The PGH-synthase system and isozyme-selective inhibition

Virtually all human cell types can express both cyclooxygenase (COX)-1 and COX-2 under appropriate circumstances. Both isoforms can subserve physiologic and pathophysiologic roles when coupled with the appropriate stimuli and downstream prostaglandin (PG)H2-isomerases and prostanoid receptors. Although the ratio of maximal biosynthetic capacity of human platelets to the basal rate of production of thromboxane A2 is approximately 5000, this ratio is much lower in the case of PGI2, thus dictating quite different requirements for the extent and duration of COX inhibition in human platelets and vascular endothelial cells to detect functional and clinical effects. The development of low-dose aspirin as an antiplatelet agent has been instrumental in characterizing the role of platelet COX-1 in atherothrombosis. Similarly, though quite unexpectedly, the development of coxibs as anti-inflammatory agents has been instrumental in elucidating the role of endothelial COX-2 in vascular occlusion. Because of differential requirements for the inhibition of thromboxane A2 versus PGI2 biosynthesis in vivo, most traditional nonsteroidal anti-inflammatory drugs tend to mimic the effects of coxibs, rather than aspirin, on prostanoid-dependent cardiovascular homeostasis.