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。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 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，原因有很多。它是中风的主要原因，加剧了共存的冠状动脉或脑血流灌注，导致跌倒和受伤，降低了生活质量，并使同时用药复杂化。这些后果在糖尿病患者身上被夸大了，并导致患者和医生感到沮丧，因为治疗方案有副作用，而且往往无效。与直立性低血压的病理生理学相关的新数据很少。我们首次发现在一组直立性低血压患者中存在针对控制主要自主神经血管和心脏活动的自主神经受体的激动剂样自身抗体，并证明了它们在此类患者中的病理生理作用。这些自身抗体经常成群出现，并在糖尿病和并发心脏病患者中观察到，这些患者经常伴有直立性低血压，在生化和功能分析中显示出激活各自受体的显著能力。根据它们的相对浓度和活性，这些抗体会产生一系列自主神经功能障碍。在抗体阳性的患者中，静息心率较快的患者的抗体以β-肾上腺素能活动为主(正变时效应)，而静息心率相对较慢且在直立性低血压时脉率反应受损的患者的抗体以毒碱活性为主(负变时效应)。在骨骼肌小动脉检测中，抗血管扩张受体(β2-肾上腺素能和M3毒扁豆碱)的抗体产生了预期的强大的血管扩张，表明这些抗体可能对全身血管扩张起作用。少数接受毒扁豆碱受体阻滞剂(奥昔布宁)治疗的患者直立位症状和体征减少。这些数据支持这样的假设，即自主神经受体的抗体激活可能通过改变潜在的体位心血管反应而导致或加剧直立性低血压。我们的新研究首次通过表征对宿主的功能影响来检验这些自身抗体与直立性低血压患者的相关性。这些数据也有助于确定它们的出现频率，它们的病理生理学意义，以及开发针对这些抗体的药物治疗策略。

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.