Kynurenine production and catabolism in fetal sheep with embolized or nonembolized placentas

OBJECTIVE: The effect of maternal tryptophan loading on fetal plasma and br ain, kynurenic acid, and quinolinic acid concentrations was compared in lat e gestation fetal sheep with either chronically embolized or nonembolized p lacentas. STUDY DESIGN: The placentas of 4 ewes were embolized by daily injection of mucopolysaccharide microspheres into the umbilical artery from 120 days ges tation in amounts sufficient to reduce the fetal arterial PO2 to less than or equal to 12 mm Hg. Four fetuses with nonembolized placentas were the con trol group. At 135 to 138 days gestation, the ewe received an infusion of t ryptophan (100 mg/kg, intravenously) or an equivalent volume of saline solu tion (100 mL) over 2 hours. Maternal and fetal arterial blood samples were obtained between 2 and 48 hours from the start of the infusion for the meas urement of plasma tryptophan and kynurenine metabolites. Brains were then o btained from embolized and nonembolized fetuses 24 hours after a further ma ternal tryptophan loading experiment and from nonembolized non-tryptophan-t reated fetuses for analysis of regional kynurenic acid and quinolinic acid content. RESULTS: Maternal tryptophan infusion resulted in a significant increase of kynurenine in fetal plasma, but this increase was significantly smaller in fetuses with an embolized placenta compared with a nonembolized placenta. Both kynurenic acid and quinolinic acid levels increased significantly in f etal plasma, with no differences between the groups. Kynurenic acid and qui nolinic acid levels were increased in all regions of the fetal brain after maternal tryptophan loading, but these increases were greater in the fetuse s with an embolized placenta, compared with a nonembolized placenta. CONCLUSION: Fetal tryptophan and kynurenine metabolism is significantly alt ered when placental function is chronically compromised in late gestation. The decreased production of kynurenine from tryptophan may result from the compromise of hepatic function in the fetus, whereas the increased producti on of kynurenic acid and quinolinic acid in the brain is likely to reflect alterations of metabolism of tryptophan and kynurenine to these neuroactive products by glial cells in the fetal brain.