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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.

本提议的长期目标是减少因以下原因造成的死亡率通过缩短急性肾功能衰竭(ARF)的持续时间疾病。以前的临床研究表明，死亡率会增加如果ARF持续超过10天，则为30%至80%。无论是临床还是实验研究表明ARF在很大程度上延长了与血管异常引起的复发性缺血性损伤有关以肾出血(RBF)为主要表现的ARF的动态变化自动调节。计划研究的具体目标是：1) 探讨不同程度的缺血对反应的影响。对不同血管运动刺激的模式(高或低敏感)，2) 确定明显相互冲突的不同响应模式是否由于大小血管缺血性损伤的差异，以及3)决定内皮和平滑肌在迷走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)梗阻，不完全性缺血肾内去甲肾上腺素(NE)。RBF与肾血管阻力(RVR) 肾灌流压(RPP)降低和肾神经的变化在输注药物前后将测定刺激性(RNS) 以前被证明会钝化过敏性反应。在不同的动物身上，血管紧张剂和内皮衍生松弛因子的反应将确定(EDRF)依赖和非EDRF依赖的血管扩张剂。还将进行形态检查，以检查性质和血管内皮细胞和平滑肌损伤的程度。在第二个实验中在隔离的灌流血管中进行的方案，直接比较来自NE的大动脉和小动脉之间的反应。 ARF和RA梗阻(RAO)-ARF肾脏对[Ca2+]i的压力变化。此外，如果[Ca~(2+)]i不能增加到血管收缩或牵拉刺激，然后释放或不刺激我们将检测肌浆网中钙离子的释放。最后，蛋白激酶C介导的增强磷酸化在血管紧张素转换酶中的作用将用佛波酯测试对[Ca~(2+)]i的敏感性。