Vascular Dysfunction in CFS

描述（由申请人提供）：体位性心动过速综合征（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、正常和高血流。数据表明，一氧化氮（NO）和血管紧张素参与生产再分配血容量减少和交感神经兴奋。本申请的总体目标是确定CFS/POTS与生物可利用NO相关的机制，并探索CFS无POTS（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进行亚组，并根据外周血流量进行POTS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）和有和没有POTS的对照（N=30），以探索以下假设：1）低流量CFS/POTS是由于与增加的血管紧张素-II（A-II）和氧化应激相关的nNOS产生的生物可利用的NO减少。这增加了异前列腺素、3-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，皮内微透析法测量NO及其代谢产物，并使用局部加热（nNOS依赖性）和乙酰胆碱反应（eNOS依赖性）结合亚型选择性NOS抑制剂来证明低流量CFS/POTS的亚型依赖性。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患者局部循环和皮肤微血管NO依赖性反应。我们将同时测量低流量CFS/POTS患者的局部血流量/容量，并在氯沙坦给药前后进行皮肤局部加热和乙酰胆碱。3)在正常流动的CFS/POTS中产生亚硝化应激，NO增加。如在1）中，我们将测量NO并使用局部加热和乙酰胆碱反应与亚型选择性NOS抑制剂组合来确定正常流动CFS/POTS的亚型依赖性。皮肤施用生长激素抑制素可以减少皮肤NO过量。4)皮下注射奥曲肽，生长抑素类似物，减少直立内脏池和皮肤微血管NO依赖性反应在正常流量CFS/POTS。我们将测量正常血流CFS/POTS患者局部血流量和血容量的变化，并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）相关的血流异常在年轻CFS患者中产生主要残疾。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。

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.