Neuroendocrine dysfunction and hypertension

项目摘要 高血压是中风、心血管疾病和肾功能衰竭的高危因素，它是 它是美国主要的死因，影响着7500万人。原发性高血压，最常见的形式 高血压与交感血管舒张性张力升高和下丘脑活动亢进有关 垂体肾上腺(HPA)轴。然而，HPA轴的过度活动在交感神经流出增加中的作用 对于原发性高血压，目前仍很大程度上尚不清楚。下丘脑室旁核(PVN)是 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，室旁核 交感前神经元活性增加，并提供兴奋性驱动以维持高度的交感 血管舒张性音调。谷氨酸能突触传入下丘脑室旁核前交感神经元 自发性高血压大鼠(SHR)。然而，PVN过度活动的细胞机制 SHR中的交感前神经元和增强的兴奋性突触输入仍然未知。这个 促肾上腺皮质激素释放激素(CRH)神经元在PVN(PVN-CRH神经元)中是必不可少的 HPA轴的组成部分。高血压时PVN-CRH神经元被激活 高血压病患者室旁核促肾上腺皮质激素释放激素蛋白和mRNA的表达水平这个 本项目的目的是确定下丘脑室旁核-促肾上腺皮质激素释放激素神经元在调节血压和 高血压病患者交感神经流出。我们的初步研究发现，PVN-CRH神经元的活性 选择性抑制或消融PVN-CRH神经元可降低SHR的血压 在SHR里。此外，选择性抑制PVN-CRH神经元也抑制了PVN前交感神经的活动 通过阻断CRH受体1，这种作用被消除。因此，我们将测试我们的中枢 PVN-CRH神经元活动增加导致PVN交感前神经元活动亢进的假说 高血压病患者交感神经流出量增加。我们将首先确定PVN-CRH的过度活动 神经元是高血压和原发性高血压患者交感神经流出增加所必需的(目标1)。 我们还将确定高血压时PVN-CRH神经元过度活动的突触机制。 (目标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。 高血压患者的神经元和增强的谷氨酸能突触输入(目标3)。我们建议的研究将极大地 提高对原发性高血压的细胞和分子机制的理解。我们 期待我们的研究提供有关原发性高血压的神经机制的新信息 高血压和开发减少交感神经的新治疗策略的重要理论基础 高血压病患者的血管舒缩功能。

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.