MYOCARDIAL PROTECTION BY THE LEUKOTRIENE SYNTHESIS INHIBITOR BAY X1005 - IMPORTANCE OF TRANSCELLULAR BIOSYNTHESIS OF CYSTEINYL-LEUKOTRIENES

Perfusion of the isolated rabbit heart with 5 x 10(6) human polymorpho nuclear leukocytes, under recirculating conditions (50 ml), and challe nge with A-23187 (0.5 mu M) caused an increase in coronary perfusion p ressure (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 mu M) (n = 6) resulted in significant protecti on against the increase in coronary perfusion pressure (76.7 +/- 12.8 mm Hg, 30 min after challenge) and in almost complete inhibition of su lfidopeptide leukotriene synthesis (3.2 +/- 1.7 pmol/ml, 30 min after challenge). In vivo experiments, ligation of the left anterior descend ing coronary artery in the rabbit (n = 10) resulted in acute myocardia l infarction marked by a mortality rate of 60% compared with sham-oper ated animals (n = 10). Intravenous treatment of the rabbits with BAY X 1005 (10 mg/kg/h, for 2 h) (n = 10) markedly reduced the mortality rat e (20%), protected the rabbits against the marked electrocardiogram de rangement and abolished the significant increase in plasma creatine ph osphokinase activity and cardiac tissue myeloperoxidase activity induc ed by coronary artery ligation. BAY X1005 exerts a significant cardiop rotection and suggests that specific leukotriene synthesis inhibitors may lead to innovative therapy in myocardial ischemia.