ABNORMAL PRESSURE NATRIURESIS IN HYPERTENSION

说明：众所周知，肾脏在心血管疾病中起着核心作用。 钠排泄的调节，从而控制血容量 还有血压。然而，这种血液背后的机制 钠排泄的压力依赖控制在很大程度上仍然是未知的。 这些机制的特征在以下方面极其重要 不仅要了解钠排泄的生理学，而且要了解 这些动态平衡机制的紊乱导致 高血压的发展。该提案的总体目标是 格兰杰博士将描述肾脏机制的特征，这些机制将 肾脏灌流到钠排泄。共有六组研究 它们旨在阐明相互关联的问题：第一 打算确定尿液中一氧化氮(NO)的排泄量和 硝酸盐(NO_3)和cGMP的排泄与 阶梯性钠排泄进行性升高 肾灌注压呈阶段性升高。据称，这是 将披露NO在多大程度上通过 允许将灌注压传递到肾脏 间质。第二组研究的目的是看看 服用L-精氨酸(一氧化氮合成的前体)可恢复 Dahl敏感大鼠通过增加乳头状肌的压力性钠尿 血液流动。以此为目的，乳头血流和直肠血管 测定盐敏感和耐盐大鼠的静水压力 静脉或腹膜腔内给药前后 L-精氨酸。NO的作用也通过测定盐类中的含量来检验 对耐药大鼠用L阻断NO合成的程度 NAME损害肾脏灌流压对肾脏的影响 给药时的血流动力学和钠排泄 在研究前进行一小时的肾间质(植入)导管。 这一观察得到了一系列显微穿刺术的补充。 这将提供有关肾单位节段的重要信息 与观察到的钠重吸收的变化有关 诱导NO合成的改变。第三组研究的目的是 为了解阻断NO合成是否与L-NAME抑制剂有关 对Dahl具有抵抗力的大鼠使它们对盐敏感。在此协议中， NO合成的抑制剂将被注入肾间质 通过植入的肾髓质导管。将进行输液 从7天到10天。钠摄入量的变化将决定血压 一直依赖于销量的扩张。第四组研究 处理一个有趣的问题，即了解为什么Dahl对盐敏感 大鼠对肾脏变化表现出钠排泄低反应 肾液体体积膨胀引起的间质压力。它是 提示这些动物的前列腺素E_2合成不足 这种化合物可以起到重要的调节压力的作用。 直接或通过控制密闭的背部渗漏排钠 交叉口。紧密连接的背面泄漏在单独的 一组研究(方案4b)，通过测量来自 肾间质至近端小管腔。 第五组讨论了一个不同的问题，即 内皮素在血压异常中的作用 各种形式高血压的利钠机制。作者 提示随着高血压的形成和内皮素的增加 功能障碍或损害发生时，内皮素在 疾病的发展。这一假设得到了初步的支持 研究表明，阻断内皮素受体A或B会产生 在自发性高血压大鼠中降低。不同的内皮素受体的能力 用于正常化肾功能和钠排泄的阻滞剂研究 这一节。这一部分还有一组研究作为补充 包括在第六节下，在那里调查的程度 哪种慢性输注内皮素受体拮抗剂会导致长时间的 各种形式的高血压患者的动脉压长期降低， 如SHR、DOCA盐等。

DESCRIPTION: It is well known that the kidney plays a central role in the regulation of sodium excretion and thereby in the control of blood volume and blood pressure. However, the mechanisms underlying this blood pressure dependent control of sodium excretion remains largely unknown. The characterization of these mechanisms is extremely important in understanding not only the physiology of sodium excretion but also the manner in which the derangement of these homeostatic mechanisms lead to the development of hypertension. The overall goal of the proposal of Dr. Granger is to characterize the renal mechanisms that link changes of renal perfusion to sodium excretion. There are six groups of studies which are designed to elucidate interrelated problems: The first intends to establish if the urinary excretion of nitric oxide (NO) and nitrate (NO3) as well as the excretion of cGMP correlates with the progressive elevation of sodium excretion which are elicited by step graded elevation of renal perfusion pressure. It is claimed that this will disclose the extent to which NO mediates pressure natriuresis by allowing the transmission of perfusion pressure to the renal interstitium. The second group of studies intends to see if the administration of L-arginine (a precursor of NO synthesis) restores pressure natriuresis in the Dahl sensitive rats by increasing papillary blood flow. With this purpose, papillary blood flow and vasa recta hydrostatic pressure are determined in salt sensitive and resistant rats before and after the intravenous- or intraperitoneal-administration of L-arginine. The role of NO is also examined by determining in salt resistant rats the extent to which the blockade of NO synthesis with L- NAME impairs the effect of renal perfusion pressure on renal hemodynamics and sodium excretion when the inhibitor is given via a renal interstitial (implanted) catheter for one hour prior to the study. This observation is complemented with a series of micropuncture studies which will yield important information on the nephron segment that is involved in the changes of sodium reabsorption observed during the induced alterations of NO synthesis. The third group of studies intends to know if the blockade of NO synthesis with L-NAME inhibitors in the Dahl resistant rats makes them salt sensitive. In this protocol, the inhibitor of NO synthesis will be infused into the renal interstitium via implanted renomedullary catheters. The infusion will be performed from 7-10 days. Changes in sodium intake will define if blood pressure has been dependent on volume expansion. The fourth group of studies deals with the interesting problem of knowing why Dahl salt sensitive rats show sodium excretion hyporesponsiveness to changes in renal interstitial pressure induced by renal fluid volume expansion. It is suggested that these animals have a deficient synthesis of PGE2 and that this compound could play an important role mediating pressure natriuresis either directly or by controlling the back leak of the tight junction. Back leak of the tight junction is determined in a separate group of studies (protocol 4b) by measuring Lanthanum fluxes from the renal interstitium to the lumen of proximal tubules. The fifth group deals with a different issue which is the importance that endothelin plays in contributing to the abnormal pressure natriuresis mechanism in various forms of hypertension. The author suggests that as hypertension becomes established and endothelin dysfunction or damage occurs, endothelin plays a greater role in the progression of the disease. The assumption is supported by preliminary studies showing the blockade of endothelin receptors A or B produces a decrease in SHR rats. The ability of different endothelin receptor blockers to normalize renal function and sodium excretion is studied in this section. This section is complemented with a group of studies included under the section six where it is investigated the extent to which chronic infusion of endothelin receptor antagonists lead to a long term reduction in arterial pressure in various forms of hypertension, such as SHR, DOCA salt, etc.