thromboxane-b2 and pobilukast

We studied the effects of two structurally unrelated sulfidopeptide leukotriene receptor antagonists on endotoxin-induced pulmonary dysfunction in chronically instrumented unanesthetized sheep. The agents employed were L-660,711 (MK-571) (Merck-Frosst, Canada) and SK&F 104,353 (Smith Kline and French, King of Prussia, PA). The efficacy and specificity of the agents were verified in sheep by administering boluses of exogenous leukotrienes (LTB4, LTC4, LTD4, and LTE4) in doses as great as 100 micrograms while monitoring lung mechanics and vascular pressures. The antagonists blocked the changes in lung mechanics and pulmonary hemodynamics induced by the sulfidopeptide leukotrienes (LTC4, LTD4, and LTE4) while having no effect on the animals' responses to LTB4. The endotoxin studies were performed by administering endotoxin alone (Escherichia coli endotoxin 0.75 microgram/kg) or endotoxin after pretreatment with one of the sulfidopeptide leukotriene receptor antagonists. In control studies, each animal received a continuous infusion of one of the receptor antagonists for a duration identical to that of the endotoxin studies. Neither L-660,711 nor SK&F 104,353 significantly altered the endotoxin-induced changes in pulmonary hemodynamics, lung mechanics, lung fluid and solute exchange, oxygenation, or leukopenia. Peak lung lymph thromboxane B2 levels were significantly lower in sheep pretreated with L-660,711. When the antagonists were given alone, no effects were seen. We conclude that (1) sulfidopeptide leukotrienes do not measurably contribute to endotoxin-induced pulmonary dysfunction in chronically instrumented sheep; (2) sulfidopeptide leukotrienes may contribute to thromboxane release after endotoxin.

Topics: Animals; Consciousness; Dicarboxylic Acids; Endotoxins; Escherichia coli; Female; Lymph; Male; Propionates; Pulmonary Circulation; Quinolines; Respiratory Distress Syndrome; Respiratory Mechanics; Sheep; SRS-A; Thromboxane B2

SKF 104353 (2(S)-hydroxyl-3(R)-carboxyethylthio)-3-[2-(8-phenyloctyl) phenyl] propanoic acid) is a synthetic structural analog of leukotrienes D4 and E4 (LTD4, LTE4). This compound binds to guinea pig and human lung LTD4 receptors with affinities (Ki) of 5 +/- 2 and 10 +/- 3 nM, respectively. The Ki values of a reference compound, FPL 55712, were 2200 and 4500 nM, respectively, approximately 400- and 500-fold less effective than SKF 104353. LTD4- and LTE4-induced biosynthesis of thromboxane B2 has been shown to be mediated by LTD4 receptors in guinea pig lung in vitro. SKF 104353 did not induce synthesis of TxB2 in this system at concentrations of 1-20 microM. When SKF 104353 and increasing concentrations of LTD4 were incubated with guinea pig lung, the dose response curve of LTD4-induced TxB2 biosynthesis was shifted to the right with a -log[KB] = 8.4 +/- 0.2. LTD4-induced phosphatidylinositol (PI) hydrolysis in guinea pig lung has been shown to be the major signal transduction mechanism. In this system, SKF 104353 (1-20 microM) did not promote PI hydrolysis. Pretreatment of the [3H]myo-inositol-labeled guinea pig lung with SKF 104353 shifted the LTD4-induced PI hydrolysis dose response curve to the right, indicating that SKF 104353 inhibited LTD4 receptor-mediated intracellular second messenger formation. These results demonstrate that SKF 104353 is a high affinity, specific LTD4 receptor antagonist. It inhibited LTD4-induced PI hydrolysis and TxB2 biosynthesis in guinea pig lung. SKF 104353 may prove to be an important research tool for research on the activities of leukotrienes and of value therapeutically in the treatment of leukotriene-mediated diseases.

Topics: Animals; Binding, Competitive; Cell Membrane; Dicarboxylic Acids; Guinea Pigs; Humans; Leukotriene E4; Lung; Phosphatidylinositols; Receptors, Leukotriene; Receptors, Prostaglandin; SRS-A; Thromboxane B2; Type C Phospholipases