Increased Plasma Nitrite, Tissue Oxygenation and Functional Changes in PAD

PAD 中血浆亚硝酸盐增加、组织氧合和功能变化

• 批准号: 8227748
• 负责人: Jason David Allen
• 金额: $ 23.82万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-16 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8227748
• 关键词: 3-nitrotyrosine; Acute; Affect; Age; Anti-Bacterial Agents; Apoptosis; Area; Arterial Occlusive Diseases; Beds; Beverages; Biological Availability; Biopsy; Blood; Blood Pressure; Blood Vessels; Blood capillaries; Blood flow; Cardiovascular Diseases; Cell Proliferation; Chronic; Citrate (si)-Synthase; Clinical; Consumption; Cyclic GMP; Deglutition; Dose; Drug Delivery Systems; Endocrine; Endothelial Cells; Exercise; Exercise Tolerance; Exercise stress test; F2-Isoprostanes; Fiber; Gastrocnemius Muscle; Goals; Growth; Hypoxia; In Situ Nick-End Labeling; Individual; Inflammation; Ingestion; Intermittent Claudication; Intervention; Ischemia; Leg; Limb structure; Measures; Modeling; Mouthwash; Mus; Muscle; Muscle Fibers; Near-Infrared Spectroscopy; Nitrates; Nitric Oxide; Nitric Oxide Donors; Nitrites; Oxidative Stress; Pain; Pain in lower limb; Patients; Perfusion; Pericytes; Peripheral; Peripheral arterial disease; Physical therapy exercises; Placebos; Plasma; Play; Population; Positron-Emission Tomography; Process; Production; Proliferating Cell Nuclear Antigen; Quality of life; Randomized; Relative (related person); Rest; Role; Saliva; Salivary; Salivary Glands; Specificity; Supplementation; Thrombosis; Time; Tissues; Training; Treadmill Tests; Vascular Diseases; Walking; Work; angiogenesis; brachial artery; capillary; claudication; density; dietary nitrate; improved; inhibitor/antagonist; interest; nitrosative stress; oral bacteria; tissue oxygenation

DESCRIPTION (provided by applicant): Peripheral artery disease (PAD) is caused by atherosclerotic occlusions in the legs. It affects 5% of the US population over 50 yrs, one third of which suffer from intermittent claudication (IC), defined as ischemic leg pain that occurs with walking and improves with rest. An intervention that could (A) acutely improve oxygenation to areas of ischemia and (B) chronically increase vessel growth to these ischemic areas would allow for greater exercise tolerance and compliance and facilitate greater improvements in function and quality of life. Plasma nitrite was once considered a biologically inert byproduct and marker of endothelial NO production. Recently, several studies have demonstrated an endocrine role for NO equivalents, including nitrite. These equivalents may be transported in the blood to peripheral tissue beds, where under hypoxic conditions they can be converted to NO and increase blood flow and O2 delivery. This may be pertinent in an arterial occlusive disease (PAD), especially during exercise when tissue ischemia is the limiting factor. The hypothesis of this proposal is that in subjects with PAD and IC, regular consumption of a high nitrate supplement which raises plasma nitrite, in conjunction with 8 weeks of supervised exercise training at the limb ischemic threshold (SET) will produce a greater clinical benefit (increases in COT and PWT) than placebo plus supervised exercise at the limb ischemic threshold (PET). In order to adequately develop, power and execute a larger study, the following specific aims will explore our hypothesis using 24 individuals (12 per group) with PAD and IC: Specific Aim 1a: To determine the segment of PAD patients that can achieve the desired level of plasma nitrite (>500nM at 180min post beverage consumption) at a tolerable volume for an 8 week study. Specific Aim 1b: In these subjects, determine differences in COT, PWT and VO2peak during a graded exercise test, between randomization to 8 weeks of SET or PET. Specific Aim 2: To determine differences in (a) tissue oxygenation (by NIRS) and (b) NO-derived species (plasma and RBC nitrite, nitrate, nitrosothiol), cGMP, oxidative and nitrosative stress (plasma nitrotyrosine and F2-isoprostane) during treadmill testing following SET or PET Specific Aim 3: To determine differences in gastrocenemius muscle (via biopsy) (a) angiogenesis and arteriogenesis (capillary density with surrounding pericytes, proliferating cell nuclear antigen, and apoptosis) and oxidative capacity (fiber type composition, citrate synthase activity), and (b) endothelial function (brachial artery FMD) after SET or PET. PUBLIC HEALTH RELEVANCE: Peripheral artery disease (PAD) is a form of cardiovascular disease (CVD) caused by atherosclerotic occlusions in the legs. It affects approximately 5% of the US population over 50 yrs of age, one third of which suffer from intermittent claudication (IC), defined as ischemic leg pain that occurs with walking and improves with rest. We propose by supplementing plasma nitrite via a beverage we can (A) acutely improve oxygenation to areas of ischemia and (B) chronically increase vessel growth to these ischemic areas, would allow for greater acute exercise tolerance, ease the burden of exercise compliance and facilitate greater improvements in function and quality of life

描述（由申请人提供）：外周动脉疾病（PAD）是由腿部动脉粥样硬化闭塞引起的。50岁以上的美国人口中有5%患有此病，其中三分之一患有间歇性跛行（IC），定义为走路时发生的缺血性腿部疼痛，休息后会好转。干预可以(A)急性改善缺血区域的氧合，(B)慢性增加这些缺血区域的血管生长，这将允许更大的运动耐受性和依从性，并促进功能和生活质量的更大改善。血浆亚硝酸盐曾被认为是一种生物惰性副产物和内皮细胞一氧化氮生成的标志。最近，一些研究已经证明了一氧化氮等价物的内分泌作用，包括亚硝酸盐。这些等效物可能在血液中被运送到周围组织床，在缺氧条件下，它们可以转化为NO，增加血流量和氧的输送。这可能与动脉闭塞性疾病（PAD）有关，特别是在运动时，组织缺血是限制因素。该建议的假设是，在PAD和IC受试者中，与安慰剂加肢体缺血阈值（PET）监督运动相比，定期摄入高硝酸盐补充剂（提高血浆亚硝酸盐），并结合8周肢体缺血阈值（SET）监督运动训练，将产生更大的临床效益（COT和PWT增加）。为了充分开展、加强和执行一项更大规模的研究，以下具体目标将使用24名PAD和IC患者（每组12人）来探索我们的假设：具体目标1a：确定在8周的研究中，能够在可耐受的量下达到所需血浆亚硝酸盐水平（在饮料消耗后180分钟内达到500nM）的PAD患者部分。具体目标1b：在这些受试者中，确定随机分配至8周SET或PET期间分级运动试验期间COT， PWT和vo2峰值的差异。特异性目标2：确定(a)组织氧合（通过近红外光谱）和(b)一氧化氮衍生物质（血浆和红细胞亚硝酸盐、硝酸盐、亚硝基硫醇）、cGMP、氧化和亚硝化应激（血浆硝基酪氨酸和f2 -异前列腺素）在跑步机测试期间的差异。(a)血管生成和动脉生成（毛细血管密度与周围周细胞、增殖细胞核抗原和凋亡）和氧化能力（纤维类型组成、柠檬酸合成酶活性），以及(b)内皮功能（肱动脉FMD）在SET或PET后的差异（通过活检）。