To gain a better understanding of the adverse pulmonary response to amphotericin B administration reported in humans, we examined the effects of this agent in the chronically instrumented awake sheep. We measured pulmonary artery and left atrial pressures (Ppa and Pla), lung lymph flow (Qlymph), dynamic lung compliance (Cdyn), resistance to airflow across the lung (RL), lymph thromboxane B2 (TxB2), lymph 6-keto-PGF1 alpha, peripheral leukocyte counts, and arterial blood gases. After at least one hour of stable baseline (BL) observation, amphotericin B (Fungizone, Squibb, 1 mg/kg) was infused intravenously over 1 h. Measurements were continued for 3 h after the start of infusion. Amphotericin caused an immediate decrease in Cdyn nadiring at 55 percent of BL and an increase in Ppa from 21 +/- 1 mm Hg at BL to 44 +/- 4 at 30 minutes. RL increased to 5.5-fold over BL by 30 minutes into infusion, and lung lymph TxB2 concentrations were increased tenfold compared with BL by the end of the 1-h infusion (p less than 0.05). In this same time interval, there were increases in Qlymph (1.5 ml/15 min at BL to 4.9 +/- 0.8), but 6-keto-PGF1 alpha concentrations did not reach maximum until 2 h after the start of infusion. There was a decrease in peripheral leukocyte count and PaO2 (80 +/- 3 mm Hg at BL to 69 +/- 4 at 1 h) that returned to BL over the remaining 2 h. The temporal relationship of the TxB2 peak with these pathophysiologic changes and previous data describing the effects of thromboxane in the sheep lung suggest that a component of these alterations is due to thromboxane release. We conclude that several pulmonary system abnormalities occur following amphotericin infusion in sheep and that these findings provide a better physiologic basis for explaining the human pulmonary response to amphotericin.