A POTENTIAL ROLE FOR ADENOSINE IN THE INHIBITION OF NONSHIVERING THERMOGENESIS IN THE FETAL SHEEP

Adenosine is released by the placenta into the fetal circulation and has potent antilipolytic properties in vitro. Nonshivering thermogenesis cannot be demonstrated by cooling fetal sheep in utero but can be induced by supplemental oxygenation and umbilical cord occlusion; this suggests the presence of inhibitor(s) of placental origin. To test whether circulating adenosine could be such an inhibitor, a series of experiments was carried out in nine fetal sheep at 136-145 d gestation. Birth was simulated in utero by sequentially cooling the fetus 2.49 +/- 0.23 degrees C with no change in the low levels of plasma FFA or glycerol; ventilating with O-2 via an exteriorized tracheostomy tube and umbilical cord occlusion. Thermogenic indices rose markedly, and plasma FFA and glycerol concentrations peaked at 725 +/- 88 mu Eq/L (p < 0.01) and 771 +/- 154 mu mol/L, (p < 0.001), respectively, O-2 consumption rose to 20 +/- 2 mL/min/kg, and temperature increased 1.99 +/- 0.35 degrees C. The long-acting adenosine analog N-6-(L-2-phenylisopropyl)-adenosine (PIA) was then infused (90 ug/kg bolus, then 300 mu g/kg/h for 30 min); plasma FFA and glycerol decreased to 265 +/- 56 mu Eq/L (p < 0.003) and 477 +/- 102 mu mol/L (p < 0.04), respectively; O-2 consumption fell rapidly to 4.5 +/- 0.3 mL/min/kg (p < 0.01); temperature decreased 1.89 +/- 0.39 degrees C (p < 0.001); and fetal arterial BP decreased to 38 +/- 5 mm Hg (p < 0.004) in 30 min. A stepped dose-response study was performed in three fetal sheep. Birth was simulated in utero and then PIA was administered in escalating doses for five sequential 30-min periods with 60-min intervals in between, starting at 0.08 mu g/kg bolus. The fetal arterial blood pressure was not affected by any of the relatively low doses of PIA used; however, all of the doses of PIA inhibited nonshivering thermogenesis in a dose-dependent manner. These results are consistent with adenosine suppression of brown adipose tissue thermogenesis in utero and suggest that adenosine may be an inhibitor of placental origin.