The microvascular pulmonary endothelium barrier is critical in preventing interstitial fluid overflow and deterioration in gas diffusion. The role of endothelium in transporting small solutes in pathological conditions, such as congestive heart failure (CHF), has not been studied. Monitoring of pulmonary gas transfer during saline infusion in CHF was used to probe this issue. Carbon monoxide diffusion (DL(CO)), its membrane diffusion (D(M)) and capillary blood volume (V(C)) subcomponents, and mean right atrial (rap) and mean pulmonary wedge (wpp) pressures after saline or 5% D-glucose solution infusions were compared with baseline in 26 moderate CHF patients. Saline was also tested in 13 healthy controls. In patients, 750 mL of saline lowered DL(CO) (-8%, P<0.01 versus baseline), D(M) (-10%, P<0.01 versus baseline), aldosterone (-29%, P<0.01 versus baseline), renin (-52%, P<0.01 versus baseline), and hematocrit (-6%, P<0.05 versus baseline) and increased V(C) (20%, P<0.01 versus baseline), without changing rap and wpp. Saline at 150 mL produced qualitatively similar results regarding DL(CO) (-5%, P<0.01 versus baseline), D(M) (-7%, P<0.01 versus baseline), V(C) (9%, P<0.01 versus baseline), rap, wpp, aldosterone (-9%, P<0.05 versus baseline), and renin (-14%, P<0.05 versus baseline). Glucose solution (750 mL), on the contrary, increased DL(CO) (5%, P<0.01 versus 750 mL of saline) and D(M) (11%, P<0.01 versus 750 mL of saline) and decreased V(C) (-9, P<0.01 versus 750 mL of saline); aldosterone (-40%), renin (-41%), hematocrit (-3%), rap, and wpp behaved as they did after saline infusion. In controls, responses to both saline amounts were similar to responses in CHF patients regarding aldosterone, renin, hematocrit, rap, and wpp, whereas DL(CO), D(M), and V(C) values tended to rise. Hindrance to gas transfer (reduced DL(CO) and D(M)) with salt infusion in CHF, despite an increase in V(C) and no variations in pulmonary hydrostatic forces, indicates an upregulation in sodium transport from blood to interstitium with interstitial edema. Redistribution of blood from the lungs, facilitating interstitial fluid reabsorption, or sodium uptake from the alveolar lumen by the sodium-glucose cotransport system might underlie the improved alveolar-capillary conductance with glucose.