To test the hypothesis that the broad spectrum protease inhibitor, aprotinin, can prevent early pathophysiology of sepsis, we administered endotoxin (0.1-0.75 microgram/kg) by a 30-min infusion to awake goats. Animals were used as their own controls receiving endotoxin with no treatment on one day and treatment with a bolus injection (10 trypsin inhibitory units, TIU, per kg) followed by a 6-hr infusion (5 TIU/kg/hr) of aprotinin on another. The effect on systemic and pulmonary hemodynamics, lung lung lymph flow (QL), lymph plasma protein ratio (L/P), and systemic eicosanoid levels were assessed. QL quickly reached 28 ml/hr (four times baseline) in both groups then slowly returned toward baseline. L/P ratio of both groups decreased by about 10% then returned to baseline. QL and L/P were not different between groups. Likewise, vascular parameters were not different between groups. Mean pulmonary artery pressure increased approximately 150% to a peak of 58 cm H2O in both groups while pulmonary artery wedge pressure doubled from a baseline of 8 cm H2O then both groups returned to baseline. Systemic arterial pressure decreased over the 6 hr experimental period by 15 Torr to 70 Torr in both groups. Cardiac output declined from 4.3 to 3 liter/min after the endotoxin, remaining at the level for 2 hr then progressively increased to about 5 liter/min in both groups. We conclude that aprotinin, in doses similar to those reported to give protection from acute lung injury of various origins, fails to modify the early cardiopulmonary pathophysiology of endotoxin.