OBESITY AND HYPERTENSION--ROLE OF 5HT RECEPTORS

肥胖和高血压——5HT 受体的作用

• 批准号: 6338850
• 负责人: Richard F Keep
• 金额: $ 19万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-10 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6338850
• 关键词: angiotensin /renin /aldosterone hypertension; biological transport; blood brain barrier; choroid plexus; desoxycorticosterone; dietary lipid; hormone metabolism; hormone receptor; hormone regulation /control mechanism; hypertension; laboratory mouse; laboratory rat; leptin; nutrition related tag; obesity; receptor expression; serotonin receptor

Acute intracerebroventicular infusions of 5-HT2 receptors agonists activate the sympathetic nervous system and increase blood pressure. Preliminary data indicate that activation of a subset of the 5-HT2 receptors in the brain, the 5-HT2C receptors, is a contributory factor to deoxycorticosterone-salt induced hypertension. The central 5-HT2C receptor are also involved in reducing food intake and body weight, 5-HT2C receptor are also involved in reducing food intake and body weight, 5-HT2C receptor knock-out mice becoming obese. This suggests that 5-HT2C receptor activation could be a link between obesity and hypertension. Specifically, this proposal examines the hypothesis that obesity causes 5-HT2C receptor activation to reduce body weight that chronic activation of this system cause hypertension. This hypothesis is supported by preliminary data that the hypertension induced by intracerebroventricular infusions of leptin, a hormone involved in reducing body weight, is blocked by 5-HET2C receptor antagonists. Leptin is secreted by adipose tissue, is transported into brain as the blood- brain and blood-CSF barriers and has hypothalamic actions. The choroid plexus (the site of the blood CSF barrier) have the highest densities of leptin and 5-HT2C receptor activation modulates blood to brain leptin transport as a feed-back mechanism. This project has four specific aims. 1) To determine chronic 5-HT2C receptor activation can induce hypertension. 2) To examine whether 5- HT2C receptor activation is the cause of hypertension in rats fed a high fat diet. 3) To determine whether leptin activities 5-HT2C receptors to produce a pressor effect. 4) To examine whether 5-HT receptor activation alters blood to brain leptin transport. Hypertension related to obesity is a major cause of morbidity and mortality in the USA. A better understanding of the basic mechanisms linking these two factors would have major therapeutic relevance.

5-HT2受体激动剂的急性脑内脑输注激活交感神经系统并增加血压。初步数据表明，5-HT2C受体在大脑中的5-HT2受体的一个子集激活是脱氧核酮盐诱导的高血压的促成因素。中央5-HT2C受体也参与减少食物摄入和体重，5-HT2C受体还参与减少食物摄入和体重，5-HT2C受体敲除小鼠变得肥胖。这表明5-HT2C受体激活可能是肥胖与高血压之间的联系。具体而言，该提案研究了以下假设：肥胖会导致5-HT2C受体激活，以减轻体重，使该系统的长期激活导致高血压。这一假设得到了初步数据的支持，即由5-HET2C受体拮抗剂阻断了瘦素脑室脑室输注诱导的高血压，这是一种减轻体重的激素。瘦素由脂肪组织分泌，作为血液和血液-CSF障碍物输入大脑，并具有下丘脑作用。脉络丛（血液CSF屏障部位）的瘦素密度最高，而5-HT2C受体激活则将血液调节为脑瘦素转运作为喂养机制。该项目具有四个具体目标。 1）确定慢性5-HT2C受体激活可以诱导高血压。 2）检查5-HT2C受体激活是否是喂养高脂饮食的大鼠高血压的原因。 3）确定瘦素是否活性5-HT2C受体产生压力效应。 4）检查5-HT受体激活是否会改变血液对脑瘦素的转运。与肥胖有关的高血压是美国发病率和死亡率的主要原因。更好地了解将这两个因素联系起来的基本机制将具有主要的治疗意义。