OBJECTIVES: Elevated endothelin-1 (ET-1) levels have been detected during sepsis. The aim of the study was to examine the role of thromboxane A2 (TXA2) and ET-1 in pulmonary vascular reactions after endotoxin (LPS) challenge. DESIGN: Prospective experimental study in rabbits. SETTING: Experimental laboratory in a university teaching hospital. SUBJECTS: Twenty-four adult rabbits of either sex. INTERVENTIONS: Experiments were performed on 30 isolated and ventilated rabbit lungs, which were perfused with a saline solution containing 10% autologous blood. MEASUREMENTS AND MAIN RESULTS: Pulmonary arterial pressure and lung weight gain were continuously registered. Perfusate samples were drawn intermittently to determine ET-1, TXA2, and prostacyclin (PGI2) concentrations. LPS isolated from Escherichia coli (0.5 mg/mL; n = 6) was added to the perfusate. A marked pulmonary arterial pressure increase followed by massive edema formation after 60 mins was observed after LPS injection. At the same time, elevated TXA2 and PGI2 levels in the perfusate were measured. ET-1 was detected 30 mins after LPS infusion (13.4+/-2.6 fmol/L). Pretreatment with the ET(A) receptor antagonist LU135252 (10(-6) M; n = 6) almost completely suppressed the pressure reaction after endotoxin injection (p < .01 at 50 and 60 mins) and reduced edema formation (p < .05). The cyclooxygenase inhibitor diclofenac (10 microg/mL; n = 6) was as effective as LU135252 in preventing vascular reactions after LPS injection. CONCLUSIONS: Pretreatment with the ET(A) receptor antagonist LU135252 and the cyclooxygenase inhibitor diclofenac reduced pulmonary vascular reactions after LPS challenge. Based on the current data, we conclude that the pulmonary arterial pressure increase and edema formation after LPS injection are related to an ET-1- and TXA2-dependent mechanism.