Differential effects of the pyrimido-pyrimidine derivatives, dipyridamole and mopidamol, on platelet and vascular cyclooxygenase activity

Abstract

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 α (6-keto-PGF 1 α ) 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 α , versus saline-treated rats. Dipyridamole showed a higher in vitro anti-aggregating effect in whole blood (IC 50 6.6 μM) than in platelet-rich plasma (PRP) (IC 50, 210μM), when ADP was used as inducer, and had no effect in the presence of arachidonic acid. Mopidamol exerted a similar effect in whole blood (IC 50 3.7–20 μM, depending on the inducer) and PRP (IC 50 11-17.3 μM), and showed a dose-dependent inhibition of platelet aggregation and thromboxane B 2 synthesis induced with arachidonic acid (IC 50 16.8–22.3 μM). Mopidamol also inhibited enzymatically induced lipid peroxidation) (IC 50 89 ± 5.9 μmol/L) and had no effect on free radical-induced lipid peroxidation. The dose-dependent increase in 6-keto-PGF 1 α in vascular samples after incubation with dipyridamole showed a negative linear correlation with inhibition of lipid peroxidation ( τ 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.