Mechanism of Ethanol's Cardiac Inotropic Depression

描述（由申请人提供）： 慢性过量乙醇（EtOH）消耗是心脏。实际上，EtOH是 负性肌力，部分通过干扰兴奋收缩 耦合，降低电触发的Ca 2+瞬变的幅度。在 低浓度时，EtOH抑制心肌收缩， Ca 2+的变化，这表明力转导是其第二个目标， 急性效应，其机制尚不清楚。该项目基于 假设EtOH的心脏舒张作用是其直接作用的结果， 对收缩器官的影响。为了验证这一假设， 将使用正常大鼠骨小梁来解决特定目的。目标1：确定 EtOH对静息刚度的剂量反应和 电刺激小梁（硬度，T0或等长张力峰值， 功和dT/dt）。这将决定改变的EtOH]的范围 细胞骨架和跨桥力学。目标2：确定下列因素的直接影响 EtOH在交叉桥力学上。将研究化学皮肤小梁， 绕过正常的兴奋-收缩通路，直接控制 收缩性器官环境。EtOH]对T0、[Ca]-张力的影响 关系，最大缩短速度，功，被动和主动刚度 将被确定。这将决定直接影响所需的[EtOH] 心脏收缩系统的力传递和功输出， 对EtOH最敏感的机械参数。目标3：确定 跨桥循环（力产生转换、磷酸盐释放、分离 速率）负责目标2的EtOH敏感机械参数。 笼状化合物的激光光解将引发或干扰 同时监测力和刚度。目标4：确定 慢性乙醇暴露对心肌力学的影响。研究相同 将对喂食EtOH的大鼠的小梁进行2 至26周和正常对照组。这些研究将描述 慢性EtOH暴露产生的力学，确定作用部位，测试 用于EtOH灵敏度的变化，并检测适应性。拟议的研究 将提供一个更完整的理解细胞和分子 乙醇对心肌细胞毒性作用的机制 收缩性

DESCRIPTION (provided by applicant): A major site for the damaging effects of chronic excessive ethanol (EtOH) consumption is the heart. Acutely, EtOH is negatively inotropic, in part, by interfering with excitation-contraction coupling, reducing the magnitude of electrically triggered Ca2+ transients. At low concentrations, EtOH inhibits myocardial contractions without detectable Ca2+ changes, suggesting that force transduction is a second target of its acute effects, whose mechanisms are unknown. This project is based upon the hypothesis that cardiodepressant effects of EtOH are the result of its direct effects on the contractile apparatus. To test this hypothesis, the following specific aims will be addressed using normal rat trabeculae. Aim 1: Determine the dose-response of EtOH on resting stiffness and the mechanics of electrically stimulated trabeculae (stiffness, T0 or peak isometric tension, work, and dT/dt). This will determine the range of EtOH] that alters cytoskeletal and cross-bridge mechanics. Aim 2: Determine the direct effects of EtOH on cross-bridge mechanics. Chemically skinned trabeculae will be studied, bypassing the normal excitation-contraction pathway, directly controlling the contractile apparatus environment. The effects of EtOH] on T0, the [Ca]-tension relation, maximum shortening velocity, work, and passive and active stiffness will be determined. This will determine the [EtOH] required to effect directly force transduction and work output by the cardiac contractile system and the mechanical parameter most sensitive to EtOH. Aim 3: Determine the step in the cross-bridge cycle (force producing transition, phosphate release, detachment rate) responsible for the EtOH-sensitive mechanical parameters from aim 2. Laser photolysis of caged-compounds will initiate or perturb contractions of skinned trabeculae while monitoring force and stiffness. Aim 4: Determine the effects of chronic ethanol exposure on myocardial mechanics. Studies identical to the previous aims will be performed on trabeculae from rats fed EtOH for 2 to 26 weeks and normal controls. These studies will characterize the changes in mechanics produced by chronic EtOH exposure, identify the site of action, test for changes in EtOH sensitivity, and detect adaptations. The proposed studies will provide a more complete understanding of the cellular and molecular mechanisms responsible for the depressant effects of ethanol on myocardial contractility.