Neuroendocrine dysfunction and hypertension

项目摘要 高血压是脑卒中、心血管疾病和肾衰竭的高危因素，也是导致高血压的主要原因之一。 这是美国的主要死因，影响着7500万人。原发性高血压，最常见的形式 与交感神经血管紧张素升高和下丘脑功能亢进有关 垂体肾上腺轴（HPA轴）。然而，HPA轴过度活跃在交感神经流出增加中的作用 原发性高血压的发病率仍不清楚。下丘脑室旁核（PVN）是下丘脑的一个核团。 整合神经内分泌和心血管功能的关键大脑区域。在原发性高血压中，PVN 前交感神经元活动增加，并提供兴奋性驱动以维持交感神经元活动的增强。 血管紧张素谷氨酸能突触输入的PVN前交感神经元增强， 自发性高血压大鼠（SHR）。然而，PVN过度活跃的细胞机制 在SHR中，交感神经元前体和增强的兴奋性突触输入仍然未知。的 PVN中含有促肾上腺皮质激素释放激素（CRH）的神经元（PVN-CRH神经元）是一种重要的神经元。 HPA轴的分量。PVN-CRH神经元在高血压中被激活， 原发性高血压患者室旁核CRH蛋白和mRNA表达水平的研究的 本项目的目的是确定PVN-CRH神经元在调节血压和 原发性高血压的交感神经流出。我们的初步研究发现，PVN-CRH神经元活动是 选择性抑制或消融PVN-CRH神经元可降低动脉血压 在SHR。此外，选择性抑制PVN-CRH神经元可抑制PVN前交感神经的活动 SHR的神经元;通过阻断CRH受体1消除该效应。因此，我们将测试我们的中央 PVN-CRH神经元活性增加导致PVN前交感神经元过度活跃的假说 和交感神经流出量升高。我们将首先确定PVN-CRH的过度活跃是否 神经元是高血压和原发性高血压中交感神经流出增加所必需的（目的1）。 我们还将确定高血压PVN-CRH神经元过度活跃的突触机制 (Aim 2）。最后，我们将确定PVN-CRH神经元在PVN前交感神经活性升高中的作用。 神经元和增强的高血压中的神经元能突触输入（Aim 3）。我们提出的研究将大大 提高对原发性高血压的细胞和分子机制的理解。我们 我希望我们的研究能提供有关原发性脑缺血的神经机制的新信息。 高血压和开发新的治疗策略，以减少交感神经系统的重要理论基础 原发性高血压的血管紧张性。

Project Summary Hypertension is a high-risk factor for stroke, cardiovascular diseases, and renal failure and it is one of the leading causes of death in the US and afflicts 75 million people. Primary hypertension, the most common form of hypertension, is associated with elevated sympathetic vasomotor tone and hyperactivity of the hypothalamic pituitary adrenal (HPA) axis. However, the role of hyperactivity of the HPA axis in elevated sympathetic outflow in primary hypertension remains largely unknown. The paraventricular nucleus (PVN) of the hypothalamus is a critical brain region that integrates neuroendocrine and cardiovascular functions. In primary hypertension, PVN presympathetic neuron activity is increased and provides excitatory drive to maintain heightened sympathetic vasomotor tone. Glutamatergic synaptic inputs to the PVN presympathetic neurons are enhanced in spontaneously hypertensive rats (SHRs). However, the cellular mechanisms underlying hyperactivity of PVN presympathetic neurons and enhanced excitatory synaptic inputs in SHRs remain unknown. The corticotrophin-releasing hormone (CRH)-containing neurons in the PVN (PVN-CRH neurons) are an essential component of the HPA axis. PVN-CRH neurons are activated in hypertension as indicated by increased expression levels of CRH protein and mRNA levels in the PVN in patients with primary hypertension. The objective of this project is to determine the role of PVN-CRH neurons in regulating blood pressure and sympathetic outflow in primary hypertension. Our pilot study found that PVN-CRH neuron activity was increased in SHRs, and selective inhibition or ablation of PVN-CRH neurons decreased arterial blood pressure in SHRs. In addition, selective inhibition of PVN-CRH neurons suppressed the activity of PVN presympathetic neurons in SHRs; the effect was eliminated by blocking CRH receptor 1. Thus, we will test our central hypothesis that increased activity of PVN-CRH neurons leads to hyperactivity of PVN presympathetic neurons and elevated sympathetic outflow in primary hypertension. We will first determine if hyperactivity of PVN-CRH neurons is required for high blood pressure and elevated sympathetic outflow in primary hypertension (Aim 1). We will also identify the synaptic mechanism underlying hyperactivity of PVN-CRH neurons in hypertension (Aim 2). Finally, we will determine the role of PVN-CRH neurons in the elevated activity of PVN presympathetic neurons and enhanced glutamatergic synaptic inputs in hypertension (Aim 3). Our proposed studies will greatly improve the understanding of the cellular and molecular mechanisms underlying primary hypertension. We expect our studies to provide novel information about the neuronal mechanisms responsible for primary hypertension and an important rationale for developing novel treatment strategies to reduce sympathetic vasomotor tone in primary hypertension.