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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）本项目的目标是测试并进一步扩展了下丘脑弓状核是一个新的心血管调节部位，肾上腺素能受体通过释放阿黑皮素原（PMOC）衍生肽β-内啡肽和α-MSH 反过来，激活不同的阿片和黑皮质素受体，孤束核（NTS）。拟议的实验将测试这个假设的几个方面。使用基因改造的老鼠，各种α-2 AR亚型，以及α-2 AR亚型特异性拮抗剂，我们将定义α-2 AR亚型在弓形体中，调节低血压和心动过缓的神经核。抑制这些抗β-内啡肽和α-MSH的抗血清在NTS中的作用，或其各自受体的拮抗剂将被视为证据，这两种肽的中介作用。我们还将测试弓状α-2 AR的刺激可促进压力感受器反射，从而间接产生降压作用。这样的相对作用间接作用与直接激活传出压力反射弧将通过比较心动过缓/心动过缓反应来确定在对照组中NTS内注射β-内啡肽或α-MSH，无压力神经的动物下丘脑α-2 AR与将通过测量生物合成来进一步测试β-内啡肽/α-MSH 慢性应激大鼠离体下丘脑中两种肽的含量用赋形剂或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的增加是否反映在α-甲基多巴后肽合成增加， α-2 AR激活是否可以不同地影响这两种肽。这一结果将有助于我们对反高血压药物的作用，并将阐明心血管机制通过POMC肽调节。