Dopamine-B-Hydroxylase in Human Cardiovascular Control

多巴胺-B-羟化酶在人类心血管控制中的作用

• 批准号: 7467804
• 负责人: DAVID HERLIE ROBERTSON
• 金额: $ 38.38万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7467804
• 关键词: Activities of Daily Living; Affect; Agonist; American; Applications Grants; Aromatic-L-Amino-Acid Decarboxylases; Blood Plasma Volume; Blood Pressure; Blood Volume; Carbidopa; Cardiovascular Diseases; Cardiovascular system; Chronic; Clinical Treatment; Condition; Data; Diet; Disabled Persons; Disease; Dopa; Dopamine; Dopamine Receptor; Dysautonomias; Emotional; Excretory function; Exercise; Exertion; Fatigue; Fenoldopam; Functional disorder; Goals; Headache; Heart Rate; Hereditary Disease; Human; Hypovolemia; Individual; Infusion procedures; Intake; Intervention; Investigation; Kidney; Knowledge; Lead; Mediating; Mixed Function Oxygenases; Monitor; Mutation; Natriuresis; Neuropathy; Norepinephrine; Orthostatic Hypotension; Palpitations; Patients; Pharmacotherapy; Plasma; Posture; Predisposition; Public Health; Purpose; Regulation; Relative (related person); Research Personnel; Role; Scheme; Sodium; Sodium Chloride; Symptoms; Syncope; Syndrome; Tachycardia; Testing; Therapeutic; Urine; Woman; experience; falls; hemodynamics; improved; noradrenaline transporter; novel; response; saluretic; urinary

DESCRIPTION (provided by applicant): Postural tachycardia syndrome (POTS) is the most common form of orthostatic intolerance, affecting an estimated 500,000 Americans, principally young women. Patients typically experience symptoms of excessive sympathetic activation with physical or emotional exertion. Upright heart rate and plasma norepinephrine are elevated. Many patients are also disabled by chronic fatigue. No genuinely effective therapy for POTS has emerged. The long-term goal of this project remains to find the fundamental causes of orthostatic intolerance and discover appropriate treatment. The most constant hemodynamic feature in POTS is hypovolemia, but the cause of this abnormality has been elusive. Our recent studies in these patients have motivated us to propose a novel dopaminergic mechanism contributing to the pathophysiology of POTS. POTS patients appear to have an impaired capacity to conserve sodium. We find that dopamine levels are unexpectedly elevated in both plasma and urine of these patients. Several investigators have implicated dopamine in the control of natriuresis in other disorders. Approximately 50% of sodium excretion appears to be under dopaminergic regulation. To test the hypothesis that impaired sodium handling by renal dopamine contributes to the hypovolemia of POTS, investigations of POTS patients and normal controls will be undertaken with careful control of sodium intake and monitoring of urinary sodium and dopamine excretion. Initial studies will determine the extent to which sodium administration engages systemic and renal dopamine and stimulates natriuresis in POTS. Additional specific aims are directed at assessing the relative dopaminergic and natriuretic responses to interventions aimed at (1) increasing plasma dopa, (2) blocking L-aromatic amino acid decarboxylase, and (3) antagonizing renal dopamine. These studies should define the role of dopamine in POTS. If hyperdopaminergic renal mechanisms do indeed underlie the hypovolemia of POTS, a specific and safe pharmacotherapy, carbidopa, will be tested for efficacy in overcoming the volume deficit in this disorder and improving the functional capacity of affected patients. PUBLIC HEALTH RELEVANCE: Postural tachycardia syndrome (POTS) is a common disorder in young women, impairing their functional capacity through symptoms like weakness, palpitations, fatigue, headaches, and exercise intolerance. The purpose of this grant proposal is to understand the abnormally low volume of blood in these patients. This knowledge will permit trials of treatment targeted at making the blood volume normal and improving symptoms in these patients

描述（由申请人提供）：姿势性心动过速综合征 (POTS) 是最常见的直立性不耐受形式，影响估计 500,000 名美国人，其中主要是年轻女性。患者通常会因体力或情绪消耗而出现交感神经过度激活的症状。直立心率和血浆去甲肾上腺素升高。许多患者还因慢性疲劳而致残。目前尚未出现真正有效的 POTS 治疗方法。该项目的长期目标仍然是找到直立不耐受的根本原因并找到适当的治疗方法。 POTS 最恒定的血流动力学特征是血容量不足，但这种异常的原因一直难以捉摸。我们最近对这些患者的研究促使我们提出一种新的多巴胺能机制，有助于 POTS 的病理生理学。 POTS 患者似乎保存钠的能力受损。我们发现这些患者的血浆和尿液中的多巴胺水平出人意料地升高。一些研究人员发现多巴胺参与了其他疾病中尿钠排泄的控制。大约 50% 的钠排泄似乎受到多巴胺能调节。为了检验肾脏多巴胺钠处理受损导致 POTS 血容量不足的假设，将对 POTS 患者和正常对照进行研究，仔细控制钠摄入量并监测尿钠和多巴胺排泄。初步研究将确定钠给药在多大程度上参与全身和肾脏多巴胺并刺激 POTS 中的尿钠排泄。其他具体目标旨在评估干预措施的相对多巴胺能和利尿钠反应，这些干预措施旨在（1）增加血浆多巴，（2）阻断L-芳香族氨基酸脱羧酶，以及（3）拮抗肾脏多巴胺。这些研究应该明确多巴胺在 POTS 中的作用。如果多巴胺能过多的肾脏机制确实是 POTS 低血容量的基础，则将测试一种特异性且安全的药物疗法卡比多巴在克服这种疾病的容量不足和改善受影响患者的功能能力方面的功效。公共卫生相关性：姿势性心动过速综合征 (POTS) 是年轻女性的一种常见疾病，通过虚弱、心悸、疲劳、头痛和运动不耐受等症状损害她们的功能能力。该拨款提案的目的是了解这些患者异常低的血容量。这些知识将允许进行旨在使这些患者的血容量正常并改善症状的治疗试验