Neurovascular Control and Blood Pressure Regulation in Humans

人类神经血管控制和血压调节

• 批准号: 8307651
• 负责人: MICHAEL J JOYNER
• 金额: $ 4.76万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8307651
• 关键词: Address; Adrenergic Agents; Adrenergic Receptor; Aging; Baroreflex; Blood Pressure; Blood Vessels; Blood Volume; Cardiac Output; Equilibrium; Genomics; Hour; Human; Hypertension; Individual; Link; Low Cardiac Output; Lower Body Negative Pressure; Measurement; Nerve; Pathway interactions; Research Personnel; Staging; Stimulus; Testing; Variant; Vasoconstrictor Agents; Woman; adrenergic; blood pressure regulation; insight; male; men; normal aging; normotensive; older men; older women; pressure; programs; receptor

DESCRIPTION (provided by applicant): This proposal explores the balance between sympathetic vasoconstrictor activity and blood pressure regulation in younger and older humans. While baseline sympathetic nerve activity (MSNA) is stable in young normotensive males, there is wide inter-individual variation in baseline MSNA and no clear relationship between MSNA and arterial pressure. Additionally, sympathetic activity increases with normal aging but is not consistently associated with marked increases in arterial pressure. In this context, our recent studies suggest a balance among sympathetic activity, cardiac output, and vasoconstrictor responsiveness to adrenergic stimuli might explain how arterial pressure remains normal when baseline sympathetic activity is high. By exploring the following specific aims we test the overall hypotheses that high baseline sympathetic activity in normotensive younger and older subjects is balanced by reciprocal changes in cardiac output and vascular adrenergic responsiveness that limit the blood pressure raising impact of the sympathoexcitation. Specific Aim 1: We will test whether the reciprocal relationship between cardiac output (CO) and sympathetic nerve activity is disrupted by normal aging. We hypothesize that this relationship is not disrupted but that healthy older subjects have lower cardiac outputs and proportionally higher sympathetic activity than young subjects. Our secondary hypothesis is that women have a similar CO-MSNA relationship to men, but for any given CO, sympathetic activity is lower in women. A tertiary hypothesis is that baseline MSNA will not be related to 24 hour ambulatory blood pressure measurements. Specific Aim 2: We will test whether changes in blood volume and CO with normal aging are linked to the increase in MSNA by using volume expansion and lower body negative pressure to manipulate CO. We hypothesize that sympathetic activity will be similar at a given CO and arterial pressure in both older and younger subjects. Specific Aim 3: We will test whether a1- versus a2-adrenergic receptors are involved in the decreased vascular responsiveness seen in normotensive subjects with high MSNA. We hypothesize there will be an inverse relationship between baseline MSNA and vascular responsiveness that will be most obvious for a1-receptors in both younger and older subjects. We also propose exploratory analysis of genomic variation in a1- and a2-adrenergic receptors and related pathways from subjects with varying levels of baseline sympathetic activity. Specific Aim 4: We will test whether baroreflex control of MSNA is related to baseline MSNA and how this changes with aging. We hypothesize that subjects with high baseline MSNA will demonstrate blunted baroreflex control of MNSA. In summary, this overall approach will permit us to understand how normotensive is maintained in humans with high baseline sympathetic activity and set the stage for understanding how these mechanisms might fail in hypertension.

描述(申请人提供)：这项建议探索交感血管收缩活动和血压调节之间的平衡在年轻人和老年人之间。在血压正常的年轻男性中，基线交感神经活动(MSNA)是稳定的，但基线MSNA存在广泛的个体差异，MSNA与动脉压之间没有明确的关系。此外，交感神经活动随着正常年龄的增长而增加，但与动脉压的显著增加并不一致。在此背景下，我们最近的研究表明，交感活动、心输出量和血管收缩反应对肾上腺素能刺激的反应之间的平衡可能解释了当基线交感活动较高时，动脉压如何保持正常。通过探索以下具体目标，我们测试了总体假设，即血压正常的年轻和老年受试者的高基线交感神经活动通过心输出量和血管肾上腺素能反应的相互变化来平衡，这些变化限制了交感神经兴奋的血压升高影响。具体目标1：我们将测试心输出量(CO)和交感神经活动之间的相互关系是否会因正常衰老而中断。我们假设这种关系没有中断，但健康的老年受试者的心输出量比年轻受试者低，交感神经活性按比例高于年轻受试者。我们的第二个假设是，女性与男性有类似的CO-MSNA关系，但对于任何给定的CO，女性的交感活动较低。第三种假设是基线MSNA与24小时动态血压测量无关。具体目标2：我们将通过使用容量膨胀和下体负压来控制CO，来测试正常衰老时血容量和CO的变化是否与MSNA的增加有关。我们假设，在给定的CO和动脉压下，老年人和年轻人的交感神经活动将是相似的。具体目标3：我们将测试a1和a2肾上腺素能受体是否与正常血压和高MSNA受试者的血管反应性降低有关。我们假设基线MSNA和血管反应性之间将存在反向关系，这在年轻和老年受试者的A1受体中都是最明显的。我们还建议对基础交感神经活性水平不同的受试者的a1和a2肾上腺素能受体和相关通路的基因组变异进行探索性分析。具体目标4：我们将测试MSNA的压力感受器反射控制是否与基线MSNA相关，以及这种关系如何随着年龄的变化而变化。我们假设，基线MSNA较高的受试者将表现出对MNSA的钝性压力感受性反射控制。总而言之，这一总体方法将使我们能够理解在具有高基线交感神经活动的人类中如何保持正常的血压，并为理解这些机制如何在高血压中失败奠定了基础。