NITRIC OXIDE IN THE REGULATION OF RENIN RELEASE

血管内皮细胞是影响血管活性因子的丰富来源。 器官灌注(血流)、器官功能和血压。我们 假设在正常情况下，内皮细胞衍生的松弛 内源性因子(EDRF)起到缓冲作用。 血管收缩药，特别是血管紧张素II(AII)，或内皮- 依赖性收缩因子(EDCF)、内源性过氧化脂质/血栓烷。我们 进一步假设，在导致AII增加的条件下， 在钠限制或高血压的发展过程中，EDRF 对AII升高和/或血压升高的反应增加 对抗血管收缩。由于肾脏富含一切，所以它的 EDRF对血流灌注的影响尤为明显。我们将使用一个有竞争力的 底物拮抗剂N-硝基-L-精氨酸(N-Arg)，以抑制内源性RF。这 将使我们能够确定EDRF对血液控制的影响 正常血压大鼠以及不同类型大鼠的血压和器官灌注量 高血压的模型，特别是当它与内源性AII有关时。在……里面 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 内源性血管收缩药等。我们将研究以下方面的影响 正常大鼠血压对N-Arg升压反应的影响。我们会 确定基础血压对升压反应的影响 N-Arg对EDRF的抑制作用，EDRF是否随血压增加而增加，以及 抑制EDRF是否增加了对外源性的升压反应 血管收缩药。我们将确定慢性L-精氨酸 给药，EDRF的底物，改变升压反应，以及 抑制内源性血管紧张剂是否会改变全身和 肾脏对N-Arg的反应。在特定的目标2中，我们假设肾脏 循环对EDRF抑制特别敏感。为了证明这一点， 我们将比较肾血管和肠系膜血管对 EDRF抑制并测定抗性的相对变化， 尤其是那些受所有人影响的人。在具体目标#3中，我们假设 高血压患者EDRF升高，尤其是AII依赖者 模特们。我们将确定EDRF是否具有降压和缓冲作用 抗血压升高，尤其是肾素-血管紧张素 高血压的依赖模型。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强， 以及这是否是不同模型的依赖关系的函数 所有人都有高血压。我们还将检查慢性EDRF抑制是否 加速高血压的发病，而补充L-精氨酸 政府延缓了它的发病。在具体目标4中，我们将研究 短暂降低肾功能的药物，如诊断性药物 造影剂，通过毒化内皮细胞而起作用 抑制EDRF的产生。我们将检查是否添加了造影剂 直接作用于分离的血管，或给大鼠用药会降低内皮- 依赖血管扩张或肾功能。这些研究的结果 将帮助我们了解内皮细胞如何调节血压和 调节肾脏的血流灌注和功能，特别是在对抗 收缩影响，如AII和EDCF。

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.