AUTONOMIC PATHOPHYSIOLOGY OF ORTHOSTATIC INTOLERANCE

直立不耐受是最常见的 自主性障碍和许多残疾的原因。多达500,000 美国人受到它的影响。然而，它是研究最少的疾病之一。 目前还没有既定的治疗方法。其病因尚不清楚，但确实如此。 假定是异质的。 在这个项目中，我们提出了一种潜在的直立位机制 不耐受，这可能代表了与 这一患者群体中的很大一部分或可能是大多数。我们 测试假设，这些患者的子组有部分或 远端自主神经功能障碍，导致临床上的血液凝集综合征， 盐分浪费，血浆容量不足，尝试但不足 相对完整的近端自主神经支配的代偿 心。 为了证明部分或远端自主神经障碍导致直立 对于一些患者的不耐受，必须满足几个标准。首先，在那里 一定是交感神经去甲肾上腺素能局部受损的证据 系统，这一证据应该建立在生化、生理 和药理学标准。第二，减值幅度应更大 远端(肢体)部位多于近端(心脏)部位。第三, 应该保留中央自主控制。最后，去神经 自主神经紊乱的区域应该是最敏感的。 最广泛的。 一项意想不到的发现抑制了血浆肾素水平 这些患者，很大程度上与低血容量成正比，并且，在 尽管有直立性心动过速和血浆去甲肾上腺素水平升高， 可能是导致低血容量的关键损伤。自.以来 初步提交，我们有许多新的初步数据与我们的 假设(见图1、2、12、13和指定的正文部分。 这种疾病的成功的机械性特征应该导致 对提高诊断率和合理设计治疗方案具有重要意义 出现之前未解释的病理性疾病的部分患者 直立不耐受。

Orthostatic intolerance is the most frequently encountered dysautonomia and the cause of much disability. As many as 500,000 Americans are affected by it. Yet it is one of the least studied diseases. There is no established therapy. Its etiology is poorly understood, but is assumed to be heterogeneous. In this project, we propose a potential mechanism for orthostatic intolerance, which may represent the pathophysiology relevant to a significant portion or perhaps a majority of this patient population. We test the hypothesis that the subgroup of these patients have partial or distal dysautonomia, giving rise to a clinical syndrome of blood pooling, salt wasting, inadequate plasma volume, and attempted but inadequate compensation of a relatively intact proximal autonomic innervation of the heart. To prove that a partial or distal dysautonomia causes orthostatic intolerance in some patients, several criteria must be met. First, there must be evidence of local impairment in the sympathetic noradrenergic system, and this evidence should be based on biochemical, physiological and pharmacological criteria. Second, the impairment should be greater at distal (lower extremity) sites than at proximal (cardiac) sites. Third, central autonomic control should be preserved. Finally, denervation hypersensitivity should be greatest in the areas where the dysautonomia is most extensive. The unexpected finding that suppressed plasma renin levels occur in these patients, largely in direct proportion to the hypovolemia, and, in spite of orthostatic tachycardia and raised plasma norepinephrine levels, could be the crucial impairment that results in the hypovolemia. Since the initial submission, we have much new preliminary data congruent with our hypothesis (see figures 1,2,12,13 and the designated sections of text. Successful mechanistic characterization of this disorder should lead to improved diagnosis and the rational design of therapy in a significant portion of individuals presenting with previously unexplained pathological orthostatic intolerance.