Clinical Applications of Nitrite

亚硝酸盐的临床应用

基本信息

批准号：
9553224
负责人：
Alan Schechter
金额：
$ 58.72万
依托单位：
NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
依托单位国家：
美国
项目类别：
财政年份：
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/9553224
关键词：
Affect Agonist Animal Model Animals Annual Reports Antihypertensive Agents Antioxidants Back Bacteria Biological Biological Assay Blood Blood Banks Blood Platelets Blood Vessels Blood coagulation Blood flow Blood specimen Brazil Cardiovascular system Cerebrovascular Circulation Clinical Clinical Protocols Clinical Research Collaborations Complement Development Diet Disease Drug Kinetics Electrodes Environment Enzymes Erythrocytes Excision Exercise Food Health Benefit Human Human body Hypertension Hypoxia Ingestion Intellectual Property International Ions Isotopes Laboratories Learning Legal patent Liquid substance Mammalian Cell Measurement Measures Meat Products Medicine Metabolic Metabolism Methods Modeling Muscle Nitrates Nitric Oxide Nitrites Nitrogen Oxides Nutritional Oral Oral Administration Oxygen Pathway interactions Patient Agents Patients Pharmaceutical Preparations Pharmacology Physiological Plants Portugal Production Property Protocols documentation Publishing Reaction Renovascular Hypertension Reporting Rest Rodent Route Safety Salivary Sampling Series Thalassemia Therapeutic Therapeutic Agents Tissues Toxicology Tracer Transfusion United States National Institutes of Health Universities Urine Vegetables Visit Water Work absorption base clinical application clinically significant experience hazard human subject human tissue improved metabolic abnormality assessment muscle physiology nutrition oxidation permissiveness response tempol volunteer

项目摘要

As was summarized previously in this and the related NO annual report (DK 025093-18) over the last two decades we have, with our immediate and international collaborators, shown a major new route for NO formation in the mammalian and human bodies, i.e., the reduction of nitrite ions to form NO. This complements, especially under hypoxic conditions, the activity of the various NOS enzymes. As a result we have focused on physiological and pharmacological effects of nitrite administration, as well as nitrate ingestion (which is converted to nitrite by salivary bacteria) and the fluxes in these nitrogen oxides in tissues and in the mammalian body. As summarized in the related report, various physiological pathways such as brain blood flow, red cell storage, platelet reactivity and blood clotting are very much influenced by the levels of these compounds. Recent work summarized in the DK 025093 series of reports suggest that some mammalian tissues can also reduce nitrate ions to nitrite and then NO. It is thus essential that we establish the utility and safety of ingestion of these compounds in foods and medicines and to examine how various factors affect their absorption from the diet. We also wish to measure their levels in various biological fluids, such as blood and urine, as well as in the environment. For some years we have been working with a group in Lisbon to develop electrode-based assays for nitrite in water and other environmental fluids; in view of the importance of nitrite in blood and other biological fluids we have now redirected this work to a more micro scale so that measurements on animal and human samples may be feasible and have recently published details of a micro-electode which may allow such assays at physiologically relevant concentrations. Detailed metabolic studies of nitrate-nitrite-NO metabolism in animals and people require tracer studies which may be approached using non-toxic heavy isotopes. Our collaborators in Newcastle are developing protocols to do this in animals and then perhaps in human subjects. The have sent us samples from various animal ingestion studies and we are using our highly sensitive and accurate chemi-luminesence methods to quantity nitrate and nitrite levels in these blood samples. (One of their staff visited our laboratory for several weeks to learn how to do these assays.) Our collaborators in Sao Paulo, Brazil have much experience in pharmacology of NO and we are working with them on various animal models of hypertension with the hope of eventual clinical studies. Our first results, recently published, show that administration of an anti-oxidant Tempol to rodents with reno-vascular hypertension improved the vascular responses to nitrite but that the anti-hypertensive responses were not affected. Lastly we have established a collaboration with a muscle physiology group in Exeter, UK and we anticipate -once all permissions are effected -measuring the levels of nitrate at rest and with exercise - in the human tissues to see if our animal results obtain for human subjects. We have also participated in an NIH-sponsored discussion of the utility and safety of orally administered nitrate and nitrite in food and as medications. These deliberations were recently published and suggest many possible health benefits of increasing nitrate and nitrite levels, especially by oral administration, and suggest new studies to see if previously postulated harmful effects of such ingestion were really valid.

如前所述，在过去的二十年中，与我们的直接和国际合作者一起，与此相关的无年度报告（DK 025093-18），显示了一条主要的新途径，在哺乳动物和人体的身体中，即减少硝酸盐离子的氮离子否。这补充了各种NOS酶的活性。结果，我们专注于亚硝酸盐给药的生理和药理作用，以及硝酸盐摄入（通过唾液细菌转化为亚硝酸盐）和在组织和哺乳动物体内的这些氮氧化物中的通量。如相关报告中总结的那样，各种生理途径，例如脑血流，红细胞储存，血小板反应性和血液凝结都受这些化合物水平的影响很大。 DK 025093系列报告中总结的最新工作表明，某些哺乳动物组织也可以减少硝酸盐离子至硝酸盐，然后否。因此，至关重要的是，我们必须在食品和药物中建立这些化合物摄入的效用和安全性，并研究各种因素如何影响其饮食中的吸收。我们还希望测量它们在各种生物液中的水平，例如血液和尿液以及环境中。几年来，我们一直在与里斯本的一个小组合作，开发基于电极的水和其他环境流体的亚硝酸盐的测定。鉴于亚硝酸盐在血液和其他生物流体中的重要性，我们现在将这项工作重定向到更微小的量表，因此对动物和人类样品的测量可能是可行的，并且最近发布了微电极的细节，该微电极可能允许在生理相关浓度上进行此类测定。对动物和人的硝酸盐非代谢的详细代谢研究需要使用无毒的重量同位素进行示踪剂研究。我们在纽卡斯尔的合作者正在开发协议，以在动物中，然后在人类受试者中进行此操作。这些已经向我们发送了来自各种动物摄入研究的样品，我们正在使用高度敏感和准确的化学透光方法来对这些血液样本中的硝酸盐和亚硝酸盐水平进行数量。（他们的一名员工访问了我们的实验室数周，以学习如何进行这些测定法。）我们在巴西圣保罗的合作者在NO的药理学方面有很多经验，我们正在与他们合作研究各种高血压动物模型，希望最终进行临床研究。我们最近发表的第一个结果表明，抗氧化tempol对具有肾血管高血压的啮齿动物的施用改善了对亚硝酸盐的血管反应，但抗高血压反应没有影响。最后，我们与英国埃克塞特市的一个肌肉生理组建立了合作，我们预计所有权限都会实现 - 在人体组织中衡量硝酸盐水平，以查看我们的动物对人类受试者的结果是否获得。我们还参加了NIH赞助的讨论，讨论了食物和药物中口服硝酸盐和亚硝酸盐的实用性和安全性。这些讨论最近发表了，并提出了增加硝酸盐和亚硝酸盐水平的许多可能的健康益处，尤其是通过口服给药，并建议新的研究以查看以前假定的这种摄入的有害影响是否真的有效。