Local Vasoconstriction in Postural Tachycardia Syndrome

姿势性心动过速综合征的局部血管收缩

• 批准号: 8293198
• 负责人: JULIAN M STEWART
• 金额: $ 38.21万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8293198
• 关键词: Accounting; Acute; Adrenergic Agents; Affect; Agreement; Allopurinol; American; Angiotensin II; Angiotensin II Receptor; Angiotensin II Type 1 Receptor Blockers; Antioxidants; Ascorbic Acid; Baroreflex; Binding; Bioavailable; Biopsy; Blood Circulation; Blood Vessels; Blood flow; Breathing; Chronic; Chronic Orthostatic Intolerance; Cross-Over Studies; Cutaneous; Cytochromes; Dose; Double-Blind Method; Epinephrine; Fluorometry; Functional disorder; Funding; Gene Expression; Gene Proteins; Heart Rate; Heating; High Pressure Liquid Chromatography; Human; Hydralazine; Hydrogen Peroxide; Immunofluorescence Immunologic; Intravenous; Intravenous infusion procedures; Label; Laser-Doppler Flowmetry; Leg; Life; Link; Losartan; Measurement; Measures; Mediating; Metabolism; Methods; Microdialysis; Microelectrodes; Molecular; Monosodium Salt Ascorbic Acid; Muscle; NADPH Oxidase; Nerve; Nervous system structure; Nitric Oxide; Nitric Oxide Synthase; Norepinephrine; Oral; Oxidases; Oxidative Stress; Pathway interactions; Patients; Peripheral; Peripheral Resistance; Peroxonitrite; Physiological; Placebo Control; Placebos; Plasma; Plethysmography; Production; Protein Isoforms; Proteins; Punch Biopsy; Reaction; Reactive Oxygen Species; Receptor, Angiotensin, Type 1; Reflex action; Regional Blood Flow; Regulation; Schools; Serum Albumin; Signal Transduction; Site; Skin; Source; Spectrophotometry; Staining method; Stains; Structure of popliteal artery; Superoxides; Sympathetic Nervous System; Symptoms; Syndrome; Tachycardia; Techniques; Testing; Therapeutic; Tissues; Translations; Tyrosine; Ultrasonography; Valsalva Maneuver; Work; Xanthine Oxidase; acetovanillone; adrenergic; antioxidant therapy; arm; ascorbate; base; drug testing; ebselen; femoral artery; glutathione peroxidase; healthy volunteer; improved; mRNA Expression; mimetics; nitration; peripheral blood; placebo controlled study; prevent; protein expression; public health relevance; receptor; research study; response; tempol; vasoconstriction; young woman

DESCRIPTION (provided by applicant): Chronic orthostatic intolerance takes the form of postural tachycardia syndrome (POTS) in many patients. One type of "Low flow POTS" (LFP) has increased vasoconstriction associated with increased angiotensin-II (Ang- II), reduced nitric oxide (NO), and increased reactive oxygen species (ROS). We hypothesize that LFP is due to increased central sympathetic activity or neurovascular sympathetic transduction caused by Ang-II binding to angiotensin type 1 receptors (AT1R) activating NADPH oxidase or Xanthine oxidase (XO) to produce ROS. ROS include superoxide which scavenges NO to produce peroxynitrite, and H2O2 which exerts important vasoactive and sympathetic effects. The proposal comprises two parts: the first explores causes of increased Ang-II; the second examines effects of Ang-II on oxidative stress, sympathetic activity and neurovascular transduction. Skin will continue as a surrogate tissue to explore NO, Ang-II and ROS. Studies will also explore connections among muscle sympathetic nerve activity (MSNA), peripheral blood flow, and arterial BP as well as potential treatments. The hypothesis will be tested by comparing patients with LFP (N=30), to patients with normal flow POTS (N=30), and to healthy volunteers (N=30) to answer the following questions: 1) Is cutaneous microvascular NO deficiency in LFP caused by Ang-II/oxidase induced oxidative stress? Experiments use intradermal microdialysis probes, laser Doppler flowmetry, and the NO-dependent local heating response to measure Ang-II and Ang-(1-7) in the skin, and to examine the effects of NADPH oxidase/XO blockade with apocynin/allopurinol, and superoxide/H2O2 reduction with tempol/ebselen. Intradermal ROS are measured using intracatheter reactions of superoxide and peroxynitrite while H2O2 is assessed using fluorescent spectrophotometry. We will determine if sodium ascorbate and losartan improve cutaneous NO and will correlate skin responses with systemic responses to intravenous ascorbic acid and oral losartan in later experiments. 2) Do cutaneous angiotensin-II receptors and NOS isoforms contribute to LFP? Skin punch biopsies will determine NOS-isoform, AT1R and AT2R, and ACE2 and ACE mRNA expression and protein content. 3) How do central sympathetic activation and neurovascular transduction contribute to vasoconstriction? Peroneal microneurography, popliteal artery ultrasound, and spontaneous BP oscillations will be used to assess MSNA, baroreflex activity, and the neurovascular transduction of MSNA to peripheral resistance. 4) Can intravenous infusion of the antioxidant ascorbic acid restore sympathetic activity, baroreflex function and orthostatic tolerance in LFP? The central and peripheral neurovascular effects will be examined. 5) Can chronic AT1R blockade with losartan restore sympathetic activity, baroreflex function and orthostatic tolerance? A double blind, placebo controlled study of chronic oral losartan treatment in LFP will be performed with reassessment of its effects on MSNA, baroreflex, and neurovascular transduction. PUBLIC HEALTH RELEVANCE: Chronic orthostatic intolerance due to the postural tachycardia syndrome (POTS) affects over a million Americans, mostly young women, who are prevented from gainful employ or school attendance. While a rapid heart rate (tachycardia) is the hallmark of the illness, patients often have activation of the sympathetic nervous system which remains unexplained. In the current proposal we will perform sophisticated tests of the circulation and nervous systems to study the causes and mechanisms in these patients and we will test drug treatments.

描述（由申请人提供）：慢性体位不耐受采用许多患者的姿势心动过速综合征（POTS）的形式。一种类型的“低流盆”（LFP）增加了与血管紧张素II（Ang-II）增加，一氧化氮（NO）和活性氧（ROS）增加的血管收缩增加。我们假设LFP是由于中枢性交感活性增加或由Ang-II与血管紧张素1型受体（AT1R）激活NADPH氧化酶或黄嘌呤氧化酶（XO）引起的血管紧张素引起的转导，从而产生ROS。 ROS包括清除脱氧化物以产生过氧亚硝酸盐的超氧化物，以及发挥重要的血管活性和交感神经作用的H2O2。该提案包括两个部分：第一个探讨了ANG-II增加的原因；第二个检查了ANG-II对氧化应激，交感神经活性和神经血管转导的影响。皮肤将继续作为替代组织，以探索否，Ang-II和ROS。研究还将探索肌肉交感神经活动（MSNA），外周血流量和动脉BP之间的联系以及潜在的治疗方法。该假设将通过将LFP患者（n = 30）与正常流动盆（n = 30）和健康志愿者（n = 30）进行比较（n = 30）来检验，以回答以下问题：1）是皮肤微血管无缺乏的，在由Ang-II/氧化酶诱导的氧化应激引起的LFP中？实验使用皮内微透析探针，激光多普勒流量和无依赖性的局部加热响应来测量皮肤中的Ang-II和Ang-（1-7），并检查NADPH氧化酶/XO酶与瞬间/杂素/无尿素/halopurinin的效果，用tempol/ebselen降低超氧化物/H2O2。使用超氧化物和过氧亚硝酸盐的运动内反应测量皮内ROS，而使用荧光分光光度法评估H2O2。我们将确定在以后的实验中，抗坏血酸钠和氯沙坦是否改善皮肤NO，并将皮肤反应与静脉注射抗坏血酸和口服Losartan的全身反应相关。 2）皮肤血管紧张素-II受体和NOS同工型是否有助于LFP？皮肤打孔活检将确定NOS-异型，AT1R和AT2R，ACE2和ACE mRNA表达和蛋白质含量。 3）中心交感神经激活和神经血管转导如何促进血管收缩？ Peroneal微功能学，popliteal动脉超声和自发的BP振荡将用于评估MSNA的MSNA和MSNA神经血管转导向外围耐药性。 4）在LFP中，静脉输注抗氧化剂抗坏血酸可以恢复交感神经活性，压力反射功能和体位耐受性吗？将检查中央和周围神经血管作用。 5）慢性AT1R可以通过Losartan恢复交感神经活动，压力反射功能和体位耐受性吗？通过重新评估其对MSNA，BaroreFlex和神经血管转导的影响，将对LFP进行慢性口服氯萨坦治疗的双盲，安慰剂对照研究。 公共卫生相关性：由于姿势心动过速综合征（POTS）导致的慢性体位不宽容会影响超过一百万的美国人，大多数是年轻妇女，这些妇女被阻止受益于有酬工作或上学。虽然心脏快速（心动过速）是疾病的标志，但患者通常会激活交感神经系统，但仍无法解释。在当前的建议中，我们将对循环系统和神经系统进行复杂的测试，以研究这些患者的原因和机制，我们将测试药物治疗。