Effect Of Stress On Vascular NOS In Aged

描述(来自应用程序的逐字记录)：行为压力是一个重要的 心血管疾病的贡献者。临界高血压大鼠(BHR) 常用于研究行为应激对心血管的影响 系统。BHR表现出对急性行为的心血管反应性增强 应激并形成持续性高血压，以应对慢性应激。 申请人之前的研究表明，接触10天的 空气喷射应激增强一氧化氮合酶(NOS)依赖的松弛 青年的冠状动脉和肠系膜动脉(3个月。老年人)BHR和受损 老年(18月龄)BHR血管对NO依赖性的松弛作用增加了…… 超氧阴离子产生与大钙依赖钾离子(BKCa)的减少 在老年BHR的血管中也观察到了通道介导的松弛。这个 这项建议的目标是确定调节行为的机制 应激引起青年和老年高血压大鼠一氧化氮合酶依赖性松弛的改变。这个 中心假说是，行为应激会导致大脑中 一氧化氮合酶、内皮型一氧化氮合酶和神经元型一氧化氮合酶的构成形式，即 热休克蛋白90(HSP90)和诱导型一氧化氮合酶的增加 (INOS)导致冠脉和冠脉血管cGMP活性增加 幼年BHR的肠系膜小动脉。在旧的BHR中，行为压力减少 超氧阴离子增加和减少引起的一氧化氮合酶依赖的弛豫 在BKCa通道的表达和/或功能上。一氧化氮合酶依赖的松弛 分离的微血管及eNOS、nNOS的表达、活性和定位 诱导型一氧化氮合酶将被确定。热休克蛋白90在增强心肌细胞一氧化氮合酶活性中的作用 幼年动物将用一种特定的抑制剂格尔达那霉素进行检测。这个 超氧阴离子在老年高血压大鼠一氧化氮合酶依赖性松弛中的作用 将通过体内处理超氧化物歧化酶模拟物和 血管超氧化物生成的测量。调解变化的机制 BKCa通道依赖的松弛将通过测量蛋白质来确定 血管组织中的表达及血管平滑肌细胞膜密度 BKCa通道电流和单通道属性。这些研究将提供 应激诱导细胞变化的机制研究新进展 冠脉和肠系膜小动脉的一氧化氮合酶依赖的松弛。这些 研究可能会导致更好地治疗相关的心血管疾病 有行为压力。

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.