Ethanol on Excitation-Contraction in Cardiac Cells

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，干扰乙醇喂养动物模型心脏的收缩功能。酒精性心肌病的特征包括心输出量减少、心肌收缩力受损和房性心律失常。酒精在急性给药期间也有直接的心脏抑制作用。酒精性心脏病的一些特征可能反映了这些急性乙醇作用引起的适应性变化。我们在上一个授权期的研究已经确定了兴奋-收缩（E-C）偶联级联反应中急性乙醇作用的一些靶点，包括肌膜Na+和Ca 2+通道，这些通道导致驱动收缩的胞浆Ca 2+（[Ca 2 +]i）瞬变的抑制。我们还确定了特定的变化，在E-C耦合在乙醇喂养的大鼠，这表明在L-型钙通道和cAMP依赖性蛋白激酶的调节的选择性病变的心脏。在这里提出的工作中，我们将进一步调查的元素E-C耦合的急性乙醇的影响，以期阐明这些可能有助于缺乏[Ca 2 +]i瞬变。然而，拟议中的研究的主要目的将是描述慢性乙醇消耗后E-C偶联的变化，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，我们将研究以下相关假设：通道亚基亚型组成和/或表达的改变导致通道在以下方面存在缺陷：（1）基础通道特性，（2）与细胞内Ca 2+释放途径偶联，（3）正常cAMP依赖性信号传导途径的调节，和/或（4）心肌细胞内的定位。这些实验将利用[Ca 2 +]i成像，电生理学和分子生物学方法的组合。拟议的工作将产生新的见解，在E-C耦合的变化，慢性乙醇消耗引起的心功能障碍的基础。这些发现也可能在阐明与心脏中其他异常适应过程的发展相关的因果因素方面具有更广泛的意义，这些过程最终导致心力衰竭

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