ANTI-AUTONOMIC RECEPTOR ANTIBODIES IN DIABETIC ORTHOSTATIC HYPOTENSION

这个子项目是利用资源的许多研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， NCRR赠款不直接向子项目或子项目工作人员提供资金。 直立性低血压是站立时血压突然显著下降，通常与糖尿病有关，有多种原因。它是卒中的主要原因，加重共存的冠状动脉或脑灌注，导致福尔斯和损伤，降低生活质量，并使同时使用药物变得复杂。这些后果在糖尿病患者中被夸大，并导致患者和医生沮丧，因为治疗选择具有副作用并且经常无效。关于直立性低血压的病理生理学的新资料很少。我们是第一个确定存在的激动剂样自身抗体的自主受体，控制主要的自主血管和心脏活动的一个亚组的患者直立性低血压，并证明其在这些患者的病理生理作用。这些自身抗体通常成簇出现，并在糖尿病和并发心脏病患者中观察到，这些患者通常伴有直立性低血压，在生化和功能测定中显示出激活其各自受体的显著能力。根据它们的相对浓度和活性，这些抗体产生一系列自主神经功能障碍。在抗体阳性患者中，静息心率较快的患者抗体主要具有β-肾上腺素能活性（正变时性效应），而静息心率相对较慢且直立性低血压时脉率反应受损的患者抗体主要具有毒蕈碱活性（负变时性效应）。血管舒张受体（β 2-肾上腺素能和M3毒蕈碱）抗体在骨骼肌小动脉试验中产生预期的强效血管舒张作用，表明这些抗体可能有助于全身血管舒张。少数接受毒蕈碱阻滞剂（奥昔布宁）治疗的患者显示直立症状和体征减少。这些数据支持了这样的假设，即抗体激活自主神经受体可能通过改变潜在的体位性心血管反应而引起或加重直立性低血压。我们的新研究是第一个研究这些自身抗体与直立性低血压患者的相关性，通过表征其对宿主的功能影响。这些数据也可用于鉴定其发生频率、其病理生理学意义和开发非靶向这些抗体的治疗策略。

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.