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 h as potent antilipolytic properties in vitro. Nonshivering thermogenesi s cannot be demonstrated by cooling fetal sheep in utero but can be in duced by supplemental oxygenation and umbilical cord occlusion; this s uggests the presence of inhibitor(s) of placental origin. To test whet her circulating adenosine could be such an inhibitor, a series of expe riments was carried out in nine fetal sheep at 136-145 d gestation. Bi rth 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 glyce rol; ventilating with O-2 via an exteriorized tracheostomy tube and um bilical 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 d egrees C. The long-acting adenosine analog N-6-(L-2-phenylisopropyl)-a denosine (PIA) was then infused (90 ug/kg bolus, then 300 mu g/kg/h fo r 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 consum ption fell rapidly to 4.5 +/- 0.3 mL/min/kg (p < 0.01); temperature de creased 1.89 +/- 0.39 degrees C (p < 0.001); and fetal arterial BP dec reased to 38 +/- 5 mm Hg (p < 0.004) in 30 min. A stepped dose-respons e study was performed in three fetal sheep. Birth was simulated in ute ro and then PIA was administered in escalating doses for five sequenti al 30-min periods with 60-min intervals in between, starting at 0.08 m u g/kg bolus. The fetal arterial blood pressure was not affected by an y of the relatively low doses of PIA used; however, all of the doses o f PIA inhibited nonshivering thermogenesis in a dose-dependent manner. These results are consistent with adenosine suppression of brown adip ose tissue thermogenesis in utero and suggest that adenosine may be an inhibitor of placental origin.