ADENOSINE AND PYRUVATE PROTECTION DURING HEART SURGERY

这项拟议的研究项目是对 腺苷和丙酮酸对两组正常人心功能的影响 和晕厥的心肌。这些研究旨在扩大 观察到腺苷和丙酮酸在 腺苷调节心脏对缺血的耐受性 A/1受体的兴奋与心肌磷酸化的增强 潜力分别为。这些代理商是有吸引力的候选人 防治可逆性缺血后心肌功能障碍 因为它们是内源性化合物，代谢迅速， 它们对心脏功能的有益作用发生在缺血和 再灌流。实验将在分离的心肌细胞和 肌浆网(SR)囊泡的电生理和 生化技术，并在完好的猪中接受区域性和 全球心肌缺血。拟议研究的具体目标 是要调查： 1)腺苷和丙酮酸的细胞和亚细胞机制 介导心肌顿抑的减弱。正常和新陈代谢衰退 新鲜采集的大鼠心室肌细胞将被用于 测定腺苷和丙酮酸对以下方面的影响：(A)慢内向 钙电流(I/Ca)，(B)细胞内钙浓度 ([Ca+2]]/i)，(C)ATP依赖性钾通道(K/ATP)电流，以及 (D)SR钙处理(SR 45/Ca~(2+)摄取和SR Ca~(2+)-ATPase活性)。 2)腺苷和丙酮酸作为治疗药物的疗效 或通过使用多巴酚丁胺消除必需的肌力支持水平 在体猪局部和全局心肌顿抑模型。剂量- 腺苷/丙酮酸和腺苷A/1受体激动剂的相关作用 就会将晕厥的心脏比作多巴酚丁胺通过测量结束 收缩压室壁厚度关系(ESPTR)、心输出量、 左心室dp/dt、冠脉血流量、心肌氧分压 消耗、心肌磷酸化电位、间质液体 在治疗前、治疗中和治疗前、治疗期间和治疗期间的嘌呤蓄积和心肌嘌呤释放 在正常和急性损伤的心脏中发生缺血后。 计划中的实验旨在阐明细胞机制。 腺苷和丙酮酸的有益作用 进一步增强药效。这些发现应该会导致 开发新的和特定的治疗策略以改善 危重病患者的血流动力学表现及存活率 但可逆性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.