OBESITY AND HYPERTENSION--ROLE OF 5HT RECEPTORS

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受体亚群5-HT2C受体的激活是脱氧皮质酮盐诱导高血压的一个促进因素。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受体敲除小鼠变肥胖。这表明5-HT2C受体的激活可能是肥胖和高血压之间的联系。具体来说，本提案检验了肥胖导致5-HT2C受体激活以减轻体重，该系统的慢性激活导致高血压的假设。这一假设得到了初步数据的支持，即脑室内输注瘦素（一种参与减轻体重的激素）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进入大脑，并在下丘脑起作用。脉络膜丛（血脑脊液屏障的位置）具有最高的瘦素密度，5-HT2C受体激活作为一种反馈机制调节血液到脑的瘦素运输。这个项目有四个具体目标。1)确定慢性5-HT2C受体激活可诱导高血压。2)探讨5- HT2C受体激活是否为高脂饮食大鼠高血压的原因。3)确定瘦素是否能激活5-HT2C受体产生升压作用。4)探讨5-HT受体激活是否改变血脑瘦素转运。在美国，与肥胖相关的高血压是发病率和死亡率的主要原因。更好地了解连接这两个因素的基本机制将具有重要的治疗意义。

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.