OPIOMELANOCORTIN PEPTIDES AND CARDIOVASCULAR REGULATION

描述：(改编自应用程序)本项目的目标是 检验并进一步扩展下丘脑弓状核的假设 是一个新的心血管调节部位，刺激α-2 肾上腺素能受体通过释放 前阿片黑素皮质素(PMOC)衍生的多肽β-内啡肽和α-MSH 进而激活不同的阿片受体和黑素皮质素受体 孤束核(NTS)。拟议中的实验将检验 这一假设的几个方面。使用缺乏转基因的小鼠 各种阿尔法-2 AR子类型，以及阿尔法-2 AR子类型特定 在大鼠中，我们将定义弓状核中的α-2受体亚型 调节低血压和心动过缓的核。对这些的抑制 抗β-内啡肽和α-MSH抗血清对NTS的影响 它们各自受体的拮抗剂将被作为证据 这两种多肽的中介作用。我们还将测试 刺激弓状体α-2AR可以促进压力感受器反射， 从而间接产生降压作用。这类机构的相对作用 传出压力反射弧的间接作用与直接激活 通过比较低血压/心动过缓反应来确定 对照组和对照组NTS内注射β-内啡肽或α-MSH 有压力神经的动物。下丘脑α-2受体和受体之间的联系 将通过测量BE生物合成来进一步测试β-内啡肽/α-MSH 慢性应激大鼠下丘脑中两种多肽的比例 用赋形剂或用α-甲基多巴治疗。这些后一种实验 将测试先前报道的下丘脑POMC mRNA的增加 反映在α-甲基多巴之后的多肽合成增加，以及 α-2受体的激活是否会不同程度地影响脑功能的加工 这两种多肽。这一结果将有助于我们对反 高血压药物的作用，并将阐明心血管的作用机制 受POMC多肽的调节。

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.