EFFECTS OF PROPENTOFYLLINE ON ADENOSINE-A1 AND ADENOSINE-A2 RECEPTORS AND NITROBENZYLTHIOINOSINE-SENSITIVE NUCLEOSIDE TRANSPORTERS - QUANTITATIVE AUTORADIOGRAPHIC ANALYSIS

Previous studies have demonstrated that the xanthine compound, propentofylline, has beneficial effects in models of cerebral ischemia and can enhance some and exhibit other effects of adenosine. We investigated the in vitro effects of propentofylline and its hydroxy metabolite, A72 0287, on the binding of [H-3]cyclohexyladenosine ([H-3]CHA), [H-3]2-[p-(2-carbonyl-ethyl)-phenylethylamino]-5'-N-ethylcarboxamido adenosine ([H-3]CGS 21680) and [H-3]nitrobenzylthioinosine ([H-3]NBMPR) to adenosine A1 and A2 receptors and NBMPR-sensitive nucleoside transporters, respectively, in 10-mu-m coronal rat brain sections. Both xanthines had micromolar affinity for each of these sites with approximately 10-fold lower affinity for A2 receptors than for A1 receptors and [H-3]NBMPR binding sites. Saturation analysis of [H-3]CHA or [H-3]CGS 21680 binding in the presence of increasing concentrations of propentofylline produced significant increases in K(D) values without affecting B(max) values; thus propentofylline is a competitive inhibitor at A1 and A2 receptors. The effects on A2 receptors apparently require higher concentrations (K(i) approximately 200-mu-M) than the effects on A1 receptors (K(i) approximately 20-mu-M). Propentofylline was also found to be a competitive inhibitor of [H-3]NBMPR binding. Therefore we conclude that propentofylline interacts with adenosine-responsive systems to increase interstitial adenosine concentrations and to selectively inhibit A1 receptors.