Characterization of Cardiac Adenosine Receptor Systems

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Cardiac function is controlled by neurotransmitters, neuromodulators, and drugs that bind to specific receptors located on the cardiac membrane. These receptors interact with various effector mechanisms to regulate cellular activity. Adenosine is locally released in the heart and acts on specific extracellular, membrane.bound receptors to cause decrease in the rate and force of contraction of the heart. Furthermore, the rate of adenosine release in the myocardium is increased during exercise, hypoxia/ischemia and in the failing heart. However, little is known concerning the pharmacological and biochemical characteristics of adenosine receptors and adenosine receptor: effector mechanisms in cardiac cells. The long term goal of this project is to elucidate the mechanisms by which activation of adenosine receptors lead to the regulation of cardiac function so that pharmacological interventions affecting this system can ultimately be used to modify cardiac function. There are two specific aims: (1) Extensive pharmacological and biochemical experiments will be performed to further characterize the adenosine receptor(s) in the heart. These experiments will utilize three approaches: (a) ligand binding studies with both agonist and antagonist radioligands; (b) photoaffinity labelling; and (c) affinity chromatography and receptor purification. These experiments will determine if more than one type of adenosine receptor exists in the heart and whether the cardiac adenosine receptors are the same or different from adenosine receptors in the CNS. (2) Additional experiments will determine which effector system(s) is/are activated by cardiac adenosine receptors to result in the physiological changes induced by activation of adenosine receptors. The mechanisms by which cardiac receptors modulate cAMP levels in the heart will be probed and the possibility that adenosine receptors couple to other effector systems will be examined. The results are anticipated to provide fundamental insights to the processes by which adenosine receptors control cardiac function.