ANTI-AUTONOMIC RECEPTOR ANTIBODIES IN DIABETIC ORTHOSTATIC HYPOTENSION

抗自主受体抗体治疗糖尿病直立性低血压

• 批准号: 8360285
• 负责人: Xichun Yu
• 金额: $ 7.23万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-09-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360285
• 关键词: Adrenergic Agents; Adverse effects; Agonist; Antibodies; Antibody Activation; Autoantibodies; Autonomic Dysfunction; Biochemical; Biological Assay; Blood Pressure; Blood Vessels; Cardiac; Cardiovascular system; Cerebrum; Coronary; Data; Diabetes Mellitus; Drops; Fc Receptor; Frequencies; Frustration; Functional disorder; Funding; Grant; Heart Diseases; Heart Rate; Injury; Lead; Mentors; Muscarinics; National Center for Research Resources; Oklahoma; Orthostatic Hypotension; Patients; Perfusion; Pharmaceutical Preparations; Physicians; Principal Investigator; Pulse Rates; Quality of life; Relative (related person); Research; Research Infrastructure; Resources; Rest; Role; Signs and Symptoms; Skeletal Muscle; Source; Stroke; Subgroup; Therapeutic; United States National Institutes of Health; Vasodilation; adrenergic; arteriole; chronotropic; cost; diabetic; diabetic patient; falls; novel; oxybutynin; receptor; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Orthostatic hypotension, a sudden, significant drop in blood pressure upon standing, is often associated with diabetes and has many causes. It is a major cause of stroke, exacerbates coexisting coronary or cerebral perfusion, causes falls and injury, impaired quality of life and complicates concurrent medication use. These consequences are exaggerated in the diabetic patient and lead to patient and physician frustration because the therapeutic options have side effects and are frequently ineffective. Very little new data exists relating to the pathophysiology of orthostatic hypotension. We are the first to identify the presence of agonist-like autoantibodies to the autonomic receptors that control major autonomic vascular and cardiac activity in a subgroup of patients with orthostatic hypotension, and to demonstrate their pathophysiological role in such patients. These autoantibodies, often occurring in clusters and observed in patients with diabetes and concurrent cardiac diseases which often have associated orthostatic hypotension, demonstrated significant capacity to activate their respective receptors in biochemical and functional assays. Depending on their relative concentrations and activity, these antibodies produced a spectrum of autonomic dysfunction. In antibody-positive patients, those with rapid resting heart rate had antibodies with predominantly beta-adrenergic activity (positive chronotropic effect), while those with a relatively slow resting heart rate and impaired pulse rate response in the face of orthostatic hypotension had antibodies with predominantly muscarinic activity (negative chronotropic effect). Antibodies to the vasodilatory receptors (beta2-adrenergic and M3 muscarinic) produced an expected potent vasodilatation in the skeletal muscle arteriole assay, suggesting these antibodies may contribute to systemic vasodilatation. A few patients treated with muscarinic blockade (oxybutynin) showed decreased orthostatic symptoms and signs. These data support the hypothesis that antibody activation of autonomic receptors may cause or exacerbate orthostatic hypotension by altering the underlying postural cardiovascular response. Our novel study is the first to examine the association of these autoantibodies in patients with orthostatic hypotension by characterizing the functional effect on their host. These data are also useful in identifying the frequency of their occurrence, their pathophysiological significance and developing therapeutic strategies that pharmacologically target these antibodies.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 体位性低血压，直立时血压突然显着下降，通常与糖尿病有关，并且有许多原因。这是中风的主要原因，加剧了并存冠状动脉或脑灌注，导致跌倒和受伤，生活质量受损，并使并发药物使用复杂。这些后果在糖尿病患者中被夸大，导致患者和医师的挫败感，因为治疗选择具有副作用，并且经常无效。与体位性低血压的病理生理学有关的新数据很少。我们是第一个确定对自主神经受体存在类似激动剂的自身抗体的存在的人，这些自主神经受体控制着具有体位性低血压的患者亚组中主要的自主性血管和心脏活性，并在此类患者中证明了其病理生理作用。这些自身抗体通常发生在簇中，并在糖尿病和同时患有相关的体位性低血压的患者中观察到，在生化和功能分析中激活其各自的受体表现出显着的能力。根据它们的相对浓度和活性，这些抗体产生了各种自主功能障碍。在抗体阳性患者中，患有快速静息心率的患者的抗体主要具有β-肾上腺素能活性（阳性的年度表现效应），而那些患有相对较慢的静息心率和相对较慢的脉搏频率反应受损的抗体，正处于体位性低位时，主要具有抗体。毒蕈碱活性（阴性的表现效应）。对血管舒张受体（β2-肾上腺素和M3毒蕈碱）的抗体产生了预期的骨骼肌动脉肌肉分析的有效血管舒张，这表明这些抗体可能有助于全身性血管舒张。一些接受毒蕈碱封锁治疗（Oxybutynin）治疗的患者表现出降低的体位症状和体征。这些数据支持以下假设：自主受体的抗体激活可能会通过改变潜在的左心血管反应来引起或加剧体位性低血压。我们的新研究是第一个检查这些自身抗体在体位性低血压患者中的关联，通过表征对宿主的功能作用。这些数据也可用于确定其发生的频率，其病理生理意义和制定药理靶向这些抗体的治疗策略。