CATECHOLS AND ADENOSINE IN MYOCARDIAL PRECONDITIONING

超出提供的空间。死于冠状动脉疾病的美国人比死于其他任何疾病的人都多。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A]A2激动剂NECA的特性和保护机制。奇怪的是，阻断A-2A受体会破坏保护作用，但它不能被A2a激动剂模仿。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。我将从G-S和磷脂酰肌醇-3-激酶途径入手，探讨NECA的信号转导途径，但也包括G-I和NO途径。因为AI/A2激动剂可以减轻缺血再灌流中的肌挛缩，所以我们观察NECA是否干扰细胞内钙离子的积聚。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在再灌注时挽救心肌是否转化为快速的功能益处。人们希望这种新的药理学方法的潜力能够被确定。表演网站========================================Section End===========================================

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===========================================