Evidence for placental-derived iron-nitrosyls in the fetal lamb circulation, and against a role for nitrite in mediating the cardiovascular transition at birth

Circulating metabolites of nitric oxide, such as nitrite, iron nitrosyls (FeNO), and nitrosothiols, have vasodilatory bioactivity. In both human and sheep neonates, plasma concentrations of these NO metabolite (NOx) concentrations fall >50% within minutes after birth, raising the possibility that circulating NOx plays a role in maintaining low fetal vascular resistance and in the cardiovascular transition at birth. To test whether the fall in plasma NOx concentrations at birth is due to either ligation of the umbilical cord or oxygenation of the fetus to newborn levels, plasma NOx concentrations were measured during stepwise delivery of near-term fetal lambs. When fetal lambs were intubated and mechanically ventilated with 100% O2 to oxygenate the arterial blood while still in utero with the umbilical circulation still intact, there was no change in plasma NOx levels. In contrast, when the umbilical cord was ligated while fetal lambs were mechanically ventilated with O2 levels that maintained fetal arterial blood gases, plasma NOx levels decreased by nearly 50%. Characterization of the individual NOx species in plasma revealed that the overall fall in NOx at birth was attributable mainly to FeNO compounds. Finally, when the typical fall in NOx after birth was prevented by intravenous nitrite infusion, birth-related changes in blood pressure, heart rate, and carotid flow changes were little affected, suggesting the cardiovascular transition at birth is not dependent on a fall in plasma NOx. In conclusion, this study shows FeNO is released from the placenta and that its decline accounts for most of the measured fall in plasma NOx at birth.