Ethanol on Excitation-Contraction in Cardiac Cells

乙醇对心肌细胞兴奋收缩的影响

• 批准号: 7856019
• 负责人: ANDREW P THOMAS
• 金额: $ 15.6万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7856019
• 关键词: Accounting; Acute; Adrenergic Agents; Affect; Alcoholic Cardiomyopathy; Alcoholism; Alcohols; Animal Feed; Animal Model; Binding; Binding Sites; Cardiac; Cardiac Myocytes; Cardiac Output; Cardiomyopathies; Cells; Chronic; Coupling; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Development; Dihydropyridines; Electrophysiology (science); Elements; Ethanol; Functional disorder; Grant; Heart; Heart Atrium; Heart Diseases; Heart failure; Human; Image; Individual; Ions; Lead; Lesion; Link; Messenger RNA; Molecular; Molecular Biology; Myocardial; Pathway interactions; Play; Precipitating Factors; Process; Property; Protein Isoforms; Proteins; Rattus; Regulation; Regulatory Element; Relative (related person); Reticulum; Role; Signal Pathway; Signal Transduction; Time; Work; adrenergic; alcohol effect; chronic alcohol ingestion; depression; dihydropyridine; feeding; indium arsenide; insight; non-alcoholic; novel; problem drinker; research study

DESCRIPTION (provided by applicant): Chronic alcoholism is a major cause of cardiomyopathy in humans and leads to a variety of changes that interfere with contractile function in the hearts of ethanol-fed animal models. Features of alcoholic cardiomyopathy include decreased cardiac output, impaired myocardial contractility and atrial dysrhythmias. There are also direct cardiodepressant effects of alcohol during acute administration. Some of the features of alcoholic heart disease may reflect adaptive changes induced by these acute ethanol actions. Our studies during the previous granting period have identified a number of targets of acute ethanol action within the excitation-contraction (E-C) coupling cascade, including sarcolemmal Na+ and Ca2+ channels, which lead to depression of the cytosolicCa2+ ([Ca2+]i) transients that drive contraction. We have also identified specific changes in E C coupling in the hearts of ethanol-fed rats, which suggest a selective lesion in the L-type Ca2+ channel and its regulation by cAMP-dependent protein kinase. In the work proposed here, we will further investigate the elements of E C coupling that are affected by acute ethanol, with a view to elucidating which of these is likely to contribute to the deficient [Ca2+]i transients. However, the principal aims of the proposed studies will be to characterize the changes in E C coupling following chronic ethanol consumption, and to determine the mechanism of these changes and how they lead to deficiencies in cardiac function. Specifically, we will investigate the following linked hypotheses: Alterations in the channel subunit isoform composition and/or expression leads to a channel that is defective, either in (1) basal channel properties, (2) coupling to intracellular Ca2+ release pathways, (3) regulation by the normal cAMP-dependent signaling pathway, and/or (4) localization within the cardiomyocyte. These experiments will utilize a combination of [Ca2+]i imaging, electrophysiology and molecular biology approaches. The proposed work will yield new insights into the changes in E C coupling that underlie cardiac dysfunction induced by chronic ethanol consumption. These findings may also have broader implications in elucidating the causal factors associated with the development of other aberrant adaptive processes in the heart, which eventually lead to cardiac failure

描述（由申请人提供）：慢性酒精中毒是人类心肌病的主要原因，并导致各种变化，这些变化会干扰乙醇喂养的动物模型的收缩功能。酒精性心肌病的特征包括心脏输出降低，心肌收缩性受损和心房心律失常。急性给药期间，酒精也有直接的心脏抑制作用。酒精性心脏病的某些特征可能反映了这些急性乙醇作用引起的自适应变化。我们在上一个授予期间的研究已经确定了激发 - 诱导（E-C）耦合级联反应中的许多急性乙醇作用，包括肌膜Na+和Ca2+通道，导致了胞质Ca2+（[Ca2+] I）的瞬时瞬时降低。我们还确定了乙醇喂养大鼠心脏中E C耦合的特定变化，这表明L型Ca2+通道中的选择性病变及其对CAMP依赖性蛋白激酶的调节。在这里提出的工作中，我们将进一步研究受急性乙醇影响的E C耦合的要素，以阐明其中哪种可能有助于缺乏[Ca2+] i瞬变。但是，拟议研究的主要目的是表征慢性乙醇消耗后E C耦合的变化，并确定这些变化的机制以及它们如何导致心脏功能的缺陷。具体而言，我们将研究以下链接的假设：通道亚基同工型组成和/或表达的改变导致通道有缺陷，在（1）基础信道特性中，（2）偶联到细胞内Ca2+释放途径中，（3）正常cAMP依赖cAMP的信号通路和/（4）在范围内定位的cark依赖cAMP信号通路和（3）。这些实验将利用[Ca2+] I成像，电生理学和分子生物学方法的组合。拟议的工作将为慢性乙醇消耗引起的心脏功能障碍的基础E C耦合的变化提供新的见解。这些发现也可能对阐明与心脏其他异常适应过程相关的因果因素具有更大的影响，这最终导致心脏衰竭