VASCULATURE DYNAMIC ABNORMALITIES IN ACUTE RENAL FAILURE

急性肾衰竭的血管动态异常

基本信息

批准号：
3241985
负责人：
JOHN D CONGER
金额：
$ 9.63万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
1989
资助国家：
美国
起止时间：
1989-04-01 至 1992-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3241985
关键词：
acute renal failure angiotensin II growth factor kidney circulation kidney pharmacology laboratory rat norepinephrine phenylephrine phorbols protein kinase C renal ischemia /hypoxia vascular resistance vasomotion

项目摘要

The long-term objective of the present proposal is to reduce mortality from ischemic acute renal failure (ARF) by shortening the duration of the disease. Previous clinical studies have shown that mortality increases from 30 to 80 % if ARF lasts more than 10 days. Both clinical and experimental investigation indicates that prolongation of ARF in large part is related to recurrent ischemic injury which is due to abnormal vascular dynamics in ARF manifested primarily by a loss of renal blood (RBF) autoregulation. The specific aims of the planned research are to 1) investigate the effects varying magnitudes of ischemia on the response patters (hyper- or hyposensitivity) to different vasomotor stimuli, 2) determine if apparently conflicting different response patterns are due to differences in large and small vessel ischemic injury, and 3) determine the roles of the endothelium and smooth muscle in the aberrant vascular reactivity. In the first experimental protocol, complete ischemia will be induced with renal artery (RA) obstruction, incomplete ischemia with intrarenal norepinephrine (NE). RBF and renovascular resistance (RVR) changes to renal perfusion pressure (RPP) reduction and to renal nerve stimulation (RNS) will be determined before and after infusion of agents previously shown to blunt hypersensitivity responses. In separate animals, responses to vasoconstrictor and endothelium-derived relaxing factor (EDRF)-dependent and EDRF-independent vasodilators will be determined. Morphologic examination will also be performed to examine the nature and extent of endothelial and smooth muscle injury. In the second experimental protocol to be carried out in isolated perfused vessels, direct comparisons of responses will be made between large and small arterial vessels from NE- ARF and RA obstruction (RAO)-ARF kidneys to pressure changes in [Ca 2+] i. In addition, if there is a failure of [Ca 2+]i to increase to vasoconstrictor or stretch stimulation, then stimulators of release or non- release of Ca2+ from the sarcoplasmic reticulum will be examined. Finally, the role of enhanced phosphorylation mediated by protein kinase C in sensitivity to [Ca2+]i will be tested with phorbol esters.

本提案的长期目标是降低死亡率通过缩短持续时间来治疗缺血性急性肾衰竭（ARF）疾病。先前的临床研究表明死亡率会增加如果 ARF 持续超过 10 天，则降低 30% 至 80%。无论是临床还是实验研究表明 ARF 的延长在很大程度上与血管异常引起的反复缺血性损伤有关 ARF 的动态主要表现为肾血损失 (RBF) 自动调节。计划研究的具体目标是 1) 研究不同程度的缺血对反应的影响对不同血管舒缩刺激的模式（过敏或过敏），2) 确定明显冲突的不同响应模式是否是由于大血管和小血管缺血性损伤的差异，3) 确定内皮和平滑肌在异常血管中的作用反应性。在第一个实验方案中，完全缺血将是肾动脉（RA）阻塞、不完全缺血引起肾内去甲肾上腺素（NE）。 RBF 和肾血管阻力 (RVR) 肾灌注压（RPP）降低和肾神经的变化刺激（RNS）将在输注药剂之前和之后确定先前已被证明可以减弱过敏反应。在不同的动物中，对血管收缩剂和内皮源性舒张因子的反应将确定 (EDRF) 依赖性和 EDRF 独立性血管扩张剂。还将进行形态学检查以检查性质和内皮和平滑肌损伤的程度。在第二次实验中在隔离的灌注血管中进行的方案，直接比较的反应将在来自NE-的大动脉和小动脉之间进行 ARF 和 RA 阻塞 (RAO)-ARF 肾脏对 [Ca 2+] 压力变化的影响 i．此外，如果[Ca 2+]i 未能增加到血管收缩或拉伸刺激，然后释放或非刺激剂将检查肌浆网中 Ca2+ 的释放。最后，蛋白激酶 C 介导的增强磷酸化作用使用佛波酯测试对 [Ca2+]i 的敏感性。