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（由申请人提供）：本提案探讨了年轻人和老年人交感血管收缩活性和血压调节之间的平衡。虽然基线交感神经活动（MSNA）在血压正常的年轻男性中是稳定的，但基线交感神经活动（MSNA）存在广泛的个体间差异，并且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衰老而增加，但与动脉压的显著增加并不一致。在这种背景下，我们最近的研究表明，交感神经活动、心输出量和血管收缩剂对肾上腺素能刺激的反应之间的平衡可能解释了当交感神经活动基线高时动脉压保持正常的原因。通过探索以下具体目标，我们测试了总体假设，即血压正常的年轻人和老年人的高基线交感神经活动是通过心输出量和血管肾上腺素能反应性的相互变化来平衡的，从而限制了交感神经兴奋对血压升高的影响。具体目的1：我们将测试心输出量（CO）和交感神经活动之间的反向关系是否被正常衰老破坏。我们假设这种关系没有被破坏，但健康的老年受试者的心输出量较低，交感神经活动比例高于年轻受试者。我们的第二个假设是，女性与男性有相似的CO- msna关系，但对于任何给定的CO，女性的交感神经活动较低。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：我们将通过体积扩张和下体负压控制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是相似的。特异性目的3：我们将测试a1-和a2-肾上腺素能受体是否参与高MSNA的正常血压受试者血管反应性降低。我们假设基线MSNA和血管反应性之间存在反比关系，这种反比关系在年轻和老年受试者中对a1受体最为明显。我们还建议探索性分析a1-和a2-肾上腺素能受体的基因组变异以及来自不同水平基线交感神经活动的受试者的相关通路。具体目标4：我们将测试气压反射控制是否与基线MSNA相关，以及它如何随年龄变化。我们假设具有高基线MNSA的受试者将表现出MNSA的钝性压力反射控制。总之，这种整体方法将使我们能够理解具有高基线交感神经活动的人如何维持正常血压，并为理解这些机制如何在高血压中失效奠定基础。