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 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.
Rossoni
G
G
Center for Cardiopulmonary Pharmacology, School of Pharmacy, University of Milan, Italy.
Sala
A
A
Berti
F
F
Testa
T
T
Buccellati
C
C
Molta
C
C
Muller-Peddinghaus
R
R
Maclouf
J
J
Folco
G C
GC
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000187:drug effects / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology; D003331:Coronary Vessels / Q000166:cytology / Q000502:physiology; D003402:Creatine Kinase / Q000187:drug effects / Q000378:metabolism; D003545:Cysteine / Q000096:biosynthesis*; D004562:Electrocardiography; D004730:Endothelium, Vascular / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D006331:Heart Diseases / Q000517:prevention & control*; D006801:Humans; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D015289:Leukotrienes / Q000096:biosynthesis*; D016859:Lipoxygenase Inhibitors / Q000627:therapeutic use*; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D009195:Peroxidase / Q000187:drug effects / Q000378:metabolism; D011804:Quinolines / Q000627:therapeutic use*; D011817:Rabbits
D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D011804:Quinolines; C079315:2-(4-(quinolin-2-yl-methoxy)phenyl)-2-cyclopentylacetic acid; D000001:Calcimycin; D007770:L-Lactate Dehydrogenase; D009195:Peroxidase; D001094:Arachidonate 5-Lipoxygenase; D003402:Creatine Kinase; D003545:Cysteine