Placebo-controlled trials of nonsteroidal antiinflammatory drugs (NSAIDs) selective for COX-2 have revealed an enhanced risk for cardiovascular events. COX-2 inhibitors (coxibs) selectively reduce vascular prostacyclin synthesis without disrupting COX-1-derived thromboxane synthesis in platelets. Removal of prostacyclin's capacity to restrain all known endogenous compounds contributing to platelet activation and vasoconstriction is a well-recognized mechanism for coxib action in the cardiovascular system which can pre-dispose to thrombosis, hypertension and atherosclerosis. Novel mouse models of selective COX-2 inhibition and disruption of microsomal prostaglandin E synthase-1 have been exploited to reveal the relative importance of prostacyclin and prostaglandin E 2 in cardiovascular homeostasis. This review discusses the background to our current understanding of coxibs and provides further information relating to recent mechanistic insights into how COX-2 inhibition promotes cardiovascular risk.

BACKGROUND

Prostaglandins (PGs) are a family of bioactive lipid mediators that are formed from arachidonic acid contained in membranes in virtually all cells of the body. 1-4 They are involved in numerous physiological and pathophysiological activities in humans and animals. Prostaglandin H synthase (PGHS), with 2 distinct catalytic activities referred to as cyclooxygenase (COX) and hydroperoxidase, respectively, 1-4 carries out the initial transformation of fatty acid. COX is a common way of referring to this prostaglandin-synthesizing enzyme. About 10 years after the initial isolation of PGD 2, PGE 2, and PGF 2α (the classical prostaglandins), between 1962 and 1964 an unstable compound, TxA 2 was identified by Samuelsson and co workers. 5-8 Moncada, Bunting, and Vane were the first to describe the formation of a prostaglandin substance, first called PGX, in 1976 as an unstable substance that inhibits platelet aggregation. 9, 10 Its chemical structure was quickly elucidated and was termed prostacyclin by the end of the same year. 11 During the early 1970s, the research of Vane, Flower, and Moncada's group led to the understanding that nonsteroidal antiinflammatory drugs (NSAIDs) can block the synthesis of prostaglandins that represented a monumental advance, explaining the mechanism of action of these most commonly consumed of all drugs. 12-14 There are additional enzymes required to transform the PGH 2 intermediate derived from COX (PGD, PGE, PGF, PGI, and Tx synthases) into the 5 prostaglandins. Until 1989, researchers were under the distinct impression that there was only 1 COX enzyme or isoform, and this was reinforced by the cloning of only 1 DNA sequence for a COX gene from sheep 15, 16 and 1 from humans 17 during 1988 and 1989.