Effects of endogenously produced leukotrienes, thromboxane and prostaglandins on coronary vascular resistance in rabbit myocardial infarction

In an effort to evaluate the synthesis and function of eicosanoids in myocardial infarction, we have developed a technique of in vivo myocardial infarction in rabbits followed by ex vivo cardiac perfusion. Isolated Langendorff perfused infarcted hearts (removed 1 or 4 d after infarction) responded to the inflammatory cell agonist N-formylmethionyl-leucyl-phenylalanine (fMLP) with (a) the release of leukotrienes B₄, C₄, and D₄; (b) the release of large amounts of thromboxane (235 ± 66 ng/5 min), prostacyclin (714 ± 285 ng/5 min), and prostaglandin E₂ (PGE₂) (330 ± 108 ng/5 min); and (c) a coronary vasoconstriction (21.1 ± 2.5% increase in coronary perfusion pressure) that was specifically inhibited by the peptidoleukotriene receptor antagonist FPL-55712. While noninfarcted hearts challenged with fMLP also released leukotrienes B₄, C₄, and D₄ they released only small amounts of the cyclooxygenase products (thromboxane, 30 ± 9 ng/5 min; prostacyclin, 120 ± 54 ng/5 min; PGE₂, 27 ± 10 ng/5 min) and showed minimal vasoconstriction (5.6 ± 2.1% increase in perfusion pressure). Similarly, hearts challenged with fMLP 30 d following infarction released only small amounts of the cyclooxygenase products (thromboxane, 42 ± 8 ng/5 min; prostacyclin, 386 ± 31 ng/5 min; PGE₂ 79 ± 25 ng/5 min). When bradykinin was administered, no leukotrienes were produced, but acutely infarcted hearts released 10 times more thromboxane, prostacyclin, and PGE₂ than normal hearts and significantly larger amounts of these products than 30-d infarcted hearts. Histologic analysis showed no inflammatory cells in normal hearts, a prominent polymorphonuclear leukocyte infiltration in 1-d infarcted tissue, fibroblast proliferation with mononuclear cell invasion in 4-d infarcted tissue, and a fibrotic scar with scanty mononuclear cell infiltrate in 30-d infarcted tissue. Inflammatory cell invasion was temporarily associated with augmented cyclooxygenase metabolism, suggesting that infiltrating leukocytes may be responsible for production of thromboxane, prostacyclin and PGE₂ in acutely infarcted hearts. The finding that endogenously produced peptidoleukotrienes are potent coronary vasoconstrictors in infarcted rabbit hearts suggests that these products may contribute to tissue injury in myocardial infarction.