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 F1 alpha (6-keto-PGF1 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 B2 and a 23.7% increase in the vascular production of 6-keto-PGF1 alpha, versus saline-treated rats. Dipyridamole showed a higher in vitro anti-aggregating effect in whole blood (IC50 6.6 microM) than in platelet-rich plasma (PRP) (IC50 210 microM), 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 microM, depending on the inducer) and PRP (IC50 11-17.3 microM), and showed a dose-dependent inhibition of platelet aggregation and thromboxane B2 synthesis induced with arachidonic acid (IC50 16.8-22.3 microM). Mopidamol also inhibited enzymatically induced lipid peroxidation) (IC50 89 +/- 5.9 mumol/L) and had no effect on free radical-induced lipid peroxidation. The dose-dependent increase in 6-keto-PGF1 alpha in vascular samples after incubation with dipyridamole showed a negative linear correlation with inhibition of lipid peroxidation (r2 = 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.
De La Cruz
J P
JP
Department of Pharmacology and Therapeutics, School of Medicine, University of Málaga, Spain.
Ortega
G
G
Sánchez de la Cuesta
F
F
D000818:Animals; D001792:Blood Platelets / Q000201:enzymology*; D001808:Blood Vessels / Q000201:enzymology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004176:Dipyridamole / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D011464:Epoprostenol / Q000096:biosynthesis; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D009012:Mopidamol / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013928:Thromboxane A2 / Q000096:biosynthesis
D016861:Cyclooxygenase Inhibitors; D009012:Mopidamol; D013928:Thromboxane A2; D004176:Dipyridamole; D011464:Epoprostenol; D011451:Prostaglandin-Endoperoxide Synthases