VASCULATURE DYNAMIC ABNORMALITIES IN ACUTE RENAL FAILURE

急性肾衰竭的血管动态异常

• 批准号: 3241982
• 负责人: JOHN D CONGER
• 金额: $ 8.47万
• 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/3241982
• 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减少死亡率 缺血性急性肾衰竭（ARF）通过缩短持续时间 疾病。 先前的临床研究表明死亡率增加 如果ARF持续10天以上，则从30％到80％。 临床和 实验研究表明，ARF在很大程度上延长 与复发性缺血性损伤有关，这是由于异常血管引起的 ARF中的动力学主要表现为肾血（RBF） 自动调节。 计划研究的具体目的是1） 研究局部缺血幅度的影响对反应的影响 对不同血管舒缩刺激的模式（超敏），2） 确定明显不同的不同响应模式是否是由于 大和小血管缺血性损伤的差异，3）确定 内皮的角色和平滑肌在异常血管中 反应性。 在第一个实验方案中，完整的缺血将是 用肾动脉（RA）阻塞诱导，缺血不完全 肾内去甲肾上腺素（NE）。 RBF和肾血管阻力（RVR） 肾脏灌注压力（RPP）减轻和肾神经的变化 刺激（RN）将在输注剂之前和之后确定 先前显示出钝性的超敏反应。 在单独的动物中， 对血管收缩和内皮衍生的放松因子的反应 （EDRF） - 依赖性和无关的血管扩张剂将被确定。 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。 在第二个实验中 在孤立的灌注船上进行的协议，直接比较 将从NE-大型和小动脉血管之间做出反应 ARF和RA阻塞（RAO） - 肾脏肾脏会导致[Ca 2+] i的压力变化。 另外，如果[Ca 2+] i失败至 血管收缩或拉伸刺激，然后释放或非刺激剂 将检查从肌浆网中释放Ca2+。 最后， 蛋白激酶C介导的增强磷酸化的作用 对[Ca2+] i的敏感性将使用佛波酯进行测试。