Vestibular Contributions to Orthostasis

描述（由申请人提供）：据估计，超过50万美国人患有直立不耐受。尽管数量庞大，但这种情况仍然缺乏了解和治疗。在过去的十年中，越来越多的证据表明前庭系统有助于姿势性血压调节。然而，尽管有这些知识，还没有开发出激活前庭系统和改善直立不耐受的干预措施。我们这个项目的长期目标是进一步了解 前庭系统的激活如何参与人体的直立性。本R21提案的具体目标是：1）检查超声骨刺激对骨组织的影响， 乳突肌（UBS）对肌肉交感神经活动（MSNA）和血管阻力的影响，以及2）确定UBS是否改善人类的立位耐力。中心假设是，瑞银增强MSNA和改善直立不耐受的人。我们制定这些假设，部分是基于我们强大的初步数据。正如在初步研究中所提出的，我们发现UBS增加了MSNA，并改善了能力下降的人的立位耐力。这项研究的基本原理是，一旦我们知道UBS可以增加MSNA并改善直立不耐受，就可以开发替代治疗方法来帮助患有这种疾病的患者。我们将通过两个具体目标来实现我们的目标。目的1：确定MSNA和血管对UBS的反应。我们的工作假设是，瑞银增加MSNA和血管阻力的腿和肾脏在人类。这一发现将是新颖的，因为以前没有研究使用UBS激活人类的MSNA。目的2：确定UBS是否改善头高位倾斜时的立位耐力。我们的工作假设，这一目标是，瑞银改善直立耐力在头向上倾斜。我们将通过测量直立不耐受受试者在有和没有UBS的情况下头高位倾斜的持续时间来检验这一假设。这一发现将是新颖的，因为这将是瑞银首次被证明可以改善人类的直立不耐受。此外，我们将测试一组老年受试者（>55岁）。老年人比年轻人更容易发生立位不耐受。在这些研究中，我们将检查预测，瑞银增强MSNA和改善直立耐力在人类。所提出的工作是创新的，因为1）它使用了新的外部设备（即，UBS）刺激MSNA和2）使用UBS改善人类的直立不耐受。在这个项目完成后，我们期望这项工作将对理解其他健康受试者的直立不耐受的原因和可能的新治疗方法的发展产生重要影响。 公共卫生相关性：目前的项目将有助于我们了解前庭对姿势介导的交感神经激活的贡献及其与人体直立不耐受或低血压的关系。直立性低血压是人类死亡率增加的危险因素。

DESCRIPTION (provided by applicant): It is estimated that over 500,000 Americans suffer with orthostatic intolerance. Despite the magnitude of the number, this condition is still poorly understood and treated. In the past decade, evidence has accumulated demonstrating that the vestibular system contributes to postural blood pressure regulation. However, despite this knowledge, no intervention has been developed to activate the vestibular system and to improve orthostatic intolerance. Our long-term goal of this project is to further our understanding of how activation of the vestibular system participates in orthostasis in humans. The specific objectives of this R21 proposal are to: 1) examine the effect of ultrasonic bone stimulation of the mastoid (UBS) on muscle sympathetic nerve activity (MSNA) and vascular resistance, and 2) determine if UBS improves orthostatic tolerance in humans. The central hypotheses are that UBS augments MSNA and improves orthostatic intolerance in humans. We formulated these hypotheses, in part, based upon our strong preliminary data. As presented in the Preliminary Studies, we found that UBS increases MSNA and improves orthostatic tolerance in humans who have diminished capacity. The rationale for the proposed research is that once we know that UBS can increase MSNA and improve orthostatic intolerance, alternative treatments can be developed to assist patients who suffer from this disorder. We will pursue our objectives via two specific aims. Aim 1: To determine MSNA and vascular responses to UBS. Our working hypothesis for this aim is that UBS increases MSNA and vascular resistance to the leg and kidney in humans. This finding will be novel because no previous studies have used UBS to activate MSNA in humans. Aim 2: To determine if UBS improves orthostatic tolerance during head-up tilt. Our working hypothesis for this aim is that UBS improves orthostatic tolerance during head-up tilt. We will test this hypothesis by measuring the duration of head-up tilt with and without UBS in subjects that are afflicted by orthostatic intolerance. The findings will be novel because it will be the first time that UBS has been demonstrated to improve orthostatic intolerance in humans. Additionally, we will test a cohort of older subjects (>55 yr). Older individuals are more prone to orthostatic intolerance than younger subjects. In these studies, we will examine the prediction that UBS augments MSNA and improves orthostatic tolerance in humans. The proposed work is innovative because 1) it uses a new external device (i.e., UBS) to stimulate MSNA and 2) uses UBS to improve orthostatic intolerance in humans. At the completion of this project, it is our expectation that this work will have important implications i understanding the cause and the development of possible new treatment of orthostatic intolerance in otherwise healthy subjects. PUBLIC HEALTH RELEVANCE: The current project will contribute to our understanding the vestibular contributions to postural-mediated sympathetic activation and its relation to orthostati intolerance or hypotension in humans. Orthostatic hypotension is a risk factor for increased mortality in humans.