Prostaglandin endoperoxides modulate the response to thromboxane synthase inhibition during coronary thrombosis.

Abstract

Prostaglandin endoperoxides (PGG2/PGH2), precursors of thromboxane (TX) A2 and prostaglandins, may accumulate sufficiently in the presence of a TXA2 synthase inhibitor to exert biological activity. To address whether this modulates the response to TXA2 synthase inhibition in the setting of thrombosis in vivo, we examined the interaction of a TXA2 synthase inhibitor (U63,557a) and a TXA2/prostaglandin endoperoxide receptor antagonist (L636,499) in a canine model of coronary thrombosis after electrically induced endothelial injury. U63,557a exerted little inhibitory effect in this model despite a marked reduction in serum TXB2 and urinary 2,3-dinor-TXB2, an index of TXA2 biosynthesis. Combination of the two drugs was more effective than either drug alone. The enhanced effect achieved upon addition of the TXA2/prostaglandin endoperoxide receptor antagonist to the TXA2 synthase inhibitor suggests that the response to the latter compound was limited by the proaggregatory effects of prostaglandin endoperoxides. The increased effect of the combination over the receptor antagonist alone may reflect metabolism of PGG2/PGH2 to platelet inhibitory prostaglandins. This is supported by the following findings: (a) urinary 2,3-dinor-6-keto-PGFia, an index of prostacyclin biosynthesis, increased after administration of the synthase inhibitor, an effect that was exaggerated in the presence of thrombosis; (b) inhibition of arachidonate-induced platelet aggregation by U63,557a was dependent on the formation of a platelet-inhibitory prostaglandin; and (c) pretreatment with aspirin abolished the synergism between these compounds. These studies demonstrate that prostaglandin endoperoxides modulate the response to TXA2 synthase inhibition in vivo and identify a drug combination of potential therapeutic efficacy in the prevention of thrombosis.

Endogenous prostaglandin endoperoxides and prostacyclin modulate the thrombolytic activity of tissue plasminogen activator. Effects of simultaneous inhibition of thromboxane A2 synthase and blockade of thromboxane A2/prostaglandin H2 receptors in a canine model of coronary thrombosis.

“…This effect was most marked at the time ofreperfusion and during rethrombosis, when platelet activation is markedly increased. Similar findings have recently been reported by Fitzgerald et al in a chronic model of coronary thrombosis (32). Another finding supporting this hypothesis has been reported in a recent study from our laboratory, in which combined TxA2 synthase inhibition and receptor blockade (by R 68070) was more effective in preventing epinephrine-induced cyclic flow variations than blockade of TxA2/PGH2 receptors alone (33).…”

Thromboxane (Tx) A2 receptor blockade and TxA2 synthase inhibition alone and in combination: comparison of anti‐aggregatory efficacy in human platelets

“…For example, in human platelet-rich plasma in vitro, the TP-receptor blocking drug, BM 13.177, markedly potentiates the anti-aggregatory activity of dazoxiben (Bertele & De Gaetano, 1982). Similarly, in an in vivo canine model of coronary thrombosis, the combination of a TP-receptor blocking drug with a thromboxane synthase inhibitor produced a substantially greater inhibition than that achieved with either compound alone, consistent with a proaggregatory effect of PGH2 limiting the effectiveness of thromboxane synthase inhibitors in vivo (Fitzgerald et al, 1988). This latter effect has also been observed clinically, where the combined oral administration of BM 13.177 and dazoxiben to human volunteers produced inhibition of ex vivo collagenand arachidonic acid-induced platelet aggregation and a prolongation of the bleeding time which were significantly greater than achieved following either treatment alone (Gresele et 1987).…”

Redirection of prostaglandin endoperoxide metabolism at the platelet-vascular interface in man.

“…TX synthase inhibitors have been shown to have synergistic effects with antagonists of the shared PG endoperoxide/TXA2 receptor both in the prevention of electrically induced coronary artery thrombosis (31) and in the abolition of platelet-dependent cyclical flow phenomena in an experimental model of partial coronary occlusion (32). In both instances synergy was abolished by pretreatment with a cyclooxygenase inhibitor, suggesting its dependence on the generation of platelet-inhibitory eicosanoids, such as PGI2 and PGD2-Study of the formation of eicosanoids in bleeding time blood also provides insight into their potential role at sites of vascular injury under physiological conditions, the temporal increase of TXB2 in bleeding time blood coincides with the phase of platelet-platelet interaction after vascular injury in the rat mesentery (33).…”