The production of leukotriene A4 (LTA4)-derived metabolites, analysed by RP-HPLC, was studied in purified bovine polymorphonuclear leukocyte (PMNL) preparations and in PMNL-platelet coincubations after challenge with the calcium ionophore A23187. The results obtained show that in bovine PMNL LTB4 represents the main LTA4 metabolite. When washed platelets were added to PMNL, LTC4 was the main enzymatic metabolite observed, indicating a substantial transfer of PMNL-derived LTA4 to platelets. The synthesis of LTC4 was accompanied by a significant decrease in LTB4, suggesting that a quota of the LTB4 synthesized in PMNL preparations is the result of transcellular metabolism of released LTA4 by neighbouring PMNL. Reduction of PMNL-PMNL interactions through dilution of cell incubates allowed us to estimate that most of the leukotriene A4 synthesized by PMNL is indeed released from the cell. LTA4, and not LTB4, represents the main 5-1ipoxygenase metabolite released by bovine PMNL.

Perfusion of the isolated rabbit heart with 5 x 10(6) human polymorphonuclear leukocytes, under recirculating conditions (50 ml), and challenge with A-23187 (0.5 microM) caused an increase in coronary perfusion pressure (from a prechallenge value of 46 +/- 1.1 to 176.2 +/- 29.7 mm Hg, 30 min after challenge, n = 6-4), which was linearly correlated (P < .006) with formation of cysteinyl leukotrienes (29.7 +/- 7.3 pmol/ml, 30 min after challenge). Pretreatment with the leukotriene synthesis inhibitor BAY X1005 (1 microM) (n = 6) resulted in significant protection against the increase in coronary perfusion pressure (76.7 +/- 12.8 mm Hg, 30 min after challenge) and in almost complete inhibition of sulfidopeptide leukotriene synthesis (3.2 +/- 1.7 pmol/ml, 30 min after challenge). In in vivo experiments, ligation of the left anterior descending coronary artery in the rabbit (n = 10) resulted in acute myocardial infarction marked by a mortality rate of 60% compared with sham-operated animals (n = 10). Intravenous treatment of the rabbits with BAY X1005 (10 mg/kg/h, for 2 h) (n = 10) markedly reduced the mortality rate (20%), protected the rabbits against the marked electrocardiogram derangement and abolished the significant increase in plasma creatine phosphokinase activity and cardiac tissue myeloperoxidase activity induced by coronary artery ligation. BAY X1005 exerts a significant cardioprotection and suggests that specific leukotriene synthesis inhibitors may lead to innovative therapy in myocardial ischemia.

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