NITRIC OXIDE IN THE REGULATION OF RENIN RELEASE

一氧化氮调节肾素释放

• 批准号: 6495725
• 负责人: WILLIAM H BEIERWALTES
• 金额: $ 7.35万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6495725
• 关键词: angiotensin /renin /aldosterone hypertension; blood pressure; enzyme induction /repression; gene targeting; hormone regulation /control mechanism; isozymes; kidney circulation; laboratory mouse; laboratory rat; low salt diet; nitric oxide; nitric oxide synthase; nutrition related tag; paracrine; prostaglandin endoperoxide synthase; renal hypertension; renin angiotensin system; tissue /cell culture; vascular endothelium; vasomotion

The endothelium is a rich source of vasoactive factors which influence organ perfusion (blood flow), organ function, and blood pressure. We hypothesize that under normal conditions, endothelium-derived relaxing factor (EDRF) serves as a buffer against the effects of endogenous vasoconstrictors, especially angiotensin II (AII), or the endothelium- dependent constricting factor (EDCF), endoperoxide/thromboxane. We hypothesize further that under conditions resulting in increased AII, such as during sodium restriction or the development of hypertension, EDRF increases in response to elevated AII and/or increased blood pressure and counteracts vasoconstriction. Since the kidney is rich in AII, its perfusion is particularly influenced by EDRF. We will use a competitive substrate antagonist, NW-nitro-L-arginine (N-Arg), to inhibit EDRF. This will allow us to determine the influence of EDRF on the control of blood pressure and organ perfusion in normotensive rats as well as in various models of hypertension, particularly as it relates to endogenous AII. In specific aim #1 we hypothesize that the contribution of EDRF to vascular resistance is proportional to the basal blood pressure and/or the level of endogenous vasoconstrictors such as AII. We will examine the effect of blood pressure on the pressor response to N-Arg in normal rats. We will determine the influence of basal blood pressure on the pressor response to EDRF inhibition with N-Arg, whether EDRF increases with blood pressure, and whether inhibition of EDRF increases the pressor response to exogenous vasoconstrictors. We will determine whether chronic L-arginine administration, the substrate for EDRF, alters pressor responses, and whether inhibiting endogenous vasoconstrictors alters the systemic and renal response to N-Arg. In specific aim #2, we hypothesize that the renal circulation is particularly responsive to EDRF inhibition. To show this, we will compare the response of the renal and mesenteric vasculatures to EDRF inhibition and determine the relative changes in resistance, particularly those influenced by AII. In specific aim #3 we hypothesize that EDRF is increased in hypertension, particularly in AII-dependent models. We will determine whether EDRF is antihypertensive and buffers against increases in blood pressure, especially in renin-angiotensin dependent models of hypertension. We will determine whether systemic pressor and renal responses to EDRF inhibition are greater in hypertension, and whether this is a function of the dependence of different models of hypertension on AII. We will also examine whether chronic EDRF inhibition accelerates the onset of hypertension, and whether supplemental L-arginine administration retards its onset. In specific aim #4 we will study whether agents which transiently decrease renal function, such as diagnostic contrast materials, act by poisoning endothelial cells and consequently inhibiting EDRF production. We will examine whether contrast agents added directly to isolated vessels, or given to rats decreases endothelium- dependent vasodilation or renal function. The results of these studies will help us understand how the endothelium regulates blood pressure and modulates renal perfusion and function, particularly in opposition to constrictor influences such as AII and EDCF.

内皮细胞是影响血管活性因子的丰富来源 器官灌注（血流量）、器官功能和血压。 我们 假设在正常条件下，内皮源性舒张 因子（EDRF）作为内源性影响的缓冲剂 血管收缩剂，尤其是血管紧张素 II (AII)，或内皮素 依赖收缩因子（EDCF）、内过氧化物/血栓烷。 我们 进一步假设在导致 AII 增加的条件下，例如 如在限制钠摄入或发生高血压期间，EDRF 因 AII 升高和/或血压升高而增加， 抵消血管收缩。 由于肾脏富含AII​​， 灌注尤其受 EDRF 影响。 我们将使用有竞争力的 底物拮抗剂 NW-硝基-L-精氨酸 (N-Arg) 可抑制 EDRF。 这 将使我们能够确定 EDRF 对血液控制的影响 正常血压大鼠以及各种动物的压力和器官灌注 高血压模型，特别是与内源性 AII 相关的模型。 在 具体目标#1 我们假设 EDRF 对血管的贡献 阻力与基础血压和/或血压水平成正比 内源性血管收缩剂，例如AII。 我们将检查效果 正常大鼠血压对 N-Arg 升压反应的影响。 我们将 确定基础血压对升压反应的影响 N-Arg 抑制 EDRF，EDRF 是否随血压升高而增加，以及 抑制 EDRF 是否会增加对外源性升压反应 血管收缩剂。 我们将确定是否存在慢性L-精氨酸 给药是 EDRF 的底物，改变升压反应，并且 抑制内源性血管收缩剂是否会改变全身和 肾脏对 N-Arg 的反应。 在具体目标#2中，我们假设肾脏 循环对 EDRF 抑制特别敏感。 为了表明这一点， 我们将比较肾和肠系膜血管系统对 EDRF抑制并确定电阻的相对变化， 特别是那些受 AII 影响的人。 在具体目标#3中，我们假设 EDRF 在高血压患者中增加，尤其是在 AII 依赖型患者中 模型。 我们将确定 EDRF 是否具有抗高血压和缓冲作用 防止血压升高，尤其是肾素-血管紧张素升高 高血压依赖性模型。 我们将确定是否系统性 高血压患者对 EDRF 抑制的升压和肾脏反应更大， 以及这是否是不同模型的依赖性的函数 AII 上的高血压。 我们还将检查慢性 EDRF 抑制是否 加速高血压的发作，补充L-精氨酸是否会加速高血压的发生 给药可延缓其发作。 在具体目标#4中，我们将研究是否 暂时降低肾功能的药物，例如诊断药物 造影剂通过毒害内皮细胞起作用，从而 抑制 EDRF 的产生。 我们会检查是否添加造影剂 直接作用于分离的血管，或给予大鼠以减少内皮细胞- 依赖性血管舒张或肾功能。 这些研究的结果 将帮助我们了解内皮细胞如何调节血压 调节肾脏灌注和功能，特别是与 AII 和 EDCF 等缩窄因子的影响。