ADENOSINE A1 AND A2 RECEPTORS IN THE MYOCARDIUM

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DESCRIPTION (Verbatim from the application): Adenosine receptors play an important role in regulating cardiac function. For example, adenosine Al receptors affect heart rhythm, contraction and metabolism and mediate ischemic preconditioning. Adenosine by interacting with adenosine Al receptors is known to be antiadrenergic in that it reduces the contractile and metabolic responsiveness of the myocardium to beta1-adrenergic stimulation. Stimulation of adenosine A2a receptors has been reported to directly increase cardiac contractility. Recently we reported that adenosine A2a receptor stimulation also limits the antiadrenergic actions of adenosine. The mechanism by which the cardiac adenosine A2a receptors affect adenosine Al receptor function is not known. Furthermore, it is not known if A2a receptor actions also effect functioning of other receptors such as muscarinic receptor functioning. The objective of this project is to investigate the molecular mechanisms by which the adenosine A2a receptor inhibits adenosine Al receptor mediated antiadrenergic actions in the heart. Using rat ventricular myocytes and myocyte membranes, the proposed studies should reveal: 1) The way in which adenosine A2a receptor activation inhibits the antiadrenergic actions resulting from adenosine Al and muscarine M2 receptor stimulation, 2) The effect of adenosine A2a receptor action on f3 1-adrenergic, and adenosine Al ligand binding and beta1-adrenergic receptor sensitive adenylyl cyclase activity, 3) The importance of protein kinases A and C, G protein kinases, and receptor phosphorylation in the adenosine A2a receptor-mediated inhibition of adenosine Al-elicited antiadrenergic actions, and 4) The action of adenosine A2a receptor activation on adenosine Al receptor-mediated changes in GTPase activity upon beta1-adrenergic receptor stimulation. The results obtained from these studies should provide new information regarding the molecular functioning of adenosine receptors in the myocardium. Additionally, the findings should significantly contribute to our basic knowledge of the molecular mechanisms of G protein coupled receptor cross-regulation in the heart.