high nitrate levels in muscle tissue. These levels are much higher than in blood and suggest either active transport into muscle or some production of NO and oxidation to nitrate in the tissue itself. Our preliminary results suggest that it is the latter process, with production via NOS1 (nNOS) and oxidation due to reaction with oxymyoglobin, that explains these observations. Most excitingly we have found that exercise, which can increase blood flow 10- or 20-fold, causes marked fall in nitrate levels and transient increases in muscle nitrite levels. We postulate that muscle tissue has a specific mechanism for nitrate reduction, possibly using xanthine oxidoreductase and this process may explain the long mysterious mechanism by which a muscle-produced agent caused marked changes in organ blood flow.

正常志愿者输注一氧化氮（NO）和实验动物输注和吸入一氧化氮的结果证实，一氧化氮可以作为激素进行运输，因此有可能成为一种药理制剂（即药物）。我们认为镰状细胞患者缺乏血管作用是由于循环血红蛋白的存在，这有助于这种和其他慢性和急性溶血性综合征的病理生理学，特别是我们发现的肺动脉高压并发症在老年患者中很严重且频率很高。我们分析了高铁血红蛋白的形成对狗的血压和其他心血管参数的影响，以确定铁类血红蛋白是否如人们所假设的那样安全——它可能受到药理学的影响。令我们惊讶的是，我们发现输注高铁血红蛋白导致血压和全身抵抗的持续升高，并认为其机制与血浆抗坏血酸将高铁血红蛋白还原为铁血红蛋白以及该物种对血浆或细胞NO和亚硝酸盐的破坏有关。我们还发现，no生物活性破坏似乎发生在组织中，其程度远远大于血管床。减轻无细胞血红蛋白影响的另一种方法是输注触珠蛋白或其他可能结合血红蛋白或其某些降解产物的药物。目前正在计划在动物和可能的病人身上对这些通路进行研究。我们最近恢复了亚硝酸盐对血小板和凝血的抑制作用，并正在使用TEG方法研究环境氧水平变化对啮齿动物模型过程的影响。