Baroreflex failure: Mechanisms and therapy

描述（由申请人提供）： 本研究旨在探讨压力感受性反射临床表现的机制 压力反射功能障碍。范德比尔特自主神经功能障碍中心提供了一个 压力反射衰竭患者转诊的独特资源。这包括患有家族性副神经节瘤综合征的患者，其导致可预测的双侧颈动脉窦传入阻滞。此外，这种疾病的零星单侧形式将使我们能够评估影响的偏侧性。我们将通过比较正常志愿者和使用电颈部迷走神经刺激治疗癫痫发作的患者对离散皮质刺激的血流动力学反应，来检验这些患者迷走神经传入活动的病理性减少改变了多个皮质和皮质下区域的活动的假设（视觉、听觉、味觉和伤害性刺激，Stroop测试和心算），血管加压素的反应，以及自主神经激活，血压和心率以及血浆 儿茶酚胺以及定义特定脑受体场的功能水平。我们将 明确支持这些患者直立性血压的机制，特别是通过 用倾斜差异研究测试前庭输入的效果。在一个独立的系列研究中， 压力反射功能障碍，我们将测试的假设，可变水平和持续时间的急性 和慢性血糖控制改变糖尿病患者的压力感受性反射功能， 压力感受器反射功能以及胰岛素钳夹研究期间的血液和血浆容量测定。 我们还将确定颈动脉内膜切除术或支架植入术对压力感受性反射功能的影响， 利用颈动脉超声评估机械/血管成分的作用。我们将 进一步评估这一假设，即在试点中已证明有效的治疗选择， 压力感受器反射衰竭和/或具有其它形式的自主功能障碍的患者的研究（例如， 可乐定、口服水、瓜氨酸和前列腺素合成的调节）对 压力反射功能障碍或失败的患者。 从这些研究中获得的数据将提供重要的信息，这些信息将有助于改善这些患者的治疗。

DESCRIPTION (provided by applicant): This proposal investigates the mechanism underlying the clinical manifestations of baroreflex failure and of baroreflex dysfunction. The Vanderbilt Autonomic Dysfunction Center provides a unique resource of patient referrals with baroreflex failure. This includes patients with the familial paraganglioma syndrome; which leads to predictable bilateral carotid sinus deafferentation. In addition, the sporadic unilateral form of this disorder will allow us to assess the laterality of effects. We will test the hypothesis that the pathologic decrease in vagal afferent activity in these patients alters the activity of multiple cortical and sub-cortical areas, by comparing in normal volunteers and in patients using electrical cervical vagal stimulation for the treatment of seizures the hemodynamic responses to discrete cortical stimuli (visual, auditory, taste and nociceptive stimuli, Stroop testing and mental arithmetic), the response of vasopressin, and autonomic activation with spectral analysis of blood pressure and heart rate and plasma catecholamines as well as defining the functional level of specific brain receptor fields. We will define mechanisms supporting orthostatic blood pressure in these patients, specifically by testing the effect of vestibular input with differential tilt studies. In a separate series of studies of baroreflex dysfunction, we will test the hypothesis that variable levels and durations of acute and chronic glycemic control alter baroreflex function in diabetics, utilizing direct assessment of baroreflex function, and blood and plasma volume determination during insulin clamp studies. We will also define the effect of carotid endarterectomy or stenting on baroreflex function and utilize carotid ultrasound to evaluate the role of the mechanical/vascular component. We will further assess the hypothesis that therapeutic options of demonstrated utility either in pilot studies of baroreflex failure and/or in patients with other forms of automomic dysfunction (e.g., clonidine, oral water, citrulline, and modulation of prostaglandin synthesis) are effective in patients with baroreflex dysfunction or failure. The data derived from these studies will provide important information that should lead to improve treatment for these patients.