We studied the effect on lung fluid filtration of 37.6 ppm inhaled nitric oxide (NO) imposed for 1 h 2.5 h after endotoxin in seven awake sheep, with seven control subjects. The effects of NO on the longitudinal distribution of pulmonary vascular resistance (PVR) before and after endotoxin were specifically addressed in six sheep. Following endotoxin, sheep developed respiratory distress; PaO2, the alveolar-arterial oxygen tension difference (AaPO2) and venous admixture (Q S/Q T) changed significantly, as did the pulmonary artery pressure (Ppa), PVR, and lung lymph flow (Q L). Inhaled NO reduced Ppa and PVR by 50%; Q L decreased from 7.8 +/- 0.34 ml/15 min to 4.7 +/- 0.80 ml/15 min (mean +/- SEM), and lymph protein clearance from 4.9 +/- 0.18 ml/15 min to 3.6 +/- 0.75 ml/15 min. Lymph/plasma protein concentration ratio (L/P) increased from 0.63 +/- 0.016 to 0.72 +/- 0.006, concomitant with the decrease in Q L. The L/P - Q L relationships shifted from left, at baseline, to the right during endotoxemia, as did the permeability surface product (PS) isolines. The rightward shift was significantly less in the NO group. Inhaled NO significantly improved PaO2, AaPO2, and Q S/Q T, reduced the increase in pulmonary microwedge pressure back to baseline and decreased upstream and downstream PVR at 3.0 through 4. 0 h. We conclude that, in sheep, inhaled NO reduces lung fluid filtration by decreasing microvascular pressure and apparently also by declining the enhanced microvascular permeability during the late phase of endotoxemia.