Renal endothelin receptor-specific function in angiotensin ll-dependent hypertens

肾脏对钠排泄的控制在确定盐敏感性和 血压。与血压钠尿受损相关的高血压明显存在于 这种疾病的主要后果是血管功能障碍和 末梢器官损伤。动物研究证实，ETA受体会导致盐依赖患者的高血压 模特们。相反，ETB受体通过促进盐分而起相反的作用 和水的排泄以及刺激血管松弛。然而，ETB受体的功能是 复杂是因为它们存在于神经和血管平滑肌上，这可以产生 在某些情况下会出现血管收缩。此外，我们最近报道说，女性， 但不是雄性，大鼠有一种类似于ETB受体的ETA依赖的利钠途径。 因此，识别受体特异性的肾血流动力学控制机制 ET-1的排泄功能有待阐明。目前的项目是基于我们最近的 观察到阻断ETA受体可减少肾脏炎症，并有相当多的证据 缺乏ETB受体功能会导致盐敏感型高血压。我们的建议将首先 提出ETA受体是一种重要的促炎机制的假设 在肾脏中，ETB受体通常起保护作用，防止这些变化。 我们进一步认为，ETB受体不能完全补偿ET-1的增加 肾延髓ETB功能受损所致的盐依赖型高血压的活动性 促进钠排泄的受体。拟议的研究将确定 与ET-1活性升高相关的大鼠模型中的炎症和氧化应激。 目的1.验证ET-1通过ETA受体直接刺激炎症的假设， 氧化应激和肾脏中肾小球通透性的增加--这些作用是相反的 通过ETB受体激活。 目的2.验证ETB依赖于血压、微循环控制的假设 在血管依赖性高血压患者中，功能和利钠功能减弱。 目的3.检验雌性大鼠对盐敏感有保护作用的假设 高血压是由于存在ETA依赖的利钠机制所致。

Renal control of sodium excretion is of obvious importance in determining salt-sensitivity and blood pressure. High blood pressure related to impaired pressure natriuresis is evident in a nnajority of human subjects and a primary consequence of this disorder is vascular dysfunction and end-organ damage. Animal studies have established that ETA receptors cause hypertension in saltdependent models. In contrast, ETB receptors function in the opposite manner by promoting salt and water excretion as well as stimulating vascular relaxation. However, ETB receptor function is complicated due to their presence on nerves and vascular smooth muscle, which can produce vasoconstriction under some circumstances. Furthermore, we have recently reported that female, but not male, rats have an ETA-dependent natriuretic pathway similar to that of the ETB receptor. Therefore, the discernment of receptor-specific mechanisms for the control of renal hemodynamic and excretory function by ET-1 requires clarification. The current project is based on our recent observations that ETA receptor blockade reduces renal Inflammation, and considerable evidence that a lack of ETB receptor function results in salt-sensitive hypertension. Our proposal will first address the hypothesis that the ETA receptor is an important pro-inflammatory mechanism in the kidney and that the ETB receptor normally functions to protect against these changes. We further propose that the ETB receptor is unable to fully compensate for increased ET-1 activity in salt-dependent hypertension due to an impaired ability of renal medullary ETB receptors to promote sodium excretion. The proposed studies will determine the role of Inflammation and oxidative stress in rat models that are associated with increased ET-1 activation. Aim 1. Test the hypothesis that ET-1, via the ETA receptor, directly stimulates inflammation, oxidative stress, and increases in glomerular permeability in the kidney - actions that are opposed by ETB receptor activation. Aim 2. Test the hypothesis that ETB dependent control of blood pressure, microcirculatory function, and natriuresis is attenuated in Ang ll-dependent hypertension. Aim 3. Test the hypothesis that female rats are protected against salt- sensitive hypertension by the existence of an ETA-dependent natriuretic mechanism.