The effect of the leukotriene D4 (LTD4) receptor antagonist, LY-171883, on the respiratory and cardiovascular changes in endotoxemia was studied in 20 unaneshetized sheep. In group 1 (n = 2), 4 mg/kg LY-171883 was injected iv. In group 2 (n = 12), Escherichia coli endotoxin (1 .mu.g/kg) was infused iv, and in group 3 (n = 6), 4 mg/kg LY-171883 was administered 15 min before and 30 min after the saem dose of endotoxin. Infusion of LY-171883 in group 1 did not alter baseline ventilatory and cardiovascular measurements. A two-phase pulmonary response was observed in group 2; an early pulmonary hypertension phase in which pulmonary artery pressure (PAP) increased from 18.7 to 51.2 mm Hg (p < 0.001), with a fall in cardiac index (CI) from 171 to 114 ml/min .cntdot. kg (p < .01). The ratio of peak inspiratory/ expiratory flow rate (P1F/PEF) increased from 1.08 to 1.35 (p < .01) and the respiratory rate from 50 to 70 breath/min (p < .005) 30 min postendotoxin. The flow rate measured at midexpiration time (.ovrhdot.V50) decreased from 81% to 25% of its peak expiration (p < .001) and the airway resistance increased from 3.8 to 32.7 cm H2O/L .cntdot. sec (p < .001). The second permeability phase was characterized by an increase in pulmonary lymph flow (.ovrhdot.QL) from 8.5 to 35.2 ml/h (p < .01), a decrease in PaO2 from 76 to 61 torr (p < .01), and an increase in pulmonary shunt ratio (.ovrhdot.Qsp/.ovrhdot.Qt) from 16% to 31% (p < .005). administration of LY-171883 in group 3 was followed by an increase in CI to 202 ml/min .cntdot. kg (p < .01) and rise in PAP only to 35.1 mm Hg (p < .01). LY-171883 treatment prevented the rise in PIFPEF and oxygen consumption (.ovrhdot.VO2) and oxygen delivery, and also prevented the decrease in .ovrhdot.V50 and the increase in pulmonary resistance after endotoxin. The changes in .ovrhdot.QL, lymph protein clearance, Hgb, WBC, PaO2, .ovrhdot.Qsp/.ovrhdot.Qt, and .ovrhdot.VO2 were similar to group 2. We conclude that pulmonary hypertension and changes in airway resistance in endotoxemia were attenuated by the LY-171883. The decrease in .ovrhdot.V50 was prevented and the CI response to endotoxemia was reversed. However, this lipoxygenase product did not show an effect on hypoxemia and the late permeability response to endotoxin.