Role of eicosanoids in the ischemic and reperfused myocardium.

Abstract

Eicosanoids represent a family of fatty acid derivatives which possess complex biological effects. The three major groups of products are synthesized from arachidonic acid via distinct enzyme complexes and include prostaglandins, leukotrienes and arachidonic acid oxidation products such as epoxides. While the exact sites of synthesis of eicosanoids still require to be determined, there is evidence that the heart has the ability to produce both cyclooxygenase and lipoxygenase derived products. In mammalian heart, activity of the third major pathway of arachidonic acid metabolism, the cytochrome P450-depen-dent monooxygenases, appears to be very low. Eicosanoids exert a myriad of actions on the cardiovascular system including the heart. For example, prostacyclin, produced by cyclooxygenase primarily in vascular endothelium, is generally considered to be a potent vasodilator. On the other hand, thromboxane A2, produced by the same enzyme primarily in platelets, exerts coronary constricting effects. The precise role of eicosanoids in the etiology of heart disease however, is still not fully understood. For example, in the ischemic and reperfused myocardium, both deleterious and beneficial effects of prostaglandins are proposed, a phenomenon which may be associated with the biphasic nature of the effects of these substances. The role of leukotrienes in myocardial ischemia and reperfusion is also complex although it is likely that a major function of these compounds is to provide a chemotactic signal for neutrophil recruitment in the ischemic zone. Initial studies with eicosatrienoic acid epoxides (epoxyeicosatrienoic acids; EETs) also reveal complex actions with respect to myocardial injury as well as modulation of intracellular calcium homeostasis. In this review we discuss the mechanisms and regulation of arachidonic acid metabolism particularly with respect to the heart and how alterations in the production of arachidonic acid metabolites can affect heart function in health and disease.