ADENOSINE ENHANCED MYOCARDIAL PROTECTION DURING SURGERY

拟议研究的广泛、长期目标是 两个方面：1)加深我们对这些机制的理解 心肌缺血的病理生理学基础；以及；2) 设计合理的治疗方案，最大限度地减少缺血 心脏受损。本提案中描述的实验 是针对腺苷和丙酮酸的有益作用 在缺血性脑损伤的存活和功能改善方面 缺血后心肌。腺苷和丙酮酸很有吸引力 临床上心脏保护的候选对象是：1)他们 建议的行动机制将在以下两个方面有益于心脏 缺血和再灌流。和；2)快速代谢 内源性化合物的副作用将是最小的。 拟议研究的具体目的是调查： 1.腺苷和丙酮酸介导的机制 缺血时的心脏保护。体外离体灌流液 大鼠心脏将被用来确定腺苷和 丙酮酸： A.缺血时的糖酵解流量。 B.缺血期间和缺血后的细胞内钙水平。 C.缺血时和缺血后的胞浆磷酸化潜能。 2.腺苷和丙酮酸作为心脏保护物质的适用性 活体内的特工。 腺苷和丙酮酸对心肌保护剂量的影响 心功能(收缩期壁增厚、冠脉血 流量、心输出量、左心室dp/dt)和胞浆 磷酸化潜力将在之前、期间和 两种活体心肌缺血后临床相关性研究 心肌缺血模型： A.局部缺血和心肌顿抑。 B.心脏停搏液诱导的心脏骤停期间的全局缺血。 建议的实验，具有临床重要性和 潜在的治疗与人类缺血性心脏病的相关性 疾病，将提供基本知识和基本见解 腺苷和丙酮酸在改善心脏疾病方面的潜在应用 急性心肌缺血再灌流中的存活与恢复 在与心脏手术相关的情况下。

The broad, long-term objectives of the proposed research are twofold: 1) to further our understanding of the mechanisms underlying the pathophysiology of myocardial ischemia, and; 2) to design rationale therapeutic regimens which will minimize ischemic damage to the heart. The experiments described in this proposal are directed at the beneficial effects of adenosine and pyruvate in the survival and functional improvement of the ischemic and post-ischemic myocardium. Adenosine and pyruvate are attractive candidates for cardioprotection clinically because: 1) their proposed mechanism of action would benefit the heart both during ischemia and reperfusion. and; 2) as rapidly metabolized endogenous compounds their side effects would be minimal. The specific aims of the proposed research are to investigate: 1. The mechanism of adenosine and pyruvate mediated cardioprotection during ischemia. The in vitro isolated perfused rat heart will be used to determine the effect of adenosine and pyruvate on: a. glycolytic flux during ischemia. b. intracellular calcium levels during and after ischemia. c. cytosolic phosphorylation potential during and after ischemia. 2. The applicability of adenosine and pyruvate as cardioprotective agents in vivo. The effect of cardioprotective doses of adenosine and pyruvate on ventricular function (systolic wall thickening, coronary blood flow, cardiac output, left ventricular dP/dt) and cytosolic phosphorylation potential will be determined before, during, and after myocardial ischemia in two in vivo clinically relevant models of myocardial ischemia: a. regional ischemia and stunned myocardium. b. global ischemia during cardioplegia-induced cardiac arrest. The proposed experiments, which are of clinical importance and potential_therapeutic relevance for humans with ischemic heart disease, will provide fundamental knowledge and basic insights into the potential use of adenosine and pyruvate to improve cardiac survival and recovery in acute myocardial ischemia and reperfusion during conditions pertinent to cardiac surgery.