Neurons expressing angiotensin type 2 receptors in the NTS as an access point for cardiovascular control.

项目摘要 高血压是心血管疾病发展的最重要危险因素，是首要原因 尽管治疗上取得了进步，但近20%-30%的高血压患者 不受控制的高血压。这种顽固性高血压与交感神经活性升高有关。 和异常的压力反射反射控制，因此称为神经源性高血压。大鼠的动物模型 神经源性高血压持续导致大脑中隔核内GABA释放增加 孤束(IntNTS)是一种重要的病理生理机制。纠正这种病理生理学 机制是降低神经源性高血压的合乎逻辑的一步。然而，GABA和 它的受体不是很好的治疗靶点，因为GABA是体内主要的抑制性神经递质。 中枢神经系统。为了绕过这一障碍，我们开始研究INNTS中表达的神经元 血管紧张素2型受体(AT2R)可以作为治疗干预的接入点，以缓解 神经性高血压。利用一种新的转基因小鼠模型(AT2R-EGFP报告鼠)，我们发现 孤束核内的GABA神经元强烈表达AT2R和光发生兴奋 显著增加血压。耐人寻味的是，DOCA-盐高血压小鼠的GABA指数增加 AT2R激动剂化合物21(C21)的合成取消了这一点 高血压和下调的GABA合成指数。与拟议的研究相关， 脑内AT2R激活的降压作用可通过从GABA神经元中删除AT2R而取消。 根据这些结果，我们推测内侧NTS中表达AT2R的GABA神经元可能是 被操纵以逆转神经源性高血压的发病。提出了两个具体目标，以 证实或驳斥这一假设。目的1结合遗传学和药理学方法来评估 删除或刺激AT2R对INNTS内GABA能神经元的影响Aim 1检验假设 激活内侧核GABA能神经元上表达的AT2R减轻DOCA-盐性高血压 通过减少这些神经元内的GABA合成酶，从而减少交感神经- 兴奋，改善压力反射功能。目的2利用体外光遗传和体内化学发生 评估DOCA-盐性高血压伴或不伴C21对脑内GABA神经递质影响的方法 压力感受性反射回路调节心血管功能。目标2验证了神经元活动的假设 在表达AT2R的INNTS中，控制压力感受性反射敏感性和交感神经流出及其选择性 抑制作用介导高血压的逆转。执行拟议的实验将确定一个离散的 可靶向控制血压并提供临床前证据的神经元群体 开发缓解顽固性高血压的新方法。

Project Summary Hypertension is the most important risk factor for the development of cardiovascular disease, the leading cause of death in the U.S. Despite therapeutic advancements, nearly 20-30% of hypertensive patients have uncontrolled high blood pressure. This resistant hypertension is associated with elevated sympathetic activity and abnormal baroreflex reflex control and thus is termed neurogenic hypertension. Animal models of neurogenic hypertension consistently implicate augmented release of GABA within the intermediate nucleus of the solitary tract (intNTS) as a contributing pathophysiological mechanism. Correcting this pathophysiological mechanism is a logical step towards decreasing high blood pressure of neurogenic origin. However, GABA and its receptors are poor therapeutic targets because GABA is the predominant inhibitory neurotransmitter in the CNS. To circumvent this impediment we began investigating whether neurons in the intNTS that express angiotensin type 2 receptors (AT2R) may serve as an access point for therapeutic interventions that relieve neurogenic hypertension. Using a novel transgenic mouse model (AT2R-eGFP reporter mouse) we discovered that GABA neurons in the intNTS robustly express AT2R and optogenetic excitation of these neurons significantly increases blood pressure. Intriguingly, DOCA-salt hypertension in mice increased indices of GABA synthesis in the intNTS but central delivery of the AT2R agonist, Compound 21 (C21), abrogated this hypertension and downregulated indices of GABA synthesis in the intNTS. Relevant to the proposed research, the antihypertensive effects of brain AT2R activation were abolished by deleting AT2R from GABA neurons. Based on these results we hypothesize that GABA neurons in the intNTS that express AT2R may be manipulated to reverse the onset of neurogenic hypertension. Two Specific Aims are proposed to substantiate or refute this hypothesis. Aim 1 combines genetic and pharmacological approaches to evaluate the consequences of deleting or stimulating AT2R on GABAergic neurons in the intNTS. Aim 1 tests the hypothesis that activation of AT2R expressed on GABAergic neurons in the intNTS alleviates DOCA-salt hypertension in mice by decreasing GABA synthetic enzymes within these neurons, which consequently decreases sympatho- excitation and improves baroreflex function. Aim 2 utilizes in vitro optogenetic and in vivo chemogenetic approaches to evaluate how DOCA-salt hypertension with or without C21 affects GABA neurotransmission within baroreflex circuits mediating cardiovascular function. Aim 2 tests the hypothesis that the activity of neurons within the intNTS that express AT2R control baroreflex sensitivity and sympathetic outflow and their selective inhibition mediates the reversal of hypertension. Execution of the proposed experiments will identify a discrete population of neurons that can be targeted to control blood pressure and provide preclinical evidence for the development of novel approaches for alleviating resistant hypertension.