CATECHOLS AND ADENOSINE IN MYOCARDIAL PRECONDITIONING

儿茶酚和腺苷在心肌预处理中的作用

• 批准号: 3369626
• 负责人: MICHAEL Victor COHEN
• 金额: $ 17.57万
• 依托单位: UNIVERSITY OF SOUTH ALABAMA
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-01 至 1996-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3369626
• 关键词: 6 hydroxydopamine; G protein; adenosine; antiadrenergic agents; catecholamines; chemoprevention; disease /disorder model; heart metabolism; heart pharmacology; laboratory rabbit; laboratory rat; microdialysis; myocardial infarct sizing; myocardial ischemia /hypoxia; phosphorylation; protein kinase C; reperfusion; species difference

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.

缺血性心脏病仍然是最常见的原因， 死亡率在美国。 血运重建成功 降低急性死亡率和减少慢性症状。 但是心肌 局部缺血仍然导致心肌梗塞和心力衰竭。 一个 难以实现的目标是保护缺血心肌或防止 不可逆转的变化 如果后者可以实现，那么梗塞 会更小，心肌功能障碍不那么明显。 最近 观察表明，短暂的冠状动脉闭塞， 更长时间的心肌梗塞 与单独发生的长时间闭塞相比， 这 一种称为预适应的现象被认为与腺苷有关， 在家兔中的保护作用可通过短暂输注 腺苷激动剂和腺苷受体阻断剂阻断。 虽然腺苷明显参与，但其他人报告说， 儿茶酚胺给药可引起预适应和初步的 本实验室获得的数据表明，酪胺， 释放去甲肾上腺素，确实可以保护缺血心肌。 这些 观察结果加上已知的多种拮抗和协同作用 腺苷和儿茶酚胺之间的关系， 缺血预适应的大鼠，这显然是不依赖于 缺血心肌腺苷的产生表明， 必须对预处理中的儿茶酚胺现象进行定义。 因此，拟议的研究项目将试图界定 腺苷与儿茶酚相互作用 阻断剂和肾上腺素能阻断剂，以确定 缺血心肌的预处理保护可以被修改或 被挡出. 此外，将确定G蛋白的参与 通过使用百日咳毒素和蛋白激酶C（PKC）的作用， 通过使用刺激性佛波醇酯、抑制性星形孢菌素 和H7，以及磷酸酶阻断剂。 儿茶酚胺的作用 将通过确定预处理是否仍然可以 在缺乏儿茶酚胺的心脏和无儿茶酚胺的心脏中诱导 肌细胞 最后，随着微透析探针的使用， 缺血预适应心肌组织中儿茶酚胺浓度的变化 将被测量，并通过腺苷受体阻断产生的变化 代理商决心 这些研究应该提供深入了解 预处理的一般机制和具体作用 儿茶酚胺 这些知识将有助于利用 这种现象的临床使用，并可能导致第一个真正的 是抢救缺血心肌，减少缺血再灌注损伤的有效手段。 缺血性心脏病的发病率和死亡率。