CATECHOLS AND ADENOSINE IN MYOCARDIAL PRECONDITIONING

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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.