Leukotriene Receptor Antagonists as Potential Therapeutic Agents

Leukotrienes are a family of bioactive lipids that have a constellation of pharmacologic effects on respiratory, cardiovascular, and gastrointestinal systems. They produce smooth muscle spasm (1, 2), cause myocardial de­ pression (3), increase vascular permeability ( l , 4) enhance mucous produc­ tion (5), decrease mucociliary transport (6), and have the chemotactic prop­ erty to attract leukocytes to a site of cellular injury (7, 8). The overwhelming evidence suggests that leukotriene synthesis and subsequent release in ex­ perimental animals and in humans are associated with certain pathophysiolog­ ical events. Disorders such as asthma, adult respiratory distress syndrome, chronic bronchitis, cystic fibrosis, septic shock, psoriasis, inflammatory bowel disease, and myocardial ischemia have all been reported to be associ­ ated with increased levels of leukotrienes (9-15). Little is known about the physiological role, if any, of these C20 fatty acids but such information appears on the horizon. For example, recent studies have explored participa­ tion of leukotrienes in the fine tuning of the immune system (16). In addition, early evidence suggests a neuromodulatory role of leukotrienes (17, 18) and other lipoxygenase metabolites in the central nervous system. Membrane phospholipids are the major source of arachidonic acid from which prostaglandins, thromboxanes, and leukotrienes are derived (Figure 1). Activation of phospholipase A2, the enzyme that cleaves arachidonic acid from the two position of the phospholipid molecule, occurs as a consequence of anaphylactoid antigen-antibody reactions, by a variety of chemicals, and in response to cell injury. Leukotrienes are formed de novo by action of a