Effects of a thromboxane synthetase inhibitor and a thromboaxane antagonist on release and activity of thromboxane A2 and prostaglandin in vitro

The TxA₂ synthetase inhibitor, dazoxiben, and the TxA₂ antagonist, ±SQ 29, 548, were examined for effects on release and vasoactivity of TxA₂ and prostacyclin. Isolated perfused guinea pig lungs were used as the enzyme source from which TxA₂ and prostacyclin were released in response to injections of arachidonic acid or bradykinin. Both dazoxiben and ±SQ 29, 548 inhibited contraction of the superfused rat aorta and bovine coronary artery after arachidonic acid injection through the lung. ±SQ 29, 548 abolished contractions of the rat aorta, but significant aorta contracting activity persisted during dazoxiben treatment. Dazoxiben significantly inhibited arachidonate-induced release of TxA₂ (immunoreactive TxB₂)iinto the superfusate, but TxA₂ release was significantly potentiated by ±SQ 29, 548. Thus, in the presence of enhanced TxA₂ concentrations, ±SQ 29, 548 effectively antagonized the vasospastic effect of TxA₂. Dazoxiben diverted a significantly greater amount of arachidonic acid into prostacyclin synthesis (immunoreactive 6-keto-PGF_1α), changing original coronary vasoconstriction into relaxation. ±SQ 29, 548 did not significantly modify lung prostacyclin synthesis. Moreover, with ±SQ 29, 548, the absence of TxA₂-mediated coronary contraction unmasked active relaxation of the superfused bovine coronary artery, coincident with thromboxane and prostacyclin release. Dazoxiben consistently inhibited TxA₂ synthesis and enhanced prostacyclin synthesis. ±SQ 29, 548 augmented TxB₂ release in response to arachidonate, but not bradykinin, and did not significantly alter 6-keto-PGF_1α release in response to either arachidonate or bradykinin. In terms of vasoactivity measured , ±SQ 29, 548 and dazoxiben produced similar anti-vasospastic effects, although this was accomplished by completely different mechanisms.