Local Vasoconstriction in Postural Tachycardia Syndrome

描述（由申请人提供）：体位性心动过速综合征（POTS）是慢性直立不耐受的最常见原因，至少影响100万美国人。 POTS不是一种单一的疾病，而是一种病理生理学类别，其特征在于与血管调节受损相关的心脏静脉回流减少。 我们的长期目标是识别和治疗POTS中的血管功能障碍。 初步数据表明，年轻人的POTS分为三组：a）肾上腺素能介导的血管收缩减少，产生外周血管舒张; B）内脏静脉收缩缺陷，产生静脉汇集; c）局部血管控制异常，产生外周动脉血管收缩、静脉收缩和外周血流量减少。 最后一组是本提案的重点。 我们假设局部血管缺陷与内皮功能障碍和一氧化氮（NO）分泌减少有关，这在皮肤中是显而易见的。 我们将通过对200名潜在受试者进行直立倾斜试验，并将其与30名健康志愿者进行比较，确定30名低流量POTS患者和30名高流量POTS患者：1）为了验证局部NO释放受损的假设，我们将使用激光多普勒血流仪（LDF）结合反应性充血和热充血测量（局部加热至42 ° C）以显示有缺陷的流动介导的血管舒张。 我们预测通过微透析降低的组织NO代谢物（NOx）水平，降低的NO合成酶抑制剂硝基-L-精氨酸（NLA）对NOx产生和LDF的影响，以及对皮肤乙酰胆碱的钝化剂量反应，但对作为受体介导的内皮依赖性和非依赖性血管扩张剂的硝普钠（SNP）没有钝化剂量反应;我们将确定局部SNP是否恢复血流介导的充血;我们将给予酚妥拉明以证实肾上腺素能机制不是血管收缩的主要原因。 2)我们将使用活体显微镜的手和脚甲床，以测试微血管收缩和静脉收缩相关的微血管大小或增强白细胞粘附的显微解剖学证据。 3)我们将通过测量前臂和小腿的血容量、钠排泄分数、血管电容、外周血流量、动脉和静脉阻力以及局部血管特性来检验小腿静脉高血压、静脉电容和静脉阻力与局部血管功能障碍相关的假设，并将这些与使用前臂和小腿静脉闭塞体积描记法进行的微血管测量相关。 这些假说将提高我们诊断和治疗人类血管病理生理学的一个重要原因的能力。

DESCRIPTION (provided by applicant): Postural tachycardia syndrome (POTS) is the most common cause of chronic orthostatic intolerance affecting at least one million Americans. POTS is not a single disease but rather a pathophysiological category characterized by decreased cardiac venous return related to impaired vascular regulation. Our long-term objective is to identify and treat vascular dysfunction in POTS. Preliminary data indicate that POTS in the young segregates into three groups: a) reduced adrenergic-mediated vasoconstriction producing peripheral vasodilation; b) defective splanchnic venoconstriction producing venous pooling; and c) abnormal local vascular control producing peripheral arterial vasoconstriction, venoconstriction and decreased peripheral blood flow. This last group is the focus of the current proposal. We hypothesize that local vascular defects relate to endothelial dysfunction and reduced nitric oxide (NO) secretion which is demonstrable in the skin. We will identify 30 low flow POTS patients and 30 high flow POTS patients by upright tilt tests of 200 potential subjects comparing them to 30 healthy volunteers: 1) To test the hypothesis that local NO release is impaired we will use laser Doppler flowmetry (LDF) combined with reactive hyperemia and thermal hyperemia measurements (local heating to 42 degrees C) to show defective flow mediated vasodilation. We predict reduced tissue levels of NO metabolites (NOx) by microdialysis, decreased effects of the NO synthase inhibitor nitro-L-arginine (NLA) on NOx production and LDF, and blunted dose-response to cutaneous acetylcholine but not to sodium nitroprusside (SNP) as receptor mediated endothelial-dependent and independent vasodilators; we will determine if local SNP restores flow mediated hyperemia; and we will administer phentolamine to verify that adrenergic mechanisms are not the primary cause of vasoconstriction. 2) We will use intravital microscopy of the hand and foot nailbeds to test for microanatomic evidence of vasoconstriction and venoconstriction related to microvascular size or enhanced leukocyte adhesion. 3) We will test the hypotheses that calf venous hypertension, venous capacitance and venous resistance are related to local vascular dysfunction by measuring blood volume, fractional excretion of sodium, vascular capacitance, peripheral blood flow, arterial and venous resistance, and local vascular properties in the forearm and calf and relate these to microvascular measurements using venous occlusion plethysmography in the forearm and calf. Verifying these hypotheses will improve our ability to diagnose and treat an important cause of vascular pathophysiology in man.