INTRINSIC MYOCARDIAL DYSFUNCTION IN CIRCULATORY SHOCK

循环休克时的心肌收缩状态很难直接 在患者或完整动物中评价是否存在间接 这些因素可能对心肌功能产生次要影响。 因此 申请人已经表征了一种可靠的分离心肌模型， 使用心房和心室肌的休克中的原发性心脏抑制 从经历内毒素休克的豚鼠中获得。 的目标 目前的研究是利用该模型来评估心脏效应， 在休克的假定治疗剂，以及使用45钙和选择 休克-药物相互作用，以提供对潜在的细胞 休克引起的心功能不全的机制。 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 心肌收缩力和对选择的 变力作用（例如，Ca++、cAMP、儿茶酚胺）和代谢 衬底（例如，丙酮酸盐、葡萄糖-胰岛素）。 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 将使用心脏组织专门评估休克中的Ca++通量 45 Ca的摄取和流出。 亚细胞膜~（45）Ca通量与细胞膜 将进行磷脂测定，并与功能相关。 改变。 选定的假定化疗药物的有效性 (e.g.,类固醇、纳洛酮、自由基清除剂）， 将评估预防休克引起的心脏功能障碍。 评估 将涉及在体内向动物施用药物的剂量方案， 休克以及直接体外给药于离体心肌 从对照组和休克组动物身上。 休克引起的心脏抑制将 也可以在出血性（低血容量）休克模型中进行验证和比较， 以及来自其他物种的分离的心脏制备物。 该项目旨在提供一个功能的相关检查 以及休克时心脏的生化紊乱， 休克状态的紊乱改变基本的 心肌的收缩过程。 重要的是， 将评价休克的化疗管理。 这些研究将 有助于预测休克对机械反应性的影响， 患者可能遇到的心脏变力性挑战 心血管休克

Cardiac contractile status in circulatory shock is difficult to directly evaluate in the patient or intact animal where the presence of indirect factors may secondarily influence myocardial function. Accordingly, the applicant has characterized a reliable isolated heart muscle model of primary cardiac depression in shock, using atrial and ventricular muscle harvested from guinea pigs experiencing endotoxin shock. The objective of the current study is to utilize this model to evaluate the cardiac effects of putative therapeutic agents in shock, as well as use 45Ca and selected shock-drug interactions to provide insight into potential cellular mechanisms involved in producing shock-induced cardiac dysfunction. Isolated, perfused hearts and cardiac muscle (left atrial and ventricular papillary) preparations will be obtained from guinea pigs subjected to endotoxin shock. Myocardial contractility and reactivity to selected inotropic influences (e.g., Ca++, cAMP, catecholamines) and metabolic substrates (e.g., pyruvate, glucose-insulin) will be determined. 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 using cardiac tissue uptake and efflux of 45Ca. Subcellular membrane 45Ca fluxes and membrane phospholipid assays will be conducted and correlated with functional alterations. Effectiveness of selected putative chemotherapeutic agents (e.g., steroids, naloxone, free radical scavengers) in reducing or preventing shock-induced cardiac dysfunction will be evaluated. Assessment will involve dose regimens of in vivo administration of drugs to animals in shock as well as direct in vitro adminstration to heart muscle isolated from control and shocked animals. Shock induced cardiac depression will also be validated and compared in a hemorrhagic (hypovolemic) shock model, and in isolated cardiac preparations from other species. This project is designed to provide a correlative examination of functional and biochemical disturbances to the heart in shock, as well as suggest potential mechanisms whereby disorders of the shock state alter basic contractile processes of the myocardium. Importantly, new directions in chemotherapeutic management of shock will be evaluated. These studies will aid in predicting effects of shock on mechanical responsiveness of the heart to inotropic challenges that may be encountered by patients experiencing cardiovascular shock.