NEURAL CONTROL OF FLUID HOMEOSTASIS IN HYPERTENSION

高血压（高血压）继续对 死亡率和发病率在大多数人群中。 这是特别 饮食中氯化钠（盐）摄入量高的情况。 因此 该项目的长期目标是提供一个了解 身体钠和水平衡的异常调节机制 促进高血压发展。 很有可能是内在肾 功能障碍在这个过程中发挥着关键作用。 核心假设 然而，促使这项工作的是，体液因素也参与了 调节体液容量和电解质浓度， 通过影响神经心血管控制来增加血压 机制（即大脑和自主神经系统）。 拟议 研究将集中在两个这样的因素-血管紧张素II和内皮素。 利用这些肽的慢性输注的实验表明， 它们通过至少两种机制影响血压：1）“快速” 升压作用，主要是由于直接血管收缩;和2）“缓慢” 升压作用，可能通过多种间接作用介导， 包括神经原性（交感）升压反应的激活。 高 盐的单独摄入强烈增强了缓慢的升压作用， 血管紧张素II和内皮素。 此外，最近的研究表明， 肾动脉狭窄与实验性慢性肾功能衰竭 （肾质量减少）也产生了这种增强（到缓慢 血管紧张素II的升压作用）。 在此提出的实验 应用程序将研究这些最近的机制和影响， 调查结果。 所有研究均在清醒的Sprague-Dawley大鼠中进行 用于直接、每日测量血压的仪器 钠/水平衡;以及用于肽的长期给药。 几 方案将寻求确定肾动脉狭窄或肾功能减退 质量增加缓慢升压机制：1）影响血浆肽 浓度，2）改变体液容量/电解质状态，或3） 通过肾感觉传入影响神经输入。 其他人将解决 高盐摄入量如何被神经原性升压器“感知”的问题 血管紧张素II和内皮素的反应机制。 总作用 内皮素在高血压大鼠慢性维持中的作用 将使用新开发的药理学方法评估肾质量降低 内皮素受体拮抗剂。 最后，一个可能的贡献， 将探讨内皮素对血管紧张素II诱导的高血压的影响。 这些 调查应提供新的见解之间的联系 肾功能和/或体液调节异常， 高血压的发病机制

High blood pressure (hypertension) continues to have a major impact on mortality and morbidity in most human populations. This is particularly the case where dietary sodium chloride (salt) intake is high. Thus, the long-term goal of this project is to provide an understanding of the mechanisms by which abnormal regulation of body sodium and water balance promote hypertension development. It is very likely that intrinsic kidney dysfunction plays a key role in this process. The central hypothesis motivating this work, however, is that humoral factors also involved in regulating body fluid volume and electrolyte concentration cause an increase in blood pressure by affecting neural cardiovascular control mechanisms (i.e. brain and autonomic nervous system). The proposed studies will focus on two such factors--angiotensin II and endothelin. Experiments utilizing chronic infusion of these peptides indicate that they influence blood pressure by at least two mechanisms: 1) "fast" pressor effects, primarily due to direct vasoconstriction; and 2) "slow" pressor effects, probably mediated via multiple indirect actions, including activation of neurogenic (sympathetic) pressor responses. High salt intake alone strongly enhances the slow pressor effects of angiotensin II and endothelin. Recent work, moreover, showed that both stenosis of a renal artery and experimental chronic renal failure (reduction in renal mass) also produced such enhancement (to the slow pressor effect of angiotensin II). The experiments proposed in this application will examine the mechanism and implications of these recent findings. All studies will be conducted in conscious Sprague-Dawley rats instrumented for direct, daily measurements of blood pressure and sodium/water balance; and for chronic administration of peptides. Several protocols will seek to establish if renal artery stenosis or reduced renal mass augment slow pressor mechanisms by: 1) affecting plasma peptide concentrations, 2) altering body fluid volume/electrolyte status, or 3) affecting neural input via renal sensory afferents. Others will address the question of how high salt intake is "sensed" by neurogenic pressor mechanisms responsive to angiotensin II and endothelin. The overall role of endothelin in the chronic maintenance of hypertension in rats with reduced renal mass will be assessed using newly developed pharmacological antagonists of endothelin receptors. Finally, a possible contribution of endothelin to angiotensin II induced hypertension will be explored. These investigations should provide new insights into the link between abnormalities in renal function and/or body fluid regulation and the pathogenesis of hypertension.