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: 3356197
• 负责人: ROBIN William ROCKHOLD
• 金额: $ 5.5万
• 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/3356197
• 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，肥胖症的发展加剧了 高血压疾病与活动的变化结合 下丘脑神经元整合交感神经分泌 响应血浆葡萄糖浓度的变化。 这 阿片类肽，β-内啡肽是主要决定因素 这种神经元的活性 下丘脑（PVH）。 该假设将在 自发性高血压（SHR）和Wistar-Kyoto（WKY）大鼠 在选择性病变对副细胞PVH神经元进行选择性病变。 兴奋毒素N-甲基-D-天冬氨酸的显微注射 （NMDA）。 饮食肥胖（DO）将通过喂食 高度可口的饮食。 最初的一系列实验将 下丘脑β-内啡肽浓度的变化相关 （放射免疫测定），血浆胰岛素水平（放射免疫测定）和 与改变的血浆儿茶酚胺浓度（HPLC-EC） 在假或NMDA质量中血压的升高速度 SHR和WKY就像所发展一样。 特定的血流动力学和肾脏 与肥胖性加速高血压相关的异常 将通过测量血浆体积的变化来识别 （放射固化的血清白蛋白稀释）和Baroreflex敏感性 在有意识的，不受约束的大鼠之后（2个月） 饮食变化。 血浆胰岛素水平之间的关系， 血糖调节和反射循环功能将是 在胰岛素的挑战之后，在慢性DO期间检查 诱发低血糖。 区域血分布的变化 流量（无线电标记的微球）和血浆儿茶酚胺 将测量水平。 肾同情的参与 观察到的对做反应中的神经将在 肾脏神经膜后未经剂量的SHR和WKY。 最后， 慢性循环系统将进行比较 DO和急性血流动力学和血浆引起的变化 儿茶酚胺反应是由β-离散注射引发的 内啡肽进入有意识的SHR和WKY的PVH。 结果 将划分特定的下丘脑的作用 调节关键代谢和循环控制的神经元 使用肥胖加速的新型实验模型的系统 高血压。 观察到的血液动力学，肾脏和 交感 - 肾上腺功能可能建议更合适，并且 有效的治疗干预措施。