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 心脏功能和酒精中毒是导致心肌病的主要原因。 酒精还通过与心脏的直接相互作用抑制心脏功能。 急性暴露期间的心肌细胞，很可能是 对这些急性效应的适应性反应导致了 酒精性心脏病。一系列针对艾滋病急性影响的目标 酒精已经被识别出来，其中几个影响了 兴奋-收缩耦合(E-C耦合)。然而，这些机制 酒精对心脏的慢性影响的潜在原因仍然不清楚。在……里面 本研究将探讨急性心肌梗死的发病机制。 酒精对分离的心室肌细胞的慢性作用 从酒精喂养方案维持的大鼠心脏中获得 在很长一段时间内，在控制动物中。我们将决定如何 酒精对E-C偶联各元素的急性影响 级联的整合导致了收缩能力的下降。在……里面 关于酒精的慢性影响，我们最近发现 心脏E-C偶联调节中一个潜在的重要损伤。 具体地说，激活的上升速度和幅度 β-肾上腺素能激动剂引起的[Ca~(2+)]i瞬变显著减少 酒精喂养的老鼠。相比之下，大脑的β-肾上腺素能刺激 松弛阶段不受影响。这一缺陷似乎是贝塔的远端缺陷- 肾上腺素能受体激活和cAMP形成。然而，L式的 这些“酒精”心肌细胞的电压依赖性钙通道给出 与它们的配对控制相比，电流减少，并且在很大程度上 抵抗异丙肾上腺素的激活。这种钙离子通道的丧失 活动与钙通道α1密度增加有关 亚基测量为二氢吡啶结合。我们将调查 这一新效应的机制及钙离子变化的研究 这些细胞收缩功能障碍中的通道特性。我们 假设长期饮酒改变了表达水平 以及钙离子通道的亚基组成。这样的缺陷可能会 有助于收缩能力的降低，并可能是一种沉淀 心脏中其他异常适应过程发展的因素 这最终会导致心力衰竭。这些研究将进行 用分子和细胞生理学方法研究其作用机制 和心肌细胞的E-C偶联成分 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.