CATECHOLS AND ADENOSINE IN MYOCARDIAL PRECONDITIONING

缺血性心脏病仍然是最常见的原因 美国的死亡率。血管重建术已经成功 降低了急性死亡率，减轻了慢性症状。但心肌梗死 缺血仍然会导致心肌梗死和心力衰竭。一个 难以实现的目标是保存缺血心肌或预防 不可逆转的变化。如果后者能够实现，那么就会发生梗塞 会更小，心肌功能障碍也不会那么明显。近期 观察表明，短暂的冠状动脉闭塞几个 在较长时间的运动前几分钟，实际上导致较少的心肌 如果长时间的闭塞是单独发生的，那么脑梗塞的发生率会更高。这 这种现象被称为预适应，被认为与腺苷有关，因为 对兔的保护可以通过简单的输注 腺苷激动剂，并被腺苷受体阻滞剂阻断。 尽管很明显与腺苷有关，但其他人报告说 儿茶酚胺给药可能导致预适应和初步 在这个实验室中获得的数据表明，酪胺会导致 去甲肾上腺素的释放，确实可以保护缺血心肌。这些 观察与已知的多重拮抗和协同作用相结合 腺苷和儿茶酚胺之间的关系以及对 大鼠缺血预适应明显不依赖于 缺血心肌产生腺苷提示其作用 必须定义儿茶酚胺在预适应现象中的作用。 因此，拟议的研究项目将试图界定 腺苷与儿茶酚的相互作用 阻滞剂和肾上腺素能阻滞剂来确定是否 缺血心肌的预适应保护可被修改或 被封锁了。此外，还将确定G蛋白的参与程度 通过使用百日咳毒素和蛋白激酶C(PKC)的作用 使用刺激剂佛波酯、抑制性星形孢子素进行研究 和H7，以及磷酸酶阻断剂。儿茶酚胺的作用 将通过确定预适应是否仍然可以 在儿茶酚胺缺乏和无儿茶酚胺的心脏中诱导 肌细胞。最后，随着微透析探头的使用， 缺血预适应时心肌儿茶酚胺浓度的变化 将被测量和腺苷受体阻断所产生的改变 探员们确定了。这些研究应该为我们提供对 预适应对机制的一般和特异化作用 儿茶酚胺。这一知识将有助于潜在地利用 这种现象用于临床，并可能导致第一批真正的 抢救缺血心肌、降低心肌梗死发生率的有效手段 缺血性心脏病的发病率和死亡率。

Ischemic heart disease continues to be the most frequent cause of mortality in the United States. Revascularization has successfully reduced acute mortality and diminished chronic symptoms. But myocardial ischemia still results in myocardial infarction and cardiac failure. An elusive goal is preservation of ischemic myocardium or prevention of irreversible changes. If the later could be realized, then infarcts would be smaller and myocardial dysfunction less obvious. Recent observations have demonstrated that a brief coronary occlusion a few minutes before a more prolonged one actually causes less myocardial infarction than if the prolonged occlusion had occurred alone. This phenomenon, termed preconditioning, is felt to involve adenosine since the protection in rabbits can be reproduced by brief infusions of adenosine agonists and blocked by adenosine receptor blocking agents. Although adenosine is clearly involved, others have reported that catecholamine administration may cause preconditioning and preliminary data acquired in this lab have demonstrated that tyramine, which causes norepinephrine release, can indeed protect ischemic myocardium. These observations coupled with the known multiple antagonisms and synergisms between adenosine and catecholamines and the further documentation of ischemic preconditioning in the rat which is apparently not dependent on adenosine production by ischemic myocardium suggest that the role of catecholamines in the preconditioning phenomenon must be defined. Accordingly, the proposed research project will attempt to define the interaction between adenosine and catechols by using both adenosine blocking agents and adrenergic blockers to determine if the preconditioning protection of ischemic myocardium can be modified or blocked. Additionally, the involvement of G proteins will be determined by use of pertussis toxin and the role of protein kinase C (PKC) will be investigated by use of stimulant phorbol esters, inhibitory staurosporine and H7, and phosphatase-blocking agents. The effects of catecholamines will be further examined by determining whether preconditioning can still be induced in catecholamine-deficient hearts and catecholamine-free myocytes. Finally, with use of microdialysis probes changes in myocardial catecholamine concentration during ischemic preconditioning will be measured and alterations produced by adenosine receptor blocking agents determined. These studies should provide insights into the mechanism of preconditioning in general and specifically into the role of catecholamines. This knowledge will assist potential harnessing of this phenomenon for clinical use, and may lead to one of the first truly effective means of salvaging ischemic myocardium and reducing the morbidity and mortality of ischemic heart disease.