VASCULAR HYPERSENSITIVITY IN ACUTE RENAL FAILURE

急性肾功能衰竭中的血管过敏

• 批准号: 2749602
• 负责人: JOHN D CONGER
• 金额: $ 13.12万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-08-01 至 2000-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2749602
• 关键词: acute renal failure; afferent nerve; angiotensin II; arterioles; calcium flux; disease /disorder model; efferent nerve; endothelin; immunocytochemistry; laboratory rat; membrane potentials; muscle tone; nitric oxide synthase; norepinephrine; paracrine; potassium channel; renal ischemia /hypoxia; reperfusion; sarcoplasmic reticulum; vascular smooth muscle; vasoconstriction; vasodilation

Abnormal vascular tone and reactivity following the induction of ischemic acute renal failure (ARF) has the potential to modify substantially the course of disease. There are direct data from experimental models and indirect evidence from clinical investigation that hypersensitivity of post-ischemic renal resistance vessels to a variety of vasomotor stimuli can predispose the kidneys to recurrent ischemic injury in the established phase of ARF. In the norepinephrine-induced model of ischemic ARF (NE-ARF), the period of most pronounced hypersensitivity to vasomotor stimuli is at 48 hr after ischemia induction, as demonstrated by markedly increased vasoconstrictor responses to agonists such as angiotensin II (AII) and endothelin-1 (ET-1) and paradoxical constriction to reduction in arterial pressure in the autoregulatory range both in vivo and in isolated renal arterioles. Neither the mechanism of increased basal vascular tone nor the mechanism of altered post-ischemic vascular sensitivity is understood. The overall proposed hypothesis for post-ischemic increased basal vascular tone and abnormal vascular sensitivity involves an increased smooth muscle cell (SMC) membrane Ca2+ leak coupled with increased sarcoplasmic reticulum (SR) storage. In response to SR Ca2+ mobilizing agonists or to reduction in vessel wall tension, there is a super- physiologic SR Ca2+ release and consequent associated exaggerated constriction. To test this hypothesis, isolated afferent (AA) and efferent arterioles (EA) from 48-hr NE-, renal artery clamp (RAC)-, and sham-ARF kidneys will be examined for abnormal SMC [Ca2+] influx and extrusion, increased SR Ca2+ storage and release, changes in SMC membrane potential and K+ channel activity, and alterations in endothelial paracrine vasodilator and vasoconstrictor balance. The goal of these experiments is to determine a pathophysiologic basis for aberrant vasoactivity in post-ischemic ARF that can form a basis for in vivo therapeutic intervention.

缺血后，异常血管张力和反应性 急性肾衰竭（ARF）有可能修改 病程。有实验模型的直接数据， 临床研究的间接证据表明 缺血后肾阻力容器到多种血管舒缩刺激 可以使肾脏倾向于在 建立的ARF阶段。在去甲肾上腺素引起的缺血模型中 ARF（NE-ARF），对血管舒缩的超敏反应的时期 刺激诱导后48小时，如明显的 增加血管收缩对激动剂（例如血管紧张素II）的反应增加 （AII）和内皮素-1（ET-1）以及悖论降低 在体内和在自动调节范围内的动脉压中 孤立的肾动脉。基础增加的机制都不 血管张力或变化后缺血后血管的机制 敏感性已被理解。 缺血后的总体假设增加了基础 血管张力和异常血管敏感性涉及增加 平滑肌细胞（SMC）膜Ca2+泄漏与增加 肌质网（SR）存储。响应SR CA2+动员 激动剂或减少血管壁张力，有一个超级 生理SR CA2+释放，因此相关的夸张 收缩。为了检验这一假设，孤立的传入（AA）和 来自48小时NE-，肾动脉夹（RAC） - 和 Sham-arf肾脏将检查异常的SMC [Ca2+]涌入和 挤出，SR CA2+存储和释放增加，SMC膜的变化 潜力和K+通道活动，以及内皮的改变 旁分泌血管扩张剂和血管收缩平衡。 这些实验的目的是确定病理生理基础 对于缺血后ARF中异常血管活性，可以形成一个基础 体内治疗干预。