ABNORMAL PRESSURE NATRIURESIS IN HYPERTENSION

描述：众所周知，肾脏在肾脏疾病中起着核心作用。 调节钠排泄，从而控制血容量 还有血压 然而，这种血液的机制 钠排泄的压力依赖性控制在很大程度上仍是未知的。 这些机制的特性是极其重要的， 不仅了解钠排泄的生理学， 这些稳态机制的紊乱导致 高血压的发展。 建议的总体目标是 博士格兰杰的目的是描述肾脏机制， 肾灌注至钠排泄。 共有六组研究 这些问题旨在阐明相互关联的问题：第一， 目的是确定尿中一氧化氮（NO）的排泄， 硝酸盐（NO3）以及cGMP的排泄与 逐步升高的钠排泄量， 肾灌注压分级升高。 据称， 将揭示NO介导压力尿钠排泄的程度， 允许灌注压传递到肾脏 interstitium. 第二组研究旨在观察 施用L-精氨酸（NO合成的前体）恢复 Dahl敏感大鼠的压力性尿钠排泄，通过增加乳头状 血流 为了达到这个目的，乳头状血流和直血管 在盐敏感和耐盐大鼠中测定流体静压 在静脉内或腹膜内施用 L-精氨酸 NO的作用也通过在盐中测定来检验 抵抗大鼠的程度，阻断NO合成与L- NAME损害肾灌注压对肾功能的影响 当抑制剂通过一种药物给药时， 肾间质（植入）导管1小时。 这一观察结果得到了一系列微穿刺研究的补充 这将产生关于肾单位部分的重要信息， 参与了钠重吸收过程中观察到的变化 诱导NO合成的改变。 第三组研究旨在 为了了解是否用L-NAME抑制剂阻断NO合成， 耐达尔的老鼠使它们对盐敏感。 在该协议中， 将NO合成抑制剂注入肾动脉 通过植入的肾髓质导管 将进行输注 7-10天。 钠摄入量的变化将决定血压 一直依赖于体积的膨胀。 第四组研究 关于为什么达尔盐敏感的有趣问题 大鼠表现出钠排泄对肾脏变化的低反应性， 肾液体积膨胀引起的间质压力。 是 表明这些动物缺乏PGE 2的合成， 这种化合物可以在调节压力方面发挥重要作用， 尿钠排泄，直接地或通过控制紧血管的回漏， 交界处。 密封接头的回漏在单独的 研究组（方案4 b）通过测量来自 近端小管腔的肾上皮细胞。 第五组涉及一个不同的问题，即 内皮素是导致血压异常的原因之一 各种形式的高血压的钠尿机制。 提交人 表明随着高血压的建立， 当发生功能障碍或损伤时，内皮素在其中发挥更大的作用。 疾病的进展。 该假设得到初步支持。 研究表明，阻断内皮素受体A或B可产生 降低SHR大鼠。 不同内皮素受体的能力 阻断剂使肾功能和钠排泄正常化的研究， 本款规定而 这一部分还补充了一组研究报告 第六条在调查的范围内， 内皮素受体拮抗剂的慢性输注导致长时间的 在各种形式的高血压中， 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.