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 高血压病与心钠素活性的变化 整合交感-肾上腺分泌的下丘脑神经元 以应对血糖浓度的变化。这个 阿片肽，β-内啡肽，是一种主要的决定因素 下丘脑室旁核内这种神经元的活动 下丘脑(PVH)。这一假设将在#年进行检验。 自发性高血压(SHR)和Wistar-京都(WKY)大鼠 在选择性损毁小细胞PVH神经元后 微量注射兴奋性毒素N-甲基-D-天冬氨酸 (NMDA)。饮食肥胖(DO)将通过喂食一种 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 (放射免疫分析)、血浆胰岛素水平(放射免疫分析)和 血浆儿茶酚胺浓度(HPLC-EC)及其变化 假手术组和NMDA损毁组大鼠的血压升高速度 SHR和WKY作为DO发展起来。特异性血流动力学和肾脏 与肥胖加速型高血压相关的异常 将通过测量血浆体积的变化来确定 (放射性碘化血清白蛋白稀释)和压力感受性反射敏感性 慢性(2个月)清醒、无拘束的大鼠 饮食的变化。血浆胰岛素水平之间的关系， 血糖调节和反射性循环功能会 在胰岛素挑战后的慢性DO期间进行检查- 诱导性低血糖。区域血液分布的变化 FLOW(放射性标记微球)和血浆儿茶酚胺 水平将被测量。肾交感神经的参与 在观察到的DO反应中的神经将在 去肾神经后的SHR和WKY。最后， 将与慢性循环进行比较 DO引起的变化与急性血流动力学和血浆 分批注射β-氨基丁酸引起的儿茶酚胺反应 清醒的自发性高血压大鼠和WKY大鼠的下丘脑室旁核内注射内啡肽。结果是 将界定特定的下丘脑组的作用 神经元在调节关键代谢和循环控制中的作用 使用一种新的加速肥胖实验模型的系统 高血压。观察到的血流动力学、肾脏和 交感神经-肾上腺功能提示更合适和 有效的治疗干预。