DIFFERENTIAL-EFFECTS OF THE PYRIMIDO-PYRIMIDINE DERIVATIVES, DIPYRIDAMOLE AND MOPIDAMOL, ON PLATELET AND VASCULAR CYCLOOXYGENASE ACTIVITY

The chronic administration of 10 mg/kg/day of dipyridamole to rats produced 33.7% inhibition of platelet aggregation induced with ADP and a 93% increase in 6-keto-prostaglandin F-1 alpha (6-keto-PGF(1 alpha)) in vascular samples, versus saline-treated rats. Mopidamol, 8.3 mg/kg/day, caused 50.6% inhibition of ADP-induced platelet aggregation, 37.6% inhibition of aggregation induced with arachidonic acid, a 47.6% decrease in serum levels of thromboxane B-2 and a 23.7% increase in the vascular production of 6-keto-PGF(1 alpha) versus saline-treated rats. Dipyridamole showed a higher in vitro antiaggregating effect in whole blood (IC50 6.6 mu M) than in platelet-rich plasma (PRP) (Ic(50) 210 mu M), when ADP was used as inducer, and had no effect in the presence of arachidonic acid. Mopidamol exerted a similar effect in whole blood (IC50 3.7-20 mu M, depending on the inducer) and PRP (IC50 11-17.3 mu M), and showed a dose-dependent inhibition of platelet aggregation and thromboxane B-2 synthesis induced with arachidonic acid (IC50 16.8-22.3 mu M). Mopidamol also inhibited enzymatically induced lipid peroxidation) (IC50 89 +/- 5.9 mu mol/L) and had no effect on free radical-induced lipid peroxidation. The dose-dependent increase in 6-keto-PGF(1 alpha) in vascular samples after incubation with dipyridamole showed a negative linear correlation with inhibition of lipid peroxidation (r(2) = 0.77). It is concluded that the phosphodiesterase inhibitors, dipyridamole and mopidamol, interfere in a different manner with platelet function. It seems that mopidamol may also exert a selective effect on platelet thromboxane synthesis.