ADENOSINE AND PYRUVATE PROTECTION DURING HEART SURGERY

这项拟议的研究项目是一项持续调查的一部分， 腺苷和丙酮酸对正常人和正常人心功能的影响 和休克心肌 这些研究旨在扩大 观察到腺苷和丙酮酸在 由于腺苷调节心脏对局部缺血的耐受性 A/1受体的激活与心肌磷酸化的增强 潜力，分别。 这些代理人是有吸引力的候选人， 预防和治疗可逆性缺血后心肌功能障碍 因为它们是快速代谢的内源性化合物， 它们对心脏功能的有益作用发生在缺血和 再灌注 实验将在分离的肌细胞中进行， 肌浆网（SR）囊泡使用电生理和 生物化学技术，并在完整的猪进行区域和 心肌缺血 拟议研究的具体目标 要调查： 1)腺苷和丙酮酸的细胞和亚细胞机制 介导的心肌顿抑衰减。 正常的新陈代谢- 供能的新鲜收获的大鼠心室肌细胞将用于 确定腺苷和丙酮酸对以下方面的影响：（a）缓慢向内 钙电流（I/Ca），（B）细胞内钙浓度 ([Ca（c）ATP依赖性钾通道（K/ATP）电流，和 (d)SR钙处理（SR 45/Ca 2+摄取和SR Ca 2 +-ATP酶活性）。 2)腺苷和丙酮酸作为治疗剂降低 或通过多巴酚丁胺消除必要的正性肌力支持水平， 局部和整体心肌顿抑的体内猪模型。 剂量- 腺苷/丙酮酸和腺苷A/1受体激动剂的相关作用 将通过测量结束时间与多巴酚丁胺进行比较。 收缩压壁厚关系（ESPTR），心输出量， 左心室dP/dt，冠脉流量，心肌氧 消耗，心肌磷酸化电位，间质液 嘌呤蓄积和心肌嘌呤释放， 在正常和急性损伤的心脏缺血后。 所提出的实验旨在阐明细胞机制 基于腺苷和丙酮酸的有益作用， 以进一步提高其功效。 调查结果应该会导致 开发新的和具体的治疗策略，以改善 危重患者的血流动力学性能和生存率 但是可逆的缺血后心肌功能障碍

This proposed research project is part of a continuing investigation of the effects of adenosine and pyruvate on cardiac function in both normal and stunned myocardium. The studies are designed to expand the observation that adenosine and pyruvate play an important role in modulating the tolerance of the heart to ischemia as a result of adenosine A/1 receptor stimulation and enhancement of the myocardial phosphorylation potential, respectively. These agents are attractive candidates for preventing and treating reversible postischemic myocardial dysfunction because they are endogenous compounds which are rapidly metabolized and their salutary effects on cardiac function occur during both ischemia and reperfusion. Experiments will be performed in isolated myocytes and sarcoplasmic reticulum (SR) vesicles using electrophysiological and biochemical techniques, and in the intact pig subjected to regional and global myocardial ischemia. The specific aims of the proposed research are to investigate: 1) the cellular and subcellular mechanisms of adenosine and pyruvate mediated attenuation of myocardial stunning. Normal and metabolically de- energized freshly harvested rat ventricular myocytes will be used to determine the effect of adenosine and pyruvate on: (a) the slow inward calcium current (I/Ca), (b) intracellular calcium concentration ([Ca+2]]/i), (c) the ATP dependent potassium channel (K/ATP) current, and (d) SR calcium handling (SR 45/Ca2+ uptake and SR Ca2+-ATPase activity). 2) the efficacy of adenosine and pyruvate as therapeutic agents to reduce or eliminate the level of requisite inotropic support by dobutamine using in vivo porcine models of regional and global myocardial stunning. Dose- related effects of adenosine/pyruvate and adenosine A/1 receptor agonists on the stunned heart will be compared to dobutamine by measuring end systolic pressure wall thickness relationships (ESPTR), cardiac output, left ventricular dP/dt, coronary blood flow, myocardial oxygen consumption, myocardial phosphorylation potential, interstitial fluid purine accumulation, and myocardial purine release before, during, and after ischemia in normal and acutely injured hearts. The proposed experiments are designed to elucidate the cellular mechanisms underlying the salutary effects of adenosine and pyruvate with the intent to further enhance their efficacy. The findings should lead to the development of new and specific therapeutic strategies to improve hemodynamic performance and therefore survival in patients with critical but reversible postischemic myocardial dysfunction.