Effect Of Stress On Vascular NOS In Aged

应激对老年人血管NOS的影响

• 批准号: 6331211
• 负责人: LESLIE C FUCHS
• 金额: $ 25.11万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-07-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6331211
• 关键词: age difference; animal old age; behavioral /social science research tag; behavioral medicine; blood pressure; cardiovascular function; coronary artery; disease /disorder proneness /risk; environment associated hypertension; environmental stressor; genetic strain; heat shock proteins; juvenile animal; laboratory rat; nitric oxide synthase; oxidative stress; potassium channel; spontaneous hypertensive rat; vasoactive agent; vasomotion

DESCRIPTION (Verbatim from the application): Behavioral stress is an important contributor to cardiovascular disease. The borderline hypertensive rat (BHR) is commonly used to study effects of behavioral stress on the cardiovascular system. BHR exhibit enhanced cardiovascular reactivity to acute behavioral stress and develop sustained hypertension in response to chronic stress. Previous studies by the applicant demonstrated that exposure to 10 days of air-jet stress enhanced nitric oxide synthase (NOS)-dependent relaxation of coronary and mesenteric arteries from young (3 mo. old) BHR and impaired NOSdependent relaxation in vessels from aged (18 mo old) BHR. An increase in superoxide anion production and a decrease in large Ca++-dependent K+ (BKCa) channel mediated relaxation was also observed in vessels from aged BHR. The goal of this proposal is to determine the mechanisms mediating the behavioral stress-induced changes in NOS-dependent relaxation in young and old BHR. The central hypothesis is that behavioral stress causes an increase in activity of the constitutive forms of NOS, endothelial (eNOS) and neuronal (nNOS), that is mediated by heat shock protein 90 (HSP9O), and an increase in the inducible NOS (iNOS) leading to an increase in vascular cGMP activity in coronary and mesenteric small arteries of young BHR. In old BHR, behavioral stress decreases NOS-dependent relaxation due to an increase in superoxide anions and a decrease in expression and/or function of BKCa channels. NOS-dependent relaxation of isolated microvessels, and expression, activity and localization of eNOS, nNOS, and iNOS will be determined. The role of HSP9O in enhancing NOS activity in young animals will be determined with a specific inhibitor, geldanamycin. The role of superoxide anions in impairing NOS-dependent relaxation in aged BHR will be determined by in vivo treatment with a superoxide dismutase mimetic and measurement of vascular superoxide generation. Mechanisms mediating changes in BKCa channel dependent relaxation will be determine by measuring protein expression in vascular tissue and smooth muscle cell membrane density of the BKCa channel current and single channel properties. These studies will provide new information on the mechanisms mediating stress-induced changes in NOS-dependent relaxation of coronary and mesenteric small arteries. These studies may lead to better treatment of the cardiovascular diseases associated with behavioral stress.

描述（申请中的逐字记录）：行为压力是一个重要的因素 心血管疾病的促成者。临界高血压大鼠（BHR）是 通常用于研究行为压力对心血管的影响 系统。 BHR 表现出增强的心血管对急性行为的反应性 压力并发展为对慢性压力的持续高血压。 申请人之前的研究表明，暴露于 10 天的 空气喷射应力增强一氧化氮合酶（NOS）依赖性松弛 来自年轻（3个月大）BHR和受损的冠状动脉和肠系膜动脉 来自老年（18 个月大）BHR 的血管 NOS 依赖性松弛。增加 超氧阴离子的产生和大量 Ca++ 依赖性 K+ (BKCa) 的减少 在老化的 BHR 血管中也观察到通道介导的松弛。这 该提案的目标是确定调节行为的机制 压力引起年轻和年老 BHR 中 NOS 依赖性松弛的变化。这 中心假设是行为压力导致活动增加 NOS 的组成形式：内皮型 (eNOS) 和神经型 (nNOS)，即 由热休克蛋白 90 (HSP9O) 介导，以及诱导型 NOS 的增加 (iNOS) 导致冠状动脉和血管中血管 cGMP 活性增加 年轻 BHR 的肠系膜小动脉。在旧的 BHR 中，行为压力减少 由于超氧阴离子的增加和减少而导致的 NOS 依赖性松弛 BKCa 通道的表达和/或功能。 NOS依赖性松弛 分离的微血管，以及 eNOS、nNOS 的表达、活性和定位， 和 iNOS 将被确定。 HSP9O 在增强 NOS 活性中的作用 幼年动物将用特定的抑制剂格尔德霉素进行测定。这 超氧阴离子在损害老年 BHR 中 NOS 依赖性松弛中的作用 将通过用超氧化物歧化酶模拟物进行体内处理来确定，并且 血管超氧化物生成的测量。调解变化的机制 BKCa 通道依赖性松弛将通过测量蛋白质来确定 血管组织中的表达和平滑肌细胞膜密度 BKCa 通道电流和单通道特性。这些研究将提供 关于介导压力引起的变化的机制的新信息 NOS 依赖性冠状动脉和肠系膜小动脉舒张。这些 研究可能会更好地治疗相关的心血管疾病 与行为压力。