The binding of catecholamines, e.g., epinephrine or norepinephrine, to .beta.-adrenergic cell surface receptors ("adrenoceptors") in the heart increases cardiac contractile and metabolic activity. The .beta.-adrenoceptor-mediated cardiac stimulation involves a chain of events that includes binding of the catecholamine to the receptor, adenylyl cyclase activation, increased adenosine 3',5'-monophosphate (cAMP) formation, protein kinase activation, and action by phosphorylated proteins. In the heart, adenosine counteracts the .beta.-adrenergic stimulation of adenylyl cyclase activity, thereby counteracting .beta.-adrenoceptor-mediated cardiac stimulation. These negative regulatory effects of adenosine have been called the "antiadrenergic" actions of adenosine. (They have also been called the "indirect inhibitory" and "retaliatory" actions of adenosine.)
The antiadrenergic actions of adenosine on the heart are mediated by type A.sub.1 adenosine receptors, which, like .beta.-adrenergic receptors, are cell surface receptors. Type A.sub.1 adenosine receptors have a high affinity for adenosine. Accordingly, the antiadrenergic actions of adenosine in the heart occur at relative low interstitial (i.e. extracellular) adenosine concentrations, i.e., 0.1-10 .mu.M. Adenosine administered to the heart, at these low concentrations, in the absence of .beta.-adrenergic stimulation, has no detectable direct effect on the above-mentioned metabolic and mechanical parameters.
A second type of cell surface receptor for interstitial adenosine, designated A.sub.2, has a lower affinity for adenosine, i.e., approximately two to three orders of magnitude lower than the adenosine affinity of A.sub.1 receptors. Type A.sub.2 adenosine receptors exist in various mammalian tissues and have been detected in mammalian ventricular myocytes.