Extracellular renal cyclic GMP mediates pressure-induced natriuresis

描述（由申请人提供）：高血压是一种与多器官系统疾病相关的常见疾病，包括心血管、脑血管和肾脏系统。原发性高血压的病因尚不清楚。虽然高血压的发病机制涉及许多因素，但肾脏在长期血压控制中起主要作用。压力诱导的尿钠排泄（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3 '5'-单磷酸（RIcGMP）是在P-N机制中起关键重要作用的分子的假设。与第一个具体目标有关的实验探索了一种可能发生这种情况的机制。针对第二个具体目的的那些实验将提供初步证据，证明两种增强RIcGMP的试剂可用作治疗人高血压的治疗剂。目标1.为了检验细胞外RIcGMP介导肾灌注压（RPP）升高后观察到的肾间质流体静压（RIHP）升高的假设，并且是产生P-N所必需的。目标2.为了检验增加的细胞外RIcGMP增加P-N的假设：（1）通过激活可溶性鸟苷酸环化酶（sGC），其从鸟苷三磷酸产生cGMP。(2)通过抑制磷酸二酯酶V（PDE V），其特异性水解cGMP。将利用独特的微透析技术在大鼠体内测量肾间质（RI）产物。还将使用微输注方法，其中可以将各种药理学试剂直接输注到Rl隔室中。这项研究将导致更全面地了解原发性高血压的根本原因。它将为7000多万美国高血压患者带来更好、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.