Vascular Dysfunction in CFS

CFS 的血管功能障碍

基本信息

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
项目类别：
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

项目摘要

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）：姿势性心动过速综合征 (POTS) 经常困扰年轻的 CFS 患者。我们根据仰卧位血流将 POTS 患者分为三种血流状态：低血流、正常血流和高血流。数据表明一氧化氮（NO）和血管紧张素参与产生再分配血容量减少和交感神经兴奋。该应用的总体目标是定义与生物可利用的 NO 相关的 CFS/POTS 机制，并探索无 POTS 的 CFS (CFS/~POTS) 的亚临床微血管异常。我们将使用直立倾斜的 POTS 对 CFS 患者（16-29 岁）进行分组，并根据外周血流量对 POTS 进行亚组。我们将比较低流量 POTS (N=30) 和正常流量 POTS (N=30)、CFS/~POTS (N=30) 和对照 (N=30)（带或不带 POTS），以探索以下假设：1)低流量 CFS/POTS 是由于与血管紧张素-II (A-II) 增加和氧化应激相关的 nNOS 产生的生物可利用 NO 减少所致。这会增加异前列烷、3-亚硝基氨酸和 IL-6，从而增加血管紧张素原。我们将使用激光流量计测量皮肤血流量，通过皮内微透析测量NO及其代谢物，并使用局部加热（nNOS依赖性）和乙酰胆碱反应（eNOS依赖性）与同种型选择性NOS抑制剂相结合来证明低流量CFS/POTS的同种型依赖性。我们将测试 A-II 受体阻滞剂氯沙坦是否可以纠正皮肤血流。 2) 口服氯沙坦可增加低流量 CFS/POTS 中的局部循环和皮肤微血管 NO 依赖性反应。我们将同时测量局部血流量/容量，并在低流量 CFS/POTS 患者服用氯沙坦之前和之后进行皮肤局部加热和乙酰胆碱治疗。 3)正常流程CFS/POTS中NO增加，产生亚硝化应激。如 1) 中所示，我们将测量 NO 并使用局部加热和乙酰胆碱反应以及异构体选择性 NOS 抑制剂来确定正常流量 CFS/POTS 的异构体依赖性。皮肤生长抑素给药可以减少皮肤NO过量。 4) 皮下注射奥曲肽（一种生长抑素类似物）可减少正常血流 CFS/POTS 中的直立性内脏汇集和皮肤微血管 NO 依赖性反应。我们将测量正常血流 CFS/POTS 患者的局部血流量和血容量的变化，并在奥曲肽给药前后以及倾斜期间进行皮肤局部加热和乙酰胆碱剂量反应。与姿势性心动过速综合征 (POTS) 相关的血流异常会导致年轻 CFS 患者出现严重残疾。这可能是由于称为一氧化氮 (NO) 的基本信号分子的缺陷造成的。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。