MYCOCARDIAL DYSFUNCTION AND CA++ FLUXES IN SHOCK

休克和脓毒症的内在心脏收缩状态很难确定， 直接评价患者或完整动物中是否存在 间接因素其次影响心肌功能。 因此，委员会认为， 本申请人已经表征了可靠的分离心肌模型， 休克时的原发性心脏抑制，使用采集的心脏制剂 实验性休克的动物。 当前项目基于 我们的假设，即内在心肌功能障碍发生作为一个 早期和后续休克状态的渐进参与者，以及 重要的是，与Ca++转运的特异性改变有关， 休克时心脏细胞兴奋-收缩偶联过程。 休克引起的心脏改变对治疗的敏感性 还将审查干预措施。 离体灌注心脏和心肌（左心房和心室 乳头状）制剂将从经受以下处理的豚鼠中获得： 内毒素休克 体外心肌收缩反应将是 与两个早期阶段的体内血流动力学参数相比， 非膨胀性内毒素中毒和随后的膨胀性休克。 左 心室功能曲线、顺应性和冠状动脉血管反应 将与对照心脏中获得的反应进行对比。 心肌 将在心脏组织中专门评估休克中的Ca++通量， 肌膜和肌浆网膜部分。 亚细胞 膜Na+-Ca++交换（活性，化学计量），被动Ca++结合， 主动Ca++转运、Ca++流出和膜磷脂测定将 与功能分析相关。 选择性Ca++依赖性肌力 将使用干预（Ca++、cAMP、Ca++通道激动剂-拮抗剂） 作为药理学探针， 功能障碍的改变和部位。 休克引起的心脏抑制， 改变的Ca++调节将在脓毒症中得到验证和比较， 出血性（低血容量）休克模型。 选定的有效性 化学治疗剂（Ca++通道拮抗剂、氧自由基 清除剂）在减少心肌抑制和改变Ca++通量将 被确定。 该项目旨在提供功能的相关检查 以及休克和败血症时心脏的生化紊乱，以及 提示Ca++相关的细胞机制， 状态改变基本的兴奋-收缩耦合过程， 心肌

Intrinsic cardiac contractile status in shock and sepsis is difficult to directly evaluate in the patient or intact animal where the presence of indirect factors secondarily influences myocardial function. Accordingly, the applicant has characterized reliable isolated heart muscle models of primary cardiac depression in shock, using cardiac preparations harvested from animals experiencing experimental shock. The current project is based on our hypothesis that intrinsic myocardial dysfunction occurs as a progressive participant of both early and subsequent shock states, and importantly, is associated with specific alterations in Ca++ transport and excitation-contraction coupling processes of the heart cell in shock. Susceptibility of the shock-induced cardiac alterations to therapeutic intervention will also be examined. Isolated, perfused hearts and cardiac muscle (left atrial and ventricular papillary) preparations will be obtained from guinea pigs subjected to endotoxin shock. In vitro myocardial contractile responses will be compared with in vivo hemodynamic parameters during both early non-hypotensive endotoxicosis and subsequent hypotensive shock. Left ventricular function curves, compliance and coronary vascular responses will be contrasted with responses obtained in control hearts. Myocardial Ca++ fluxes in shock will be specifically assessed in cardiac tissue and sarcolemmal and sarcoplasmic reticulum membrane fractions. Subcellular membrane Na+-Ca++ exchange (activity, stoichiometry), passive Ca++ binding, active Ca++ transport, Ca++ efflux, and membrane phospholipid assays will be correlated with functional analyses. Selected Ca++-dependent inotropic interventions (Ca++, cAMP, Ca++-channel agonists-antagonists) will be used as pharrmacologic probes to delineate functional and biochemical alterations and sites of dysfunction. Shock induced cardiac depression and altered Ca++ regulation will be validated and compared in sepsis and hemorrhagic (hypovolemic) shock models. Effectiveness of selected chemotherapeutic agents (Ca++ channel antagonists, oxygen radical scavengers) in reducing myocardial depression and altered Ca++ fluxes will be determined. This project is designed to provide a correlative examination of functional and biochemical disturbances to the heart in shock and sepsis, as well as suggest Ca++-related cellular mechanisms whereby disorders of the shock state alter basic excitation-contraction coupling processes of the myocardium.