Fetal-maternal nitrite exchange in sheep: Experimental data, a computational model and an estimate of placental nitrite permeability

- Nitrite is a potential source of NO in the fetus.
- The placental permeability for nitrite has not been previously determined.
- The placental permeability of nitrite was determined to be many-fold higher than expected based on nitrite's size and charge.
- The results suggest the placental transfer of nitrite is not by simple diffusion through water-filled channels.

IntroductionNitrite conveys NO-bioactivity that may contribute to the high-flow, low-resistance character of the fetal circulation. Fetal blood nitrite concentrations depend partly on placental permeability which has not been determined experimentally. We aimed to extract the placental permeability-surface (PS) product for nitrite in sheep from a computational model.MethodsAn eight-compartment computational model of the fetal-maternal unit was constructed (Matlab® (R2013b (8.2.0.701), MathWorks Inc., Natick, MA). Taking into account fetal and maternal body weights, four variables (PS, the rate of nitrite metabolism within red cells, and two nitrite distribution volumes, one with and one without nitrite metabolism), were varied to obtain optimal fits to the experimental plasma nitrite profiles observed following the infusion of nitrite into either the fetus (n = 7) or the ewe (n = 8).ResultsThe model was able to replicate the average and individual nitrite-time profiles (r2 > 0.93) following both fetal and maternal nitrite infusions with reasonable variation of the four fitting parameters. Simulated transplacental nitrite fluxes were able to predict umbilical arterial-venous nitrite concentration differences that agreed with experimental values. The predicted PS values for a 3 kg sheep fetus were 0.024 ± 0.005 l∙min−1 in the fetal-maternal direction and 0.025 ± 0.003 l∙min−1 in the maternal-fetal direction (mean ± SEM). These values are many-fold higher than the reported PS product for chloride anions across the sheep placenta.ConclusionThe result suggests a transfer of nitrite across the sheep placenta that is not exclusively by simple diffusion through water-filled channels.