OBESITY AND HYPERTENSION--ROLE OF 5HT RECEPTORS

肥胖和高血压——5HT 受体的作用

• 批准号: 6604762
• 负责人: Richard F Keep
• 金额: $ 22.14万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6604762
• 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.

急性脑室内输注 5-HT2 受体激动剂可激活交感神经系统并升高血压。初步数据表明，大脑中 5-HT2 受体的一个子集（5-HT2C 受体）的激活是脱氧皮质酮盐诱发高血压的一个促成因素。中枢5-HT2C受体也参与减少食物摄入和体重，5-HT2C受体也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和高血压之间的联系。具体来说，该提案检验了肥胖导致 5-HT2C 受体激活以减轻体重的假设，而该系统的长期激活会导致高血压。这一假设得到了初步数据的支持，即脑室内注射瘦素（一种与减轻体重有关的激素）引起的高血压可被 5-HET2C 受体拮抗剂阻断。瘦素由脂肪组织分泌，作为血脑和血脑脊液屏障转运至大脑，具有下丘脑作用。脉络丛（血脑脊液屏障的部位）具有最高密度的瘦素，5-HT2C 受体激活作为反馈机制调节血液到大脑的瘦素转运。该项目有四个具体目标。 1) 确定5-HT2C受体慢性激活可诱发高血压。 2) 检查5-HT2C受体激活是否是高脂饮食大鼠高血压的原因。 3)确定瘦素是否激活5-HT2C受体产生升压作用。 4) 检查 5-HT 受体激活是否会改变血液到大脑的瘦素转运。与肥胖相关的高血压是美国发病和死亡的主要原因。更好地理解连接这两个因素的基本机制将具有重大的治疗意义。