FUNCTIONAL ANALYSIS OF VASCULAR ANGIOTENSIN II

建议的研究是为了进一步了解 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，和 ACE和肾素抑制剂阻断这种张力是否有助于 抗高血压作用。 四个具体目标源于最近 该实验室将继续进行调查。 具体目标1是 基于β-肾上腺素受体刺激肾素释放的发现 导致在肾脏中产生局部形成的AII。 股血管床 在麻醉家兔中进行的实验， 测量血压和股动脉血流将涉及 急性和24小时i.a.股动脉灌注兔肾素 床，看看是否外源性肾素从循环血液和/或采取了 这些船只被用于当地生产的AII。 此外， 循环或结合的肾素导致AII的形成和增强 股床中的肾上腺素能反应是这些研究的另一个目的。 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 功能将被确定。 假设是内皮细胞-或 平滑肌产生的AII受到这些阈值剂量的抑制 导致肾血管张力降低而不影响AII- 调节肾小管功能。 乳头状和皮质的相对变化 在这些实验中将测量血流。 阈值效应 这些药剂的剂量也将在一个肾1-夹中确定 高血压兔子。 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;内过氧化物模拟物，U46619，PGE 2;灌注 压力和一氧化氮，在兔Krebs灌注肾内 动脉网（IAN）。 IAN灌注液中AII的测量 HPLC分离后用放射免疫法测定。 肾素活性将 通过灌注液孵育提取物的AI生成来确定。 具体目标4是扩大对长期机制的研究， ACE抑制剂的作用。 结果表明，在正常对照组和正常对照组， 兔肾在急性和6天赖诺普利后进行对比 治疗 据推测，较高的血压，肾 长期应用血管紧张素转换酶对血液动力学和肾上腺素能抑制作用 抑制是由于肾产生的AII的更大减少。 这 研究的目的是确定当地形成的AII在以下方面发挥的作用： 肾和股血管床，以及血管内皮细胞是否 和/或平滑肌是调节血管张力的AII的来源。 这些考虑因素对于参与 高血压局部形成的AII。

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.