J Pharmacol Exp Ther. 1996 Jan;276(1):335-41. Related Articles, Links
Myocardial protection by the leukotriene synthesis inhibitor BAY X1005: importance of transcellular biosynthesis of cysteinyl-leukotrienes.
Rossoni G, Sala A, Berti F, Testa T, Buccellati C, Molta C, Muller-Peddinghaus R, Maclouf J, Folco GC.
Center for Cardiopulmonary Pharmacology, School of Pharmacy, University of Milan, Italy.
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.
J Physiol Pharmacol. 1997 Dec;48(4):529-36. Related Articles, Links
Potential anti-inflammatory effects of 5-lipoxygenase inhibition--exemplified by the leukotriene synthesis inhibitor BAY X 1005.
Muller-Peddinghaus R.
BAYER AG, Business Group Pharma Institute for Cardiovascular and Arteriosclerosis Research Wuppertal, Germany.
Leukotrienes have been identified in various pathophysiologies. The leukotrienes LTB4 and LTC4 are assigned to inflammation. 5-lipoxygenase inhibitors which inhibit the synthesis of LTA4 being the precursor of both LTB4 and LTC4 appear to have only a limited antiinflammatory potential. 5-lipoxygenase inhibitors are represented by direct and indirect inhibitors, the latter competing with substrate transfer from the five-lipoxygenase activating protein (FLAP) to the 5-lipoxygenase enzyme. 5-lipoxygenase inhibition under experimental condition results in inhibition of edema formation, neutrophil infiltration, smooth muscle contraction after antigen challenge and prevention of early and late allergic reactions. Only in the cysteinyl-leukotriene-driven pathophysiology of allergic asthma and allergic rhinitis 5-lipoxygenase inhibition appears to provide symptomatic relief. Yet, the overall-antiinflammatory effect in man in far less than expected, but may be outweighed by the nearly total lack of any side effects of 5-lipoxygenase inhibition per se. |
