Extracellular renal cyclic GMP mediates pressure-induced natriuresis

描述(申请人提供)：高血压是一种常见的疾病，与多个器官系统的疾病有关，包括心血管、脑血管和肾脏系统。高血压病的病因尚不清楚。虽然高血压的发病机制涉及很多因素，但肾脏在长期控制血压方面起着主要作用。压力诱导性钠尿(P-N)是这种控制的主要机制，其中动脉血压升高导致尿钠和水排泄增加。本申请中概述的实验将检验细胞外肾间质环鸟苷(RIcGMP)是一种在P-N机制中发挥关键作用的分子的假设。与第一个特定目的有关的实验探索了一种可能发生这种情况的机制。这些针对第二个特定目的的实验将提供初步证据，证明两种增强RIcGMP的药物可能在治疗人类高血压方面有用。目的1.验证细胞外RIcGMP介导肾灌注压(RPP)升高后肾间质静水压力(RIHP)升高的假说，该假说是导致P-N所必需的。目的2.验证细胞外增加的RIcGMP增强P-N的假说：(1)通过激活可溶性鸟苷酸环化酶(SGC)，sGC从三磷酸鸟苷中产生cGMP。(2)抑制特异性降解cGMP的磷酸二酯酶V(PDE V)。将利用一种独特的微透析技术在大鼠体内测量肾间质(RL)产物。还将使用一种微量输注方法，其中可以将各种药理物质直接注入RL隔室。这项研究将使人们对原发性高血压的潜在原因有一个更全面的了解。它将为7000多万患有高血压的美国人带来更好、更具体的治疗方法。

DESCRIPTION (provided by applicant): Hypertension is a common condition associated with disease in multiple organ systems, including the cardiovascular, cerebrovascular, and renal systems. The etiology of essential hypertension is unknown. While many factors have been implicated in the pathogenesis of hypertension, the kidney plays the primary role in long-term blood pressure control. Pressure-induced natriuresis (P-N), wherein an increase in arterial blood pressure leads to an increase in urinary sodium and water excretion, is the dominant mechanism for this control. The experiments outlined in this application will test the hypothesis that extracellular renal interstitial cyclic guanosine 3'5'-monophosphate (RIcGMP) is a molecule that plays a critically important role in the mechanism of P-N. The experiments pertaining to the first specific aim explore one mechanism by which this may occur. Those experiments addressing the second specific aim will provide preliminary evidence that two agents which augment RIcGMP may be useful as therapeutic agents in treating human hypertension. Aim 1. To test the hypothesis that extracellular RIcGMP mediates the rise in renal interstitial hydrostatic pressure (RIHP) observed after an increase in renal perfusion pressure (RPP) and is necessary for the resulting P-N. Aim 2. To test the hypothesis that increased extracellular RIcGMP augments P-N: (1) by activating soluble guanylyl cyclase (sGC), which generates cGMP from guanosine triphosphate. (2) by inhibiting phosphodiesterase V (PDE V), which specifically hydrolyzes cGMP. A unique microdialysis technique for measuring renal interstitial (Rl) products in vivo in the rat will be utilized. A microinfusion method wherein various pharmacologic agents can be infused directly into the Rl compartment will also be used. This research will lead to a more complete understanding of the underlying cause of essential hypertension. It will lead to better, more specific therapies for the more than 70 million Americans with high blood pressure.