Mechanism of Ethanol's Cardiac Inotropic Depression

乙醇抑制心脏正性肌力的机制

• 批准号: 6624025
• 负责人: EDWARD B LANKFORD
• 金额: $ 31.4万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6624025
• 关键词: alcoholism /alcohol abuse; biomechanics; calcium ion; cardiotoxin; cytoskeleton; ethanol; heart contraction; heart function; laboratory rat; myocardium

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.

描述（由申请人提供）：是损害效果的主要站点 慢性过度乙醇（ETOH）消耗是心脏。敏锐的，etoh是 负性核中，部分通过干扰激发反应 耦合，减少电触发的Ca2+瞬变的大小。在 低浓度，ETOH抑制心肌收缩，无法检测到 Ca2+变化，表明力转导是其的第二个目标 急性效应，其机制未知。该项目基于 假设ETOH的心脏抑制作用是其直接的结果 对收缩设备的影响。为了检验这一假设，以下 特定目标将使用正常的大鼠小梁。目标1：确定 ETOH的剂量反应在静止刚度和机制 电刺激的小梁（刚度，T0或峰值等距张力， 工作，DT/DT）。这将确定ETOH的范围] 细胞骨架和杂交力学。目标2：确定直接影响 EtoH在跨桥的力学上。将研究化学皮肤的小梁 绕过正常的兴奋 - 收缩途径，直接控制 收缩设备环境。 ETOH]对T0的影响[CA]张力 关系，最大缩短速度，工作以及被动和主动刚度 将确定。这将确定直接作用所需的[ETOH] 心脏收缩系统和武力转导和工作输出 机械参数对ETOH最敏感。目标3：确定步骤 跨桥循环（力产生过渡，磷酸盐释放，脱离 速率）负责AIM 2的ETOH敏感机械参数。 笼子化合物的激光光解会引发或扰动收缩 在监测力和刚度的同时，剥皮的小梁。目标4：确定 慢性乙醇暴露对心肌力学的影响。研究相同 对先前的目标将在饲喂EtoH的大鼠的小梁上进行2 至26周和正常对照。这些研究将表征变化 由慢性ETOH暴露产生的力学，识别作用部位，测试 用于ETOH敏感性的变化并检测适应性。提出的研究 将提供对细胞和分子的更完整的理解 负责乙醇对心肌抑制作用的机制 收缩力。