Vascular Dysfunction in CFS

CFS 的血管功能障碍

• 批准号: 7597133
• 负责人: JULIAN M STEWART
• 金额: $ 38.57万
• 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/7597133
• 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; Impedance Plethysmography; 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; 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; nitrosative stress; 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）：体位性心动过速综合征（POTS）常发生在年轻的CFS患者身上。我们根据仰卧位血流将POTS患者分为三种血流模式——低、正常和高血流。数据表明一氧化氮（NO）和血管紧张素参与了再分配性低血容量和交感神经兴奋的产生。本申请的总体目的是明确CFS/POTS与生物可利用NO相关的机制，并探讨无POTS的CFS （CFS/~POTS）的亚临床微血管异常。我们将CFS患者（16-29岁）通过直立倾斜的POTS进行分组，并根据外周血流量对POTS进行分组。我们将比较低流量的锅（N=30）和正常流量的锅（N=30），以及有和没有锅的CFS/~锅（N=30）和对照（N=30），以探讨以下假设：1)低流量的CFS/锅是由于nNOS产生的生物可利用NO减少，与血管紧张素- ii （A-II）和氧化应激增加有关。这增加了异前列腺素，3-亚硝基酪氨酸和IL-6增加血管紧张素原。我们将用激光血流仪测量皮肤血流量，皮内微透析测量NO及其代谢物，并使用局部加热（nNOS依赖）和乙酰胆碱反应（eNOS依赖）联合异型选择性NOS抑制剂来证明低流量CFS/POTS的异型依赖性。我们将测试A-II受体阻滞剂氯沙坦是否能纠正皮肤血流。2)口服氯沙坦增加低流量CFS/POTS患者的局部循环和皮肤微血管NO依赖性反应。我们将在低流量CFS/POTS患者给予氯沙坦前后同时测量局部血流量/容量，并进行皮肤局部加热和乙酰胆碱。3)正常流动的CFS/POTS中NO升高，产生亚硝化应激。如1)中所述，我们将测量NO，并使用局部加热和乙酰胆碱反应结合异构体选择性NOS抑制剂来确定正常流动CFS/POTS的异构体依赖性。皮肤生长抑素可以减少皮肤NO的过量。4)皮下奥曲肽，一种生长抑素类似物，可减少正常血流CFS/POTS患者的直立性内脏池和皮肤微血管NO依赖性反应。我们将测量局部血流量和血容量的变化，并对正常血流的CFS/POTS患者在奥曲肽给药前后和倾斜期间进行皮肤局部加热和乙酰胆碱剂量反应。与体位性心动过速综合征（POTS）相关的血流异常是年轻CFS患者的主要残疾。这可能是由于一种叫做一氧化氮（NO）的基本信号分子的缺陷。在当前的应用中，我们将确定NO如何在CFS患者中产生POTS，以及改变NO的药物是否可以改善患者的健康。