Arachidonic acid metabolites in the cardiovascular system.

A rachidonic acid metabolism yields an array of biologically active molecules so diverse that it is impossible to discuss them all in depth within a series of short reviews. However, appearing in this and the next issue of the Journal, we present four papers that focus on issues of major import to the cardiovascular system. Each paper provides insights into our knowledge of the biochemistry of these pathways and relates the metabolic pathways to the physiological or pathophysiological roles of the lipid mediators. In my view, this set of reviews is particularly important because the numbers of structures derived from arachidonic acid metabolism and the number of systems in which they are generated are highly complex, frequently causing the physiologists and medical students with whom I routinely speak to roll their eyes and groan. That we cannot neatly summarize the synthesis and actions of these lipid mediators does nothing to detract from their central role in the cardiovascular and other systems. The organization of this series is such that we will present discussions of the three major enzymatic pathways of arachidonic acid metabolism: namely the cyclooxygenase, lipoxygenase, and cytochrome P450 systems, as well as an underrecognized nonenzymatic oxidative pathway that leads to the generation of molecules known as isoprostanes. Each review presents a current overview of important topics in arachidonic acid metabolism. Equally important, albeit largely unstated, is what most of the reviews are not able to discuss—the limited progress in developing useful pharmacologic tools to modulate the function of these lipids as they relate to human disease. This is true with one obvious exception, the cyclooxygenase pathway. This pathway has, however unknowingly, been the target of pharmacological intervention at least since the time of ancient Egypt where willow was used as an analgesic. Thousands of years of folk medicine ultimately led to one of the first chemically synthesized pharmaceutical agents, acetylsalicylic acid, a nonsteroidal anti-inflammatory drug (NSAID), more popularly known as aspirin. This amazing molecule has been widely consumed since the 1800s but a recent intense research effort by the pharmaceutical industry has led to the development of a new potent and efficacious class of NSAIDs, the coxibs, which are specific for COX-2, one of the two cyclooxygenase isoforms. Despite some early warnings of potentially deleterious cardiovascular effects from inhibitors of this pathway, these compounds (marketed as Celebrex and Vioxx) hit the market with a blast of direct-to-consumer advertising. They instantly became blockbuster drugs. Only after the numbers of consumers of the drugs had grown to significant proportions did postmarketing research begin to reveal potentially lifethreatening cardiovascular events associated with Vioxx. This ultimately led to its withdrawal from the market and spawned a costly series of lawsuits against Merck, the developer of the drug. One consequence of the public’s emerging understanding of these negative effects of Vioxx has been a loss of confidence in the entire system of drug approval leading from pre-clinical data accumulation through evaluations by the U.S. Food and Drug Administration. Nevertheless, the importance of NSAIDs in dealing with chronic and painful conditions, particularly as our population ages, has led to widespread analysis of this topic in both the lay and scientific press. The initial review in our series by Funk and FitzGerald explores the mechanistic basis for the increased cardiovascular risk associated