ADENOSINE ENHANCED MYOCARDIAL PROTECTION DURING SURGERY

拟议研究的广泛和长期目标是 二是：1）进一步了解机制 心肌缺血的病理生理学基础，和; 2） 设计合理的治疗方案， 对心脏的伤害。 本提案中所述的实验 是针对腺苷和丙酮酸的有益作用 在缺血性脑卒中患者的存活率和功能改善方面， 缺血后心肌 腺苷和丙酮酸很有吸引力 临床上的心脏保护候选人，因为：1）他们的 提出的作用机制将有利于心脏， 缺血和再灌注。 （2）快速代谢 内源性化合物，它们的副作用将是最小的。 拟议研究的具体目标是调查： 1. 腺苷和丙酮酸介导的细胞凋亡机制 缺血期间的心脏保护。 体外离体灌流 将使用大鼠心脏来确定腺苷的作用， 丙酮酸： a. 糖酵解流量。 B. 缺血期间和缺血后的细胞内钙水平。 C. 在缺血期间和之后的胞质磷酸化潜力。 2. 腺苷和丙酮酸作为心脏保护剂的适用性 体内的代理商。 心脏保护剂量的腺苷和丙酮酸对 心室功能（收缩期室壁增厚，冠状动脉血 流量、心输出量、左心室dP/dt）和细胞溶质 磷酸化潜力将在之前，期间， 在两种临床相关的体内心肌缺血后 心肌缺血模型： a. 局部缺血和顿抑心肌。 B. 心脏停搏引起的心脏骤停期间的全身缺血。 建议的实验，这是临床重要性， 对缺血性心脏病患者的潜在治疗相关性 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功能中潜在用途 急性心肌缺血再灌注后存活与恢复 在心脏手术相关的条件下。

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.