Cardiovascular and renovascular implications of COX-2 inhibition

A group of chemical mediators, the eicosanoids, is critical players in a multitude of physiological processes. Generated by the action of the cyclooxygenase (COX) enzyme on arachidonic acid they are responsible for diverse and often opposing actions such as platelet function. vasomotor tone. gastric cytoprotection and inflammation. Since their discovery several decades ago, our knowledge concerning their synthesis, function as natural ligands and methods to manipulate their activity through drug development has expanded. Traditional Non Steroidal Anti-Inflammatory Drugs (NSAIDs) are nonselective inhibitors of the COX enzyme, of which treatment in the management of pain and inflammation associated with acute and chronic inflammatory conditions that I gastrointestinal toxicity affect more than 10 million Americans. Their efficacy in this regard is not questioned. However. arising from chronic NSAID ingestion is common and limits their use in clinical practice. Gastrointestinal toxicity has been attributed to the blockade of the COX-1 mediated generation of the cytoprotective prostanoids, such as PGE(2) and PGI(2). Selective COX-2 inhibitors were designed to inhibit the production of COX-2 dependent inflammatory prostanoids and to leave intact the cytoprotective COX-1 products. The first of a new class of these selective COX-2 inhibitors - the coxibs- were introduced to the market in 1999. These compounds.. while exhibiting similar efficacy to traditional NSAIDs, were associated with a reduced incidence of surrogate or actual indices of G1 toxicity. Questions have been raised concerning the cardiovascular and renal profiles of these agents based on data from both small and large clinical Studies. More recently, our increasing understanding of the relative contributions of both isoforms of the COX enzyme to individual components of vascular homeostais has allowed us to appreciate the cardiovascular and renovascular implications of selective COX-2 inhibition.