Adenosine mediates decreased cerebral metabolic rate and increased cerebral flow during acute moderate hypoxia in the near-term fetal sheep

Exposure of the fetal sheep to moderate to severe hypoxic stress results in both increased cortical blood flow and decreased metabolic rate. Using intravenous infusion of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective adenosine A₁ receptor antagonist that is permeable to the blood brain barrier, we examine the role of adenosine A₁ receptors in mediating cortical blood flow and metabolic responses to moderate hypoxia. The effects of DPCPX blockade are compared to controls as well as animals receiving intravenous 8-(p-sulfophenyl)-theophylline) (8-SPT), a non-selective adenosine receptor antagonist which has been found to be blood brain barrier impermeable. Laser Doppler flow probes, tissue P_O2, and thermocouples were implanted in the cerebral cortices of near-term fetal sheep. Catheters were placed in the brachial artery and sagittal sinus vein for collection of samples for blood gas analysis. Three to seven days later responses to a 30-min period of fetal hypoxemia (arterial P_O2 10-12 mmHg) were studied with administration of 8-SPT, DPCPX, or vehicle. Cerebral metabolic rate was determined by calculation of both brain heat production and oxygen consumption. In response to hypoxia, control experiments demonstrated a 42 ± 7% decrease in cortical heat production and a 35 ± 10% reduction in oxygen consumption. In contrast, DPCPX infusion during hypoxia resulted in no significant change in brain heat production or oxygen consumption, suggesting the adenosine A₁ receptor is involved in lowering metabolic rate during hypoxia. The decrease in cerebral metabolic rate was not altered by 8-SPT infusion, suggesting that the response is not mediated by adenosine receptors located outside the blood brain barrier. In response to hypoxia, control experiments demonstrated a 35 ± 7% increase in cortical blood flow. DPCPX infusion did not change this increase in cortical blood flow, however 8-SPT infusion attenuated increases in flow, indicating that hypoxic increases in cerebral blood flow are mediated by adenosine but not via the A₁ receptor. In summary, adenosine appears to play a key role in fetal hypoxic defences, acting to increase O₂ delivery via adenosine A₂ receptors and to decrease metabolic rate via A₁ receptors inside the blood brain barrier. These data show for the first time in the mammalian fetus that the adenosine A₁ receptor is an important mediator of brain metabolic rate during moderate hypoxia.