PLATELET-ACTIVATING-FACTOR (PAF)-INDUCED PLATELET-AGGREGATION - MODULATION BY PLASMA ADENOSINE AND METHYLXANTHINES

This study examined the role of plasma adenosine in the modulation of platelet-activating factor (PAF) activity on platelet aggregation and serotonin (5-HT) release in human platelet-rich plasma (PRP). In addit ion, the effects of methylxanthines (e.g. theophylline and caffeine) w ere studied on PAF-induced platelet aggregation in PRP isolated from b lood samples from healthy subjects. Also, PAF-induced platelet aggrega tion was examined in PRP samples of patients receiving theophylline tr eatment. These studies demonstrate that plasma adenosine levels (0.1 t o 0.3 mu M) play a key role in negative modulation of PAF activity on platelet aggregation and 5-HT release. After depletion of plasma adeno sine, the platelet-aggregating activity of PAF was increased greatly ( > 10-fold). PAF at concentrations of 0.1 to 12 mu M caused no 5-HT rel ease in PRP containing normal amounts of adenosine (blood collected in the presence of 2'-deoxycoformycin and dilazep), whereas PAF at 0.1 m u M caused 5-HT release (45%) in adenosine-depleted PRP, demonstrating that plasma adenosine is much more inhibitory of 5-HT release than pl atelet aggregation. The adenosine antagonists theophylline (50 mu M), caffeine (50 mu M) and a xanthine derivative, 3,7-dimethyl-1-propargyl xanthine (DMPX, 10 mu M) (a more specific adenosine A(2) receptor anta gonist), potentiated PAF activity on platelet aggregation in PRP sampl es containing adenosine. Also, patients receiving theophylline treatme nts showed significantly greater platelet aggregation induced by PAF i n their PRP samples. PAF induced a rapid increase (80% in 15 sec) in i ntracellular Ca2+ mobilization, which was strongly inhibited by adenos ine (IC50, 0.3 mu M). Our studies suggest that agents that can increas e plasma adenosine levels (e.g. inhibitors of adenosine uptake and ade nosine metabolism) or methylxanthines may be useful in altering (inhib iting or enhancing, respectively) PAF actions on platelets and other t issues.