Mechanism of Ethanol's Cardiac Inotropic Depression

描述(由申请人提供)：一个主要的破坏影响的地点 慢性过量乙醇(Etoh)的摄入是心脏。尖锐地说，艾托是 负性肌力作用，部分是通过干扰兴奋收缩 耦合，减少电触发的钙瞬变的幅度。在… 低浓度乙醇抑制心肌收缩而不被检测到 CA2的变化，表明力传递是其第二个靶点 急性效应，其机制尚不清楚。这个项目是基于 假设乙醇的心脏抑制作用是其直接作用的结果 对收缩器官的影响。要检验这一假设，请看以下内容 特定的目标将使用正常的大鼠小梁来解决。目标1：确定 乙醇对静息僵硬的剂量效应及力学机制 电刺激小梁(硬度，T0或峰值等长张力， 工作和DT/DT)。这将决定[Etoh]改变的范围 细胞骨架和跨桥力学。目标2：确定 Etoh谈跨桥力学。我们将研究化学剥皮的骨小梁， 绕过正常的兴奋收缩途径，直接控制 收缩器械环境。乙醇对[Ca]-张力T0的影响 最大缩短速度、功、被动和主动刚度之间的关系 将会被确定。这将决定直接生效所需的[Etoh] 心脏收缩系统的力传递和功输出 对乙醇最敏感的力学参数。目标3：确定 跨桥循环(作用力转换、磷酸盐释放、脱离 Rate)负责来自目标2的乙醇敏感的机械参数。 笼状化合物的激光光解将引发或扰动血管的收缩 蒙皮的小梁，同时监测力和僵硬。目标4：确定 慢性酒精暴露对心肌力学的影响。研究相同 与以前的目的相比，将在饲喂乙醇2次的大鼠的小梁上进行 至26周和正常对照组。这些研究将表征这些变化 慢性乙醇暴露产生的力学，确定作用部位，测试 用于乙醇敏感性的变化，并检测适应情况。建议进行的研究 将提供对细胞和分子的更完整的理解 乙醇对心肌抑制作用的机制 伸缩性。

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.