OPIOMELANOCORTIN PEPTIDES AND CARDIOVASCULAR REGULATION

阿片黑皮质素肽和心血管调节

基本信息

批准号：
2901176
负责人：
GEORGE KUNOS
金额：
$ 19.73万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-01-14 至 2000-05-31
项目状态：
已结题

项目摘要

DESCRIPTION: (Adapted from the application) The goal of this project is to test and further extend the hypothesis that the hypothalamic arcuate nucleus is a novel site of cardiovascular regulation, where stimulation of alpha-2 adrenergic receptors lowers blood pressure and heart rate by the release of the proopiomelanocortin (PMOC)-derived peptides beta-endorphin and alpha-MSH which, in turn, activate distinct opiate and melanocortin receptors located in the nucleus tractus solitarii (NTS). The proposed experiments will test several aspects of this hypothesis. Using genetically modified mice lacking the various alpha-2 AR sub types, as well as alpha-2 AR sub-type-specific antagonists in rats, we will define the alpha-2 AR sub-types in the arcuate nucleus which mediate hypotension and bradycardia. Inhibition of these effects in the NTS by anti-sera against the beta-endorphin and alpha-MSH or by antagonists of their respective receptors will be taken as evidence for the intermediary role of the two peptides. We will also test whether stimulation of arcuate alpha-2 AR can facilitate the baroreceptor reflex, and thus produce depressor effects indirectly. The relative role of such an indirect effect versus direct activation of the efferent baroreflex arc will be determined by comparing the hypotensive/ bradycardic response to intra-NTS injections of beta-endorphin or alpha-MSH in control and barodenervated animals. The link between hypothalamic alpha-2 AR and beta-endorphin/alpha-MSH will be further tested by measuring be biosynthetic rate of the two peptides in isolated hypothalami from rats chronically pre treated with vehicle or with alpha-methyldopa. These latter experiments will test whether the previously reported increase in hypothalamic POMC mRNA is reflected in increased peptide synthesis following alpha-methyldopa, and whether alpha-2 AR activation can differentially affect the processing of the two peptides. The results will help our understanding of anti hypertensive drug action, and will clarify the mechanism of cardiovascular regulation by POMC peptides.

描述：（改编自应用程序）该项目的目标是检验并进一步扩展了下丘脑弓状核的假设是心血管调节的一个新位点，其中刺激α-2 肾上腺素能受体通过释放肾上腺素能受体来降低血压和心率阿片黑皮质素原 (PMOC) 衍生肽 β-内啡肽和 α-MSH 反过来，激活不同的阿片受体和黑皮质素受体位于孤束核 (NTS) 中。拟议的实验将测试这个假设的几个方面。使用缺乏基因改造的小鼠各种 alpha-2 AR 子类型，以及特定于 alpha-2 AR 子类型的大鼠中的拮抗剂，我们将定义弓状肌中的 α-2 AR 亚型介导低血压和心动过缓的核。抑制这些 β-内啡肽和 α-MSH 抗血清对 NTS 的影响或通过各自受体的拮抗剂将被视为证据两种肽的中介作用。我们还将测试是否刺激弓形α-2 AR可以促进压力感受器反射，从而间接产生抑制作用。这样的相对作用传出压力反射弧的间接效应与直接激活相比通过比较低血压/心动过缓反应来确定对照和 NTS 内注射 β-内啡肽或 α-MSH 神经缺失的动物。下丘脑 α-2 AR 与 β-内啡肽/α-MSH 将通过测量生物合成来进一步测试长期暴露于大鼠下丘脑的两种肽的比例用载体或α-甲基多巴处理。后面这些实验将测试先前报道的下丘脑 POMC mRNA 是否增加反映在α-甲基多巴后肽合成的增加，并且 alpha-2 AR 激活是否会不同地影响两种肽。研究结果将有助于我们了解反高血压药物的作用，并将阐明心血管的机制 POMC 肽的调节。