CATECHOLS AND ADENOSINE IN MYOCARDIAL PRECONDITIONING

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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.