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：（从应用程序改编）该项目的目标是测试并进一步扩展了下丘脑弧形核的假设是心血管调节的新型部位，其中刺激α-2 肾上腺素能受体通过释放降低血压和心率 proOpiomelanocortin（PMOC）衍生的肽β-内啡肽和α-MSH 反过在核曲纳氏菌（NTS）中。提出的实验将测试该假设的几个方面。使用缺乏转基因的小鼠各种alpha-2 ar sub类型以及alpha-2 ar sub type特异性大鼠的拮抗剂，我们将定义弧形中的alpha-2 AR子类型介导低血压和心动过缓的细胞核。抑制这些反sera对β-内啡肽和α-MSH的效果或由他们各自受体的对抗者作为证据两种肽的中介作用。我们还将测试是否刺激弧形α-2 ar可以促进压力感受器反射，从而间接产生抑郁效应。这样的相对作用间接效应与传出的Baroreflex弧的直接激活将通过比较降压/心动过心的反应来确定在对照和巴培动物。下丘脑α-2 AR和 β-内啡肽/α-MSH将通过测量生物合成进一步测试来自大鼠的分离下丘脑中两个肽的速率长期前期用车辆或Alpha-Methyldopa处理。这些后一个实验将测试先前报道的下丘脑POMC mRNA的增加反映在α-甲基甲基甲基烷基后增加的肽合成中，并且 Alpha-2 AR激活是否可以差异地影响两个肽。结果将有助于我们理解反对高血压药物作用，并将阐明心血管的机制 POMC肽调节。