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.

脑缺血诱导后血管张力和反应性的异常 急性肾功能衰竭(ARF)有可能显著改变 病程。有来自实验模型的直接数据和 来自临床研究的间接证据表明超敏反应 缺血后肾血管对多种血管运动刺激的抵抗 可使肾脏容易受到反复的缺血性损伤。 建立ARF阶段。在去甲肾上腺素诱导的脑缺血模型中 ARF(NE-ARF)，对血管运动最明显的敏感期 刺激是在缺血诱导后48小时，如明显的 血管紧张素II等激动剂的血管收缩反应增强 (AII)和内皮素-1(ET-1)与还原的矛盾收缩 在体内和体内动脉压在自动调节范围内 孤立的肾小动脉。既不是基础设施增加的机制 血管张力或缺血后血管改变的机制 敏感是可以理解的。 脑缺血后基础值升高的总体假设 血管张力和异常血管敏感性涉及 血管平滑肌细胞(SMC)膜钙离子外泄与细胞内钙离子浓度升高 肌浆网(SR)储藏。对肌质网钙离子动员的响应 激动剂或能降低血管壁张力，有一种超强的 生理性肌质网钙释放及其相关的夸大 收缩。为了验证这一假设，分离的传入(AA)和 来自48小时NE-的传出小动脉(EA)，肾动脉夹(RAC)-，以及 假ARF肾脏将检查SMC[Ca~(2+)]异常内流和 挤压，增加肌浆网钙储存和释放，改变SMC膜 电势和K+通道活性与内皮细胞的变化 旁分泌血管扩张剂和血管收缩药平衡。 这些实验的目的是确定病理生理学基础。 对于缺血后ARF中异常的血管活动，这可以构成 体内治疗性干预。