Elza Kriuger

Abstract

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.

Transcellular biosynthesis of eicosanoids

“…It is important to note that in the same in vivo experimental model, pretreatment with the 5-lipoxygenase activating protein inhibitor, BAY X1005, caused significant cardioprotection and reduced mortality. This suggests that inhibition of LTA 4 biosynthesis and, ultimately, of transcellular biosynthesis to the cysteinyl leukotrienes played a significant role in the cardiac events [36]. Indeed, the elevation of urinary LTE 4 had been reported previously in human subjects with acute myocardial infarctions or unstable angina [7], as well as in human subjects with atherosclerotic coronary artery disease prior to bypass surgery [1].…”

Leukotriene biosynthesis inhibition ameliorates acute lung injury following hemorrhagic shock in rats

“…MK-886 prevented the biochemical changes and protected the lung morphology after HS. Although leukotrieneshave been known to be associated with the I/R injury in other tissues, including intestine [24] kidney [25], myocardium [26] and liver [27], there are only a few studies describing the correlation between hemorrhagic shock-induced lung injury and 5-lipoxygenase pathway products, where two studies demonstrated that the 5-lipoxygenase pathway products meditate acute lung injury following hemorrhagic shock [28,29]. And it has been demonstrated that LTB4 levels were significantly increased in the rat lungs following T/HS [30].…”