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: 3356195
• 负责人: ROBIN William ROCKHOLD
• 金额: $ 5.76万
• 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/3356195
• 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; endorphins; experimental brain lesion; glucose; hemodynamics; high performance liquid chromatography; hormone regulation /control mechanism; hypertension; image processing; insulin; kidney function; laboratory rat; neuroendocrine system; neurons; norepinephrine; nutrition related tag; obesity; opiate alkaloid; overeating; paraventricular nucleus; pathogenic diet; radioimmunoassay; spontaneous hypertensive rat; 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，肥胖的发展加剧了 高血压疾病与活动的变化， 整合交感-肾上腺分泌的下丘脑神经元 对血浆葡萄糖浓度变化的反应。 的 阿片肽，β-内啡肽，是一个主要的决定因素， 室旁核内的这些神经元的活动 下丘脑（PVH）。 这一假设将在 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， 微量注射兴奋毒素N-甲基-D-天冬氨酸 （NMDA）。 饮食性肥胖症（DO）将通过喂食 非常可口的饮食。 最初的一系列实验将 下丘脑β-内啡肽浓度的相关变化 （放射免疫测定法）、血浆胰岛素水平（放射免疫测定法）和 血浆儿茶酚胺浓度（HPLC-EC）变化 在假手术或NMDA损伤的血压升高率中， SHR和WKY随DO的发展而变化。 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确定 （放射性碘化血清白蛋白稀释）和压力反射敏感性 在慢性（2个月）给药后清醒、无约束大鼠中 饮食的变化。 血浆胰岛素水平， 血糖调节和反射循环功能， 在胰岛素激发后的慢性DO期间检查- 诱发低血糖。 区域血液分布的变化 流量（放射性标记微球）和血浆儿茶酚胺 水平将被衡量。 肾交感神经参与 将评估观察到的对DO的反应中的神经， SHR和WKY大鼠肾脏失神经支配后。 最后， 将在慢性循环系统之间进行比较 DO引起的急性血流动力学和血浆变化 不连续注射β- 内啡肽进入清醒SHR和WKY的PVH。 结果 将划分出下丘脑的一个特定群体的作用， 神经元调节关键代谢和循环控制 系统使用一种新的实验模型的肥胖加速 高血压 观察到的血液动力学、肾脏和 交感-肾上腺功能可能提示更合适的， 有效的治疗措施。