SQ 22536, an Adenylate-Cyclase Inhibitor, Prevents the Antiplatelet Effect of Dazoxiben, a Thromboxane-Synthetase Inhibitor

Summary

This study shows that dazoxiben, a selective inhibitor of thromboxane A₂-synthetase in human platelets, inhibited arachidonic acid-induced platelet aggregation in platelet-rich plasma samples from four out of 16 healthy volunteers. In these four “responder” samples, the anti-aggregating effect of dazoxiben was prevented by the compound SQ 22536, a 9-substituted adenine analogue, endowed with an inhibitory activity on adenylate-cyclase. The compound SQ 22536 also counteracted the antiaggregating effect of prostaglandin D₂, a known activator of platelet adenylate-cyclase. When platelet thromboxane A₂-syn- thetase was blocked by dazoxiben, a marked increase of prostaglandin D₂ was concomitantly observed both in “responder” and “non responder” samples. The compound SQ 22536 blunted the increase in platelet cAMP caused by either dazoxiben and sodium arachidonate or prostaglandin D₂. It is suggested that the antiaggregating effect of dazoxiben is mediated by newly synthesized prostaglandin D₂. The latter acts by stimulating adenylate-cyclase and increasing cAMP levels. The compound SQ 22536 prevents both phenomena. In “non responder” samples some factors - still to be defined - might counteract similarly to the compound SQ 22536 the antiaggregating activity of PGD₂.

Key Words

Thromboxane synthetase inhibitors - Adenylate cyclase inhibitors - Prostaglandin D₂ - Cyclic AMP

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