Thromboxane synthase inhibition potentiates washed platelet activation by endogenous and exogenous arachidonic acid

The effect of the thromboxane (TX) synthase inhibitors dazoxiben and imidazole on platelet activation by endogenous and exogenous arachidonic acid (AA) was tested with human washed platelets. Dazoxiben (1-20 microM) inhibited the formation of TXB2 and markedly enhanced the shape change, aggregation, and (3H)serotonin release induced by added AA or when prostaglandin synthesis from endogenous AA was triggered by collagen, hydrogen peroxide or methyl mercury chloride (methyl-Hg). Platelet activation by hydrogen peroxide (20-1200 microM) or methyl-Hg (1-5 microM) was entirely dependent on endogenous prostaglandin (PG) synthesis since acetylsalicylic acid (ASA), indomethacin or the cyclic endoperoxide/TXA2-antagonist BM 13.177 counteracted these stimulants with and without dazoxiben. Apparently, the potentiation is due to accumulating cyclic endoperoxides which during TX synthase inhibition reach greater platelet-activating potency than TXA2. Albumin or human platelet-poor plasma inhibited the platelet activation by hydrogen peroxide and methyl-Hg and suppressed the potentiation by dazoxiben. The latter effect of albumin may result from its PGD isomerase activity which redirects the cyclic endoperoxide metabolism to the platelet-inhibitory PGD2. The results show that non-platelet factors such as albumin are necessary to prevent a potentiating effect of TX synthase inhibitors on platelet activation.