VASCULATURE DYNAMIC ABNORMALITIES IN ACUTE RENAL FAILURE

急性肾衰竭的血管动态异常

• 批准号: 3241984
• 负责人: JOHN D CONGER
• 金额: $ 8.78万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 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/3241984
• 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

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将死亡率从 缺血性急性肾功能衰竭（ARF），通过缩短 疾病 先前的临床研究表明， 如果ARF持续超过10天，则从30%到80%。 临床和 实验研究表明，ARF的延长在很大程度上 与由于异常的血管紧张素转换酶抑制剂引起的反复缺血性损伤有关， ARF的动力学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 对不同血管刺激的模式（超敏或低敏），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，以及3）确定 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 诱导肾动脉（RA）阻塞，不完全缺血， 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 将在输注药物之前和之后确定刺激（RNS） 先前显示可钝化超敏反应。 在不同的动物身上， 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非依赖性血管扩张剂。 还将进行形态学检查，以检查性质和 内皮和平滑肌损伤程度。 在第二个实验中， 在离体灌注血管中进行的方案，直接比较 的反应将作出之间的大和小动脉血管从NE- ARF和RA梗阻（RAO）-ARF肾内压变化[Ca 2+] i. 此外，如果[Ca 2+]i不能增加到 血管收缩剂或牵张刺激，然后是释放刺激剂或非 将检测Ca 2+从肌浆网的释放。 最后， 蛋白激酶C介导的磷酸化增强在 用佛波醇酯测试对[Ca 2 +]i的敏感性。