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: 8103920
• 负责人: JULIAN M STEWART
• 金额: $ 38.79万
• 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/8103920
• 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; Woman; 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

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）：许多患者的慢性直立性不耐受表现为体位性心动过速综合征（POTS）。一种类型的“低流量 POTS”(LFP) 具有与血管紧张素 II (Ang-II) 增加、一氧化氮 (NO) 减少和活性氧 (ROS) 增加相关的血管收缩增加。我们推测 LFP 是由于 Ang-II 与血管紧张素 1 型受体 (AT1R) 结合，激活 NADPH 氧化酶或黄嘌呤氧化酶 (XO) 产生 ROS，引起中枢交感神经活动或神经血管交感神经转导增加。 ROS包括清除NO产生过氧亚硝酸盐的超氧化物和发挥重要血管活性和交感神经作用的H2O2。该提案包括两部分：第一部分探讨Ang-II增加的原因；第二部分探讨Ang-II增加的原因。第二个研究检查 Ang-II 对氧化应激、交感神经活动和神经血管转导的影响。皮肤将继续作为替代组织来探索 NO、Ang-II 和 ROS。研究还将探索肌肉交感神经活动（MSNA）、外周血流量和动脉血压之间的联系以及潜在的治疗方法。该假设将通过比较 LFP 患者 (N=30)、血流正常 POTS 患者 (N=30) 和健康志愿者 (N=30) 来回答以下问题来检验： 1) 皮肤微血管 NO 是否缺乏在由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、激光多普勒血流计和 NO 依赖性局部加热反应来测量皮肤中的 Ang-II 和 Ang-(1-7)，并检查夹竹桃麻素/别嘌呤醇对 NADPH 氧化酶/XO 阻断的影响，以及用 tempol/ebselen 还原超氧化物/H2O2。皮内 ROS 使用超氧化物和过氧亚硝酸盐的导管内反应进行测量，而 H2O2 使用荧光分光光度法进行评估。我们将在以后的实验中确定抗坏血酸钠和氯沙坦是否改善皮肤一氧化氮，并将皮肤反应与静脉注射抗坏血酸和口服氯沙坦的全身反应相关联。 2) 皮肤血管紧张素-II 受体和 NOS 亚型是否有助于 LFP？皮肤穿刺活检将测定 NOS 同工型、AT1R 和 AT2R、ACE2 和 ACE mRNA 表达和蛋白质含量。 3）中枢交感神经激活和神经血管转导如何促进血管收缩？腓骨显微神经造影、腘动脉超声和自发血压振荡将用于评估 MSNA、压力反射活动以及 MSNA 对外周阻力的神经血管转导。 4) 静脉输注抗氧化剂抗坏血酸能否恢复 LFP 的交感神经活性、压力反射功能和直立耐受性？将检查中枢和周围神经血管的影响。 5) 用氯沙坦长期阻断 AT1R 能否恢复交感神经活动、压力感受反射功能和直立耐受性？将进行一项长期口服氯沙坦治疗 LFP 的双盲、安慰剂对照研究，重新评估其对 MSNA、压力反射和神经血管转导的影响。 公共卫生相关性：由于体位性心动过速综合征 (POTS) 导致的慢性直立性不耐受影响了超过 100 万美国人，其中大部分是年轻女性，她们无法获得有酬就业或上学。虽然心率过快（心动过速）是该疾病的标志，但患者的交感神经系统经常被激活，而这种情况仍无法解释。在当前的提案中，我们将对循环和神经系统进行复杂的测试，以研究这些患者的病因和机制，并将测试药物治疗。