Effect of sulfidopeptide leukotriene receptor antagonists on endotoxin-induced pulmonary dysfunction in awake sheep

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.