ETHANOL AND ADENOSINERGIC ACTIONS IN THE HEART

乙醇和腺苷在心脏中的作用

基本信息

批准号：
2457495
负责人：
RICHARD ALLAN FENTON
金额：
$ 7.66万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-08-01 至 1999-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2457495
关键词：
G protein adenosine alcoholism /alcohol abuse beta antiadrenergic agent cardiotonic agents drug interactions ethanol heart contraction high performance liquid chromatography laboratory rat neurotransmitter receptor receptor coupling statistics /biometry toxicant interaction western blottings

项目摘要

APPLICANT'S ABSTRACT: Alcohol abuse is a societal problem which exists with citizens from adolescence to the elderly. Chronic alcohol consumption has significant detrimental impact on the cardiovascular system, including the development of alcoholic heart muscle disease (AHMD). Subclinical depression of heart function observed with alcohol use is also associated with arrhythmogenesis, including ventricular tachycardia which may degenerate to fibrillation and sudden death. Circulating levels of the beta-adrenergic neurotransmitter, norepinephrine, are elevated with acute and chronic alcoholism. Beta- adrenergic overdrive is cardiotoxic, by inducing Ca2+ overload, and arrhythmogenic, by eliciting triggered automaticity. Adenosine normally released from the heart is an agent which attenuates the functional expression of beta-adrenoceptor activation (antiadrenergic action). Preliminary evidence presented herein indicates that the antiadrenergic action of adenosine is enhanced in the alcohol-treated heart. It is HYPOTHESIZED that the enhanced antiadrenergic action of adenosine provides protection for the heart against the action of high levels of norepinephrine observed in chronic alcoholism, thereby attenuating Ca2+ overload and arrhythmogenesis. The GOAL of this project is to study the mechanism(s) by which ethanol enhances the antiadrenergic action of adenosine. The experiments utilize techniques for assessing contractile function and receptor transduction at the organ and membrane levels. The Specific Aims are to determine, with the isolated perfused heart and cardiomyocyte preparations, the effects of chronic ethanol treatment on the antiadrenergic action of adenosine with respect to contractile function (LVP, left ventricular pressure; +dPt max, the rate of pressure development; -dP/dT max, the rate of relaxation) and G protein expression. Results obtained from the proposed experiments will enhance our understanding of processes which, in the future, may be utilized to reduce injury in the alcoholic myocardium.

申请人摘要：酗酒是一个存在的社会问题与公民从青少年到老年人一起。长期酗酒食用对心血管有显着的不利影响系统，包括酒精性心肌病的发展（AHMD）。酒精观察到的亚临床心功能抑制使用还与心律失常发生有关，包括心室心动过速可能会恶化为颤动和猝死。 β-肾上腺素能神经递质的循环水平，去甲肾上腺素随急性和慢性酒精中毒而升高。贝塔- 肾上腺素能过度驱动会导致 Ca2+ 超载，从而具有心脏毒性，并且通过引发触发的自动性而致心律失常。腺苷通常从心脏释放的物质会减弱功能 β-肾上腺素受体激活的表达（抗肾上腺素作用）。本文提供的初步证据表明，抗肾上腺素能药物经酒精处理的心脏中腺苷的作用增强。这是假设腺苷增强抗肾上腺素能作用保护心脏免受高水平的作用在慢性酒精中毒中观察到去甲肾上腺素，从而减弱 Ca2+ 超负荷和心律失常。该项目的目标是研究乙醇增强抗肾上腺素作用的机制腺苷。实验利用评估收缩性的技术器官和膜水平的功能和受体转导。具体目标是确定，用离体灌注心脏和心肌细胞制剂，长期乙醇治疗对心肌细胞的影响腺苷对收缩的抗肾上腺素作用功能（LVP，左心室压力；+dPt max，压力变化率发展; -dP/dT max，松弛率）和G蛋白表达。从拟议的实验中获得的结果将增强我们对流程的理解在未来可能会被用来减少酒精对心肌的损伤。