Adenosine A(1) and A(2A) receptor subtypes modulate metabolism in adult mammals. This study was designed to determine the role of these receptors in regulating plasma levels of insulin, glucose, and lactate in 20 chronically catheterized fetal sheep (>0.8 term). In normoxic fetuses (Pa(O(2)) approximately 24 Torr), systemic blockade of A(1) receptors with DPCPX (n = 6) increased plasma concentrations of insulin, glucose, and lactate, but antagonism of A(2A) receptors with ZM-241385 (n = 5) had no significant effects. Intravascular administration of adenosine (n = 9) reduced insulin concentrations and elevated glucose and lactate levels. DPCPX (n = 6) augmented the glycemic and lactatemic responses of adenosine. In contrast, ZM241385 (n = 5) virtually abolished adenosine-induced hyperglycemia and hyperlactatemia. Isocapnic hypoxia (Pa(O(2)) approximately 13 Torr) suppressed insulinemia and enhanced glycemia and lactatemia, but only the hyperglycemia was blunted by blockade of A(1) (n = 6) or A(2A) (n = 6) receptors. We conclude that 1) endogenous adenosine via A(1) receptors depresses plasma concentrations of insulin, glucose, and lactate; 2) exogenous adenosine via A(2A) receptors increases glucose and lactate levels, but these responses are dampened by stimulation of A(1) receptors; and 3) hypoxia, which increases endogenous adenosine concentrations, induces hyperglycemia that is partly mediated by activation of A(1) and A(2A) receptors. We predict that adenosine, via A(1) receptors, facilitates at least 12% of glucose uptake and utilization in normoxic fetuses.