Myocardial Salvage Induced by REV-5901: an Inhibitor and Antagonist of the Leukotrienes

Lipoxygenase metabolites of arachidonic acid have been implicated in myocardial injury induced by coronary artery occlusion and reperfusion, as dual inhibitors of the lipoxygenase and cyclooxygenase enzymes, but not selective cyclooxygenase inhibitors, reduce infarct size. However, interpretation of these studies has been clouded by the lack of specificity of the drugs previously used. A specific 5-lipoxygenase inhibitor, REV-5901, has recently been developed. This drug inhibits A23187-induced immunoreactive leukotriene B4 generation by canine neutrophils (IC50 approximately 2.5 microM), and when given intravenously, attenuates the formation of a leukotriene D4-like material in blood ex vivo. The release of bioassayable leukotriene-like material from rabbit hearts infarcted in vivo and subsequently perfused in vitro is prevented by REV-5901. Moreover, the inhibitor also acts as an end-organ antagonist to prevent the spasmogenic effects of the peptide-containing leukotrienes in vitro with an IC50 approximately 0.1 microM. REV-5901 (10 + 2 mg/kg i.v.) reduces infarct size produced by coronary artery occlusion and reperfusion in the anesthetized dog from 56.6 +/- 2 to 28.6 +/- 3.7% of the hypoperfused zone. Salvage of the ischemic myocardium occurs independently of any apparent hemodynamic effect of the drug, but is accompanied by a diminution in neutrophil accumulation in the ischemic heart. It is proposed that inhibition of leukotriene B4 formation by REV-5901 suppresses the accumulation of neutrophils, thereby attenuating neutrophil-mediated cardiac damage.