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.

诱导缺血性脑卒中后血管张力和反应性异常 急性肾功能衰竭（ARF）有可能大大改变 病程。有来自实验模型的直接数据， 来自临床研究间接证据表明， 缺血后肾阻力血管对各种血管刺激的反应 可使肾脏易发生反复缺血性损伤， 建立ARF阶段。在去甲肾上腺素诱导的缺血模型中， ARF（NE-ARF），对血管紧张素最明显的超敏反应期 刺激是在缺血诱导后48小时，如明显的 对血管紧张素II等激动剂的血管收缩反应增加 (AII)和内皮素-1（ET-1）和反常收缩减少 在体内和体内的自动调节范围内， 孤立的肾小动脉基础胰岛素增加的机制 血管张力也不是缺血后血管张力改变的机制 敏感性被理解。 缺血后基础胰岛素水平升高的总体假设 血管张力和异常血管敏感性涉及增加的 平滑肌细胞（SMC）膜Ca 2+渗漏与增加 肌浆网（SR）储存。响应SR Ca 2+动员 激动剂或降低血管壁张力，有一个超级- 生理性SR Ca 2+释放和随之而来的相关过度 收缩。为了验证这一假设，分离传入（AA）和 48小时NE-、肾动脉钳夹（RAC）-和 将检查假ARF肾脏的异常SMC [Ca 2 +]内流， 挤压，增加SR Ca 2+储存和释放，SMC膜的变化 电位和K+通道活性，以及内皮细胞 旁分泌血管扩张剂和血管收缩剂平衡。 这些实验的目的是确定一个病理生理基础 缺血后ARF的异常血管活性可形成 体内治疗干预。