AUTONOMIC PATHOPHYSIOLOGY OF ORTHOSTATIC INTOLERANCE

直立不耐受的自主病理生理学

• 批准号: 6242728
• 负责人: DAVID HERLIE ROBERTSON
• 金额: $ 18.83万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-20 至 1998-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6242728
• 关键词: autonomic nervous system; clinical research; disease /disorder classification; disease /disorder etiology; human subject; hypovolemia; nervous system disorder; neuroregulation; norepinephrine; pathologic process; postural hypotension; tachycardia

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.

直立性不耐受是最常见的 自主神经功能障碍和许多残疾的原因。多达50万 美国人深受其害，但它是研究最少的疾病之一。 没有既定的治疗方法。其病因学知之甚少，但 假设是异质的。 在这个项目中，我们提出了一个潜在的机制，直立 不耐受，这可能代表了与 很大一部分或可能是大多数患者。我们 检验这些患者的亚组具有部分或 远端自主神经功能障碍，引起血液汇集的临床综合征， 盐浪费，血浆容量不足，尝试但不充分 的相对完整的近端自主神经支配的补偿 心 证明部分或远端自主神经功能障碍导致直立性 在某些患者中，必须满足几个标准。一是 必须是交感神经去甲肾上腺素能神经系统局部受损的证据 系统，而这一证据应基于生物化学，生理学 和药理学标准。第二，减值应大于 远端（下肢）部位比近端（心脏）部位更明显。第三、 应该保留中央自主控制。 最后，去神经 超敏反应应该是最大的地区，其中植物神经功能障碍是 最广泛的。 这一意想不到的发现，抑制血浆肾素水平发生在 这些患者，很大程度上与低血容量成正比， 尽管直立性心动过速和血浆去甲肾上腺素水平升高， 可能是导致血容量不足的关键损伤。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和正文指定部分）。 这种疾病的成功机制特征应该导致 改善诊断和合理设计治疗， 出现先前无法解释的病理性 立位不耐受