Adenosine A(1) receptor mediated suppression of adrenal activity in near-term fetal sheep

Activation of the hypothalamic-pituitary-adrenal (HPA) axis is a critical response to perinatal hypoxia. Recent data show that adenosine appears to inhibit baseline levels of fetal cortisol and to restrict the increase in ACTH and cortisol during moderate hypoxia. Because adenosine increases substantially during profound asphyxia, it is possible, but untested, that counterintuitively it might restrict the HPA response to more severe insults. It is unclear which receptors mediate the effects of adenosine on the HPA axis; however, adenosine A(1) receptor activation is important for adaptation to hypoxia. We therefore investigated whether adenosine A(1) receptor blockade modulates ACTH and cortisol levels in fetal sheep at 118 to 126 days gestation, randomly allocated to receive an intravenous infusion of either vehicle (vehicle-occlusion, n = 7) or 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, an A(1) receptor antagonist, DPCPX-occlusion, n = 7) infused 60 min before and during 10 min of umbilical cord occlusion, or infusion of DPCPX for 70 min without occlusion (DPCPX-sham, n = 6). Experiments were terminated after 72 h. Fetal ACTH levels increased significantly (P < 0.01) during occlusion, but not sham occlusion, and returned to baseline values by 60 min after occlusion. In the vehicle-occlusion group, fetal cortisol and cortisone plasma levels increased significantly (P < 0.05) 60 min after the occlusion and returned to baseline values by 24 h. In contrast, there was a marked increase in both fetal cortisol and cortisone during DPCPX infusion before occlusion to a level greater even than the maximum rise seen after occlusion alone. This increase was sustained after occlusion, with increased cortisol levels compared with occlusion alone up to 72 h. In conclusion, fetal cortisol concentrations are suppressed by adenosine A(1) receptor activity, largely though a direct adrenal mechanism. This suppression can be partially overcome by supraphysiological stimuli such as asphyxia.