Studies of the metabolic and circulatory response of the fetus in utero to severe hypoxic stress have focused on exposure of short duration with the presumption that such responses as bradycardia and lactic acidemia were signs of progressive deterioration resulting in death. We have recently demonstrated that ovine fetal arterial O2 content in the severely hypoxic range between 1.0 to 1.5 mM can be experimentally maintained with evidence of metabolic and circulatory recovery by the fetus. After """"""""clamping"""""""" fetal arterial O2 content in this range, we have observed that lactic acid accumulates steadily for 4 to 6 hours, reaches a plateau with fetal arterial lactate concentrations between 10 and 18 MM by 4 hours, and then decreases toward control levels over the next 24 hours. The first hypothesis to be tested in this project is that fetal hepatic lactate utilization and oxidation increase both in absolute terms and relative to the whole fetus during severe prolonged hypoxia. The second hypothesis is that the synthesis of non-essential amino acids from lactate carbon by the fetal liver increases under these conditions. The third hypothesis is that these amino acids enter the placenta where they are oxidized. To test these hypotheses, we will utilize fetal infusions of both 14C-1- and 13C-U-lactate tracers. We will perform studies using blood flow measurements, and arteriovenous concentration differences of tracee and tracer lactate and their metabolic products across the maternal uterine, umbilical and fetal hepatic circulations. Tissue analysis will be used to define the major routes of lactate disposal in the placenta, fetal organs and non-visceral fetal carcass. Comparison to the normally oxygenated fetus will be made after 6 hours of hypoxia and after 24 hours of hypoxia. An understanding of these newly recognized physiological responses to severe hypoxia in utero is not only of basic interest but is also central to the clinical management of the chronically hypoxic human fetus as well.
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