INTRINSIC MYOCARDIAL DYSFUNCTION IN CIRCULATORY SHOCK

循环休克时的心脏收缩状态难以直接判断 评估在患者或完整动物中存在的间接 影响心肌功能的因素可能是继发性的。因此， 申请者已经确定了一个可靠的分离心肌模型 休克时的原发性心脏抑制，使用房肌和室肌 取自经历内毒素休克的豚鼠。的目标是 目前的研究是利用这一模型来评估心脏效应。 休克中可能的治疗药物，以及使用45Ca和选定的 休克-药物相互作用为深入了解潜在的细胞 休克所致心功能障碍的发生机制。 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。选定的心肌的收缩和反应性 变力作用(如钙离子、cAMP、儿茶酚胺)和代谢 将测定底物(例如丙酮酸、葡萄糖-胰岛素)。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Ca++流量将使用心脏组织进行专门评估 ~(45)Ca的摄取和外流。亚细胞膜~(45)Ca通量和膜 将进行磷脂分析，并将其与功能 改装。部分推定化疗药物的疗效 (如类固醇、纳洛酮、自由基清除剂)在减少或 将对预防休克引起的心功能障碍进行评估。评估 将涉及体内给药给药的剂量方案 休克及体外直接给药对分离心肌的影响 受到控制和惊吓的动物。休克引起的心脏抑制将 也可以在失血性(低血容量)休克模型中进行验证和比较， 以及从其他物种分离的心脏制剂中。 该项目旨在提供相关的功能检查 以及休克时心脏的生化紊乱，以及提示 休克状态紊乱改变基础状态的可能机制 心肌的收缩过程。重要的是，新的方向 将对休克的化疗治疗进行评估。这些研究将 辅助预测休克对心脏机械反应性的影响 患者可能遇到的心脏对肌力的挑战 正在经历心血管休克。

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.