Effects on aggregation of human platelets of two xanthines and their interactions with adenosine

Adenosine receptor antagonism has been suggested to be the cellular basis for many extrapulmonary actions of xanthine derivatives, such as theophylline. Enprofylline (3-propylxanthine) is a poor adenosine antagonist but is five times as potent as theophylline as a bronchodilator in man. Adenosine is a potent inhibitor of platelet aggregation, but also xanthines are considered to exert this action. In the present study, effects of theophylline and enprofylline on ADP-induced aggregation of human platelets were studied in vitro. Theophylline alone in concentrations exceeding 280 microM inhibited platelet aggregation concentration-dependently. Enprofylline alone mimicked this effect but was about five times more potent than theophylline. At the lowest concentrations used, corresponding to upper therapeutic levels, neither of the two xanthines affected platelet aggregation by ADP. The interactions between these low concentrations of the xanthines and adenosine were then evaluated. In the presence of theophylline 110 microM the inhibitory effect of adenosine 4 microM was attenuated, whereas the presence of enprofylline 21 microM enforced the inhibitory effect of adenosine. Thus, at low concentrations where neither theophylline nor enprofylline inhibits platelet aggregation theophylline antagonizes the antiaggregatory effect of adenosine, whereas enprofylline acts in synergy with this nucleoside.