BRAIN G-ALPHA SUBUNIT CONTROL OF BLOOD PRESSURE IN SALT-SENSITIVE HYPERTENSION

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 在对盐敏感的受试者中，高盐摄入会导致中枢交感神经流出增加、钠滞留和全身动脉血压升高。我们证明，中心G？i2-亚基蛋白介导了对GPCR激活的交感神经抑制、心血管和肾脏排泄反应，并且是降低耐盐受试者高血压所必需的。这一应用将验证PVN G？i2亚单位蛋白门控通路在中枢神经控制钠和水排泄以及全身动脉血压调节中发挥关键作用的总体假设。当盐摄入量增加时，内源性上调PVNG？i2蛋白将增强内源性交感神经抑制机制以对抗盐敏感型高血压的发展，而内源性上调PVNG？i2蛋白将加剧血压失调。为了验证这一假说，将进行以下具体目标：具体目标1：建立1)脑G？i2-亚单位蛋白门控通路，介导对生理和药物刺激的中枢诱发的肾交感神经抑制反应；2)中枢G？i2-亚单位蛋白内源性上调，作为一种反向调节机制，以减缓Spraogue-Dawley大鼠的盐敏感性高血压的发展。特定目的2：建立下丘脑PVN作为一个特定的脑部位，在此部位G？i2亚单位蛋白在内源性上调，以加强肾交感神经抑制和钠尿途径，以维持水和电解质的动态平衡，并对抗盐敏感型高血压的发展。具体目的3：证实：1)高盐摄入不能上调PVN G？i2-亚基蛋白，导致Dahl盐敏感大鼠内源性反向调节肾交感抑制和利钠反应减弱，盐敏感型高血压；2)PVN慢病毒过表达G？i2-亚基蛋白将恢复肾交感神经抑制和利钠机制，延缓Dahl盐敏感型高血压的发展。这些创新研究将进一步发展中枢神经系统自主调节和高血压研究领域，潜在地确定高血压治疗的新治疗靶点。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. In salt-sensitive subjects, high salt intake results in increased central sympathetic outflow, sodium retention and elevated systemic arterial blood pressure. We demonstrate that central G¿i2-subunit proteins mediate the sympathoinhibitory, cardiovascular and renal excretory responses to GPCR activation and are required to attenuate hypertension in salt-resistant subjects. This application will test the overall hypothesis that PVN G¿i2-subunit protein-gated pathways play a critical role in the central neural control of sodium and water excretion and systemic arterial blood pressure regulation. Endogenous up-regulation of PVN G¿i2 proteins in response to increased salt-intake will potentiate endogenous sympathoinhibitory mechanisms to counter the development of salt-sensitive hypertension whereas failure to endogenously up-regulate PVN G¿i2 proteins will exacerbate blood pressure dysregulation. The following Specific Aims will be conducted to test this hypothesis: Specific Aim 1: To establish that 1) brain G¿i2-subunit protein-gated pathways mediate centrally evoked renal sympathoinhibitory responses to physiological and pharmacological stimuli and, 2) central G¿i2-subunit proteins are endogenously up-regulated as a counter regulatory mechanism to attenuate the development of salt-sensitive hypertension in Sprague-Dawley rats. Specific Aim 2: To establish the hypothalamic PVN as a specific brain site in which G¿i2-subunit proteins are endogenously up-regulated to potentiate renal sympathoinhibitory and natriuretic pathways to maintain fluid and electrolyte homeostasis and counter the development of salt-sensitive hypertension in Sprague-Dawley rats. Specific Aim 3: To establish that 1) failure to up-regulate PVN G¿i2-subunit proteins, in response to high-salt intake, leads to attenuation of endogenous counter-regulatory renal sympathoinhibitory and natriuretic responses and salt sensitive hypertension in Dahl salt-sensitive rats, and 2) PVN lentiviral overexpression of G¿i2-subunit proteins will restore renal sympathoinhibitory and natriuretic mechanisms and attenuate the development of Dahl salt-sensitive hypertension. These innovative studies will further the fields of CNS autonomic regulation and hypertension research potentially indentifying new therapeutic targets for hypertension treatment.