Renal Sensory Nerve Contribution to Hypertension

项目总结/摘要： 高血压是世界范围内发病率和死亡率的主要原因，并极大地促进了高血压的发生。 多种心血管疾病。虽然肾交感神经一直是许多基础研究的重点， 和临床研究，肾传入（感觉）神经在介导高血压中的作用仍然很差 明白肾传入神经的激活可以潜在地兴奋或抑制全局交感神经活动 从而增加或降低血压，但控制血压平衡的精确机制 肾传入神经的兴奋性与抑制性反射作用目前尚不清楚。我们最近 确定内皮素-1（ET-1）系统显著调节肾传入神经。我们的中央 假设肾传入神经上内皮素A（ETA）受体激活增加交感神经 内皮素B（ET B）受体激活对肾传入神经的影响 神经减少交感神经活动和血压。我们将用啮齿类动物来验证这一假设 模型在正常生理和高血压的设置。肾神经上的ETA或ETB受体将是 在装有无线电遥测装置的大鼠中直接激活，该装置允许记录血压 和交感神经活动的标志物。这些实验将 还包括肾传入神经的体外培养、成像和电生理检查， 关于传入神经激活机制的重要新信息。 高盐和高脂肪含量是典型的西方饮食的共同特征， 在许多心血管疾病如高血压的发展中起作用。我们的初步证据 表明这些因素也增加了ET-1和ETA受体的肾传入神经表达。因为 这种联系的增加异常肾传入神经活动和血压，我们也将测试 假设高盐或高脂肪饮食增加传入神经ET-1表达， ETA至ETB受体信号传导促进传入神经活动、交感神经张力和血液循环增加。 压力这一假设将通过使用具有特定药理学抑制的大鼠模型进行检验 肾传入神经上的ETA和/或ETB受体，并且动物将被喂食高盐或高脂肪饮食。 总之，这些研究将提供一个机制的理解，如何兴奋与抑制， 肾传入神经有助于高血压，因此可能导致特异性和有效的治疗方法。 治疗高血压的干预措施。这项研究和拟议的指导培训计划将 为申请人提供成功过渡到独立所需的具体科学培训。

PROJECT SUMMARY/ABSTRACT: High blood pressure is a leading cause of morbidity and mortality worldwide and greatly contributes to a multitude of cardiovascular disease. Although the renal sympathetic nerves have been the focus of many basic and clinical studies, the role of the renal afferent (sensory) nerves in mediating hypertension remains poorly understood. Activation of renal afferents can potentially either excite or inhibit global sympathetic nerve activity and thereby increase or decrease blood pressure, but the precise mechanisms controlling the balance of the excitatory vs. inhibitory reflex actions of the renal afferent nerves are currently unknown. We have recently determined that the endothelin-1 (ET-1) system significantly modulates renal afferent nerves. Our central hypothesis is that endothelin A (ETA) receptor activation on renal afferent nerves increases sympathetic nerve activity and blood pressure, and that endothelin B (ETB) receptor activation on renal afferent nerves decreases sympathetic nerve activity and blood pressure. We will test this hypothesis using rodent models in the settings of both normal physiology and hypertension. ETA or ETB receptors on renal nerves will be directly activated in rats instrumented with radiotelemetry devices, which allow for recording of blood pressure and markers of sympathetic nerve activity in unrestrained, conscious animals. These experiments, which will also include in vitro culturing, imaging, and electrophysiological examination of renal afferent nerves will provide important new information about the mechanisms of afferent nerve activation. High salt and high fat content are common features of the typical Western diet and are well-known to play a role in the development of many cardiovascular diseases such as hypertension. Our preliminary evidence indicates that these factors also increase renal afferent nerve expression of ET-1 and ETA receptors. Because of this connection to increases in abberant renal afferent nerve activity and blood pressure, we will also test the hypothesis that high salt or high fat diet increases afferent nerve ET-1 expression and a preponderance of ETA to ETB receptor signaling promoting increased afferent nerve activity, sympathetic tone, and blood pressure. This hypothesis will be tested through the use of rat models with specific pharmacological inhibition of ETA and/or ETB receptors on renal afferent nerves, and animals will be fed a high salt or high fat diet. Together, these studies will provide a mechanistic understanding of how excitation versus inhibition of renal afferent nerves contributes to hypertension and thus could lead to specific and efficient therapeutic interventions for the treatment of hypertension. This research study and the proposed mentored training plan will provide the applicant with the specific scientific training needed for successful transition into independence.