Selective and nonselective inhibition of thromboxane formation

Abstract

Thromboxane A2, the predominant cyclooxygenase product of arachidonic acid in the platelet, is a potent vasoconstrictor and stimulus of platelet aggregation. Prostacyclin, the principal cyclooxygenase metabolite formed in the vascular endothelium, inhibits platelet aggregation and dilates blood vessels. A therapeutic objective in the treatment of human vascular occlusive disease has been the inhibition of thromboxane formation without coincident reduction in prostacyclin biosynthesis. We compared the biochemical selectivity and platelet inhibitory actions of single doses of aspirin, a cyclooxygenase inhibitor, with imidazo(1,5-2)pyridine-5-hexanoic acid (CGS 13080), an inhibitor of thromboxane synthase. Aspirin, 325 mg, prolonged the bleeding time markedly, inhibited aggregation and nucleotide release in whole blood and platelet-rich plasma, and maximally inhibited thromboxane generation in serum. The effects of aspirin, 20 mg, were considerably less marked but, as with the higher dose, persisted throughout the study period (24 hr after dosing). CGS 13080 also prolonged bleeding time and inhibited thromboxane formation. In contrast to aspirin, these effects were reversible and inhibition of aggregation was less marked. Endogenous prostacyclin biosynthesis was measured by excretion of the major urinary metabolite 2,3-dinor-6-keto-PGF1 alpha (PGI-M). Whereas aspirin, 325 mg, reduced PGI-M excretion a mean 29%, excretion increased 48% and 100% after CGS 13080, 100 mg and 200 mg. Aspirin, 20 mg, did not alter prostacyclin biosynthesis. Inhibition of thromboxane synthase permits selective inhibition of thromboxane formation in man. Although drugs of greater potency and longer duration of action are desirable, enhanced prostacyclin synthesis may be an important component of the platelet inhibitory actions of thromboxane synthase inhibitors in man.