HYPOTHALAMIC OPIATES IN OBESITY-ACCELERATED HYPERTENSION

下丘脑阿片类药物治疗肥胖加速性高血压

• 批准号: 3356194
• 负责人: ROBIN William ROCKHOLD
• 金额: $ 5.43万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-07-01 至 1992-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3356194
• 关键词: acute disease /disorder; appetite regulatory center; autonomic nervous system; baroreceptors; blood chemistry; blood pressure; blood volume; caloric dietary content; cardiac output; cardiovascular disorder epidemiology; catecholamines; chronic disease /disorder; denervation; disease /disorder model; eating; experimental brain lesion; glucose; hemodynamics; high performance liquid chromatography; hormone regulation /control mechanism; hypertension; hypothalamus; image processing; insulin; kidney function; neuroendocrine system; neurons; norepinephrine; nutrition related tag; obesity; opiate alkaloid; overeating; pathogenic diet; radioimmunoassay; statistics /biometry; urinalysis; vascular resistance

It is postulated that the development of obesity exacerbates hypertensive disease in conjunction with changes in the activity of hypothalamic neurons which integrate sympatho-adrenal secretion in response to changes in plasma glucose concentrations. The opioid peptide, beta-endorphin, is a major determinant of the activity of such neurons within the paraventricular nucleus of the hypothalamus (PVH). This hypothesis will be tested in spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats following selective lesioning of parvocellular PVH neurons by microinjection of the excitotoxin, N-methyl-D-aspartic acid (NMDA). Dietary obesity (DO) will be produced by feeding with a highly palatable diet. An initial series of experiments will correlate changes in hypothalamic beta-endorphin concentration (radioimmunoassay), plasma insulin levels (radioimmunoassay) and plasma catecholamine concentrations (HPLC-EC) with alterations in the rate of rise of blood pressure in sham or NMDA-lesioned SHR and WKY as DO develops. Specific hemodynamic and renal abnormalities associated with obesity-accelerated hypertension will be identified by measuring alterations in plasma volume (radio-iodinated serum albumin dilution) and baroreflex sensitivity in conscious, unrestrained rats following chronic (2 month) changes in diet. Relationships between plasma insulin levels, blood glucose regulation and reflex circulatory function will be examined during chronic DO following the challenge of insulin- induced hypoglycemia. Changes in distribution of regional blood flow (radio-labelled microspheres) and plasma catecholamine levels will be measured. The participation of renal sympathetic nerves in the observed responses to DO will be assessed in unlesioned SHR and WKY following renal denervation. Finally, comparisions will be made between the chronic circulatory changes caused by DO and the acute hemodynamic and plasma catecholamine responses triggered by discrete injection of beta- endorphin into the PVH of conscious SHR and WKY. The results will demarcate the role of a specific group of hypothalamic neurons in regulation of key metabolic and circulatory control systems using a novel experimental model of obesity-accelerated hypertension. The observed changes in hemodynamics, renal and sympatho-adrenal function may suggest more appropriate and effective therapeutic interventions.

据推测，肥胖的发展会加剧 高血压疾病与活动的变化有关 整合交感肾上腺分泌的下丘脑神经元 响应血浆葡萄糖浓度的变化。 这 阿片肽，β-内啡肽，是 室旁核内此类神经元的活动 下丘脑（PVH）。 该假设将在 自发性高血压 (SHR) 和 Wistar-Kyoto (WKY) 大鼠 选择性损伤小细胞 PVH 神经元后 显微注射兴奋毒素 N-甲基-D-天冬氨酸 （国家药品管理局）。 饮食性肥胖（DO）是通过喂养 非常适口的饮食。 最初的一系列实验将 关联下丘脑 β-内啡肽浓度的变化 （放射免疫测定）、血浆胰岛素水平（放射免疫测定）和 血浆儿茶酚胺浓度 (HPLC-EC) 的变化 假手术或 NMDA 损伤的血压升高率 SHR 和 WKY 随着 DO 的发展而发展。 特定血流动力学和肾脏 与肥胖加速高血压相关的异常 将通过测量血浆容量的变化来识别 （放射性碘血清白蛋白稀释液）和压力反射敏感性 在慢性（2个月）后有意识、不受约束的大鼠中 饮食的改变。 血浆胰岛素水平之间的关系， 血糖调节和反射性循环功能将 在胰岛素挑战后的慢性 DO 期间进行检查 诱发低血糖。 局部血液分布的变化 流（放射性标记微球）和血浆儿茶酚胺 将测量水平。 肾交感神经的参与 观察到的对溶解氧的反应中的神经将被评估 肾去神经支配后未损伤的 SHR 和 WKY。 最后， 将在慢性循环之间进行比较 DO 引起的急性血流动力学和血浆变化 不连续注射β-引发儿茶酚胺反应 内啡肽进入有意识的 SHR 和 WKY 的 PVH。 结果 将划分下丘脑特定组的作用 调节关键代谢和循环控制的神经元 使用新型肥胖加速实验模型的系统 高血压。 观察到的血流动力学、肾功能和 交感肾上腺功能可能建议更合适和 有效的治疗干预。