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(申请人提供)：高血压困扰着很多人，是心血管疾病的一个主要危险因素。动态运动训练可降低高血压，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起关键作用，而肾脏机制在更大程度上参与容量调节和长期的压力控制。肾交感神经调节钠重吸收和肾素分泌。因此，神经和肾脏机制以一种整合和协调的方式发挥作用，调节动脉压。运动训练可能通过调节这一综合系统来发挥其效益。我们推测，在2肾一夹高血压(2K-1C HTN)这一肾素-血管紧张素-醛固酮系统激活和交感神经活动增加的高血压大鼠模型中，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能抑制而降低肾交感神经传出活动(RSNA)。反过来，传出的RSNA的减少将通过减少远端肾单位上皮钠通道(ENaC)的丰度和功能而增加尿钠排泄。我们有三个具体目标：(1)评估自愿车轮运动是否会降低2K-1C HTN大鼠的全身动脉压，降低传出交感血管舒张性，增加动脉压力感受性反射敏感性；(2)确定自愿车轮运动是否会增强PVN内的一氧化氮信号，导致NO诱导的传出RSNA的GABA能抑制增加，并改善2K-1C HTN大鼠的压力感受性反射功能；(3)研究减毒的RSNA联合车轮运动是否会减少2K-1C HTN远端肾单位内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。我们将使用经典的药理学方法以及将神经元型一氧化氮合酶(NNOS)的显性负性结构体内转移到安静和运动训练的假手术和2K-1C HTN大鼠的PVN中，并在清醒、自由状态下测定它们的血流动力学参数、RSNA和压力感受器反射功能。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，静坐和运动训练大鼠在正常和急性钠负荷条件下的肾功能和尿钠排泄。这些研究将为指导心血管健康的战略性药理学和非药理学干预提供数据，这些干预可能很容易转化为临床实践。