The mammalian fetus can survive O2, deprivation for longer periods than the adult. This seems paradoxical because fetal metabolic Fate is high and O2 reserves are low. How fetal tolerance to hypoxia is achieved remains unknown, but reduction in metabolic rate during hypoxia, effectively rationing available O2, probably plays an essential role. Our recent studies have pointed to adenosine, a powerful metabolic suppressor in the adult, as the mediator of fetal tolerance. We have found fetal adenosine concentration to be 3 to 5 times higher than maternal levels in the sheep, well above the concentrations that induce inhibition adult tissues. Moreover, adenosine concentration increases rapidly when O2 needs outstrip O2 supply, and falls rapidly after cord occlusion. From these observations it is hypothesized that: 1) adenosine is normally released into the circulation from fetal tissues, especially by the placenta; 2) the rate of adenosine release increases as a direct response to hypoxia; 3) circulating adenosine suppresses metabolic rate during hypoxia in a dose-dependent manner; 4) the effects are specific, tending to conserve O2 for critical organs such as the heart and brain. To test these hypotheses, we propose a series of experiments using fetal sheep. The first will measure changes in circulating adenosine in response to fetal hypoxia. The second, its mirror image, will measure changes in fetal oxygenation in response to infused adenosine. The two sets of results will enable us to calculate the strength of feedback interactions between adenosine and fetal oxygen, and estimate the physiological importance of this interplay. A third group of experiments will investigate the role of catecholamines in modulating fetal O2 use, and their interaction with adenosine. Finally, we shall determine the relative importance of the placenta, liver, and skeletal muscle in fetal adenosine release and uptake. The results of these studies are relevant to possible prevention of hypoxic tissue damage and to understanding fetal growth limitations.
