MYCOCARDIAL DYSFUNCTION AND CA++ FLUXES IN SHOCK

休克和脓毒症患者的心脏固有收缩状态很难 直接评估患者或完整动物中存在的 间接因素对心肌功能的影响是次要的。因此， 申请者已经确定了可靠的分离心肌模型 使用收集的心脏制剂在休克时的原发性心脏抑制 从经历实验性休克的动物身上。当前项目基于 根据我们的假设，固有的心肌功能障碍作为一种 早期和随后的休克状态的渐进性参与者，以及 重要的是，它与钙转运和钙离子的特殊变化有关 休克时心脏细胞的兴奋-收缩耦合过程。 休克所致心脏改变对治疗的敏感性 还将研究干预措施。 隔离、灌流的心脏和心肌(左房和左室 乳头状)制剂将从豚鼠身上获得 内毒素休克。体外心肌收缩反应将是 比较两组早期在体血流动力学参数 非低血压内毒素血症和随后的低血压休克。左边 心功能曲线、顺应性和冠脉血管反应 将与在对照心脏中获得的反应进行对比。心肌 休克时的钙离子流量将在心脏组织和 肌膜和肌浆网膜组分。亚细胞 膜钠钙交换(活性，化学计量比)，被动钙结合， 主动钙转运、钙外流和膜磷脂分析将 与功能分析相关。选择性钙依赖性变力作用 将使用干预措施(钙、cAMP、钙通道激动剂-拮抗剂) 作为药物学探针描绘功能和生化 功能障碍的改变和部位。休克引起的心脏抑制和 钙调节改变将在脓毒症和 失血性(低血容量)休克模型。入选的有效性 化疗药物(钙通道拮抗剂、氧自由基 清道夫)在减少心肌抑制和改变钙流量方面将 要下定决心。 该项目旨在提供相关的功能检查 以及休克和败血症时心脏的生化紊乱，以及 提示与钙相关的细胞机制，即休克的紊乱 状态改变基本的激发-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.