Neural Control of Sodium Balance in Hypertension: Exercise

高血压钠平衡的神经控制：运动

• 批准号: 7450954
• 负责人: Noreen F Rossi
• 金额: $ 31.1万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7450954
• 关键词: Acute; Affect; Angiotensin II; Animal Model; Area; Attenuated; Baroreflex; Blood - brain barrier anatomy; Blood Pressure; Brain; Cardiovascular system; Cell Nucleus; Chromosome Pairing; Chronic; Clinical; Clip; Condition; Conscious; Data; Denervation; Distal; Dominant-Negative Mutation; Elevation; Equilibrium; Excretory function; Exercise; Feedback; Goals; Health; High Blood Pressure; Homeostasis; Human; Hypertension; Individual; Intervention; Kidney; Lead; Location; Macula densa; Measures; Mediating; Microsomes; Modeling; Morbidity - disease rate; Nephrons; Nerve; Neurons; Nitric Oxide; Nitric Oxide Synthase Type I; Nucleus solitarius; Numbers; Output; Physiological; Play; Population; Pressoreceptors; Rattus; Regulation; Renal function; Renin; Renin-Angiotensin-Aldosterone System; Role; Signal Transduction; Site; Sodium; Spinal Cord; Stress; Subfornical Organ; Sympathetic Nervous System; Synapses; System; Training; Translating; Tubular formation; Vasomotor; Very Light Exercise; base; blood pressure regulation; cardiovascular risk factor; epithelial Na+ channel; hemodynamics; improved; in vivo; kidney cortex; mortality; neuromechanism; neuroregulation; paraventricular nucleus; pressure; relating to nervous system; response; urinary

DESCRIPTION (provided by applicant): Hypertension afflicts a great number of individuals and is a major cardiovascular risk factor. Dynamic exercise training decreases high blood pressure, but the mechanisms are incompletely understood. Neural mechanisms play a key role in regulating acute changes in arterial pressure, whereas renal mechanisms participate to a greater extent in volume regulation and long term control of pressure. Renal sympathetic nerves modulate sodium reabsorption and renin secretion. Thus, neural and renal mechanisms function in an integrated and concerted manner to regulate arterial pressure. Exercise training may exert its benefit by modulating this integrated system. We hypothesize that in 2 kidney-1 clip hypertension (2K-1C HTN), a rat model of hypertension with an activated renin-angiotensin-aldosterone system and increased sympathetic activity, voluntary dynamic exercise training will decrease efferent renal sympathetic nerve activity (RSNA) by enhancing nitric oxide-induced GABAergic inhibition within the paraventricular nucleus (PVN). In turn, the decrease in efferent RSNA will increase urinary Na excretion by decreasing the abundance and function of the epithelial Na channel (ENaC) in the distal nephron. We have 3 specific aims: (1) To assess whether voluntary wheel exercise will decrease systemic arterial pressure, decrease efferent sympathetic vasomotor tone, and increase arterial baroreflex sensitivity in 2K-1C HTN rats; (2) To ascertain whether voluntary wheel exercise will enhance nitric oxide signaling within the PVN, resulting in increased nitric oxide-induced GABAergic inhibition of efferent RSNA and improved baroreflex function in 2K-1C HTN rats; and (3) To determine whether the attenuated RSNA associated with voluntary wheel exercise will decrease the number of ENaC in the distal nephron of 2K-1C HTN, thereby increasing urinary Na excretion and enhancing the ability to respond to physiological stress such as acute Na loading. We will use a classic pharmacologic approach as well as in vivo transfer of dominant negative constructs for neuronal nitric oxide synthase (nNOS) into the PVN in sedentary and exercise trained sham-clipped and 2K-1C HTN rats and ascertain their hemodynamic parameters, RSNA and baroreflex function in the conscious, unrestrained state. We will measure the abundance of ENaC in microsomes of rat renal cortex and evaluate renal function and urinary Na excretion in sedentary and exercise trained rats with and without renal denervation under normal and acute Na loading conditions. These studies will provide data to direct strategic pharmacologic and nonpharmacologic interventions for cardiovascular health that may be readily translated into clinical practice.

描述（由申请人提供）：高血压困扰着许多个体，是主要的心血管危险因素。动态运动训练可以降低高血压，但其机制尚不完全清楚。神经机制在调节动脉压力的急性变化中起关键作用，而肾脏机制在更大程度上参与容积调节和长期压力控制。肾交感神经调节钠的重吸收和肾素的分泌。因此，神经和肾脏机制以综合和协调的方式调节动脉压。运动训练可以通过调节这一综合系统发挥其益处。我们假设，在肾素-血管紧张素-醛固酮系统激活和交感神经活动增加的2肾-1 clip高血压（2K-1C HTN）大鼠模型中，自愿动态运动训练将通过增强一氧化氮诱导的室旁核（PVN）内gaba能抑制来降低肾交感神经的输出活动（RSNA）。反过来，输出RSNA的减少会通过降低远端肾元上皮钠通道（ENaC）的丰度和功能来增加尿钠排泄。我们有三个具体目的：(1)评估随意轮运动是否会降低2K-1C HTN大鼠的全身动脉压，降低交感血管舒缩张力，增加动脉压力反射敏感性；(2)确定自愿轮式运动是否会增强PVN内的一氧化氮信号，从而增加一氧化氮诱导的对输出RSNA的gaba能抑制，改善2K-1C HTN大鼠的调压反射功能；(3)确定随轮运动相关的RSNA减弱是否会减少2K-1C HTN远端肾单位ENaC的数量，从而增加尿钠排泄，增强对急性钠负荷等生理应激的反应能力。我们将采用经典的药理学方法，并在体内将神经元一氧化氮合酶（nNOS）的显性阴性结构转移到久坐和运动训练的假夹和2K-1C HTN大鼠的PVN中，并确定它们在有意识、不受约束状态下的血流动力学参数、RSNA和压力反射功能。我们将测量大鼠肾皮质微粒体中ENaC的丰富度，并评估在正常和急性钠负荷条件下，久坐和运动训练的大鼠（有和没有肾去神经支配）的肾功能和尿钠排泄。这些研究将为心血管健康的直接战略性药物和非药物干预提供数据，这些数据可能很容易转化为临床实践。