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。它影响着 5% 超过 50 岁的美国人口，其中三分之一患有间歇性跛行 (IC)，其定义为行走时发生的缺血性腿部疼痛，休息后会改善。能够（A）急剧改善缺血区域的氧合和（B）长期增加这些缺血区域的血管生长的干预措施将允许更大的运动耐量和依从性，并促进功能和生活质量的更大改善。血浆亚硝酸盐曾经被认为是一种生物惰性副产物和内皮NO产生的标志物。最近，一些研究表明一氧化氮当量（包括亚硝酸盐）的内分泌作用。这些等价物可以在血液中转运到周围组织床，在缺氧条件下它们可以转化为一氧化氮并增加血流量和氧气输送。这可能与动脉闭塞性疾病（PAD）有关，尤其是在运动期间，组织缺血是限制因素。该提案的假设是，在患有 PAD 和 IC 的受试者中，定期食用可提高血浆亚硝酸盐含量的高硝酸盐补充剂，并结合在肢体缺血阈值 (SET) 下进行 8 周的监督运动训练，将产生更大的临床益处。与安慰剂加肢体缺血阈值 (PET) 下的监督运动相比，COT 和 PWT 有所增加。为了充分开发、推动和执行更大规模的研究，以下具体目标将使用 24 名患有 PAD 和 IC 的个体（每组 12 人）来探索我们的假设： 具体目标 1a：确定能够实现预期目标的 PAD 患者群体在为期 8 周的研究中，血浆亚硝酸盐水平（饮用饮料后 180 分钟时 >500nM）处于可耐受的量。具体目标 1b：在这些受试者中，确定分级运动测试期间随机分组至 8 周 SET 或 PET 之间 COT、PWT 和 VO2peak 的差异。具体目标 2：确定 (a) 组织氧合（通过 NIRS）和 (b) NO 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-异前列烷）的差异在 SET 或 PET 后的跑步机测试中 具体目标 3：确定腓肠肌的差异（通过活检） (a) 血管生成和SET 或 PET 后的动脉生成（周围周细胞的毛细血管密度、增殖细胞核抗原和细胞凋亡）和氧化能力（纤维类型组成、柠檬酸合酶活性），以及 (b) 内皮功能（肱动脉 FMD）。 公共卫生相关性：外周动脉疾病 (PAD) 是一种由腿部动脉粥样硬化闭塞引起的心血管疾病 (CVD)。它影响了大约 5% 的 50 岁以上的美国人口，其中三分之一患有间歇性跛行 (IC)，其定义为行走时发生的缺血性腿部疼痛，休息后会改善。我们建议通过饮料补充血浆亚硝酸盐，我们可以（A）急剧改善缺血区域的氧合，（B）长期增加这些缺血区域的血管生长，从而提高急性运动耐力，减轻运动依从性的负担并促进功能和生活质量的更大改善