Inhibition of Platelet Aggregation by Sulfinpyrazone

Abstract

The action mechanism of sulfinpyrazone (SUL) was examined with rabbit platelets by testing its influence on the aggregations induced by ADP and collagen, on platelet content of cyclic AMP, on the generation of labile aggregation-stimulating substance (LASS) by platelets, and on platelet aggregation induced by LASS. The generation of LASS was examined by incubating 20μg/ml of arachidonic acid (AA) with washed platelets in the presence or absence of SUL, and measuring platelet aggregation when the incubated mixture was added to platelet-rich plasma (PRP) containing 20μM indomethacin. SUL was administered in a dose of 200mg or 400mg to healthy adults, and plasma concentrations and aggregations induced by ADP, collagen, and epinephrine were measured before and 1, 2, 4, and 6 hours after administration.At 3mM concentration, SUL exhibited little inhibitory effect on ADP-induced aggregation of rabbit platelets; but at concentrations of 1mM and above SUL inhibited collagen-induced aggregation, showing suppression of the release reaction. At 10mM, SUL elicited no change in platelet levels of cyclic AMP, and did not promote the PGE1-induced increase in cyclic AMP. LASS-induced aggregation was slightly inhibited by 3mM SUL. LASS formation was markedly inhibited by 0.3mM SUL, and at higher concentrations the inhibition increased dose-dependently. After administration of SUL in a dose of 200mg, the plasma level of the drug reached a maximum (average 10.5μg/ml) after 1 hour and after 6 hours had fallen to one-third of that level (3.0μg). With a does of 400mg, the plasma levels reached a maximum (35.5μg/ml) after 2 hours and fell to approximately one-third of that level (12.7μg/ml) after 6 hours. The maximum inhibition of platelet aggregation was seen between 4 and 6 hours after administration, showing a discrepancy with the peak plasma level.SUL inhibited the secondary but not the primary aggregation induced by ADP, only slightly inhibited collagen-induced aggregation, but strongly suppressed epinephrine-induced aggregation. SUL also inhibited the biosyntheses of PG endoperoxides and thromboxane A2, and at high concetration showed a direct inhibitory effect against these mediators. The results can be interpreted in terms of the mechanism of inhibition of LASS generation, in view of the report that SUL, unlike aspirin, does not inhibit the activity of cyclo-oxygenase at concentrations that inhibit platelet aggregation.