EFFECTS OF ETHANOL ON EXCITATION CONTRACTION COUPLING IN CARDIAC MYOCYTES

长期饮酒会导致心脏收缩功能的改变， 心脏功能和酗酒是心肌病的主要原因。 酒精也通过与心脏的直接相互作用抑制心脏功能。 在急性暴露期间， 对这些急性效应的适应性反应有助于 酒精性心脏病一些目标的急性影响， 酒精已经被确定，其中一些影响的途径， 兴奋-收缩偶联（E-C偶联）。然而，机制 酒精对心脏的慢性影响的根本原因仍然不清楚。在 这项研究，我们将调查机制负责的急性 酒精在离体心室肌细胞中的慢性作用 从保持酒精喂养方案的大鼠心脏获得 以及对照组动物。我们将决定如何 酒精对E-C偶联的单个元素的急性效应 级联被整合以引起收缩性的抑制。在 在酒精的慢性影响的背景下，我们最近发现， 在心脏E-C耦合调节中的潜在重要损伤。 具体而言，激活的上升速率和振幅的 [Ca2β-肾上腺素能激动剂的+]i瞬变大大降低， 酒精喂养的老鼠 相比之下，β-肾上腺素能刺激的 松弛阶段不受影响。这个缺陷似乎是远端的β- 肾上腺素能受体活化和cAMP形成。然而，L型 这些“酒精性”心肌细胞的电压依赖性钙通道 与配对对照相比，电流降低，并且在很大程度上 抗异丙肾上腺素激活。这种Ca 2+通道的丧失 活性与Ca 2+通道α 1密度增加相关 亚基测量为二氢吡啶结合。 我们将调查 这一新的影响机制，并检查改变的Ca 2+的作用， 这些细胞收缩功能障碍的通道特性。 我们 假设长期饮酒改变了表达水平， 和Ca 2+通道的亚基组成。这种缺陷可能 有助于抑制收缩性，可能是一种促进 心脏其他异常适应过程的发展因素 最终导致心力衰竭这些研究将在 利用分子和细胞生理学方法研究其机制， 和心肌E-C偶联的组成部分， 对照组和酒精喂养的大鼠。

Chronic alcohol consumption leads to alterations in the contractile function of the heart and alcoholism is a leading cause of cardiomyopathy. Alcohol also depresses heart function through a direct interaction with the cardiac muscle cells during acute exposure and it is likely that adaptive responses to these acute effects contribute to the etiology of alcoholic heart disease. A number of targets for the acute effects of alcohol have been identified and several of these impact on the pathway of excitation-contraction coupling (E-C coupling). However, the mechanisms underlying the chronic effects of alcohol on the heart remain obscure. In this study we will investigate the mechanisms responsible for the acute and chronic actions of alcohol in isolated ventricular muscle cells obtained from the hearts of rats maintained on an alcohol feeding protocol for prolonged periods, and in control animals. We will determine how the acute effects of alcohol on individual elements of the E-C coupling cascade are integrated to give rise to the depression of contractility. In the context of the chronic effects of alcohol, we have recently identified a potentially important lesion in the regulation of cardiac E-C coupling. Specifically, the activation of the rate of rise and amplitude of the [Ca2+]i transients by beta-adrenergic agonists is greatly decreased in alcohol-fed rats. By contrast, the beta-adrenergic stimulation of the relaxation phase is unaffected. This defect appears to be distal to beta- adrenergic receptor activation and cAMP formation. However, the L-type voltage-dependent Ca2+ channels of these "alcoholic" cardiomyocytes give reduced currents compared to their paired controls, and are largely resistant to activation by isoproterenol. This loss of Ca2+ channel activity is associated with an increased density of Ca2+ channel alpha1 subunit measured as dihydropyridine binding. We will investigate the mechanism of this novel effect and examine the role of the altered Ca2+ channel properties in the contractile dysfunction of these cells. We hypothesize that chronic alcohol consumption modifies the expression level and subunit composition of the Ca2+ channels. Such a defect could contribute to the depression of contractility and may be a precipitating factor in the development of other aberrant adaptive processes m the heart that eventually lead to cardiac failure. These studies will be carried out using molecular and cellular physiology approaches to study the mechanisms and components of cardiac muscle E-C coupling in cardiomyocytes from control and alcohol-fed rats.