Neural Control of Na Balance in Hypertension: Exercise

高血压钠平衡的神经控制：运动

• 批准号: 7115381
• 负责人: Noreen F Rossi
• 金额: $ 32.38万
• 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/7115381
• 关键词: angiotensin /renin /aldosterone hypertension; disease /disorder model; electrolyte balance; exercise; gamma aminobutyrate; hypertension; laboratory rat; neuroregulation; nitric oxide; nitric oxide synthase; paraventricular nucleus; peripheral nervous system; renal tubular transport; saluresis; sodium channel; vascular smooth muscle nervous control

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）：高血压困扰着很多人，是一个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的急性变化中发挥关键作用，而肾脏机制在更大程度上参与容量调节和压力的长期控制。肾交感神经调节钠重吸收和肾素分泌。因此，神经和肾脏机制以综合和协调的方式发挥作用来调节动脉压。运动训练可以通过调节这个综合系统来发挥其益处。我们假设，在 2 肾 1 夹高血压（2K-1C HTN）（一种具有激活的肾素-血管紧张素-醛固酮系统和增加的交感神经活动的高血压大鼠模型）中，自愿动态运动训练将降低传出肾交感神经活动（RSNA）通过增强一氧化氮诱导的室旁核 (PVN) 内的 GABA 能抑制。反过来，传出 RSNA 的减少将通过降低远端肾单位上皮 Na 通道 (ENaC) 的丰度和功能来增加尿 Na 排泄。我们有 3 个具体目标：（1）评估自愿轮运动是否会降低 2K-1C HTN 大鼠的全身动脉压、降低传出交感血管舒缩张力并增加动脉压力反射敏感性； (2) 确定随意轮运动是否会增强PVN内的一氧化氮信号传导，从而增加一氧化氮诱导的GABA能对传出RSNA的抑制并改善2K-1C HTN大鼠的压力反射功能； (3) 确定与自愿轮运动相关的减弱的RSNA是否会减少2K-1C HTN远端肾单位中ENaC的数量，从而增加尿Na排泄并增强对急性Na负荷等生理应激的反应能力。我们将使用经典的药理学方法以及体内将神经元一氧化氮合酶 (nNOS) 的显性失活结构转移到久坐和运动训练的假剪发大鼠和 2K-1C HTN 大鼠的 PVN 中，并确定其血流动力学参数、RSNA 和压力感受反射在有意识、不受约束的状态下发挥作用。我们将测量大鼠肾皮质微粒体中 ENaC 的丰度，并评估在正常和急性钠负荷条件下经过或不经过肾去神经支配的久坐和运动训练的大鼠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，这些数据可以很容易地转化为临床实践。