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（来自应用程序的逐字）：行为压力是一个重要的 心血管疾病的诱因。临界高血压大鼠（BHR）是 常用于研究行为压力对心血管的影响 系统BHR表现出对急性行为的心血管反应性增强 压力并因慢性压力而产生持续的高血压。 申请人先前的研究表明，暴露于10天的 喷气应激增强一氧化氮合酶（NOS）依赖性舒张 冠状动脉和肠系膜动脉从青年（3个月），BHR和受损 老年（18月龄）BHR血管的NOS依赖性舒张。增加 超氧阴离子产生和大Ca++依赖性K+（BKCa）减少 在来自老年BHR的血管中也观察到通道介导的舒张。的 这项建议的目标是确定介导行为的机制， 年轻和老年BHR中NOS依赖性舒张的应激诱导变化。的 核心假设是，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 热休克蛋白90（HSP 90）介导的，和诱导型NOS的增加， 诱导型一氧化氮合酶（iNOS）导致冠状动脉和 幼年BHR的肠系膜小动脉。在旧的BHR中，行为压力减少 NOS依赖性松弛由于超氧阴离子的增加和减少 BKCa通道的表达和/或功能。NOS依赖性弛豫 分离的微血管和eNOS，nNOS， 和诱导型一氧化氮合酶热休克蛋白90在增强一氧化氮合酶活性中的作用 用特异性抑制剂格尔德霉素测定年幼动物。的 超氧阴离子对老年BHR NOS依赖性舒张功能的影响 将通过用超氧化物歧化酶模拟物进行体内处理来测定， 血管超氧化物生成的测量。调节环境变化的机制 BKCa通道依赖性舒张将通过测量蛋白质 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 新的信息的机制调解压力引起的变化， 冠状动脉和肠系膜小动脉的NOS依赖性舒张。这些 研究可能会导致更好的治疗心血管疾病相关的 行为压力