FUNCTIONAL ANALYSIS OF VASCULAR ANGIOTENSIN II

建议进行的研究是为了加深我们对 血管肾素-血管紧张素系统。一个主要目标是提供一个 更好地了解局部血管紧张素II(AII)的作用- 在正常和高血压状态下诱导肾血管张力，以及 血管紧张素转换酶和肾素抑制剂对这种语调的阻断是否有助于 它们的降压作用。四个具体目标源自最近的 这个实验室的调查将继续进行。具体目标1是 基于β-肾上腺素受体刺激肾素释放的发现 从肾脏中产生局部形成的AII 股骨血管床。在麻醉的兔身上进行的实验 测量血压和股动脉血流量将涉及到 急性和24小时内注射。兔肾素注入股血管内的实验研究 床上检查循环血液中的外源性肾素和/或是否被吸收 由船只用于当地生产的所有二号船。另外，无论是 循环或结合肾素导致All的形成和增强 股骨床中的肾上腺素能反应是这些研究的另一个目标 实验。作为第二个具体目标，阈值剂量的影响 卡托普利和肾素抑制剂EMD 58265对肾血流动力学和肾功能的影响 功能将被确定。假设是内皮细胞-或 这些阈值剂量抑制了由平滑肌产生的AII 导致肾血管张力降低而不影响所有 调节肾小管功能。乳头状和皮质的相对变化 血流量将在这些实验中被测量。阈值的影响 这些药物的剂量也将在一个肾脏1-夹子中确定 戈德布拉特高血压兔。具体目标3是描绘 影响肾素和AII释放的调节因素，即β- 肾上腺素能受体激动剂；内过氧化类似物，U46619，PGE2；灌流 兔肾内Krebs灌流时压力和一氧化氮的变化 动脉网(Ian)。伊恩灌流液中ALI的测定 经高效液相色谱分离后用放射免疫法测定。肾素活性将 取决于灌流液孵化提取物的AI生成。 具体目标4是扩展对长期治疗机制的研究 血管紧张素转换酶抑制剂的作用。IAN和ACE活动中的所有内容 赖诺普利急性给药和6天给药后兔肾的对比 治疗。据推测，较高的血压、肾脏 血管紧张素转换酶长期应用对血流动力学和肾上腺素能抑制作用的影响 抑制是由于肾脏产生的AII的更大程度的减少。这 研究的目的是确定当地形成的AII在 肾和股血管床，以及血管内皮细胞 和/或平滑肌是调节血管张力的所有物质的来源。 这些考虑可能对于涉及到 高血压时局部形成的ALI。

The studies proposed are to further our knowledge of the role of the vascular renin-angiotensin system. A major objective is to provide a better understanding of the contribution of local angiotensin II (AII) - induced renal vascular tone in the normal and hypertensive state, and whether blockade of this tone by ACE and renin inhibitors contributes to their antihypertensive action. Four specific aims derived from recent investigations from this laboratory will be pursued. Specific aim 1 is based on the finding that beta-adrenoceptor stimulated release of renin from the kidney leads to the production of locally formed AII in the femoral vascular bed. Experiments conducted in anesthetized rabbits in which blood pressure and femoral blood flow are measured will involve acute and 24 hr i.a. infusion of rabbit renin into the femoral vascular bed to see if exogenous renin from the circulating blood and/or taken up by the vessels is utilized for locally produced AII. also, whether the circulating or bound renin leads to AII formation and potentiation of adrenergic responses in the femoral bed is another objective of these experiments. As a second specific aim, the effects of threshold doses of captopril and renin inhibitor, EMD 58265 on renal hemodynamics and function will be determined. The hypothesis is that endothelial- or smooth muscle-generated AII is inhibited by these threshold doses resulting in decreased renal vascular tone without affecting AII- regulated tubular function. Relative changes in papillary and cortical blood flow will be measured in these experiments. Effects of threshold doses of these agents will also be ascertained in one kidney 1-clip Goldblatt hypertensive rabbits. Specific aim 3 is to delineate the regulatory factors affecting renin and AII release, i.e., beta- adrenoceptor agonist; endoperoxide-mimetic, U46619, PGE2; perfusion pressure and nitric oxide, in the rabbit Krebs-perfused intrarenal arterial network (IAN). Measurement of AII in the perfusate from the IAN will be by radioimmunoassay after HPLC separation. Renin activity will be determined by AI generation of incubated extracts of the perfusate. Specific aim 4 is to extend studies on the mechanism of the long term action of ACE inhibitors. AII content of the IAN and ACE activity in the rabbit kidney will be contrasted after acute and 6-day lisinopril treatment. It is hypothesized that greater blood pressure, renal hemodynamic and adrenergic suppressant effects of long term ACE inhibition is due to greater decrease in renally generated AII. This research is intended to define the role that locally formed AII plays in the renal and femoral vascular beds, and whether vascular endothelium and/or smooth muscle are the sources of AII that regulate vascular tone. These considerations may be important in relation to the involvement of locally formed AII in hypertension.