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)是影响至少100万美国人的慢性直立不耐受的最常见原因。POTS不是一种单一的疾病，而是一种病理生理类型，其特征是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的血管功能障碍。初步数据显示，年轻人的POTS分为三组：a)肾上腺素介导的血管收缩减少，产生外周血管扩张；b)内脏静脉收缩缺陷，导致静脉聚集；c)局部血管控制异常，导致外周动脉血管收缩，静脉收缩和外周血流量减少。这最后一组是当前提案的重点。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，这在皮肤中是明显的。我们将通过200名潜在受试者的直立倾斜试验来确定30名低流量POTS患者和30名高流量POTS患者，并将他们与30名健康志愿者进行比较：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摄氏度)来显示血流介导的血管扩张缺陷。我们预测微透析可以降低组织中NO代谢产物(NOx)的水平，NO合成酶抑制剂硝基-L-精氨酸(NLA)对NOx产生和LDF的影响减少，对作为受体介导的内皮依赖性和非依赖性血管扩张剂的皮肤乙酰胆碱而不是硝普钠(SNP)的剂量反应减弱；我们将确定局部SNP是否能恢复血流介导的充血；我们将给予酚妥拉明来验证肾上腺素机制不是血管收缩的主要原因。2)我们将使用手和脚甲床的活体显微镜来测试血管收缩和静脉收缩的显微解剖学证据，这些证据与微血管大小或白细胞粘附性增强有关。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、动静脉阻力和局部血管特性来验证小腿静脉高压、静脉容量和静脉阻力与局部血管功能障碍有关的假设，并将这些与使用前臂和小腿静脉闭塞体积图的微血管测量相关联。 验证这些假设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.