Propentofylline and a hydroxy metabolite augment A2-receptor mediated cyclic AMP accumulation and attenuate A1-receptor mediated inhibition of acetylcholine release in the rat hippocampus.

In contrast to the adenosine receptor antagonist theophylline, the xanthine derivative propentofylline (HWA 285) is reported to protect against ischaemic cell damage. We examined the effect of propentofylline on two adenosine actions in the rat hippocampus; the A2-mediated stimulation of 3H-cAMP accumulation and the A1-mediated inhibition of 3H-ACh release. Propentofylline (0.5-1 mM) increased the adenosine (3 and 30 microM) -induced 3H-cAMP accumulation. This effect was shared by its metabolite A 72 0287. The mechanism may be a decreased inactivation of adenosine, since the effect of the stable adenosine derivative NECA was not altered. In contrast, the inhibitory effect of adenosine on evoked 3H-ACh release was inhibited by propentofylline and by its metabolite A 72 0287, but enhanced by the uptake inhibitor dipyridamole. The effect of the stable, A1-receptor selective analogue R-PIA (1 microM) was also blocked by propentofylline and by A 72 0287. In addition, propentofylline (0.5 mM) blocked the presynaptic inhibitory effect of carbachol (1 and 50 microM). Thus, propentofylline and one of its metabolites inhibits adenosine A1-receptor mediated presynaptic inhibition while it enhances adenosine A2-mediated cAMP accumulation in the rat hippocampus differently. This selectivity in action can only partly be explained by receptor subtype selectivity, and effects at sites other than the adenosine receptor are of major importance.