CATECHOLS AND ADENOSINE IN MYOCARDIAL PRECONDITIONING

超出所提供的空间。冠状动脉疾病杀死的美国人比其他任何疾病都多。冠脉血运重建术采用导管（PTCA）、手术（CABG）或溶栓药物（TPA）均可降低冠状动脉闭塞的发病率和死亡率。然而，在急性心肌梗死的症状发作和冠状动脉血流重建之间总是有一个延迟。延迟会导致心肌坏死。虽然心脏的血运重建对于挽救心肌至关重要，但现在已经很明显，缺血一段时间后恢复血流的行为会引起其自身形式的损伤，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、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引起的损伤不同。在再灌注治疗中，试图减轻所造成的损伤具有临床潜力。针对动物模型再灌注损伤的治疗是否有效尚无共识。然而，一种新的腺苷（A1/A2）激动剂AMP 579显示出了希望。由于这种药物仍然具有专利性质，我将研究另一种A] a2激动剂NECA的特性和保护机制。奇怪的是，a - 2a受体阻断会终止保护，但A2A激动剂无法模仿。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At和A2激动剂的组合是否可以模拟保护。我将探讨NECA的信号转导途径，从G s和磷脂酰肌醇3-激酶途径开始，但也包括G I和NO途径。由于AI/ a2激动剂可以减轻缺血再灌注时的挛缩，因此我们需要观察neca是否干扰细胞内Ca ++的积累。我还将确定NECA是否能减少细胞内渗透和减轻肿胀。最后，我将看到ifNECA对心肌再灌注的挽救转化为快速的功能益处。希望这种新的药理学方法的潜力可以被定义。网站性能 ======================================== 节结束 ===========================================

EXCEED THE SPACE PROVIDED. 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 ofNa + 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 adenosin( 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 A]A 2 agonist. Oddly, A-2Areceptor 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 At and A2 agonists can mimic protection. I will explore NECA's signal transduction pathway leading to protection starting with the G s and phosphatidylinositol 3-kinase pathways, but also including G i and NO pathways. Because an AI/A 2 agonist can attenuate contracture in ischemia]reperfusion, I pl_ to see ifNECA interferes with accumulation of intracellular Ca ++. I will also determine whether NECA decreases intracellular osmolytes and attenuates swelling. Finally, I will see ifNECA'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. PERFORMANCE SITE ========================================Section End===========================================