OPIOMELANOCORTIN PEPTIDES AND CARDIOVASCULAR REGULATION

阿片黑皮质素肽和心血管调节

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/2901176
• 关键词: alpha adrenergic receptor; antihypertensive agents; baroreflex; blood pressure; cardiovascular function; endorphins; genetically modified animals; heart rate; hormone regulation /control mechanism; hypothalamic hormones; hypothalamus; immunologic assay /test; laboratory mouse; laboratory rat; melanocyte stimulating hormone; neuropharmacology; opioid receptor; peptide hormone biosynthesis; proopiomelanocortin; radiotracer; receptor expression; solitary tract nucleus; spontaneous hypertensive rat

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：（改编自申请）这个项目的目标是

项目成果

Hemodynamic effects of cannabinoids: coronary and cerebral vasodilation mediated by cannabinoid CB(1) receptors.

• DOI: 10.1016/s0014-2999(01)01112-8
• 发表时间: 2001-07
• 期刊: European journal of pharmacology
• 影响因子: 5
• 作者: J. Wagner;Zoltán Járai;S. Batkai;George Kunos

The rat alpha 1B adrenergic receptor gene middle promoter contains multiple binding sites for sequence-specific proteins including a novel ubiquitous transcription factor.

大鼠 α1B 肾上腺素能受体基因中间启动子含有多个序列特异性蛋白质的结合位点，包括一种新型普遍存在的转录因子。

• DOI: 10.1074/jbc.270.10.5614
• 发表时间: 1995
• 期刊: The Journal of biological chemistry
• 作者: Gao,B;Spector,MS;Kunos,G
• 通讯作者: Kunos,G

alpha-2-Adrenergic activation of proopiomelanocortin-containing neurons in the arcuate nucleus causes opioid-mediated hypotension and bradycardia.

弓状核中含有原阿黑皮质素的神经元的 α2-肾上腺素能激活会导致阿片类药物介导的低血压和心动过缓。

• DOI: 10.1159/000126966
• 发表时间: 1996
• 期刊: Neuroendocrinology
• 影响因子: 4.1
• 作者: Li,SJ;Scanlon,MN;Járai,Z;Varga,K;Gantenberg,NS;Lazar-Wesley,E;Kunos,G
• 通讯作者: Kunos,G

Alpha-adrenergic inhibition of proliferation in HepG2 cells stably transfected with the alpha1B-adrenergic receptor through a p42MAPkinase/p21Cip1/WAF1-dependent pathway.

通过 p42MAPkinase/p21Cip1/WAF1 依赖性途径稳定转染 α1B 肾上腺素受体的 HepG2 细胞中，α 肾上腺素能抑制增殖。

• DOI: 10.1016/s0014-5793(98)01074-6
• 发表时间: 1998
• 期刊: FEBS letters
• 影响因子: 3.5
• 作者: Auer,KL;Spector,MS;Tombes,RM;Seth,P;Fisher,PB;Gao,B;Dent,P;Kunos,G
• 通讯作者: Kunos,G

Cardiovascular effects of endocannabinoids--the plot thickens.

内源性大麻素对心血管的影响——情节变得更加复杂。

• DOI: 10.1016/s0090-6980(00)00056-3
• 发表时间: 2000
• 期刊: Prostaglandins & other lipid mediators
• 影响因子: 2.9
• 作者: Kunos,G;Járai,Z;Varga,K;Liu,J;Wang,L;Wagner,JA
• 通讯作者: Wagner,JA