In the heart catecholamines produce an increase in contractility and glycogenolysis. Adenosine 3', 5'-monophosphate (cyclic AMP) appears to be important in mediating the mechanical and metabolic effects. Adenosine, another naturally occurring compound that is a potent coronary vasodilator and continually released from the myocardium, appears to play an important role in the regulation of coronary blood flow when demands for oxygen by the heart increase such as in the case with catecholamine stimulation. It is the purpose of this project to study the modulation of catecholamine-induced increases in cardiac contractility and glycogenolysis caused by endogenous myocardial adenosine. Earlier work supports the hypothesis that in addition to serving as an important vasoactive metabolite controlling coronary flow, adenosine serves as a negative-feedback regulator controlling the formation of cyclic AMP, activation of cyclic AMP-dependent protein kinase, adenylate cyclase and phosphorylase and enhanced contractile state elicited by catecholamines. The hypothesis will be investigated by studying the effects of endogenous adenosine on the metabolic and mechanical responses to catecholamine stimulation in an isolated working heart preparation of the guinea pig. The relationship between the endogenous adenosine concentration in extracellular fluid and coronary perfusates to the degree of the antiadrenergic effects caused by the nucleoside will be determined. The influence of adenosine on the binding of catecholamines to their membrane receptors will be investigated. The effect of endogenous adenosine on the metabolic and contractile responses elicited by other inotropic interventions including acetylcholine will be considered. To investigate the mechanism of action of adenosine further, the effects of the nucleoside on adenylate cyclase and phosphodiesterase, the enzymes responsible for cyclic AMP synthesis and degradation, respectively will be studied in addition to the effect of the nucleoside on the enzymes responsible for its own synthesis and degradation. The knowledge gained from these experiments should elucidate the mechanisms involving endogenous adenosine that regulate catecholamine induced changes in contractility and glycogenolysis in the normal, hypoxic and failing heart.
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