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.高血压与压力性尿钠排泄受损有关， 大多数人类受试者都患有这种疾病，这种疾病的主要后果是血管功能障碍， 终末器官损伤动物研究已经证实，ETA受体会导致盐依赖性高血压 模型相比之下，ETB受体通过促进盐以相反的方式发挥作用 和水排泄以及刺激血管舒张。然而，ETB受体功能是 由于它们存在于神经和血管平滑肌上而变得复杂， 血管收缩在某些情况下。此外，我们最近报告说，女性， 但非雄性大鼠具有与ETB受体类似的ETA依赖性利钠尿途径。 因此，识别控制肾血流动力学的受体特异性机制 ET-1的排泄功能需要澄清。目前的项目是基于我们最近的 ETA受体阻断剂可减少肾脏炎症的观察结果， 缺乏ETB受体功能会导致盐敏感性高血压。我们的建议将首先 阐明ETA受体是重要的促炎机制的假设 ETB受体在正常情况下起保护作用，以防止这些变化。 我们进一步提出，ETB受体不能完全补偿增加的ET-1 盐依赖性高血压中由于肾髓质ETB能力受损而引起的活性 促进钠排泄的受体。拟议的研究将确定以下方面的作用： 大鼠模型中的炎症和氧化应激与ET-1激活增加相关。 目标1.测试ET-1通过ETA受体直接刺激炎症的假设， 氧化应激和肾脏肾小球渗透性增加--这些作用是相反的 通过ETB受体激活。 目标2.检验ETB依赖控制血压、微循环的假设 在Ang II依赖性高血压中，尿钠排泄减弱。 目标3：验证雌性大鼠对盐敏感的假设 高血压是由于ETA依赖性利钠机制的存在。

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.