CATECHOLS AND ADENOSINE IN MYOCARDIAL PRECONDITIONING

描述(由申请人提供)：冠状动脉疾病比其他任何疾病导致的美国人死亡人数都多。使用导管(PTCA)、手术(CABG)或溶栓剂(TPA)进行冠状动脉血运重建术可以降低冠状动脉闭塞的发病率和死亡率。然而，急性心肌梗死症状的出现和冠状动脉血流的重建之间总是有延迟的。而延迟则会转化为心肌坏死。虽然如果要挽救心肌，心脏血运重建是至关重要的，但现在已经很明显的是，在一段时间的缺血后恢复血流的行为本身就会造成自身形式的损害，即所谓的再灌注损伤。可能的原因有很多：自由基、白细胞损伤和毛细血管堵塞、Na+和Ca++移位、肌挛缩、细胞凋亡。再灌注损伤的组织学特征和可能的功能特征与缺血损伤不同。在再灌流时进行治疗，试图减少由此产生的损伤，具有临床潜力。在动物模型中，针对再灌注损伤的治疗是否有效还没有达成共识。然而，一种新的腺苷A1/A2激动剂AMP579已经显示出希望。由于该药仍属专利性质，我将研究另一种A1/A2激动剂NECA的特性和保护机制。奇怪的是，阻断A2A型受体可以破坏保护作用，但A2A型激动剂不能模仿它。我将首先定义NECA对再灌注损伤保护的剂量要求，并确定选择性A1和A2激动剂的组合是否可以模拟保护。我将从Gs和磷脂酰肌醇3-激酶途径开始探讨NECA的信号转导途径，但也包括GI和NO途径。由于AI/A2激动剂可以减轻缺血/再灌流中的肌挛缩，我计划观察NECA是否干扰细胞内钙离子的积累。我还将确定NECA是否减少细胞内渗透压并减轻肿胀。最后，我将看看NECA在再灌流时挽救心肌是否能迅速转化为功能优势。人们希望这种新的药理学方法的潜力能够被确定。

DESCRIPTION (provided by applicant): Coronary artery disease kills more Americans than any other disease. Coronary revascularization with either catheters (PTCA), surgery (CABG), or thrombolytic agent (TPA) has reduced morbidity and mortality from coronary occlusion. Yet there is always a delay between onset of symptoms in acute myocardial infarction and re-establishment of coronary flow. And delay translates into myocardial necrosis. Although it is critical to revascularize the heart if myocardium is to be salvaged, it has now become apparent that the very act of resuming flow after a period of ischemia causes its own form of damage, so-called reperfusion injury. There are many possible causes: free radicals, leukocyte damage and capillary plugging, shifts of Na+ and Ca++, contracture, apoptosis. Histologic features and probably functional characteristics of reperfusion injury are distinct from those caused by ischemia. Treatment at reperfusion in an attempt to attenuate resulting inury has clinical potential. There is no consensus that treatment targeted at reperfusion injury in animal models has been effective. However, a novel adenosine A1/A2 agonist AMP 579 has shown promise. Because of the still proprietary nature of this agent, I will examine properties and mechanisms of protection of NECA, another A1/A 2 agonist. Oddly, A2A receptor blockade aborts protection, but it cannot be mimicked by A2A agonists. I will first define dosing requirements for NECA's protection against reperfusion injury and determine whether a combination of selective A1 and A2 agonists can mimic protection. I will explore NECA's signal transduction pathway leading to protection starting with the Gs and phosphatidylinositol 3-kinase pathways, but also including Gi and NO pathways. Because an AI/A2 agonist can attenuate contracture in ischemia/reperfusion, I plan to see if NECA interferes with accumulation of intracellular Ca++. I will also determine whether NECA decreases intracellular osmolytes and attenuates swelling. Finally, I will see if NECA's salvage of myocardium at reperfusion translates into rapid functional benefits. It is hoped that the potential of this new pharmacologic approach can be defined.