Borland CD, Dunningham H, Bottrill F, Vuylsteke A, Yilmaz C, Dane DM, Hsia CC. Significant blood resistance to nitric oxide transfer in the lung. J Appl Physiol 108: 1052-1060, 2010. First published February 11, 2010; doi:10.1152/japplphysiol.00904.2009.-Lung diffusing capacity for nitric oxide (DL(NO)) is used to measure alveolar membrane conductance (DM(NO)), but disagreement remains as to whether DM(NO) = DL(NO), and whether blood conductance (theta(NO)) = infinity. Our previous in vitro and in vivo studies suggested that (theta(NO)) = infinity. We now show in a membrane oxygenator model perfused with whole blood that addition of a cell-free bovine hemoglobin (Hb) glutamer-200 solution increased diffusing capacity of the circuit (D) for NO (DNO) by 39%, D for carbon monoxide (DCO) by 24%, and the ratio of DNO to DCO by 12% (all P < 0.001). In three anesthetized dogs, DL(NO) and DL(CO) were measured by a rebreathing technique before and after three successive equal volume-exchange transfusions with bovine Hb glutamer-200 (10 ml/kg each, total exchange 30 ml/kg). At baseline, DL(NO)/DL(CO) = 4.5. After exchange transfusion, DL(NO) rose 57 +/- 16% (mean +/- SD, P = 0.02) and DL(NO)/DL(CO) = 7.1, whereas DL(CO) remained unchanged. Thus, in vitro and in vivo data directly demonstrate a finite theta(NO). We conclude that the erythrocyte and/or its immediate environment imposes considerable resistance to alveolar-capillary NO uptake. DL(NO) is sensitive to dynamic hematological factors and is not a pure index of conductance of the alveolar tissue membrane. With successive exchange transfusion, the estimated in vivo theta(NO) [5.1 ml NO.(ml blood.min.Torr)(-1)] approached 4.5 ml NO.(ml blood.min.Torr)(-1), which was derived from in vitro measurements by Carlsen and Comroe (J Gen Physiol 42: 83-107, 1958). Therefore, we suggest use of theta(NO) = 4.5 ml NO.(min.Torr.ml blood)(-1) for calculation of DM(NO) and pulmonary capillary blood volume from DL(NO) and DL(CO).