Vascular Dysfunction in CFS

CFS 的血管功能障碍

• 批准号: 7364034
• 负责人: JULIAN M STEWART
• 金额: $ 37.63万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7364034
• 关键词: 3-nitrotyrosine; Accounting; Acetylcholine; Adrenergic Agents; Amides; Angiotensin II; Angiotensin II Receptor; Angiotensin Receptor; Angiotensinogen; Angiotensins; Attenuated; Bioavailable; Biochemical; Biological Assay; Biological Availability; Blood Circulation; Blood Vessels; Blood Volume; Blood flow; Cardiac Output; Chronic Fatigue Syndrome; Classification Scheme; Cutaneous; Data; Defect; Dependence; Dose; Filtration; Flowmetry; Functional disorder; Health; Heart Rate; Heating; Hypovolemia; Interleukin-6; Isometric Exercise; Isoprostanes; Laser-Doppler Flowmetry; Lasers; Life; Losartan; Measurement; Measures; Mediating; Microdialysis; Microelectrodes; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nitroarginine; Octreotide; Oral; Oxidative Stress; Pallor; Patients; Peripheral; Peripheral Nervous System Diseases; Peripheral Resistance; Peroxonitrite; Pharmaceutical Preparations; Phenotype; Phentolamine; Plasma; Plethysmography; Protein Isoforms; Regional Blood Flow; Regulation; Signaling Molecule; Skin; Somatostatin; Stimulus; Stress; Stroke Volume; Subgroup; Superoxides; Syndrome; Tachycardia; Techniques; Testing; Tissues; Valsalva Maneuver; Vasodilation; Venous; Viral; adrenergic; aged; aminoguanidine; base; blood flow impedance; disability; hemodynamics; improved; inhibitor/antagonist; peripheral blood; receptor; response; somatostatin analog; subcutaneous; vasoconstriction; volunteer

DESCRIPTION (provided by applicant): Postural tachycardia syndrome (POTS) often afflicts younger CFS patients. We classified POTS patients into three flow regimes - low, normal, and high flow based on supine blood flow. Data suggest the involvement of nitric oxide (NO) and angiotensin in producing redistributive hypovolemia and sympathoexcitation. The overall objective of the application is to define mechanisms of CFS/POTS related to bioavailable NO, and to explore the subclinical microvascular abnormalities in CFS without POTS (CFS/~POTS). We will subset CFS patients (16-29 years) by POTS using upright tilt, and subgroup POTS based on peripheral blood flow. We will compare low flow POTS (N=30) and normal flow POTS (N=30), to CFS/~POTS (N=30) and control (N=30) with and without POTS to explore the following hypotheses: 1) Low flow CFS/POTS is due to decreased bioavailable NO produced by nNOS related to increased angiotensin-II (A-II) and oxidative stress. This increases isoprostanes, 3- nitrityrosine, and IL-6 increasing angiotensinogen. We will measure skin blood flow with laser flowmetry, NO and its metabolites by intradermal microdialysis, and use local heating (nNOS dependent) and acetylcholine response (eNOS dependent) combined with isoform selective NOS inhibitors to demonstrate isoform dependence of low flow CFS/POTS. We will test whether A-II receptor blocker, losartan, corrects cutaneous flow. 2) Oral losartan increases regional circulation and cutaneous microvascular NO dependent responses in low flow CFS/POTS. We will simultaneously measure regional blood flows/volumes, and perform cutaneous local heating and acetylcholine before and after losartan administration in low flow CFS/POTS patients. 3) NO is increased in normal flow CFS/POTS producing nitrosative stress. As in 1) we will measure NO and use local heating and acetylcholine response combined with isoform selective NOS inhibitors to ascertain isoform dependence of normal flow CFS/POTS. Cutaneous somatostatin administration can reduce skin NO excess. 4) Subcutaneous octreotide, a somatostatin analog, reduces orthostatic splanchnic pooling and cutaneous microvascular NO dependent responses in normal flow CFS/POTS. We will smeasure changes in regional blood flows and blood volumes, and perform cutaneous local heating and acetylcholine dose-response before and after octreotide administration and during tilt in normal flow CFS/POTS patients. Blood flow abnormalities associated with the postural tachycardia syndrome (POTS) produce major disability in younger CFS patients. These may be due to defects in a fundamental signaling molecule called nitric oxide (NO). In the current application we will determine how NO produces POTS in CFS patients and whether drugs that alter NO can improve patient health.

描述（由申请人提供）：姿势心动过速综合征（POTS）经常折磨年轻的CFS患者。我们将POTS患者分为三个流动状态 - 基于仰卧流动的低，正常和高流量。数据表明，一氧化氮（NO）和血管紧张素参与产生再分配低血容量和交感神经兴趣。该应用的总体目的是定义与生物可用性NO相关的CFS/POTS的机制，并探索没有POTS的CFS中的亚临床微血管异常（CFS/〜Pots）。我们将使用直立倾斜的锅和基于外周血流量的亚组盆中的盆中将CFS患者（16-29岁）子组成。我们将比较低流盆（n = 30）和正常流量盆（n = 30），cfs/〜锅（n = 30）和对照（n = 30），有或没有盆中以探索以下假设：1）低流量CFS/锅是由于NNOS与NNOS相关的生物含量降低而与Angiotenin-Ii-II-II-II-II II-I-II-II-II-I-II-I-II II-I-II-II-I-II II-I-II-II-II-II-II-II-II-II II（A-A-II）相关。这增加了异前列腺，3-硝基胺和IL-6增加血管紧张素原。我们将通过激光流量金属测量皮肤血​​流，NO及其代谢产物通过皮内微透析，并使用局部加热（NNOS依赖性）和乙酰胆碱反应（ENOS依赖性）与同种型NOS NOS抑制剂相结合，以证明低流量CFS/POTS的同一个同类抑制剂。我们将测试A-II受体阻滞剂Losartan是否纠正皮肤流量。 2）口服Losartan在低流量CFS/POTS中增加了区域循环和皮肤微血管无依赖性反应。我们将同时测量区域血液流量/体积，并在低流量CFS/POTS患者的劳萨坦给药之前和之后进行皮肤局部加热和乙酰胆碱。 3）在正常流量CFS/盆中产生亚硝化应激的正常流量增加。如1）我们将测量NO并使用局部加热和乙酰胆碱反应，并结合了同工型选择性NOS抑制剂来确定正常流量CFS/POTS的同工型依赖性。皮肤生长抑素给药可以减少皮肤没有过多。 4）在正常流量CFS/POTS中，降低原位的斑点合并和皮肤微血管无依赖性反应。我们将缩略于区域血液流量和血量的变化，并在给药前后进行皮肤局部加热和乙酰胆碱剂量反应以及在正常流量CFS/POTS患者中倾斜期间的倾斜度。与姿势心动过速综合征（POTS）相关的血流异常会在年轻的CFS患者中产生主要的残疾。这些可能归因于称为一氧化氮（NO）的基本信号分子中的缺陷。在当前的应用中，我们将确定CFS患者中没有生产盆以及改变NO的药物是否可以改善患者的健康状况。