Clinical Applications of Nitrite

亚硝酸盐的临床应用

• 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
• 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

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.

正如以前在本报告和相关的NO年度报告(丹麦克朗025093-18)中总结的那样，在过去20年中，我们与我们的直接和国际合作者一起，显示了在哺乳动物和人体中形成NO的一条主要的新途径，即将亚硝酸根离子还原为NO。这补充了各种一氧化氮合酶的活性，特别是在低氧条件下。因此，我们重点研究了亚硝酸盐的生理和药理作用，以及硝酸盐的摄取(由唾液细菌转化为亚硝酸盐)以及这些氮氧化物在组织和哺乳动物体内的通量。如相关报道所述，这些化合物的水平对脑血流、红细胞储存、血小板反应和凝血等多种生理途径都有很大的影响。最近在DK 025093系列报道中总结的工作表明，一些哺乳动物组织也可以将硝酸根离子还原为亚硝酸盐，然后再还原为NO。因此，我们必须确定在食品和药品中摄入这些化合物的效用和安全性，并检查各种因素如何影响它们从饮食中的吸收。我们还希望测量血液和尿液等各种生物液体以及环境中它们的水平。 多年来，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中亚硝酸盐的分析方法；鉴于血液和其他生物流体中亚硝酸盐的重要性，我们现在将这项工作重新定向到更微观的范围，以便对动物和人类样本进行测量可能是可行的，并最近公布了一种微电子的细节，该方法可能允许在生理上相关的浓度下进行这种分析。对动物和人体内硝酸盐-亚硝酸盐-一氧化氮代谢的详细代谢研究需要示踪研究，可以使用无毒的重同位素进行研究。我们在纽卡斯尔的合作者正在开发在动物身上做到这一点的方案，然后可能在人类试验中做到这一点。我们已经向我们提供了各种动物摄取研究的样本，我们正在使用我们高度灵敏和准确的化学发光方法来定量这些血液样本中的硝酸盐和亚硝酸盐水平。(他们的一名工作人员访问了我们的实验室几周，了解如何进行这些检测。)我们在巴西圣保罗的合作者在NO的药理学方面拥有丰富的经验，我们正在与他们合作建立各种高血压动物模型，希望最终能进行临床研究。我们最近发表的第一个结果表明，给患有肾血管性高血压的啮齿动物服用抗氧化剂坦普尔可以改善血管对亚硝酸盐的反应，但抗高血压反应不受影响。最后，我们已经与英国埃克塞特的一个肌肉生理学小组建立了合作关系，我们预计-一旦所有许可生效-测量人体组织中休息和运动时的硝酸盐水平，看看我们的动物结果是否适用于人类受试者。 我们还参加了由美国国立卫生研究院发起的关于在食品和药物中口服硝酸盐和亚硝酸盐的效用和安全性的讨论。这些讨论最近发表，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，特别是通过口服，并建议进行新的研究，以确定之前假设的此类摄入的有害影响是否真的有效。