Mepacrine blockade of arachidonate-induced washed platelet aggregation: Relationship to mepacrine inhibition of platelet cyclooxygenase

Mepacrine, in addition to its established antilipolytic activity, was also found to inhibit the conversion of ¹⁴C-arachidonic acid to ¹⁴C-thromboxane B₂ in human washed platelets. In the concentration range of 3.33-33 μM, mepacrine exerted a dose dependent inhibition of arachidonate conversion to thromboxane B₂ in parallel to inhibition of arachidonate-induced platelet aggregation. Mepacrine inhibition of thromboxane formation was not accompanied by a concomitant increase in other cyclooxygenase products. Furthermore, mepacrine did not affect platelet transformation of added prostaglandin H₂ to thromboxane A₂ and other products. These results indicate that mepacrine inhibits the cyclooxygenase enzyme and not thromboxane synthase. In washed platelets, mepacrine inhibition of arachidonic acid conversion to thromboxane A₂ appears to be a major factor in the overall inhibitory effect of the compound on the combined process of arachidonate release from cellular phospholipids and its conversion to proaggregatory products.