OBESITY AND HYPERTENSION--ROLE OF 5HT RECEPTORS

急性脑室注射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受体的一个亚群5-HT2C受体的激活是脱氧皮质酮-盐诱导性高血压的一个促成因素。中枢5-HT2C受体也参与减少摄食量和体重，5-HT2C受体也参与减少食物摄入量和体重，5-HT2C受体基因敲除的小鼠变胖。这表明5-HT2C受体的激活可能是肥胖和高血压之间的一个联系。具体地说，这项建议检验了肥胖导致5-HT2C受体激活以减轻体重的假设，即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，即脑室内注射瘦素诱导的高血压可以被5-HET2C受体拮抗剂阻断。瘦素是一种参与减肥的激素。瘦素由脂肪组织分泌，通过血脑和血脑脊液屏障进入脑内，具有下丘脑作用。脉络丛(血脑脊液屏障的位置)的瘦素密度最高，5-HT2C受体的激活作为一种反馈机制调节血到脑的瘦素运输。这个项目有四个具体目标。1)确定慢性5-HT2C受体激活可诱发高血压。2)探讨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受体以产生升压效应。4)研究5-羟色胺受体激活是否改变瘦素从血到脑的转运。与肥胖相关的高血压是美国发病率和死亡率的主要原因。更好地了解连接这两个因素的基本机制将具有重大的治疗意义。

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.