Effects of a selective inhibitor of thromboxane synthetase on human blood platelet behaviour

The use of enzyme inhibitors to clarify the role of thromboxane A2 in vasoocclusive disease has been complicated by their nonspecific action. To address this problem we have examined the effects of thromboxane A2/prostaglandin endoperoxide receptor antagonism in a canine model of platelet-dependent coronary occlusion. Two structurally distinct thromboxane A2/prostaglandin endoperoxide receptor antagonists, 3-carboxyl-dibenzo and/or endoperoxide formation in vivo.

Section: Introductionmentioning

confidence: 99%

Coronary vascular occlusion mediated via thromboxane A2-prostaglandin endoperoxide receptor activation in vivo.

Fitzgerald¹,

Doran²,

Jackson³

et al. 1986

“…Additional mechanisms by which these compounds may influence platelet function include stimulation of platelet adenylate cyclase (11), either directly or via enhanced prostaglandin (PG)lD2 production, and thromboxane receptor antagonism (15,16). However, it has been suggested that rediversion of accumulated endoperoxide substrate towards prostacyclin biosynthesis (17,18) may represent the dominant mode of action of these compounds (11). Biochemical evidence consistent with such a mechanism occurring in vivo is lacking.…”

Section: Introductionmentioning

confidence: 99%

Endogenous prostacyclin biosynthesis and platelet function during selective inhibition of thromboxane synthase in man.

FitzGerald¹,

Brash²,

Oates³

et al. 1983

136

A B S T R A C T The consequences of inhibiting the metabolism of prostaglandin G2 to thromboxane A2 in man were studied by using an inhibitor of thromboxane synthase, 4-[2-(IH-imidazol-1-yl)ethoxy] benzoic acid hydrochloride (dazoxiben). Single doses of 25, 50, 100, and 200 mg of dazoxiben were administered to healthy volunteers at 2-wk intervals in a randomized, placebo-controlled, double-blind manner. Serum thromboxane B2 and aggregation studies in whole blood and platelet-rich plasma were measured before dosing and at 1, 4, 6, 8, and 24 h after dosing. Both serum thromboxane B2 and the platelet aggregation response to arachidonic acid (1.33 mM) were reversibly inhibited in a dose-dependent manner. Aggregation induced by 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (0.4 and 4.0 ,uM) in platelet-rich plasma as well as both aggregation and nucleotide release induced by collagen (95 Zg/ml) in platelet-rich plasma and whole blood were unaltered by dazoxiben. Additional evidence for a platelet-inhibitory effect of the compound was a significant prolongation of the bleeding time at 1 h after administration of the highest dose (200 mg) of dazoxiben. Endogenous prostacyclin biosynthesis was assessed by measurement of the major urinary metabolite of prostacyclin, 2,3-dinor-6-ketoPGFia (PGI-M). PGI-M excretion was increased by

“…Despite their biochemical selectivity, TXA2 synthase inhibitors are weak platelet inhibitors in vitro (7, [15][16][17] and exert variable effects in vivo (18)(19)(20)(21). This may reflect the continued formation of platelet prostaglandin endoperoxides that activate a receptor, shared with TXA2, mediating platelet activation and vasoconstriction (7,15,17).…”

Section: Introductionmentioning

confidence: 99%

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

Fitzgerald¹,

J²,

FitzGerald³

1988

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.